Note: Descriptions are shown in the official language in which they were submitted.
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RESVERATROL-CONTAINING COMPOSITIONS FOR MODULATING
GENE PRODUCT CONCENTRATION OR ACTIVITY
[0001]
Field of the Invention:
[0002] The present invention relates to a resveratrol-containing composition
capable of modulating
gene expression to an extent greater than that observed with resveratrol alone
or with calorie
restriction. The invention particularly pertains to such resveratrol-
containing compositions that
comprise resveratrol, a chelator, hyaluronic acid, and/or vitamin D and which,
upon administration to
a recipient, increases the concentration or activity of a survival/longevity
gene product and/or
decreases the concentration or activity of a gene product that induces or
causes cellular damage. The
invention particularly relates to the use of such compositions in the
treatment or prevention of cancer,
cardiovascular disease, diseases associated with aging, and other conditions
and illnesses.
Background of the Invention:
[0003] Despite a high level of risk factors such as cholesterol, diabetes,
hypertension and a high
intake of saturated fat, French males display the lowest mortality rate from
ischaemic heart disease and
cardiovascular diseases in Western industrialized nations (36% lower than the
USA and 39% lower
than the UK). The so-called 'French Paradox' (a low mortality rate
specifically from cardiovascular
diseases) may be due mainly to the regular consumption of wine (Renaud, S. et
al. (1998) "The French
Paradox And Wine Drinking," Novartis Found. Symp. 216:208-222, 152-158).
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[0004] Resveratrol (3,4',5-trihydroxy-trans-stilbene) is a naturally occurring
phenolic
compound found, for example in grape skins, that has been demonstrated to have
beneficial
properties relating to health of humans (Das, S. et al. (2007) "Resveratrol: A
Therapeutic
Promise For Cardiovascular Diseases," Recent Patents Cardiovasc. Drug Discov.
2(2):133-
138; Mancuso, C. et al. (2007) "Natural antioxidants in Alzheimer's disease,"
Expert Opin.
Investig. Drugs. 16(12):1921-1931; Baumann L. (2007) "Botanical Ingredients In
Cosmeceuticals," J. Drugs Dermatol. 6(11):1084-1088; Meeran, S.M. et al.
(2008) "Cell Cycle
Control As A Basis For Cancer Chemoprevention Through Dietary Agents," Front.
Biosci.
13:2191-2202; de la Lastra, C.A. et al. (2007) "Resveratrol As An Antioxidant
And Pro-Oxidant
Agent: Mechanisms And Clinical Implications," Biochem. Soc. Trans. 35(Pt
5):1156-1160;
Das, S. et al. (2007) "Anti-Inflammatory Responses Of Resveratrol," Inflamm.
Allergy Drug
Targets 6(3):168-173; Cucciolla, V. et al. (Epub 2007 Jul 31) "Resveratrol:
From Basic
Science To The Clinic," Cell Cycle 6(20):2495-2510; Opie, L.H. et al. (Epub
2007 Jun 7) "The
Red Wine Hypothesis: From Concepts To Protective Signaling Molecules," Eur.
Heart J.
28(14):1683-1693; Chen, Y. et al. (2007) "Review. Pro- And Anti-Angiogenesis
Effects Of
Resveratrol," In Vivo 21(2):365-370 [Erratum in: In Vivo 21(6):1172 and
21(5):955]; Holme,
A.L. et al. (2007) "Resveratrol In Cell Fate Decisions," J. Bioenerg.
Biomembr. 39(1):59-63;
Athar, M. et al. (Epub 2007 Jan 3) "Resveratrol: A Review Of Preclinical
Studies For Human
Cancer Prevention," Toxicol. Appl. Pharmacol. 224(3):274-283). In particular,
resveratrol is
believed to be beneficial to the functioning of the heart and in extending the
life of human cells.
Resveratrol, when used in dietary supplements, is generally produced as an
alcohol extract from
plant sources.
[0005] Calorie restricted diets have been shown to enhance survival and
longevity by up-
regulating survival/longevity genes or down-regulating genes whose expression
enhances
cellular damage (Edwards, M.G. et al. (2007) "Gene Expression Profiling Of
Aging Reveals
Activation Of A P53-Mediated Transcriptional Program," BMC Genomics 8:80;
Anderson,
R.M. et al. (2006) "Calorie Restriction: Progress During Mid-2005-Mid-2006,"
Exp. Gerontol.
41(12):1247-1249; Weindruch, R. et al. (2001) "Microarray Profiling of Gene
Expression in
Aging and Its Alteration by Caloric Restriction in Mice," J. Nutrition
131:918S-923S; Lee, K.-
C. et al. (2003) "Transcriptional Profiles Associated With Aging And Middle
Age-Onset
Caloric Restriction In Mouse Hearts," Proc. Natl. Acad. Sci. (U.S.A.) 99(23):
14988-14993;
Weindruch, R. et al. (2002) "Effects Of Caloric Restriction On Gene
Expression," Nestle Nutr.
Workshop Ser. Clin. Perform. Programme 6:17-28; 28-32; Mulligan, J.D. et al.
(Epub 2007
Nov 1) "Downregulation Of Plasma Insulin Levels And Hepatic Ppar gamma
Expression
During The First Week Of Caloric Restriction In Mice," Exp. Gerontol.
43(3):146-153;
Rodgers, J.T. et al. (Epub 2007 Nov 26) "Metabolic Adaptations Through The PGC-
1 Alpha
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And SIRTI Pathways," FEBS Lett. 582(1):46-53; Swindell, W.R. (2007) "Gene
Expression
Profiling Of Long-Lived Dwarf Mice: Longevity-Associated Genes And
Relationships With
Diet, Gender And Aging," BMC Genomics. 8:353; Zhu, M. et al. (Epub 2007 Jun 6)
"Adipogenic Signaling In Rat White Adipose Tissue: Modulation By Aging And
Calorie
Restriction," Exp. Gerontol. 42(8):733-744; Chiarpotto, E. et al. (2006)
"Molecular
Mechanisms Of Calorie Restriction's Protection Against Age-Related Sclerosis,"
IUBMB Life.
58(12):695-702; Lu, J. et al. (2007) "Different Gene Expression Of Skin
Tissues Between Mice
With Weight Controlled By Either Calorie Restriction Or Physical Exercise,"
Exp. Biol. Med.
(Maywood). 232(4):473-480; Masternak, M.M. et al. (2007) "pPARS In Calorie
Restricted And
Genetically Long-Lived Mice," pPAR Res. 2007:28436; Fu, C. et al. (2006)
"Tissue Specific
And Non-Specific Changes In Gene Expression By Aging And By Early Stage CR,"
Mech.
Ageing Dev. 127(12):905-916). As indicated by the above-cited references, mice
have been
used extensively as a model for genetic expression comparisons with humans.
Without
limitation, the validity of murine models to human gene expression reflects
the fact that 98% of
human and murine gene are homologous, and that mice and humans have about the
same
number of genes (e.g., approximately 30,000).
[0006] Despite the established benefits of a calorie restricted diet, the
severity of the
required dietary regime has limited adoption of this approach to increasing
longevity. It would
therefore be desirable to provide an alternative route to obtaining the
benefits of calorie
restriction that would avoid the need for dietary regulation and that would be
amenable to
widespread adoption. The present invention is directed to this and other
needs.
Summary of the Invention:
[0007] The present invention relates to a resveratrol-containing composition
capable of
modulating gene expression to an extent greater than that observed with
resveratrol alone or
with calorie restriction. The invention particularly pertains to such
resveratrol-containing
compositions that comprise resveratrol, a chelator, hyaluronic acid, and/or
vitamin D and
which, upon administration to a recipient, increases the concentration or
activity of a
survival/longevity gene product and/or decreases the concentration or activity
of a gene product
that induces or causes cellular damage. Most preferably, the resveratrol-
stabilizing
composition will comprise the chelator phytic acid (inositol hexaphosphate;
IP6), hyaluronic
acid, and vitamin D. The invention further pertains to the use of such
compositions to up-
regulate a survival/longevity gene or down-regulate a gene whose expression
enhances cellular
damage upon administration to a recipient. The invention particularly relates
to the use of such
compositions in the treatment or prevention of cancer, cardiovascular disease,
diseases
associated with aging, and other conditions and illnesses.
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[0008] In detail, the invention provides a resveratrol-containing composition
that, upon
administration to a recipient, modulates the concentration or activity,
relative to resveratrol
alone or calorie restriction, of the product of a survival/longevity gene or
the product of a gene
whose expression enhances cellular damage. Administration is preferably by
oral ingestion.
[0009] The invention further provides the embodiments of such compositions
wherein the
modulation alters:
(A) oxidative phosphorylation;
(B) actin filament length or polymerization;
(C) intracellular transport;
(D) organelle biogenesis;
(E) insulin signaling;
(F) glycolysis;
(G) gluconeogenesis; or
(H) fatty acid metabolism.
[0010] The invention further provides the embodiments of such compositions
wherein the
gene product is a survival/longevity gene product, and especially wherein the
gene product is
sSirtuin 1, or the forkhead Foxo1 transcription factor.
[0011] The invention further provides the embodiments of such compositions
wherein the
gene product is a gene product that enhances cellular damage, and especially
wherein the gene
product is encoded by the uncoupling protein 3, Pgc-1, or pyruvate
dehydrogenase kinase 4
genes.
[0012] The invention further provides the embodiments of such compositions
wherein the
composition comprises:
(a) trans-resveratrol; and
(b) a metal chelating agent;
wherein the trans-resveratrol is encapsulated to thereby substantially
preserve the ability of the
composition to modulate the concentration or activity of the product of the
survival/longevity
gene or the product of the gene whose expression enhances cellular damage,
from loss due to
exposure of the trans-resveratrol to light or oxygen.
[0013] The invention further provides a method of ameliorating a symptom
associated with
an existing disease of an individual or for preventing the onset of the
symptom in an individual
prior to the occurrence of the disease in the individual, which comprises
administering to the
individual, a resveratrol-containing composition that modulates the
concentration or activity,
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relative to resveratrol alone or calorie restriction, of the product of a
survival/longevity gene or
the product of a gene whose expression enhances cellular damage, wherein the
resveratrol is
provided in an amount effective to cause a modulation of the concentration or
activity of the
gene that ameliorates the symptom of the disease, and wherein the disease is
selected from the
group consisting of: cardiovascular disease, cancer, macular degeneration, a
disease associated
with aging, and inflammation.
[0014] The invention further provides the embodiments of such method wherein
the
modulation alters:
(A) oxidative phosphorylation;
(B) actin filament length or polymerization;
(C) intracellular transport;
(D) organelle biogenesis;
(E) insulin signaling;
(F) glycolysis;
(G) gluconeogenesis; or
(H) fatty acid metabolism.
[0015] The invention further provides the embodiments of such method wherein
the
survival/longevity gene product is Sirtuin 1 or the forkhead Foxol
transcription factor. The
invention further provides the embodiments of such method wherein the gene
whose expression
enhances cellular damage encodes uncoupling protein 3 or pyruvate
dehydrogenase kinase 4.
[0016] The invention further provides the embodiments of such method wherein
said
composition comprises:
(a) trans-resveratrol; and
(b) a metal chelating agent;
wherein the trans-resveratrol is encapsulated to thereby substantially
preserve the ability of the
composition to modulate the concentration or activity of the product of the
survival/longevity
gene or the product of the gene whose expression enhances cellular damage,
from loss due to
exposure of the trans-resveratrol to light or oxygen.
[0017] The invention further provides the embodiments of such method wherein
the disease
is cancer, or a disease associated with aging (especially a neurodegenerative
disease).
[0018] The invention further provides the embodiments of such method wherein
the
composition additionally comprises quercetin, hyaluronic acid and/or vitamin
D.
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[0019] The invention further provides the embodiments of such method wherein
the
modulation is relative to resveratrol alone or wherein the modulation is
relative to calorie
restriction.
[0020] The invention further provides the embodiments of such methods wherein
the gene
product is a survival/longevity gene product, and especially wherein the gene
product is Sirtuin
1, or the forkhead Foxo 1 transcription factor.
[0021] The invention further provides the embodiments of such methods wherein
the gene
product is a gene product that enhances cellular damage, and especially
wherein the gene
product is encoded by the uncoupling protein 3, Pgc-1, or pyruvate
dehydrogenase kinase 4
gene.
Brief Description of the Figures:
[0022] Figure 1 shows the change in body weight of mice administered
resveratrol or a
composition of the present invention (Longevinex ) relative to control animals
and animals
maintained on a calorie restricted diet.
[0023] Figure 2 shows the serum insulin level of mice administered resveratrol
or a
composition of the present invention (Longevinex ) relative to control animals
and animals
maintained on a calorie restricted diet.
[0024] Figure 3 shows the serum glucose level of mice administered resveratrol
(P = 0.97)
or a composition of the present invention (Longevinex ) (P = 0.07) relative to
control animals
and animals maintained on a calorie restricted diet (P = 0.10).
[0025] Figure 4 shows a schematic of a mechanism of action that is consistent
with the
observed biological activities of the compositions of the present invention.
Description of the Preferred Embodiments:
[0026] The present invention relates to a resveratrol-containing composition
(and especially
a resveratrol-containing dietary composition (i.e., a composition amenable for
oral ingestion by
a recipient)) capable of modulating gene expression to an extent greater than
that observed with
resveratrol alone or with calorie restriction. The invention particularly
pertains to such
resveratrol-containing compositions that comprise resveratrol, a chelator,
hyaluronic acid,
and/or vitamin D and which up-regulate a survival/longevity gene or down-
regulate a gene
whose expression enhances cellular damage upon administration to a recipient.
Most
preferably, the resveratrol-stabilizing composition will comprise the chelator
phytic acid
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(inositol hexaphosphate; IP6), hyaluronic acid, and vitamin D. The invention
further pertains to the
use of such compositions to up-regulate a survival/longevity gene or down-
regulate a gene whose
expression enhances cellular damage upon administration to a recipient. The
mineral chelators of the
present invention provide anti-aging effects, as evidence in differentiation
of the genome.
A. Resveratrol
[0027] As used herein, the term "resveratrol" refers to the phytoalexin:
3,4',5-trihydroxy-trans-
stilbene having the structure:
OH
HO
OH
[0028] Resveratrol has been ascribed multiple beneficial biological effects
(see, United States
Patent No. 7,345,178), including preventing or treating cardiovascular disease
(see, e.g., Das, S. et
at. (2007) "Resveratrol: A Therapeutic Promise For Cardiovascular Diseases,"
Recent Patents
Cardiovasc. Drug Discov. 2(2):133-138), Opie, L.H. et al. (Epub 2007 Jun 7)
"The Red Wine
Hypothesis: From Concepts To Protective Signaling Molecules," Eur. Heart J.
28(14):1683-1693;
Bertelli, A.A. (Epub 2007 May 24) "Wine, Research And Cardiovascular Disease:
Instructions For
Use," Atherosclerosis 195(2):242-247; Providencia, R. (2006) "Cardiovascular
Protection From
Alcoholic Drinks: Scientific Basis Of The French Paradox," Rev. Port. Cardiol.
25(11):1043-1058;
Maulik, N. (2006) "Reactive Oxygen Species Drives Myocardial Angiogenesis?"
Antioxid. Redox
Signal. 8(11-12):2161-2168; Olas, B. et al. (2005) "Resveratrol, A Phenolic
Antioxidant With Effects
On Blood Platelet Functions," Platelets 16(5):251-260; Bradamante, S. et al.
(2004) "Cardiovascular
Protective Effects Of Resveratrol," Cardiovase Drug Rev. 22(3):169-188; Hao,
H.D. et al. (2004)
"Mechanisms Of Cardiovascular Protection By Resveratrol," J. Med. Food
7(3):290-298), preventing
or treating cancer (Jang, M. et al. (1997) "Cancer Chemopreventive Activity Of
Resverairol, A
Natural Product Derived From Grapes," Science 275:218-220; Das, S. et al.
(2007) "Anti-
Inflammatory Responses Of Resveratrol," Inflamm. Allergy Drug Targets 6(3):168-
173; de la Lastra,
C.A. et al. (2007) "Resveratrol As An Antioxidant And Pro-Oxidant Agent:
Mechanisms And Clinical
Implications," Biochem. Soc. Trans. 35(Pt 5):1156-1160; Athar, M. et al. (Epub
2007 Jan 3)
"Resveratrol: A Review Of Preclinical Studies For Human Cancer Prevention,"
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Toxicol. Appl. Pharmacol. 224(3):274-283), Meeran, S.M. et al. (2008) "Cell
Cycle Control As
A Basis For Cancer Chemoprevention Through Dietary Agents," Front. Biosci.
13:2191-2202;
Shankar, S. et al. (2007) "Chemoprevention By Resveratrol: Molecular
Mechanisms And
Therapeutic Potential," Front. Biosci. 12:4839-4854; Delmas, D. et al. (2006)
"Resveratrol As
A Chemopreventive Agent: A Promising Molecule For Fighting Cancer," Curr. Drug
Targets
7(4):423-442; Signorelli, P. et al. (2005) "Resveratrol As An Anticancer
Nutrient: Molecular
Basis, Open Questions And Promises," J. Nutr. Biochem. 16(8):449-466;
preventing or
treating macular degeneration (United States Patent Application Serial No.
61/023,234;
King, R.E. et al. (2005) "Resveratrol reduces oxidation and proliferation of
human retinal
pigment epithelial cells via extracellular signal-regulated kinase
inhibition," Chem. Biol.
Interact. 151(2):143-149; Sparrow, J.R. et al. (2003) "A2E-epoxides damage DNA
in retinal
pigment epithelial cells. Vitamin E and other antioxidants inhibit A2E-epoxide
formation," J.
Biol. Chem. 278(20):18207-18213), attenuating or preventing diseases
associated with
aging, and other conditions and illnesses, including the incidence or severity
of
neurodegenerative diseases such as Alzheimer's Disease and Parkinson's Disease
(Baxter,
R.A. (2008) "Anti-Aging Properties Of Resveratrol: Review And Report Of A
Potent New
Antioxidant Skin Care Formulation," J. Cosmet. Dermatol. 7(1):2-7; Engel, N.
et al. (2008)
"Aging And Anti-Aging: Unexpected Side Effects Of Everyday Medication Through
Sirtuinl
Modulation," Int. J. Mol. Med. 21(2):223-232; Bickenbach, K.A. et al. (Epub
2007 Dec 21)
"Resveratrol Is An Effective Inducer Of Carg-Driven Tnf-Alpha Gene Therapy,"
Cancer Gene
Ther. 15(3):133-139; Putics, A. et al. (2008) "Resveratrol Induces The Heat-
Shock Response
And Protects Human Cells From Severe Heat Stress," Antioxid. Redox Signal.
10(1):65-75;
Bass, T.M. et al. (Epub 2007 Aug 14) "Effects Of Resveratrol On Lifespan In
Drosophila
melanogaster And Caenorhabditis elegans," Mech. Ageing Dev. 128(10):546-552;
Stefani, M.
et al. (Epub 2007 Sep 5) "The Effect Of Resveratrol On A Cell Model Of Human
Aging," Ann.
N.Y. Acad. Sci. 1114:407-418; Heiss, E.H. et al. (Epub 2007 Jul 11) "Chronic
Treatment With
Resveratrol Induces Redox Stress- And Ataxia Telangiectasia-Mutated (Atm)-
Dependent
Senescence In P53-Positive Cancer Cells," J. Biol. Chem. 282(37):26759-26766;
Mayo Clinic
(2007) "A Compound In Red Wine Makes Mice Live Longer, Healthier," Mayo Clin.
Health
Lett. 25(5):4; Kim, D. et al. (Epub 2007 Jun 21) "Sirtl Deacetylase Protects
Against
Neurodegeneration In Models For Alzheimer's Disease And Amyotrophic Lateral
Sclerosis,"
EMBO J. 26(13):3169-3179), and anti-inflammatory activity (Das, S. et al.
(2007) "Anti-
Inflammatory Responses Of Resveratrol," Inflamm. Allergy Drug Targets 6(3):168-
173).
[0029] Reseveratrol may be synthesized chemically (Farina, A. et al. (2006)
"An Improved
Synthesis Of Resveratrol," Nat. Prod. Res. 20(3):247-252), or, more
preferably, may be
extracted from plant sources. Resveratrol is found in at least 72 species of
plants distributed
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among 31 genera and 12 families (see, Counet, C. et al. (2006) "Chocolate And
Cocoa: New
Sources Of Trans-Resveratrol And Trans-Piceid," Food Chem. 98:649-657; Jang,
M. et al.
(1997) "Cancer Chemopreventive Activity Of Resveratrol, A Natural Product
Derived From
Grapes," Science 275:218-220; Wang, Y. et al. (2002) "An LC-MS Method For
Analyzing
Total Resveratrol In Grape Juice, Cranberry Juice, And In Wine," J. Agricult.
Food Chem.
50(3):431-435). All of the families found to contain resveratrol belong to the
spermatophytes
division: Vitaceae, Myrtaceae, Dipterocarpaceae, Cyperaceae, Gnetaceae,
Leguminosae,
Pinaceae, Moraceae, Fagaceae, Liliaceae (Langcake, P. et al. (1976) "The
Production Of
Resveratrol By Vitis Vinifera And Other Members Of The Vitaceae As A Response
To Infection
Or Injury," Physiol. Plant Pathol. 9:77-86; Yoshiaki, T. et al. (2002)
"Biogenic Reactions On
Stilbenetetramers From Vitaceaeous Plants," Tetrahedron 58:9265-9271).
Resveratrol has
most often been reported in nonedible plants: vine, eucalyptus, spruce, and
the tropical
deciduous tree Bauhinia racemosa, Pterolobium Hexapetallum (Cassady, A. et al.
(2000)
"Isoflavones, Lignans, And Stilbenes-Origins, Metabolism And Potential
Importance To
Human Health," J. Science Food Agric. 80:1044-1062; Soleas, G. J. et al.
(1997) "Resveratrol:
A Molecule Whose Time Has Come? And Gone?," Clin. Biochem. 30:91-113).
Reseveratrol is
particularly found in grape skins and Giant Knotweed (see, Burns, J. et al.
(2002) "Plant Foods
and Herbal Sources of Resveratrol," J. Agric. Food Chem. 50(11):3337 -3340),
cocoa and
chocolate (Counet, C. et al. (2006) "Chocolate And Cocoa: New Sources Of Trans-
Resveratrol
And Trans-Piceid," Food Chem. 98:649-657). Peanut sprouts are also a rich
source of
resveratrol.
B. Modulation of Gene Product Concentration or Activity
[0030] The invention pertains to compositions that, upon administration to a
recipient,
increase the concentration or activity of a survival/longevity gene product
and/or decrease the
concentration or activity of a gene product that induces or causes cellular
damage. As used
herein, such increase (or decrease) in concentration or activity may be
accomplished by any
mechanism. For example, such increase (or decrease) may reflect a modulation
of gene
expression resulting in either increased (or decreased) expression of the gene
encoding the
survival/longevity gene product, or a gene that regulates (e.g., induces or
represses) or whose
product regulates such expression or activity. Alternatively, or
conjunctively, such increase (or
decrease) in concentration or activity may reflect a modulation of the
recipient's ability to
degrade or stabilize any such gene products. Alternatively, or conjunctively,
such increase (or
decrease) in concentration or activity may reflect a modulation of the
recipient's ability to
enhance, accelerate, repress or decelerate the activity of any such gene
products.
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[0031] The modulation of concentration or activity discussed above may be a
modulation of
intracellular, intercellular and/or tissue concentration or activity of such
survival/longevity gene
products or such gene products that induce or cause cellular damage. Such
modulation may be
identified by assays of DNA expression, assays of gene product activity,
assays of the level of
gene product, assays of the rate of gene product turnover, etc. conducted in
one or more types
of cells, tissues, etc.
[0032] An increase in the concentration of a survival/longevity gene product
may result
from, for example, increased transcription of the gene that encodes the
survival/longevity gene
product, increased transcription of a gene that induces the expression of the
gene that encodes
the survival/longevity gene product, decreased transcription of a gene that
represses the
expression of the gene that encodes the survival/longevity gene product,
decreased degradation
or enhanced stabilization of expressed molecules of the survival/longevity
gene product
(leading to the enhanced accumulation of the survival/longevity gene product).
Similarly, a
decrease in the concentration of a survival/longevity gene product may result
from, for
example, decreased transcription of the gene that encodes the
survival/longevity gene product,
decreased transcription of a gene that induces the expression of the gene that
encodes the
survival/longevity gene product, increased transcription of a gene that
represses the expression
of the gene that encodes the survival/longevity gene product, increased
degradation or
decreased stabilization of expressed molecules of the survival/longevity gene
product (leading
to the enhanced dissipation of the survival/longevity gene product).
[0033] One aspect of the present invention thus relates to the use of
resveratrol and
resveratrol-containing compositions to modulate gene expression, and in
particular, to modulate
the expression of "survival/longevity" genes and/or "damage inducing" genes.
As used herein,
a compound is said to "modulate" gene expression if its administration results
in a change in
expression (relative to a control) of such genes of at least 10%. Modulation
may involve an
increase in expression ("up-regulation") or it may involve a decrease in
expression ("down-
regulation"). The term up-regulate thus denotes an increase of expression of
at least 10%, at
least 20%, at least 50%, at least 2-fold, at least 5-fold, or most preferably
at least 10-fold
(relative to a control). The term down-regulate conversely denotes a decrease
of expression of
at least 10%, at least 20%, at least 50%, at least 2-fold, at least 5-fold, or
most preferably at
least 10-fold (relative to a control).
[0034] A second aspect of the present invention thus relates to the use of
resveratrol and
resveratrol-containing compositions to modulate the concentration or activity
of expressed
products of "survival/longevity" genes and/or "damage inducing" genes. As used
herein, a
compound is said to "modulate" the concentration or activity of such expressed
products if its
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administration results in a change in an intracellular, intercellular or
tissue concentration or
activity (relative to a control) of such gene products of at least 10%.
Modulation may, for
example, involve an "enhanced accumulation" or an "enhanced activity" or, for
example, it
may involve a "diminished accumulation" or a "diminished activity." The term
"enhanced
accumulation" (or "enhanced activity") denotes an increase in concentration
(or activity) of at
least 10%, at least 20%, at least 50%, at least 2-fold, at least 5-fold, or
most preferably at least
10-fold (relative to a control). The term "diminished accumulation" or
"diminished activity."
conversely denotes a decrease in concentration (or activity) of at least 10%,
at least 20%, at
least 50%, at least 2-fold, at least 5-fold, or most preferably at least 10-
fold (relative to a
control).
[0035] As used herein, a "survival/longevity" gene is a gene whose expression
contributes
to an increase in the survival or longevity of a subject (e.g., a mammal, and
particularly a
human) expressing such gene. Conversely, a "damage inducing" gene is a gene
whose
expression contributes to DNA, cellular, or tissue damage in such subject.
Such genes are
responders to biological stressors, they initiate action in response to
stressors such as radiation
(e.g., sunlight, gamma rays, UV light, etc.), radiomimetic agents (e.g.,
vitamin D), heat, near
starvation (calorie restriction, or its mimetic, resveratrol) by modulating
their expression.
[0036] Examples of survival/longevity genes are provided in Table 1. Examples
of genes
whose expression enhances cellular damage are provided in Table 2. These
Tables provide the
gene's NCBI "ENTREzGENE" accession number. Most preferably, such genes are
human
genes. The Sirtuin 1 gene is known to control the rate of aging of living
organisms by virtue of
its ability to produce DNA repair enzymes and mimics the beneficial effects of
calorie
restriction. The trans form of resveratrol (but not cis-resveratrol) activates
the Sirtuin 1 gene
(Alcendor, R.R. (2007) "Sirtl Regulates Aging And Resistance To Oxidative
Stress In The
Heart," Circulation Research 100(10):1512-1521; Howitz, K.T. et al. (2003)
"Small Molecule
Activators Of Sirtuins Extend Saccharomyces Cerevisiae Lifespan," Nature
425:191-196). The
invention particularly pertains to compositions that increase the
concentration of the Sirtuin 1
survival/longevity gene product. The invention further particularly pertains
to compositions
that increase the concentration of the forkhead Foxol (daf-16, dFoxO)
transcription factor
survival/longevity gene product.
Table 1
Exemplary Survival/Longevity Genes
39329 A430102J17Rik Ppp2ca Shb Tnfrsf11a
39340 A4301 1 ON23Rik Ppp2r2d Shmt2 Tnfrsf18
0610007C21 Rik A530082C11 Rik Ppp2r3c Shroom3 Tnfrsfla
0610007LO1 Rik A730008LO3Rik Ppp2r5c Sirt1 Tnfsf5ipl
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Table 1
Exemplary Survival/Longevity Genes
061001OF05Rik A830018L16Rik P 4r1I Skit Tnipl
0610037L13Rik A930001N09Rik Ppp5c Skiv212 Tnkslbpl
0610037P05Rik A930006D11 Rik Ppp6c Slain2 Tnni3
0610040B1ORik A930018M24Rik Ppt2 SIclOal Tnni3k
0610042E11 Rik A930026122Rik P Ic1 SIc12a4 Tnnt2
1110001AO7Rik Ahc ll Prdm4 SIc12a5 Tnpol
1110002BO5Rik Amdl Prdm5 SIcl6al Tnpo2
1110003008Rik Ank Prdx2 SIc16a4 Tnrc6a
1110005AO3Rik Arh a 18 Prdx3 SIc1a5 Tns4
1110007L15Rik Arh a 20 Preb SIc1a6 Tnxb
1110007MO4Rik Arh a 24 Prei4 SIc2Oa1 Toel
11 10008F1 3Rik Arh a 29 Prkab2 SIc22a17 Tollip
1110008JO3Rik Arh a 4 Prkaca SIc22a5 Tomm22
1110008P14Rik Arh a 5 Prkcbpl SIc25a11 Tomm34
1110014KO8Rik Arh a 9 Prkcdbp SIc25a12 Tomm40
1110018J18Rik Arhgdia Prkch SIc25a17 Tomm70a
1110019JO4Rik Arhgefl Prkcn SIc25a22 Topl
1110020G09Rik Arh ef12 Prkcsh SIc25a28 To 2b
1110028AO7Rik Arh ef17 Prkcz SIc25a3 To ors
1110028C15Rik Arhgef2 Prkrir SIc25a32 Torlaip2
1110032E23Rik B230117015Rik Prlr SIc25a33 T cn1
1110033MO5Rik B230118HO7Rik Prmt7 SIc25a34 Tpml
1110036003Rik B230219D22Rik Prodh SIc25a36 T p-3
1110038B12Rik B230312A22Rik Prosc SIc25a4 Tpm4
11 10038D1 7Rik B230337E12Rik Pr f6 SIc25a42 T 1
11 10054005Rik B230380D07Rik Prpsapl SIc25a46 Tpp2
1110058L19Rik B3gaInt2 Prr12 S1c26a11 Tppp3
1110059E24Rik B630005N14Rik Prrcl SIc27a1 T pr
1110059G1ORik B830007DO8Rik Prss12 SIc29a1 T rkb
1110067D22Rik B830028B13Rik Prune SIc31al Tpstl
1190017012Rik B930093H17Rik Psap SIc35a2 Traf3ip2
130001OM03Rik C030002C1 1 Rik Pscd1 SIc35a3 Traip
1300012G16Rik 0030007101 Rik Psd3 SIc35b1 Trak2
1500002101 Rik C030044B11 Rik Psenen SIc35b2 Trappc2
1500002020Rik C030046101 Rik Pskh1 SIc36a2 Trappc2l
1500005K14Rik C130057MO5Rik Psma2 SIc39a1 Trem3
1500011B03Rik C130065N1ORik Psma5 SIc39a10 Trexl
1500011 K1 6Rik C230091 D08Rik Psma6 SIc39a8 Triml 1
1500031L02Rik C430003N24Rik Psma8 SIc4Oa1 Trim12
1500034JOl Rik C730025P13Rik Psmb7 Slc44a1 Trim23
1600012FO9Rik Cdc73 Psmd11 Slc47a1 Trim26
1600015H2ORik Co11Oal Psmd12 SIc4a2 Trim29
1600027N09Rik Coll9al Psmd4 SIc4a4 Trim3
1700001022Rik Collal Psmd6 SIc4a7 Triobp
1700011B04Rik Col1a2 Psmd8 SIc6a19 Tri 4
1700017HOl Rik Co123a1 Pstk SIc6a6 Trmt11
1700020C11 Rik Co127a1 Ptdss2 SIc6a9 Tro
1700021C14Rik Col4a3bp Ptgfrn SIc7al Troa
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Table 1
Exemplary Survival/Longevity Genes
1700021F05Rik Col5al Ptms SIc7a4 Trpcl
1700023DO9Rik Co16a2 Ptp4a3 SIc7a7 Trpc4ap
1700029FO9Rik D03001 101 ORik Pt la SIc9al Tr m4
1700029M20Rik D030051 N 1 9Ri k Pt n1 SIco1a4 Tsc22dl
170003OK09Rik D230019N24Rik Pt n11 SIco3al Tsc22d4
170004OL02Rik D330001F17Rik Pt n12 SIco5al Tsfm
1700051A21 Rik D330017J2ORik Pt n20 SIit3 Ts a10
1700113122Rik D430015BO1 Rik Pt n3 SImap Tsnax
1700127D06Rik D430018EO3Rik Ptpra SImo2 Ts an13
1810007M14Rik D530037H12Rik Pt r Smarca2 Ts an18
181001101 ORik D630023B12Rik Ptprs Smarcc2 Tspan4
1810012P15Rik D830046C22Rik Ptt 1 Smarcd3 Tspan7
1810013L24Rik D930017JO3Rik Puf6O Smchdl Tssc4
1810015CO4Rik D93002OB18Rik Puml Smcr7 Tsta3
181002OD17Rik E030018N11Rik Pusl Smn1 Ttcl
1810021J13Rik E130014JO5Rik Pxmp3 Smndcl Ttc28
1810022K09Rik E130303BO6Rik Pxn Smoc2 Ttc32
1810026B05Rik E330021D16Rik Qk Smpdl Ttc33
1810029B16Rik E43001ON07Rik Rabl Smpdl3a Ttc35
1810030N24Rik E430018J23Rik Rabl1a Smtn Ttc9c
1810034K20Rik EG226654 Rabllb Smtn12 Tub
1810035L17Rik EG622645 Rab2 Smut Tuba4a
1810044A24Rik EG633640 Rab20 Smurfl Tuba8
1810049H13Rik ENSMUSG00000050599 Rab2l Smydl Tubb2c
1810058124Rik ENSMUSG00000071543 Rab24 Smyd4 Tubb5
1810059G22Rik ENSMUSG00000074466 Rab30 Snapap Tufm
1810063B05Rik ENSMUSG00000074670 Rab33b Snapcl Tugl
1810073N04Rik ENSMUSG00000075401 Rab35 SnflIk2 TuIp4
2010106GO1 Rik ExdI1 Rab3a Snora65 Tws 1
2010109N14Rik G3bpl Raba a 1 Snrk Txlna
2010111101 Rik GaInt3 Raba a 2 Snr 70 Txlnb
2010200016Rik GaInt4 Rab3ill Snrpb2 Txndcl
2010305A19Rik GaIntI4 Rab43 Snrpd3 Txndcl0
2010309E21 Rik Gart Rab6 Snx12 Txndcl2
2010315B03Rik Kcna5 Rab8b Snx13 Txndcl4
2010320M18Rik Kcna7 Rabepl Snx16 Txndc4
2010321M09Rik Kcng2 Rab a ll Socs3 Tx 'I
221001OL05Rik Kcnj3 Rac1 Socs4 Txn11
2210020MOl Rik Kcnj5 Rad17 Sorbsl Txn14
2210408121 Rik Kcnk3 Rad23b Sorcs2 Txnl4b
2310001A20Rik Kcnv2 Rad5412 Sort1 Tyk2
2310002L09Rik Kctd10 Ra 1a 1 Sost Uaca
2310007011 Rik Kctd2 Ral s2 Sox17 Ubacl
2310011J03Rik Kctd7 Ram p2 Sox4 Ubapl
2310014D1 1 Rik LOC100044376 Ranb 10 Sox9 Ubash3a
2310014F07Rik LOC100044968 Ranbp2 S p3 Ubd
2310016C16Rik LOC100045002 Rapla S a 9 Ubelc
2310026E23Rik LOC100045020 Rap1gap Spcsl Ubel12
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Table 1
Exemplary Survival/Longevity Genes
231003OG06Rik LOC100045522 Rap2a S eer7- sl Ubelx
2310033F14Rik LOC100045629 Rap2b Spg3a Ube2b
2310036022Rik LOC100046086 Raphl Spg7 Ube2d2
2310038H17Rik LOC100046343 Rara Spinl Ube2d3
2310042E22Rik LOC100046855 Rarb SpinklO Ube2el
2310043N10Rik LOC100047028 Rarg Spna2 Ube2f
2310044H10Rik LOC100047385 Rasal Spnbl Ube2h
2310046A06Rik LOC100047539 Rasa3 Spnb2 Ube2n
2310047A01 Rik LOC100047601 Ras12-9 Spop Ube2o
2310047H23Rik LOC100047794 Rassf7 S r 2 Ube2 2
2310047M10Rik LOC100047915 Rblccl S stmt Ube2vl
2310061J03Rik LOC100048376 Rbbp6 Srd5a212 Ube2v2
2310067B10Rik LOC100048397 Rbj Srebfl Ube2w
2310076G13Rik LOC100048439 Rbml2 Srebf2 Ube3a
2410001C21Rik LOC100048863 Rbm20 Sri Ub14
2410002022Rik LOC640441 Rbm24 Sri Ub17
2410003K15Rik LOC668206 Rbm27 Sr 19 Ublc 1
2410004B18Rik LOC675709 Rbm28 Sr pr Ubtf
2410005016Rik LOC677447 Rbm38 Ssbp3 Ubxd7
2410012H22Rik Mtm1 Rbm39 Ssbp4 Uch15
2410017PO7Rik OTTMUSG00000001 305 Rbmsl Ssh1 Ucp2
2410017P09Rik OTTMUSG00000016644 Rbms2 Ssr3 Ucp3
2410018C17Rik P2ry5 Rbmxrt Sstr5 Ufml
2410018C20Rik P2ry6 Rbpms Ssu72 U c 12
2410019A14Rik Pabpc3 Rcan2 5t13 Ugp2
2410022L05Rik Pah Rc11 St3ga16 Umps
2410042D21Rik Paics Rdh13 St6 alnac6 Ung
2510003E04Rik Paipl Ree 5 St7 Unk
2510042H12Rik Paip2 Rem2 St8sia2 U cc
2610001J05Rik Palm Retsat St8sia4 U crcl
2610008E1 1 Rik Pa dl Rev1 Stabl U crfsl
2610019F03Rik Pa d5 Rfc2 Stard10 Us 11
2610024B07Rik Pa oia Rfc4 Stat6 Us 19
2610028D06Rik Pa of Rfesd Stbd1 U2
2610029101 Rik Pa r7 Rfng Stch Us 21
2610030H06Rik Pa r9 Rfwd3 Stipl Us 22
2610101N1ORik Pard3 Rfx1 Stk11 Us 34
2610200G18Rik Pard6g R 11 Stk19 Us 36
2610209M04Rik Par 12 Rgma Stk38 Us 45
2610301F02Rik Pbefl R s12 Stk39 Us 47
2610507811 Rik Pbld R s5 Stom Us 52
2610528E23Rik Pbrml Rhbdd2 Strn3 Us 54
2700029M09Rik Pcbp2 Rhbdd3 Stx6 Us 9
2700038N03Rik Pcca Rhbdfl Stxbp2
Ut 6
2700097009Rik Pcdh7 Rhd Styx Utrn
2810004N23Rik Pcdh9 Rhobtbl Suhw3 Uvrag
2810008M24Rik Pc f3 Rhobtb2 Suif2 Uxt
2810410M20Rik Pc f6 Rhog Su t5h V1 ra5
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Table 1
Exemplary Survival/Longevity Genes
2810422020Rik Pcm1 Ric8 Su v311 Vamp4
2810423A18Rik Pcmtl Ringl Surf4 Vasn
2810430111 Rik Pcnt RIb 1 Svepl Vbpl
2810455D13Rik Pcnx Rmndl S b11 Vdacl
2900002H16Rik Pc p4 Rmnd5b Syk Vdac2
2900006B1 1 Rik Pc 411 Rnaset2a Syn2 Vdac3
2900008ClORik Pcsk7 Rndl S n r2 Vdp
2900011G08Rik Pctk1 Rnf11 Synj2bp Vegfa
2900024010Rik Pctk2 Rnf13 S n o Vegfb
3010003L21 Rik Pctk3 Rnf139 S 1 Vegfc
3010027C24Rik Pdcd1O Rnf14 Taf2 Vezf1
3110003A17Rik Pdcd4 Rnf149 Taf6 Vkorc111
3110031B13Rik Pdcd6 Rnf167 Tanc1 VIdIr
3110043021 Rik Pdc1 Rnf168 Taok2 V s16
3110073HOlRik Pdc13 Rnf187 Taok3 V s18
3110080E11Rik Pdela Rnf2 Tapl Vps29
3110082117Rik Pde2a Rnf31 Tap2 Vps35
3222402P14Rik Pde4dip Rnf34 Taptl Vps36
3321401 G04Rik Pde6a Rnf5 Tardbp Vps37b
4432414F05Rik Pde7a Rnf6 Tatdn3 V s4b
4631424J17Rik Pd fa Rockl TbcldlOb V s54
4632404M16Rik Pdhal Rorc Tbc1d15 Vwf
4632411B12Rik Pdia3 RP23-136K12.4 Tbc1d19 Wac
4732416N19Rik Pdia6 r p9 Tbc1d20 Waal
4732418C07Rik Pdk4 R a 2 Tbcld2b Was
4832420A03Rik Pdhim4 Rpe Tbc1d5 Wbp4
4833408C14Rik Pdhim5 R 115 Tbcld7 Wdfyl
4833439L19Rik Pds5b Rp127a Tbcb Wdrl3
4921506J03Rik Pdssl R p137 Tbcc Wdr2l
4921509007Rik Pdxk R p139 Tbce Wdr22
4921513H07Rik Pdzd11 R p131 Tbce1 Wdr23
4921517N04Rik Pecaml R p1711 Tbkbpl Wdr3
4930402E16Rik Pef1 R p18 Tb 11 Wdr47
4930426L09Rik Pert R 12 Tbx19 Wdr5b
4930429B21Rik Per3 Rol-3 Tbx20 Wdr92
4930432L08Rik Perp Rol-4 Tcap Wdsof1
4930432021 Rik Pexl1c R 30 Tceal Wfdc3
4930448F12Rik Pex12 R rm1 Tcea3 Wipi2
4930453009Rik Pex19 R s11 Tcf15 Wnkl
4930455C21 Rik Pex5 Rps26 Tcf20 Wtap
4930466F19Rik Pex6 Rps6 Tcf25 Wwp2
4930486A15Rik Pex7 Rps6kal Tcfe2a Xbpl
4930505020Rik Pfdnl Rps6ka4 Tcof1 Xdh
4930513N2ORik Pfd n4 Rrad Tcpl XIr5a
4930523C07Rik Pfdns Rragc Tc 1112 X n e 1
4930524007Rik Pfkp Rragd Tcta Xprl
4930544L04Rik Pfn2 Rras2 Tead4 Xrccl
4930551A22Rik Pgam2 Rrbpl Tef Xrcc6
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Table 1
Exemplary Survival/Longevity Genes
4930554H23Rik Pgbd5 Rrpl Teskl Yapl
4930557J02Rik Pggtl b Rrp9 Tex2 Yeats2
4930570003Rik Pgr Rsadl Tex261 Yifla
493057OE01 Rik Phc2 Rs r l Tfam Yi f3
4930573021 Rik Phc3 Rtp3 Tfb2m Yipf4
4930579G24Rik Phf14 Rufyl Tfpi Yi pf7
4932442K08Rik Phf17 Rufy3 Tfrc Y e12
4933402C05Rik Phf2OI1 Ruscl T gds Y e13
4933403F05Rik Phf3 Rwddl Tgfbrl Ywhag
4933404K13Rik Phf6 Rxrb Thbs4 Zadhl
4933407118Rik Phka2 Rxrg Thns12 Zbed3
4933411 K20Rik Phkb Ryk Thocl Zbtb43
4933413C19Rik Phkgl Ryr2 Thoc4 Zbtb5
4933421A08Rik Phldal S3-12 Thrb Zc3hlla
4933426M11Rik PhIdb1 Sae2 Tiel Zc3hl2c
4933428L01 Rik Phptl Safb Ti d2 Zc3h15
4933429D07Rik Phyh Samd5 Timm22 Zc3h6
4933433P14Rik Pias4 Samd8 Timm50 Zc3h8
4933434E20Rik Picalm Samd91 Tim p3 Zcchc6
4933440H19Rik Piz Saps3 Tim p4 Zdhhcl3
5033414KO4Rik Pik3ca Sarla Tina 1 Zdhhc3
5033421C21Rik Pik3ipl Sars Tjapl Zebl
5033423K11 Rik Pi 5k1 c Satl Tk2 Zfand5
503343OJ17Rik Pir Satb2 TIe6 ZfmI
5330423111 Rik Pitpna Sbds TIk2 Zf 106
5330439A09Rik Pitpnb Sbf2 TInl Zfp110
5430402E10Rik Pitpncl Sbk1 TIocl Zf 187
5430402P08Rik Pitpnml Sc4mol Tm2dl Zf 191
5430407P10Rik Pkd1 Scam p3 Tm2d2 Zfp213
5730470L24Rik Pkia Scap Tm2d3 Zfp236
5730507A1 1 Rik Pkm2 Scara5 Tm4sf 1 Zfp238
5730536A07Rik Pk p2 Scarbl Tm6sf2 Zfp26
5730601 F06Rik PIa2 10 Scarb2 Tm9sf2 Zfp260
5830404H04Rik PIa2 2d Sccpdh Tm9sf3 Zfp277
5830415L20Rik PIa2 5 Scfdl Tmcl Zfp289
5830428H23Rik PIcd1 Schipl Tmccl Zf 30
5830432E09Rik PIcel Scmh1 Tmcc3 Zfp313
5830436119Rik PId3 Scn4b Tmcol Zfp319
5830457010Rik PIdn Scoc Tmed7 Zfp322a
5830469G19Rik Pled Scube2 Tmem103 Zfp335
5830487K18Rik Plekhh3 Sc l1 Tmem109 Zf 341
5930434B04Rik Plekhjl Sc 13 Tmeml 10
Zf 35
6230429P13Rik Plekhm2 Sdcbp Tmeml12b Zfp383
6330403M23Rik Plekhnl Sdcca 10 Tmeml15 Zfp384
6330407G11Rik PIod3 Sdha Tmem119 Zf p414
6330409N04Rik PI p2 Sdhd Tmem123 Zfp422
6330415G19Rik PIs3 Sds Tmem126b Zf 422-rsl
6330417G04Rik PItp Sec11a Tmem132a Zf 512
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Table 1
Exemplary Survival/Longevity Genes
6330503C03Rik Pivap Sec1411 Tmem142a Zfp516
6330564D18Rik PIxnb2 Sec22b Tmem142c Zfp560
6330569M22Rik Pmml Sec23a Tmem147 Zfp568
6430548M08Rik Pnol Sec3la Tmeml4c Zfp579
6530404N21Rik Pn Ial Sec6lal Tmem157 Zfp597
6530413G14Rik PnpIa2 Sec6la2 Tmem159 Zfp608
6620401M08Rik PnpIa6 Sete Tmem167 Zfp628
6720462K09Rik Pnrc2 Sema3b Tmem168 Zfp629
6720475J19Rik Podn Sephs2 Tmeml6f Zfp639
6820401 HO1 Rik Poldi 3 Seppl Tmem176a Zf p644
7030402D04Rik PoIg2 Serbpl Tmem176b Zfp650
7030407E18Rik PoIr2d Serinc1 Tmem182 Zfp651
7420416PO9Rik PoIr2f Serpinb6a Tmem188 Zfp667
8030463A06Rik PoIr2h Serpinb9 Tmem19 Zfp672
8030475D13Rik PoIr2i Sertad2 Tmem30a Zfp68
8430436014Rik PoIr2k Set Tmem37 Zfp703
9030411M15Rik PoIr3gI Setd7 Tmem38a Zfp715
9030418K01 Rik PoIr3k Setd8 Tmem38b Zfp719
9030425P06Rik Potla Setx Tmem4la Zfp740
9130011J15Rik Pou6fl Sf3al Tmem4lb Zfp758
923011 OF1 1 Rik P a 2b Sf3b1 Tmem46 Zfp 817
9230114K14Rik Ppard Sf3b2 Tmem50a Zf 82
9330109K16Rik Pparg Sfr 5 Tmem55b Zfyve2l
9330120H11Rik P ar cla Sfrsl Tmem57 Zhx2
9430010003Rik P hIn1 Sfrsl0 Tmem64 Zhx3
9430013L17Rik Ppic Sfrs2ip Tmem69 Zic2
9530018H14Rik Ppif Sfrs7 Tmem70 Zkscan17
9530018107Rik P i Sfrs9 Tmem77 Zmat2
9530097N15Rik P i12 Sfxn3 Tmem85 Zmat5
9930024M15Rik P PI Sgca Tmem86a Zmym4
A030007L17Rik P m1f S c Tmem93 Zm nd10
A230046K03Rik Ppmel Sgk2 Tmem9b Znrf1
A230051G13Rik P 1ca Sgta Tmlhe Zrsrl
A230062G08Rik P 1rl1 Sh2d3c Tmodl Zscan12
A230067G21 Rik P 1 r12a Sh2d4a Tmod4 Zswim6
A230091 C14Rik P 1 r12c Sh3b rl Tmubl Z 11 b
A330043J11Rik P 1rl31 Sh3bp5I Tmub2 Z x
A330076H08Rik P 1r2 Sh3d19 Tnfaipl
Zzefl
A430005L14Rik Ppp1 r3c Sh3kbpl Tnfaip811
Table 2
Exemplary Genes Whose Expression Enhances Cellular Damage
AA407175 Blvra Ddah2 Gltscr2 LI 11
AA415038 Bmil Ddbl GIudl Lmbrdl
AA987161 Bmp6 Ddb2 Glul LmIn
Aadacll Bm rla Ddit3 Gm104 Lmna
Aars Bnip3 Ddrl Gm561 Lmo4
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Table 2
Exemplary Genes Whose Expression Enhances Cellular Damage
Aasdhppt Brd3 Ddr2 Gmebl Lmtk2
AB182283 Btafl Ddx1 Gmfb LOC100040515
Abca4 Btbdl4b Ddx17 Gmppa LOC100043489
Abca7 Btbd2 Ddx39 Gna-rsl LOC100046468
Abcb4 Btbd3 Ddx5l Gnb2 LOC100046982
Abcb7 Btbd6 Ddx54 Gnb4 LOC552902
Abcdl Btf314 Ddx58 Gne Lonpl
Abcel Btn19 Ddx6 Gn 1O Lor
Abhdl Bxdc2 Debt Gn13 Lpgatl
Abad12 C130094E24 Dedd Gnpdal L hn1
Abhd4 C2 Defbl GoIga2 Lrchl
Abi1 C77058 Defb5 GoIga7 Lrch4
Abi2 C78441 Defcrl5 Gol b1 Lr l0
Ablim2 C78651 Depdc7 Gott Lrp2bp
Abra C79741 Der12 Got2 Lrp6
Abtb1 C86942 Des Gpaal Lr a l
Acaa2 C87259 Dfna5h Gam Lrrcl
Acad11 Cab39 Dgat2 Gpatchl Lrrc20
Acad9 Cabinl Dgcr2 G b l Lrrc39
Acadl Cacnalg Dgka G b 111 Lrrc3b
Acads Cacnalh Dgke Gpcl Lrrc4O
Acadvl Cacybp Dguok Gpc6 Lrrc44
Acbd3 Cadm4 Dhodh G d1I Lsml4a
Acbd5 Calml Dhrsl G per Lsml4b
Acbd6 Cair Dhrs7 Gpkow Lsm3
Ace CaIr3 Dhx30 Gpr115 Ltb4dh
Aco2 Caml Dhx32 G r137 Ltbp3
Acot5 Camsapl Dhx34 G r175 Ltbp4
Acox3 Cand2 Dhx8 Gpr22 Ly6a
AcsI1 Canx Dhx9 Gpr4 Lyplal
Acss2 Capg Diablo Gpr98 LypIa2
Acta1 Ca n1 Dial Gpsn2 Lyrm4
Actb Capnsl Dirasl Gpt2 L rm5
Actn1 Caprinl Dirc2 Gpx3 Lysmd2
Actn2 Card 10 Dkk3 Gramdla Lysmd3
Actn4 Caskin2 DId Grb14 Lztfl1
Actrl b Cas 8a 2 D114 Grina Lztrl
Actr2 Casp9 Dist Grk1 M6 rb l
Acvrl b Cas l Dmd GrkS Macfl
Acvr2a Cavl Dmpk GrIf1 Macrodl
Acvr11 Cav2 Dmtfl Grm8 Mafl
Acypl Cbfb Dmwd Grn Ma ea5
Acyp2 Cblb Dmx12 Gr e12 Ma eel
Adal Cbrl Dnahc9 Gsdmdcl Ma i3
Adam1O Cbx3 Dnaja3 Gsn Mall
Adam15 Ccarl Dnajbl Gsta4 Man2bl
Adam2l Ccdc12 Dnajb4 Gstcd Maob
Adamtsl0 Ccdc122 Dnajb9 Gstml Ma lic3a
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Table 2
Exemplary Genes Whose Expression Enhances Cellular Damage
Adamts2 Ccdc125 Dnajcl2 Gstm2 Ma lIc3b
Adamts7 Ccdc127 Dnajc3a Gstm5 Map2klipl
Adamts9 Ccdc3 Dnajc7 Gstm7 Ma 2k2
Adar Ccdc34 Dnm2 Gstpl Map3kl
Adcyl Ccdc47 Dockl 1 Gsttl Ma 3kl2
Adcy2 Ccdc58 Dock6 Gtf2al Ma 3k2
Adcy3 Ccdc69 Dom3z Gtf2a2 Ma 3k7
Adcy6 Ccdc7 Do e l Gtf2el Ma 3k7i l
Addl Ccdc72 Dot11 Gtf2e2 Ma 4k5
Adh5 Ccdc85b D a tl Gtf2h3 Mapbpip
Adralb Ccdc88a Dph3 Gtf2h4 Ma k14
Adrbkl Ccdc90a Dpp8 Gtf3c1 Ma k6
Aebpl Ccdc90b Dpp9 Gtf3c4 Ma ka k2
Aes Cc19 D s12 Gt b l Ma ref
Afa 111 Ccm2 D s13 Gt b 2 Marcks
Aff4 Ccnd3 Drl Gulo Mat2a
Af 311 Ccngl Drgl Gyg Mat2b
Aga Ccnh Dstn Gyk Matn4
A b15 Ccni Dtnbpl Gysl Maz
Agpatl Ccn12 Dus31 H2afv Mbc2
Agpat5 Ccnt2 Duspl H2afy Mbd2
A gm Ccrl Dusp6 H2-BI Mbd3
A trla Ccr1I1 Dusp8 H2-Oa Mbd5
A xt212 Ccr5 Dv12 H2-T24 Mboat5
Ahdcl Ccs Dynclhl H6 pd Mbtpsl
Ahr Cct5 DynclIi2 Hadh Mbtps2
Ahsal Cct7 Dyrkla Hadha Mcf21
All18078 Cd151 E2f6 Hadhb Mctp2
A1225934 Cd163 Eafl Hand2 Mdfic
A1413194 Cd200 Eapp Hars Mdh2
A1428479 Cd207 Ears2 Hars2 Med13
A1429363 Cd36 Ebag9 Hatt Med16
A1462493 Cd38 Ecel Haxl Med19
A1480535 Cd74 Ecml Hccs Med25
A1506816 Cd83 Ecm2 Hcfcl rl Med30
A1597468 Cd93 Edaradd Hcfc2 Med7
A1662270 Cd97 Ed g3 Hdac2 Mef2b
A1662476 Cdadcl Eeal Hdac4 Mef2c
A1747699 Cdc27 Eeflal Hdac7a Mef2d
A1790298 Cdc215 Eef1 b2 Hdhd2 Me fl 1
A1837181 Cdc216 Eeflel HdIbp Me f8
A1848100 Cdc37 Eef2 Heatr5b Me113
A1852064 Cdc42ep3 Efcab2 Heatr6 Mertk
A1987944 Cdgap Efemp2 Hectdl Mesdc2
Ak7 Cdh13 Efnb3 He ph Metrnl
Aka 13 Cdipt Egf Herpudl MettlOd
Aka p2 Cdk5rap3 E f17 Heyl Mex3c
Ak 2 Cdk7 E flam Hfe2 Mfap4
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Table 2
Exemplary Genes Whose Expression Enhances Cellular Damage
Akr1 a4 Cdv3 Egfr Hgs Mfge8
Akrlb8 Cebpz Eglnl Hhatl Mfn1
Akr7a5 Cenpa EgIn3 Had Mfsd8
Aktls1 Cen E rl Hiatl1 M gam
Alasl Cental Ehb 111 Hibadh Mgatl
AIdhla3 Centa2 Ehd4 Hifla Mgat4b
AIdh2 Centb2 Ei24 Hi dlb M
Aldh4al Centdl Eiflay Hint3 Mgrnl
Aldh7al Centd2 Eif2akl Hirip3 Mif4gd
Aldh9al Cent g2 Eif2s2 Hive p2 MkI1
AI 12 Cetn3 Eif3e Hk3 Mknk1
AI 13 CfI1 Eif4al HIf Miff
AI g5 Cflar Eif4a2 Hmcnl MIk1
Alkbh6 C nI1 Eif4b Hm 20b M112
Alkbh8 Cgrrfl Eif4e2 Hmgbl Mild
AIs2cr2 Chad Eif4ebpl Hmgb3 MIIt6
Ana c10 Chac2 Eif4g3 Hmgcl MIX
Ana c2 Chchd4 Eif5 Hmgcsl MIxip
An t12 Chdl Eif5b Hnrpab MI cd
Ankl Chd2 EIac2 Hnrph3 Mme
Ankhdl Chd4 EIf2 Hnrpk Mm 15
Ankrdl Chmplb EIk3 Hnr 1 Mm lb
Ankrdl0 Chmp2b Ell Hnr 11 Mm p2
Ankrd13a Chordcl E112 Hnrpr Mmrn2
Ankrd13c Chrac1 Elov15 Hnr uil Mobk13
Ankrd13d Chrd EIp3 Hoxd11 Mocos
Ankrd25 Chrng EI 4 Hrasls Mocs2
Ankrd28 Chst14 Eltd1 Hrc Morc2a
Ankrd32 Chuk Emb Hs2stl Mosc2
Ankrd37 Churcl Emd Hsd17bl1 Mospdl
Ankrd38 Ciaol Eme2 Hsd17bl3 M a21
Ankrd9 Cibl Emgl Hsd17b4 Mpp6
An 32b Cic Emilinl Hsd12 M v17
Anxa3 Cil 2 Em12 Hs 110 Mrfapl
Anxa6 Cisd2 End Hs al b Mrgprf
Aoc3 Cish Eng Hs a5 Mr 11
A 1s2 Ckm Eno3 Hs b2 Mr 115
Ap2a2 Ckmt2 Enpep Hs b3 Mr 117
Ap2bl CIcn5 Enpp5 Hs b6 Mr 119
Ap2ml Cldndl Ent d5 Hs b7 Mr 128
Ap4ml Clec2d Ent d6 Hs el Mr 130
Ap4sl CIicl E p300 Htral Mr 132
Apbbl Clic4 E b4.113 Htra3 Mr 136
A 12 Clintl Epha4 Husl Mr 138
Apobec2 CIk3 Ephbl H a14 Mr 14
A pod CIn5 Ephb4 Iahl Mr 141
Apoe Clock E m2ai l Ibrdc2 Mr sl7
A pool CI tm1 E n1 Idl Mrpsl8c
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Table 2
Exemplary Genes Whose Expression Enhances Cellular Damage
A 11 Clstn1 E s1511 Ide Mr s22
App12 CItc Erc1 Idh3a Mrps5
Arf1 Cmpk Ergic3 Idh3b Mrs21
Arf3 Cm a5 Erlin1 Ifi3O Ms131
Arg2 Cndp2 Ero11b Ifit3 Msra
Arid4b Cnot61 Errfi1 Ifnar1 Msrb2
Arl1 Cnot7 Escol Ifnar2 Msrb3
Arl2bp Cntfr Esd Ifn r1 Msx1
Ar13 Cntn4 Esf1 Ifn r2 Mtap4
Arl4a Commd1 Esrrg Ift122 Mta 7d1
Arl5b Commd3 Etfa Ift57 Mtbp
Ar c1a Commd4 Etnk1 I fb 4 Mtch2
Ar c1b Commd5 Ets2 I fb 6 Mterf
Arpc2 comp Ewsr1 I sf11 Mterfd1
Arpc4 Cope Exoc5 I sf3 Mterfd2
Arrb1 Co Exosc1 I sf8 Mterfd3
Art5 Co s2 Exosc10 Ih k1 Mtif3
Asb1 Cops7a Exosc7 Ikbkap Mtmr1
Asb14 Co 1Ob Exosc9 1110rb Mtmr3
Asb5 Co q9 Ext1 Ill 3ra1 Mtrr
Ascc311 Coro 1b Eya3 1118bp Mustn1
Asnsd1 Cox11 F11r 116st Mxd4
Ash Cox4i2 F13b Ilk Mxi1
Atad2b Cox5a F5 IIvb1 Mxra8
Atf3 Cox8a Fads3 Imm 11 M bb 1a
Atg10 Cp Fahd2a Immp21 Mybpc3
At g3 Cpeb4 Fam18b Immt Myc
At 4d c pm Fancg Im 3 Mycbp
At g5 C sf1 Fap Im a2 M ct1
At 11b C sf3 Fas Im ad1 M d116
At 13a1 C t1a Fastkd1 Ints8 Myd88
Atp 1 a2 C t1 b Fastkd2 I mk Myef2
At 5h Cram 11 FbIn1 I o13 M h14
At 5s Crat FbIn2 I o7 Myh6
At 6a 2 Crbn Fbp2 I o8 M y14
Atp6vOa2 Creb1 Fbx12 I sect M y17
At 6vOd1 Creb311 Fbx16 I wd1 Mylip
At 6v1b2 Crebbp Fbxo3 Irf4 M Y010
At 6v1f Crebzf Fbxo30 Irs1 M o1c
At 9a Cre 1 Fbxw4 Isca2 Myo9b
At 9b Cri 1 Fbxw5 Is 2O Myocd
At af1 Crip2 Fcer2a Is na1 M om1
At bd1c Cript Fcgr4 Itf 3 Mypn
At if1 Crnk11 Fdx1 It b1 b 1 N6amt1
Atr Crot Fem1 c It b1 b p2 N6amt2
Atxn2 Cr 1 Fert2 It b1b 3 Naca
Atxn711 Crab F fr1 op It b2 Nagpa
AU020772 Cr bb1 Fihi 1 It b5 Nars
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Table 2
Exemplary Genes Whose Expression Enhances Cellular Damage
AU041133 Cryz FkbplO Itih3 Nat5
Aupl Csdc2 Fkbp5 Itk Nbeall
AV009015 CselI Fkbp8 Itm2b Ncka 11
AV024533 Csf2ra FIcn Itm2c Ndst4
AV025504 Cs1 Fiji It r3 Ndufa5
Av rla Csnklal FIotl Ivnslabp Ndufabl
AW046287 Csnkld FIot2 Jam2 Ndufafl
AW112010 Csnk2al FI wchl Jmjdlc Ndufb3
AW209491 Cst3 Fmn1 Jmjd2a Ndufb7
AW555464 Cst8 Fmo2 Jmjd6 Ndufb8
AW556556 Cstf2 Fmr1 Josd2 Ndufcl
AW742931 Ctage5 Fnb l i Jtv1 Ndufc2
Azi2 Ctcf Fnipl Jun Ndufsl
Azinl Ctgf Foxa3 Kbtbd10 Ndufs2
Bachl Ctps Foxj2 Kbtbd5 Ndufs3
Bag4 Ctsb Foxk1 Kcnip2 Ndufs5
Bambi Ctsf Foxk2 Khk Ndufs7
Banp Ctss Foxol Kiflb Ndufs8
Batla Ctsz Foxpl Kiflc Ndufvl
Bat2 Cttnb 2nl Fragl Kif2la Ndufv2
Bazla Cull Frapl Kif2a Nedd4
Bazlb Cu13 Frmd4b Kif3a Neill
BB217526 Cxcl12 Frmd5 Kif5b Nek3
Bbc3 Cxcl14 Fscn1 KIc3 Nf2
Bbs1O Cxxcl Fthl KIf11 Nful
80003331 Cxxc5 Ft11 KIfl3 Ngiyl
80003885 Cyb561 Fuca2 KIf15 Ngrn
80003965 Cyb5b Fundc2 KIf16 Nidl
BC010304 Cyb5r3 Furin KIf4 Nif311
BC010981 Cyb5r4 Fus KIf7 Ninjl
BC011248 Cybasc3 Fxcl Klhdcl Ni b1
BC013529 C cl Fxydl Klhdc3 Nkirasl
BC016495 C i l Fxyd5 KIh113 Nkiras2
BC019943 Cyplbl Fzd1O KIh122 NI n2
BC020077 Cyp27al Fzd2 KIh123 Nmnatl
BC021395 Cyp2f2 Fzd9 KIh124 Npcl
BC023882 C sl GOs2 KIh14 Nppb
BC024659 D030063E12 G6 c2 KIh19 Nras
BC024814 DOH4S114 Gaa KIM b24 Nrdl
BC025076 D1OErtd641e Gabl Kpnal Nrpl
BC028440 D13Ertd787e Gab pa Kpna4 Nrp2
BC028528 D14Ertdl6e Gadd45b Krrl Nrtn
BC030183 D14Ertd581e Gadd45g Kti12 Nsmaf
BC030308 D15Ertd5Oe Gale Ktn1 Nt5c2
BC030336 D16H22S680E Gaikl Llcam Nt5c3
BC031353 D19Ertd721e Gapdh 17Rn6 Nubl
BC031781 D19Ertd737e Gapvdl Lacel Nwdl
BC032203 D19Wsu162e Garnil Lactb Oas12
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Table 2
Exemplary Genes Whose Expression Enhances Cellular Damage
BC034069 D1Bw 1363e Gas6 Lama2 Oggl
BC037034 D2Ertd391e Gata4 Lamb2 Oplah
BC037112 D3Ertd254e Gba2 Laptm4a Pfkfb2
BC038479 D3WsulO6e Gbas Larpl Pfkfb4
BC039210 D4Ertd429e Gbel Larp2 P c1
BC043098 D4Ertd571e Gbf1 Larp4 P Is
BC043476 D6Wsu176e Gcdh Larp5 Pygb
BC048679 D8Ertd457e Gdil Lcmtl Rars
BC049349 D8Ertd54e Gdi2 Lcmt2 Rars2
BC057893 D8Ertd620e Gdpdl Ldbl Rere
Bcam D8Ertd82e Gdpd5 Ldb3 Rn e ll
Bcat2 D9Ertd4O2e Gemin5 Ldhb RP23-233B9.8
Bckdha Daaml Ggtal Ldhd Rsrc2
Bckdk Dadl Ghitm Leol Smadl
Bc12I13 Dap Gimap4 Lgals3bp Smad3
BcI6b Da k2 Gimap8 L als7 Smad6
Bclafl Daxx Git1 Lgmn Ucp3
Bdpl Dbh Gja3 Lgr4 X83328
Bed Dcn GlelI Lgr6 Xk
Bgn Dctnl GI 1 Lias Xpo4
Bhlhb2 Dctn2 GIi1 Limdl Xpo6
Bhlhb3 Dcunldl Glol Lims2 X pot
Bicd2 Dcunld2 GIod4 Lie Xrnl
Birc4 Dcunld5 GIs Lix1I
C. Preferred Compositions of the Present Invention
[0037] The invention particularly pertains to resveratrol-containing
compositions in which
the specific activity of the resveratrol has been stabilized or enhanced. As
used herein, the term
"specific activity" refers to the ratio of the extent of gene modulation
(relative to control) per
amount (mass) of administered resveratrol.
[0038] Preferably, such compositions will comprise a chelator, hyaluronic
acid, and/or
vitamin D. The invention particularly pertains to such compositions that
comprise resveratrol
(preferably, the compositions of the present invention will provide a
composition dosage of
from about 10 mg to about 2 g, more preferably from about 100 mg to about 500
mg), and at
least one compound selected from the group consisting of an antioxidant
(chelator), hyaluronic
acid, and vitamin D. Preferably, the compositions of the present invention
will contain
resveratrol, an antioxidant, hyaluronic acid, and vitamin D.
[0039] As used herein the term "chelator" refers to an organic compound that
bonds with
and removes free metal ions from solution. Examples of suitable chelators
include
ethylenediaminetetraacetic acid (EDTA), histidine, antibiotic drugs of the
tetracycline family,
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pyridoxal 2-chlorobenzoyl hydrazone, desferrioxamine, dexrazoxane,
deferasirox, pyoverdine,
pseudan, citrate, NDGA (nordihydroguaiaretic acid: 1,4-bis[3,4-
dihydroxyphenyl]2,3-
dimethylbutane), ferulic acid and phytic acid. Preferably, the compositions of
the present
invention will provide a composition dosage of chelator of from about 1 g to
about 15 g, more
preferably from about 2 g to about 12 g.
[0040] Phytic acid is a particularly preferred chelator for the purposes of
the present
invention. As used herein, the term "phytic acid" refers to inositol
hexaphosphate ((2,3,4,5,6-
pentaphosphonooxycyclohexyl) dihydrogen phosphate; also known as "IP6";) (see,
Thorne
Research, Inc. (2002) "Inositol Hexaphosphate. Monograph," Altern. Med. Rev.
7(3):244-248;
Vucenik, I. et at. (2006) "Protection Against Cancer By Dietary IP6 And
Inositol," Nutr.
Cancer. 55(2):109-125; Lopez, M.A. et al. (2004) "Iron Availability: An
Updated Review," Int.
J. Food Sci. Nutr. 55(8):597-606; Singh, R.P. et al. (2005) "Prostate Cancer
And Inositol
Hexaphosphate: Efficacy And Mechanisms," Anticancer Res. 25(4):2891-2903;
Vucenik, I. et
al. (2006) "Cancer Inhibition By Inositol Hexaphosphate (IP6) And Inositol.:
From Laboratory
To Clinic," J. Nutr. 133(11 Suppl 1):3778S-3784S; Raboy, V. (2003) "Myo-
Inositol-
1,2,3,4,5,6-Hexakisphosphate," Phytochemistry. 64(6):1033-19043; Vohra, A. et
al. (2003)
"Phytases: Microbial Sources, Production, Purification, And Potential
Biotechnological
Applications," Crit. Rev. Biotechnol. 23(1):29-60; Fox, C.H. et al. (2002)
"Phytic Acid (IP6),
Novel Broad Spectrum Anti-Neoplastic Agent: A Systematic Review," Complement
Ther. Med.
10(4):229-234; Grases, F. et al. (1999) "Phytate (IP6) Is A Powerful Agent For
Preventing
Calcifications In Biological Fluids: Usefulness In Renal Lithiasis Treatment,"
Anticancer Res.
19(5a):3717-3722; Jariwalla, R.J. (1999) "Inositol Hexaphosphate (IP6) As An
Anti-Neoplastic
And Lipid-Lowering Agent," Anticancer Res. 19(5a):3699-3702; Katayama T.
(1999)
"Hypolipidemic Action Of Phytic Acid (IP6): Prevention Of Fatty Liver,"
Anticancer Res.
19(5a):3695-3698). The structure of phytic acid is provided below:
OH
HO-P=0 OH
OH I
0 HO-P=0
HO-P=0
O 0
HO-, P~ HO /OH
P
HO 0l \O
O
1
0=P-OH
OH
[0041] Phytic acid is found in substantial amounts in whole grains, cereals,
legumes, nuts,
and seeds, and is the primary energy source for the germinating plant (Graf,
E. (1983)
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"Applications of Phytic Acid," J. Am. Oil. Chem. Soc 60:1861-1867). Phytic
acid and its lower
phosphorylated forms (such as IP3) are also found in most mammalian cells,
where they assist
in regulating a variety of important cellular functions (Szwergold, B.S. et
al. (1987)
"Observation Of Inositol Pentakis- And Hexakisphosphates In Mammalian Tissues
By 31P
NMR," Biochem. Biophys. Res. Commun. 264:874-881). Phytic Acid is preferably
provided in
the form of rice bran (Srinivasan, M. (2007) "Ferulic Acid: Therapeutic
Potential Through Its
Antioxidant Property," J. Clin. Biochem. Nutr. (2007) 40(2):92-100; Kim, M.J.
et al. (2007)
"Ferulic Acid Supplementation Prevents Trimethyltin-Induced Cognitive Deficits
in Mice,"
Biosci. Biotechnol. Biochem. (2007) 71(4):1063-1068). Phytic acid is reported
to function as
an antioxidant by chelating divalent cations such as copper and iron, thereby
preventing the
generation of reactive oxygen species responsible for cell injury and
carcinogenesis (Harland,
B.F. et al. (1987) "Phytate In Foods," World Rev. Nutr. Diet 52:235-259). The
preferred
composition dosage of phytic acid (for example, as rice bran) is in the range
of 2000-12,000
mg.
[0042] As used herein, the term "hyaluronic acid" (also known as hyaluronan)
refers to
linear polymer composed of repeating disaccharides of D-glucuronic acid and D-
N-
acetylglucosamine, linked together via alternating (3-1,4 and (3-1,3
glycosidic bonds ([-(3 (1,4)-
G1cUA-(3 (1,3)-G1cNAc-]õ ). Hyaluronic acid can be 25,000 disaccharide repeats
(n) in length:
O- CHZOH
H O H H H
O -O HO O
HO O O
I I
H OH H NH
H H H
O H __~
CH3
Glucuronic Acid N-Acetyl-Glucosamine n
[0043] Hyaluronic acid is a water-retaining molecule that is generated
naturally in the
human body but in decreasing amounts as the body ages. Hyaluronic acid is a
multifunctional
glycosaminoglycan that forms the basis of the pericellular matrix of cells.
Hyaluronic acid is
synthesized by 3 different but related enzymes (hyaluronan synthases: HAS 1,
HAS2 and HAS3
(Weigel, P.H. et al. (1997) "Hyaluronan Synthases," J. Biol. Chem. 272:13997-
14000; Tammi,
M.I. et al. (2002) "Hyaluronan And Homeostasis: A Balancing Act," J. Biol.
Chem. 277:4581-
4584; Kakehi, K. et al. (2003) "Hyaluronic Acid: Separation And Biological
Implications," J.
Chromatogr. B Analyt. Technol. Biomed. Life Sci. 797(1-2):347-355; Radaeva,
LF. et al.
(1997) "Hyaluronic Acid: Biological Role, Structure, Synthesis, Isolation,
Purification, And
Application (Review)" Prikl. Biokhim. Mikrobiol. 33(2):133-137; Stoolmiller,
A.C. et al.
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(1970) "The Biosynthesis Of Hyaluronic Acid By Group A Streptococcus," Expos.
Annu. Biochim.
Med. 30:65-78). U.S. Patent Application Publication 2004/0234497 discloses the
use of hyaluronic
acid for cancer drug delivery.
10044] Hyaluronic acid has been traditionally extracted from rooster combs,
from bovine or fish
vitreous humor, from microbial production or from other sources (Rangaswamy,
V. et al. (Epub 2007
Oct 24) "An Efficient Process For Production And Purification Of Hyaluronic
Acid From
Streptococcus Equi Subsp. Zooepidemicus," Biotechnol. Lett. 30(3):493-496;
Gao, F. et al. (2006)
"Preparation And Characterization Of Hyaluronan Oligosaccharides For
Angiogenesis Study," J.
Biomed. Mater. Res. B Appl. Biomater. 78(2):385-392; Blank, L.M. et al. (2005)
"Stable Production
Of Hyaluronic Acid In Streptococcus Zooepidemicus Chemostats Operated At High
Dilution Rate,"
Biotechnol. Bioeng. 90(6):685-693; Kakehi, K. et al. (2003) "Hyaluronic Acid:
Separation And
Biological Implications," J. Chromatogr. B Analyt. Technol. Biomed Life Sci.
797(1-2):347-355;
Volpi, N. et al. (2003) "Purification And Characterization Of Hyaluronic Acid
From The Mollusc
Bivalve Mytilus Galloprovincialis," Biochimie 85(6):619-625; Tawada, A. et al.
(2002) "Large-Scale
Preparation, Purification, And Characterization Of Hyaluronan Oligosaccharides
From 4-hers To
52-Mers," Glycobiology. 2002 Jul;12(7):421-426; Mahoney, D.J. et al. (2001)
"Novel Methods For
The Preparation And Characterization Of Hyaluronan Oligosaccharides Of Defined
Length,"
Glycobiology. 11(12):1025-1033; Mcdonald, J. et al. (2002) "Hyaluronan
Minireview Series," J. Biol.
Chem. 277(7):4575-4579; Radaeva, I.F. et al. (1997) "Hyaluronic Acid:
Biological Role, Structure,
Synthesis, Isolation, Purification, And Application (Review)" Prikl. Biokhim.
Mikrobiol. 33(2):133-
137). Most preferably, the hyaluronic acid of the present invention is
obtained from rooster combs.
Hyaluronic acid is widely available commercially, and such preparations are
suitable for the purposes
of the present invention. Preferably, the compositions of the present
invention will provide a
composition dosage of hyaluronic acid of from about I mg to about 400 mg, more
preferably from
about 50 mg to about 200 mg.
10045] As used herein, the term "Vitamin D" refers to a fat-soluble
prohormone. Two major forms
of vitamin D are vitamin D2 (ergocalciferol) and vitamin D3 (cholecalciferol)
(DeLuca, H.F. et al.
(1998) "Mechanisms And Functions Of Vitamin D," Nutr. Rev. 56: S4-S 10):
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IH IH
HO" HO"
Ergocalciferol (Vitamin D2) Cholecalciferol (Vitamin D3)
[0046] Vitamin D exhibits many biological actions. While vitamin D is widely
known for
its ability to stave off bone disease (rickets in growing children,
osteoporosis in senior adults),
it is becoming a central player in the battle against cancer. Regarding the
role of vitamin D in
immunity and cancer, vitamin D improves the chemotactic (affinity for)
neutrophils to mobilize
and migrate. Patients with rickets due to vitamin D deficiency are observed to
have sluggish
neutrophils that cannot migrate properly. Vitamin D stimulates the maturation
of monocytes to
macrophages. This results in an enlarged army of immune fighting cells to
mount against
tumors. Vitamin D is widely available commercially, and such preparations are
suitable for the
purposes of the present invention.
[0047] Vitamin D is essential for optimal muscle, bone, brain, immune and
cardiovascular
health and is undergoing re-discovery by aging researchers worldwide. Vitamin
D
supplementation up to 2000 IU has been shown to significantly reduce mortality
rates, thus
adding vitamin D to the lineup of molecules now considered to be true
longevity factors
(Autier, P. et at. (2007) "Vitamin D Supplementation And Total Mortality: A
Meta-Analysis Of
Randomized Controlled Trials," Arch Intern Med. 167(16):1730-1737). Its anti-
calcifying
properties (Zittermann, A. et al. (2007) "Vitamin D And Vascular
Calcification," Curr. Opin.
Lipidology 18(1):41-46) qualify vitamin D as another powerful agent that
inhibits progressive
overmineralization in the human body with advancing age and parallels the
action of other
mineral chelators in the compositions of the present invention. While the 1200
IU dose is
three times more than the Recommended Daily Allowance, it is well within the
Safe Upper
Limit established by the National Academy of Sciences (2000 IU) and
corresponds with a
supplemental dosage recently found to be beneficial in a human clinical trial
(Lappe, J.M. et al.
(2007) "Vitamin D and calcium supplementation reduces cancer risk: results of
a randomized
trial," Amer. J. Clin. Nutr. 85(6):1586-1591). A 2,000 IU dosage is roughly
equivalent the
natural vitamin D3 produced by 15-30 minutes of total-body summer sun exposure
at noontime
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at a southern latitude, for which no side effects have been reported.
Preferably, the
compositions of the present invention will provide a composition dosage of
vitamin D of from
about 100 IU to about 100,000 IU, more preferably from about 1,000 IU to about
50,000 IU.
[0048] The compositions of the present invention may contain additional
components,
including additional active components that act to enhance resveratrol
biological activity and
inactive compounds (e.g., flavorants, sweeteners, dyes, vitamins, amino acids
(e.g., lysine,
proline, etc.), minerals, nutrients, etc.).
[0049] In particular, quercetin (3,3',4',5,7-pentahydroxy-2-phenylchromen-4-
one)
OH
OH
HO O
OH
OH O
Quercetin
[0050] butein, fisetin, myricetin, kaempferol, cis-resveratrol or piceatannol
may be added to
the compositions.
OH
OH OH
HO
HO O OH
OH
OH O O
Butein [3,4,2',4'-tetrahydroxychalcone] Fisetin [3,3'4',7-Tetrahydroxyflavone]
OH
OH
OH
HO O OH HO O \
OH ):? OH
OH O OH O
Myricetin [3,5,7-Trihydroxy-2-(3,4,5- Kaempferol [3,5,7-trihydroxy-2-
trihydroxyphenyl)-4-chromenone] (4-hydroxyphenyl)-4H-1-
benzopyran-4-one]
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/ OH
HO
\ OH
OH
Piceatannol [5-[(E)-2-(3,4-dihydroxyphenyl)vinyl]benzene-1,3-diol]
[also known as 3,4,3',5'-tetrahydroxy-trans-stilbene]
[0051] Such compounds are described, for example by Stecher, G. et at. (2001)
("Determination Of Flavonoids And Stilbenes In Red Wine And Related Biological
Products By
HPLC And HPLC-ES[-MS-MS," Fresenius J. Anal Chem. 2001 Sep;371(1):73-80).
[0052] Resveratrol is glucuronated in the human liver, which may reduce its
bioavailability.
Flavonoids, such as quercetin, inhibit resveratrol glucuronidation and thus
may act to improve
resveratrol bioavailability (see, de Santi, C. et at. (2000) "Glucuronidation
Of Resveratrol, A
Natural Product Present In Grape And Wine, In The Human Liver," Xenobiotica
30(11):1047-
1054); De Santi, C. et al. (2000) "Sulphation Of Resveratrol, A Natural
Compound Present In
Wine, And Its Inhibition By Natural Flavonoids," Xenobiotica 30(9):857-866; De
Santi, C. et
al. (2000) "Sulphation Of Resveratrol, A Natural Product Present In Grapes And
Wine, In The
Human Liver And Duodenum," Xenobiotica 30(6):609-617). Quercetin may also act
synergistically with resveratrol or independently of resveratrol to provide
beneficial function
(Kampkotter, A. et al. (Epub 2007 Oct 16) "Increase Of Stress Resistance And
Lifespan Of
Caenorhabditis Elegans By Quercetin," Comp. Biochem. Physiol. B Biochem. Mol.
Biol.
149(2):314-323). (See also, Kaindl, U. et al. (2008) "The Dietary Antioxidants
Resveratrol
And Quercetin Protect Cells From Exogenous Pro-Oxidative Damage, " Food Chem.
Toxicol.
46(4):1320-1326; Melzig, M.F et al. (2002) "Induction Of Neutral Endopeptidase
And
Angiotensin-Converting Enzyme Activity Of Sk-N-Sh Cells In Vitro By Quercetin
And
Resveratrol," Pharmazie. 57(8):556-558; Hsu, C.L. et al. (2006) "Induction Of
Cell Apoptosis
In 3T3-L1 Pre-Adipocytes By Flavonoids Is Associated With Their Antioxidant
Activity,"
Molec. Nutr. Food Res. 50(11):1072-1079; Chan, M.M. et al. (2000) "Synergy
Between
Ethanol And Grape Polyphenols, Quercetin, And Resveratrol, In The Inhibition
Of The
Inducible Nitric Oxide Synthase Pathway," Biochem. Pharmacol. 60(10):1539-
1548; Nicholson
S.K. et al. (2008) "Effects Of Dietary Polyphenols On Gene Expression In Human
Vascular
Endothelial Cells," Proc. Nutr. Soc. 67(1):42-47; Lemos, C. et al. (2007)
"Modulation Of
Folate Uptake In Cultured Human Colon Adenocarcinoma Caco-2 Cells By Dietary
Compounds," Eur. J. Nutr 46(6):329-336).
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[0053] Emulsifiers, fillers, binding agents, and the like may also be included
in the
compositions of the present invention.
[0054] In one embodiment, the compositions of the present invention comprise a
novel
combination of. small molecules such as quercetin and resveratrol with
widespread preventive
and therapeutic health properties; and/or collagen-building nutrients (such as
vitamin C-
ascorbate, lysine, proline, etc.); and a glycosaminoglycan such as a shortened
(low molecular
weight) chain of hyaluronic acid (HA) or its singular components (glucosamine,
glucuronate)
or chondroitin sulfate, which are linear disaccharides (sugar-like molecules)
that serve as
structural components of cartilage, but in this combination serve as
synergistic co-healing
agents in non-cellular (connective) tissue that surrounds living cells. The
combination of
glycosaminoglycans (hyaluronan, glucuronate or chondroitin) and/or ascorbate,
lysine or
proline, to encourage the generation of collagen, and small molecules, that
operate on intra-
cellular basis, comprise therapeutic or preventive action that encompasses the
total tissue
matrix. The combination of the present invention is intended for human or
animal oral intake
as a dietary supplement. In a sub-embodiment thereof, such compositions may
comprise a
combination of resveratrol and hyaluronan in a dietary supplement that serves
to heal a variety
of illnesses including some cancers. Resveratrol is known to be an anti-cancer
molecule and to
have other healing and longevity enhancing properties. Hyaluronan (hyaluronic
acid, HA) is
taken as an oral supplement or can be given intravenously to target cancer
cells. When
combined with or attached to other molecules, hyaluronan will deliver other
anti-cancer and
healing agents such as resveratrol to tumor sites. The combination may or may
not include a
chelating agent, an antioxidant and/or an emulsifier as described in my above-
referenced co-
pending patent application. When encapsulated or otherwise applied together,
with or without
those additives, resveratrol and HA have powerful healing properties for
animals and humans.
[0055] Most preferably, the compositions of the present invention stabilize
resveratrol
specific activity such that the resveratrol of the compositions has a specific
activity that is
greater than that of resveratrol maintained in the presence of oxygen gas, or
maintained in the
absence of a chelator, hyaluronic acid, or vitamin D. Preferably, the amounts
of the non-
resveratrol constituents of the compositions will stabilize the composition's
resveratrol so that
it exhibits at least 10% more activity, at least 20% more activity, at least
50% more activity, at
least 2-times the activity, at least 5-times the activity, or at least 10-
times the activity of
resveratrol maintained in the presence of oxygen gas, or maintained in the
absence of a
chelator, hyaluronic acid, or vitamin D and so that it remains capable of
exhibiting such
specific activity over extended periods (for example, 1, 2, 4, 6, 10, 12, 18,
24, or 36 months or
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longer) at ambient conditions of temperature and humidity (i.e., without need
for special precautions
as to temperature or humidity).
D. Packaging of the Preferred Compositions of the Present Invention
[0056] Resveratrol is typically unstable to light and oxidation (Shaanxi
University of Science &
Technology, Xianyang China (2007) "Study On The Stability Of Resveratrol In
Rhizoma Polygoni
cuspidate," Zhong Yao Cai. 30(7):805-80). The resveratrol of the present
invention is preferably
prepared, packaged and/or stored in a manner that maximizes its specific
activity. It is preferred to
prepare, package and/or store resveratrol in low light (or in the dark) and/or
in low oxygen, so as to
minimize light-induced degradation (e.g., photo-isomerization) or oxygen-
induced degradation. The
preferred compositions of the present invention are formulated as dietary
supplements for oral
ingestion in the form of a pill, lozenge, capsule, elixir, syrup, etc. Other
modalities of administration
may alternatively be employed (e.g., intranasal, parenteral, intravenous,
intraarterial, topical, etc.).
[0057] In a first example of such preferred packaging, the compositions of the
present invention are
formulated as air-tight capsules in which encapsulation is conducted so as to
prevent or minimize
exposure to oxygen. In one embodiment, such encapsulation is conducted in an
oxygen-free
environment. For example, the components of the compositions of the present
invention may be
inserted into a capsule in an inert gas (e.g., nitrogen, argon, etc.)
environment. Preferably, a nitrogen
bubble (e.g., 5-20% of the capsule volume) may be introduced into the capsule
to further stabilize and
protect the components against oxidation (see, PCT Publication No. WO
01/08631). That
international application has a corresponding U. S. patent application.
Suitable capsules useful in the
encapsulation of resveratrol and other oxidation prone ingredients of dietary
supplements include
Licaps (Capsugel), an air-tight gelatin capsule. The presence of phytic acid,
which has the ability to
protect the components from metal-induced oxidation, augments such anti-
oxidation precautions. A
particularly preferred example of such a resveratrol-containing composition is
Longevinex
(Resveratrol Partners, LLC, San Dimas, CA), which comprises resveratrol and
phytic acid.
Longevinex contains as active ingredients (per capsule): 5 mg Vitamin E (as
mixed tocopherols),
215 mg total resveratrol (obtained from French red wine and giant knotwood
(Polygonum
cuspidatum), and providing 100 mg of trans-resveratrol), 25 mg quercetin
dehydrate, 75 mg phytic
acid (rice bran extract), 380 mg rice bran oil, 55 mg sunflower lecithin.
[0058] Once a composition has been sealed into an air-tight capsule, it is
important to maintain a
low or no-oxygen environment in the packaging surrounding the capsules in
order to
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protect the composition from oxidation should a break or leak occur in the
sealed capsule.
Therefore, an oxygen absorbing packette is preferably employed to reduce the
presence of free
oxygen. Vacuum or nitrogen-flushed packaging (bottles, pill cases, etc.) in
air-tight materials is
desirable.
[0059] In an alternative embodiment, the components and compositions of the
present
invention may be prepared as a microencapsulated process (see, generally,
Rubiana, M. et al.
(2004) "Drug Delivery Systems: Past, Present, and Future," Current Drug
Targets, 5(5):449-
455). Micro-encapsulation is a process by which tiny particles or droplets
(ranging in size from
a few nanometers to one micron) are coated with a protective layer to create
small capsules
with controlled properties. Suitable micron-sized, encapsulated, preparations
can be obtained
using the microencapsulation processes of Maxx Performance Inc. (Chester, NY),
Blue
California (Rancho Santa Margarita, CA), Southwest Research Institute (San
Antonio, TX),
Coating Place, Inc. (Verona, WI), Microtek Laboratories (Dayton, OH), Particle
Sciences, Inc.
(Bethlehem, PA), etc. 3rd-generation Longevinex ("Longevinex-3 ")
(Resveratrol Partners,
LLC), which contains Vitamin D3, Vitamin E, Resveratrol, Quercetin, and Phytic
Acid is a
particularly preferred microencapsulated form of the compositions of the
present invention.
[0060] The present invention further comprises a practical method of
stabilizing quercetin
and other easily oxidized dietary supplement ingredients which may come in
contact with
oxidizing metals.
E. Utility of the Compositions of the Present Invention
[0061] The compositions of the present invention enhance resveratrol's
specific activity.
The compositions of the present invention therefore find utility in the
treatment of diseases (or
in the amelioration of the symptoms of diseases) such as cardiovascular
disease, cancer,
macular degeneration, aging, neurodegenerative diseases (e.g., Alzheimer's
Disease,
Parkinson's Disease, etc.) and inflammation in which the modulation of
expression of
"survival/longevity" genes and/or "damage inducing" genes is desired. Over
time, as minerals
such as calcium and iron accumulate in the human body, genes respond in
deleterious ways.
Liu, Y. et al. (2005) "Global Genomic Approaches To The Iron-Regulated
Proteome," Ann.
Clin. Lab. Sci. 35(3):230-239; Templeton, D.M. et al. (2003) "Genetic
Regulation Of Cell
Function In Response To Iron Overload Or Chelation," Biochim. Biophys. Acta.
1619(2):113-
124; Ikeda, H. et al. (1992) "Evidence That An Iron Chelator Regulates
Collagen Synthesis By
Decreasing The Stability Of Procollagen mRNA," Hepatology 15(2):282-287. The
present
invention has particular utility in the treatment of macular degeneration,
cancer and the
conditions of aging.
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1. Macular Degeneration
[0062] The prolongation of the human lifespan over the past few decades in the
US has
spawned the proliferation of macular degeneration, an age-related eye disease.
While not
resulting in total vision loss, the disease robs older adults of their central
vision used for reading
as well as color vision. Macular degeneration affects the visual center of the
eye, called the
macula. The macula is part of the retina where color-vision cells (cones) are
located.
[0063] Macular degeneration is a progressive, age-related disease that can be
broken down
into four stages:
1. Beginning in about the third decade of life, the inability of the "garbage
cleaning" cells,
called the retinal pigment epithelia (RPE), to engulf and remove cellular
debris from
the back of the eyes, results in the formation of small microscopic deposits
called
lipofuscin (ly-poh-fus-kin). Lipofuscin is from by iron and copper-induced
oxidation
of cellular debris and its accumulation correlates with premature aging and
shortened
lifespan of organisms. The prevalence of macular degeneration is greater in
Caucasians than persons with darkly-pigmented skin and Caucasians have more
lipofuscin deposits in their retinas. Some of this cellular debris in the
retina is
comprised of used-up vitamin A that is shed from night-vision (rod) cells each
morning
in the human eye. The failure of the RPE cells to function results from
accumulation of
iron and calcium within the RPE.
2. Later, in about the fifth decade of life, there is progressive
calcification of an
underlying cellophane-thin retinal layer called Bruch's membrane, which
resides
between the RPE and the blood supply layer (choroid). While drusen that forms
within
the retina is partially composed of cholesterol, this lipid does not originate
from the
blood circulation or the liver where most cholesterol is produced.
Calcifications within
Bruch's membrane further impairs the exit of lipids (fats), protein, and
cellular debris,
from the photoreceptor layer, which results in the formation of yellow spots
called
drusen on the retina. Drusen can be observed during an eye examination using
an
ophthalmoscope. There is currently no method of removing drusen.
3. The death of the RPE cells is the third stage of this progressive disease.
This is
sometimes called RPE dropout. As the RPE cells are either impaired or have
died, and
Bruch's membrane is clogged with calcium, the photoreceptors then cannot be
nourished and also begin to die off. There is currently no treatment for
stages 1-3 of
macular degeneration. Stage 1-3 is called the "dry" form of macular
degeneration
because it has not resulted in hemorrhage or edema or new blood vessel
formation.
About 85% of macular degeneration patients have the "dry" form of this
disease.
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4. As breaks in Bruch's membrane occur, or Bruch's membrane becomes totally
calcified,
the photoreceptor layer is deprived of oxygen and new blood vessels form
(called
neovascularization) which can invade the photoreceptor layer in the macula and
impair
vision; or there may be leakage of blood serum or frank release of red blood
cells,
which results in edema or hemorrhage. This is the more advanced and sight-
threatening form of macular degeneration, often called "wet" macular
degeneration
because of the presence of the leakage of blood serum or red blood cells into
the
photoreceptor layer. This stage of the disease, if caught early, can be
treated with laser
beams, which can seal up leaky blood vessels. However, this treatment is only
effective in delaying the progression of the disease, not curing it.
[0064] The cell cleansing process facilitated by the lysosomes cannot keep up
with the
accumulation of metabolic waste over a lifetime. The parafoveal ring, where
rod cell density is
highest, and therefore more discs of used-up vitamin A are shed, is where
macular degeneration
begins, and where the highest concentration of lipofuscin is observed in the
retina. Eventually,
the RPE cells die off with advancing age, which increases the burden on the
remaining RPE
cells to maintain a healthy retina.
[0065] In the past, lipofuscin has been considered a harmless wear-and-tear
byproduct of
cellular metabolism. One aspect of the present invention relates to the
recognition that
lipofuscin, which forms from iron and copper-induced oxidation, and hardens
within lysosomal
bodies within retinal pigment epithelial cells, sensitizes the retina to
damage by mild amounts
of radiation and oxidation. The retina becomes increasingly sensitive to blue-
light damage with
advancing age. Drusen formation within the retina is associated with RPE cell
inability to
produce superoxide dismutase, an endogenous antioxidant enzyme. Mice deficient
in
superoxide dismutase develop features that are typical of age-related macular
degeneration in
humans. Superoxide dismutase protects retinal cells against unbound (free)
iron. High iron
diets and cellular environments have been shown to reduce superoxide dismutase
activity.
[0066] Retinal photoreceptors and retinal pigment epithelial cells are
believed to be
especially vulnerable to damage by low-molecular weight complexes of iron.
Since
antioxidants in the blood circulation may not always be able to cross the
blood-retinal barrier,
the retina produces its own protective antioxidants that bind iron. Iron
chelators inhibit the
adverse effects of unbound (free) iron (not bound to proteins). Herne
oxygenase also serves in
a similar manner to iron chelators to prevent retinal damage induced by loose
iron.
[0067] Numerous agents have been used experimentally to clear up lipofuscin
and drusen.
Statin drugs, commonly used to reduce blood serum levels of cholesterol, have
also been tested
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to prevent lipofuscin deposits in animals. Statin drugs reduced lipofuscin
formation but were
toxic to the liver and brought about the early death of these animals.
Piracetam, a derivative of
the neurotransmitter GABA, now available as a dietary supplement, has been
used successfully
to reduce lipofuscin formation in brain tissues. Sorbinil is an enzyme
inhibiting drug (aklose
reductase inhibitor) that underwent unsuccessful human trials in the 1990s to
prevent retinal
problems associated with diabetes. Sorbinil has been shown to partially reduce
lipofuscin
deposits in the retinal pigment epithelium cells of rodents. Hydergine is a
drug used to treat
senile dementia. In a rodent study, hydergine was reported to have reduced
brain lipofuscin
levels, but also led to the early demise of the animals. The East Indian spice
turmeric contains
an antioxidant molecule called curcumin. Curcumin has been used in an
experimental mouse
study to reduce lipofuscin in the brain. Purslane is a flowering plant rich in
magnesium, beta
carotene and omega-3 oil. The provision of purslane to mice has been shown to
reduce
lipofuscin deposition in the brain of mice.
[0068] In a lab dish study, sulforaphane, an antioxidant molecule found in
Brussels sprouts
and broccoli in 1992, has been used successfully to reduce lipofuscin deposits
in RPE cells
exposed to blue light.
[0069] Intraperitoneal administration of lipoic acid to aged rats leads to a
reduction and
elevation in lipofuscin and enzyme activity, respectively, in the cortex,
cerebellum, striatum,
hippocampus, and hypothalamus of the brain. These results suggest that lipoic
acid, a natural
metabolic antioxidant, should be useful as a therapeutic tool in preventing
neuronal dysfunction
in aged individuals. Lipoic acid, a natural antioxidant produced within living
tissues, and also
available as a dietary supplement, has been shown to protect RPE cells from
oxidative damage
in lab dish studies.
[0070] Lipofuscin formation dramatically increases in brain tissues following
alcohol
consumption. Supplementation with high-dose grape seed flavonols prevents
increase
lipofuscin formation. Lipofuscin is an end-product of lipid peroxidation which
dramatically
increases following ethanol consumption.
[0071] Oolong and green tea drinks reverse the cognitive impairment and
lipofuscin
formation in mice. Epigallocatechin-3-gallate (EGCG), the major constituent of
green tea,
upregulates the activity of heme oxygenase in lab dish studies. Herne
oxygenase is a protective
enzyme against iron-induced oxidation, which occurs in the retina.
[0072] It has been shown that the provision of supplemental estrogen decreases
lipofuscin
deposition in brain tissues. In a lab dish study, the provision of lutein and
zeaxanthin to RPE
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cells reduced lipofuscin formation. In rodents given supplemental acetyl-L-
carnitine, a decline
in lipofuscin deposits has been measured in brain cells.
[0073] U. S Patent No. 5,747,536 describes the combined therapeutic use of L-
carnitine,
lower alkanoyl L-carnitines or the pharmacologically acceptable salts thereof,
with resveratrol,
resveratrol derivatives or resveratrol-containing natural products, for
producing a medicament
for the prophylaxis and treatment of cardiovascular disorders, peripheral
vascular diseases and
peripheral diabetic neuropathy.
[0074] Melanin is an iron-binding antioxidant in the retina. As melanin levels
decline in the
retina with advancing age, there is a greater accumulation of lipofuscin.
[0075] In one embodiment, the present invention relates to a composition
comprising a
combination of:
(a) A chelator such as inositol hexaphosphate (IP6), trans resveratrol,
quercetin, or
any polyphenol or bioflavonoid for metal(s) such as iron, copper, heavy
metals;
(b) A calcium chelator, such as inositol hexaphosphate (IP6);
(c) A heme oxygenase activator, such as trans resveratrol, piceatannol, or any
of
resveratrol's natural analogs, or similar small molecules such as fisetin,
myricetin, quercetin or other bioflavonoids;
(d) An agent that lowers the affinity of oxygen for red blood cells, such as
inositol
hexaphosphate (IP6); and, optionally
(e) Other antioxidants such as vitamin E, lutein/zeaxanthin, alpha lipoic
acid.
[0076] The formulation functions to:
(1) Limit oxidation in retinal tissues (photoreceptors, retinal pigment
epithelial
cells (RPE), choroid, specifically mitochondria and lysosomes in RPE cells);
(2) Inhibit accumulation of lipofuscin deposits;
(3) Inhibit formation of drusen; and
(4) Limit calcifications to retinal tissues, especially Bruch's membrane.
2. Cancer
[0077] A major challenge in cancer therapy is to selectively target cytotoxic
agents to tumor
cells (Luo, Y. et al. (2000) "A Hyaluronic Acid-Taxol Antitumor Bioconjugate
Targeted To
Cancer Cells," Biomacromolecules 1(2):208-218). To decrease undesirable side
effects of
small molecule anticancer agents, many targeting approaches have been
examined. One of the
most promising methods involves the combination or covalent attachment of the
cytotoxin with
a macromolecular carrier, and in particular with hyaluronic acid (Luo, Y. et
al. (1999)
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"Synthesis And Selective Cytotoxicity Of A Hyaluronic Acid-Antitumor
Bioconjugate,"
Bioconjug. Chem. 10(5):755-763; Luo, Y. et at. (2000) "A Hyaluronic Acid-Taxol
Antitumor
Bioconjugate Targeted To Cancer Cells," Biomacromolecules 1(2):208-218; Luo,
Y. et al.
(1999) "Hyaluronic Acid-N-Hydroxysuccinimide: A Useful Intermediate For
Bioconjugation,"
Bioconjug. Chem. 12(6):1085-1088; Luo, Y. et al. (2002) "Targeted Delivery Of
Doxorubicin
By HPMA Copolymer-Hyaluronan Bioconjugates," Pharm. Res. 19(4):396-402).
[0078] In one embodiment, the present invention relates to a resveratrol- and
hyaluronic
acid-containing composition for the treatment of cancer comprising:
resveratrol, hyaluronan,
and optionally vitamin D and/or IP6. It is believed that these components act
synergistically
with one another to mediate an effect in curing and/or in preventing cancer in
humans and/or in
improving immunity (e.g., immune system response) in patients threatened by
tumors. This
aspect of the present invention is based in part upon the recognition that
natural molecules can
boost cancer immunity, possibly in a manner similar to that observed in cancer-
proof mice.
[0079] Upon provision with such composition, the sentinels of the innate
immune system,
dendritic cells, can be alerted and neutrophils, macrophages and natural
killer cell activity can
be significantly enhanced. The enhancement of vitamin D receptors via
resveratrol is yet
another major advantage of a combination approach to treat or prevent cancer.
This approach
appears to be more appropriate for senior adults, the highest risk group for
cancer, who are
often immune-compromised due to poor nutrition or lack of nutrient absorption.
The fact that
this therapy can now be immediately measured for effectiveness by non-invasive
cancer cell
counting technology means that expensive and equivocal tests on animals may
not be required
to prove efficacy.
[0080] Vitamin D exhibits many biological actions. While vitamin D is widely
known for
its ability to stave off bone disease (rickets in growing children,
osteoporosis in senior adults),
it is becoming a central player in the battle against cancer. Only recently is
it also gaining
attention as an antibiotic. Vitamin D-deficient mice exhibit a defective
response from
phagocyte cells in the face of infection or inflammation. Vitamin D deficiency
is frequently
associated with recurrent infections. Only about half of the macrophage cells
accumulate at the
site of inflammation in vitamin D-deficient animals compared to animals whose
vitamin D
levels are adequate.
[0081] To delve deeper into the role of vitamin D in immunity and cancer,
vitamin D
improves the chemotactic (affinity for) neutrophils to mobilize and migrate.
Patients with
rickets due to vitamin D deficiency are observed to have sluggish neutrophils
that cannot
migrate properly. Vitamin D stimulates the maturation of monocytes to
macrophages. This
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results in an enlarged army of immune fighting cells to mount against tumors.
Greater attention
is now being given to vitamin D as an anti-cancer weapon because of studies
which show
supplemental vitamin D drastically reduces the risk for all types of cancer. A
study that
employed 1100 IU of vitamin D3 produced a 60-77% reduction in cancer risk
among women in
Nebraska in just a 4-year period.
[0082] Even though cancer risk is lowest in sunnier and Equatorial areas
geographically,
where vitamin D levels are higher in sun-exposed populations, the protective
effect of vitamin
D against cancer has been repeatedly dismissed or discounted. The consumption
of vitamin D
orally eliminates the concern of skin cancer emanating from overexposure to
unfiltered sun
rays. One of the latest analyses shows that the risk of colon cancer can be
halved by taking
2000 IU of vitamin D per day and that the risk for breast cancer can be halved
by taking 3500
IU of vitamin D per day. The median dietary intake of vitamin D is only about
230 IU per day,
so the prospect of food fortification or supplementation to prevent or treat
cancer now becomes
real.
[0083] In order for tissues to utilize and benefit from vitamin D they must
have proteins in
their outer coat (cell membrane) that are designed to receive and bind to
vitamin D. For
example, about 80% of human breast tumors produce vitamin D cell receptors,
though gene
expression (production) of vitamin D receptor is at low levels.
[0084] Vitamin D's ability to inhibit cancer may be heightened when it is
aided by weak
estrogen-like molecules in the diet. Resveratrol, an estrogen-like molecule
commonly found in
red wine, upregulates the vitamin D receptor in breast cancer cells without
increasing cancer
growth. Resveratrol, in effect, can sensitize breast cancer cells to the anti-
cancer properties of
vitamin D.
[0085] Laboratory experiments show that low-dose vitamin D3 does not reduce
breast
tumor cell growth but when combined with resveratrol, tumor cell numbers
declines by 40%.
At higher concentrations vitamin D3 reduces the number of breast cancer cells
in a lab dish by
about 25%, and this decline improves to 50% when combined with resveratrol.
Whereas
estrogen increases vitamin D receptor gene expression, it also stimulates
breast tumor growth.
Resveratrol does not have this drawback. Resveratrol potentiates or
"weaponizes" the cancer-
inhibiting effect of vitamin D.
[0086] Furthermore, resveratrol by itself has been shown to calm the response
of phagocytes
to foreign invaders like germs and tumor cells. Resveratrol dampens production
of reactive
oxygen species (free radicals) and normalizes particle ingestion in macrophage
cells.
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Therefore, resveratrol prevents the over-response of immune cells that can
produce
autoimmunity.
[0087] Resveratrol blocks cancer in so many ways that it is difficult to find
a pathway for
cancer that is not obstructed by resveratrol. Resveratrol induces the cell
energy compartments
in tumor cells, called mitochondria, to release an enzyme called cytochrome C
oxidase that
usually leads to a cascade of other enzymes that induce programmed cell death,
called
apoptosis. But a recent experiment also shows that resveratrol releases
cytochrome C from
ovarian tumor cells that leads to rapid cell death via a process called
autophagy, a process
where enzymes produced inside the tumor cell actually digest its innards (kind
of a form of
intracellular cannibalism). This is a form of cell suicide that resveratrol
activates in tumor
cells, but not healthy cells.
[0088] The contribution of innate immunity in surveillance of tumors is
comparatively
neglected in cancer biology. Phagocytosis, or "cell eating" is the cornerstone
of the innate
immune response. Focus has been directed to dendritic cells which are believed
to be sentinels
of the innate immune response. A limited number of immune-boosting agents have
been
investigated.
[0089] Skepticism surrounds interest in innate immune approaches to cancer
treatment. For
example, patients taking immune-suppressing don't necessarily develop cancer
with more
frequency. However, this may be misunderstood. An over-responsive immune
system may
lead to more tissue and organ damage that can be mortal to cancer patients.
Most of the drugs
used for breast cancer therapy induce immune suppression.
[0090] Nature's most potent iron chelator is inositol hexaphosphate (IP6),
which is found in
seeds and the bran fraction of whole grains. A low dosage of IP6 has been
found to suppress
the growth of rhabdomyosarcoma cells by 50%. Removal of IP6 allows these tumor
cells to
recover and grow once again. IP6-treated mice with injected tumors exhibit
tumors that are 50
times smaller than non-treated mice. IP6 has also been shown to reduce the
growth of injected
fibrosarcoma cells in mice and prolong their survival.
[0091] In examining the immune enhancing properties of IP6 it has been shown
that it
boosts production of free radicals (superoxide) and the cell digesting action
of neutrophils in
the presence of bacteria. IP6 increases the release of interleukin-8.
[0092] The action of natural killer cells, which are involved in tumor cell
destruction, is
enhanced by IP6.
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[0093] In one embodiment, the hyaluronic acid of such composition is
conjugated to a
chemotherapeutic agent. The invention particularly pertains to such
compositions in which the
chemotherapeutic agent is taxol. The invention particularly pertains to such
compositions that
additionally and preferably comprise a chelator, and/or vitamin D. Most
malignant solid
tumors contain elevated levels of Hyaluronic Acid (Rooney, P. et al. (1995)
"The Role Of
Hyaluronan In Tumour Neovascularization (Review)," Int. J. Cancer 60(5):632-
636) and these
high levels of HA production provide a matrix that facilitates invasion (Hua,
Q. et al. (1993)
"Internalization Of Hyaluronan By Chondrocytes Occurs Via Receptor-Mediated
Endocytosis,"
J. Cell. Sci. 106(Pt 1):365-375; Luo, Y. et al. (2000) "A Hyaluronic Acid-
Taxol Antitumor
Bioconjugate Targeted To Cancer Cells," Biomacromolecules 1(2):208-218). Thus
chemotherapeutic agents that are conjugated to Hyaluronic Acid target tumor
cells, and can
provide an effective anti-tumor dosage at lower overall concentration.
[0094] In brief, a preferred method of conjugation entails forming an NHS (N-
hydroxy-
succimimide derivative of the chemotherapeutic agent. Such a derivative can be
made by
adding a molar excess of dry pyridine to a stirred solution of Taxol and
succinic anhydride in
CH2Clz at room temperature. The reaction mixture is then stirred for several
days at room
temperature and then concentrated in vacuo. The residue is dissolved in 5 ml
of CH2Clz and the
produced Taxol-2'-hemisuccinate can be purified on silica gel (washed with
hexane; eluted with
ethyl acetate) to give the desired product (Luo, Y. et al. (1999) "Synthesis
And Selective
Cytotoxicity Of A Hyaluronic Acid-Antitumor Bioconjugate," Bioconjug. Chem.
10(5):755-
763).
[0095] The N-hydroxy-succimimide derivative of the chemotherapeutic agent is
then
conjugated to adipic dihydrazido-functionalized hyaluronic acid. Adipic
dihydrazido-
functionalized hyaluronic acid is preferably prepared as described by Pouyani,
T. et al. (1994)
("Functionalized Derivatives Of Hyaluronic Acid Oligosaccharides - Drug
Carriers And Novel
Biomaterials," Bioconjugate Chem. 5:339-347); Pouyani, T. et al. (1994)
("Novel Hydrogels Of
Hyaluronic Acid: Synthesis, Surface Morphology, And Solid-State NMR," J. Am.
Chem. Soc.
116:7515-7522); Vercruysse, K.P. et al. (1997) ("Synthesis And In Vitro
Degradation Of New
Polyvalent Hydrazide Cross-Linked Hydrogels Of Hyaluronic Acid," Bioconjugate
Chem.
8:686-694). Thus, hyaluronic acid is preferably dissolved in water and an
excess of adipic
dihydrazide (ADH). The pH of the reaction mixture is adjusted to 4.75 by
addition acid. Next,
1 equivalent of 1-Ethyl-3-[3-(dimethylamino)-propyl]carbodiimide (EDCI) is
added in solid
form. The pH of the reaction mixture is maintained at 4.75 by addition of
acid. The reaction is
quenched by addition of 0.1 N NaOH to adjust the pH of reaction mixture to
7Ø The reaction
mixture is then transferred to pretreated dialysis tubing (Mw cutoff 3,500)
and dialyzed
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exhaustively against 100 mM NaCl, then 25% EtOH/H2O and finally water. The
solution is
then filtered through 0.2 in cellulose acetate membrane, flash frozen, and
lyophilized (Luo, Y.
et al. (1999) "Synthesis And Selective Cytotoxicity Of A Hyaluronic Acid-
Antitumor
Bioconjugate," Bioconjug. Chem. 10(5):755-763).
3. Aging
[0096] Calcification and rusting are major accelerators of aging. The human
body is
composed of cells that must continually be replaced or renewed from within,
and a gooey
substance that fills space between cells called collagen or connective tissue
which also must be
continually regenerated. As the human body ages at the cellular level, there
is a slow
accumulation of cellular debris called lipofuscin. The formation of lipofuscin
is facilitated by
the progressive accumulation of iron and calcium within cell bodies called
lysosomes and
mitochondria. A cell cleansing and renewal process called autophagy prevents
the
accumulation of lipofuscin. Progressive inability to remove cellular debris
results in declining
cell function and then premature death of the cell. A young cell efficiently
removes debris from
within. An old cell cannot efficiently remove debris and accumulates
lipofuscin.
[0097] Calcification and rusting of cells impairs the cleansing of cellular
debris (lipofuscin)
from cells by enzymes produced by lysosomes, and results in impairment of
cellular energy
(ATP) produced by the mitochondria within cells. The compositions of the
present invention
inhibit and/or reverse cellular aging and/or connective tissue aging, and in
particular, inhibit
and/or reverse cellular aging and/or connective tissue aging caused by an
accumulation of
major minerals (e.g., iron, calcium, etc.). As a consequence, recipients of
the compositions of
the present invention exhibit enhanced longevity and enhanced cellular and
connective tissue
health and structure.
[0098] The human body ages at the cellular level by the slow accumulation of
cellular
debris called lipofuscin, which is facilitated by the progressive accumulation
of iron and
calcium within cell bodies called lysosomes and mitochondria. A cell cleansing
and renewal
process called autophagy prevents the accumulation of lipofuscin during the
years of youthful
growth, but this lysosomal mechanism declines once full growth is achieved due
to
accumulation of intracellular iron and calcium. Progressive inability to
remove cellular debris
results declining cell function and then premature death of the cell. A young
cell efficiently
removes debris from within. An old cell cannot efficiently remove debris and
accumulates
lipofuscin. The mitochondria, which provides cellular energy for lysosomal
bodies to perform
their cell cleansing activity, also becomes progressively calcified and
ironized once childhood
growth ceases. Only about 5% of mitochondria are functioning by age 80. Iron
and calcium
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chelators are proposed to remedy mitochondrial aging which impacts cellular
functions such as
lysosomal enzymatic activity
[0099] The human body ages within connective tissue by failure of cells called
fibroblasts to
regenerate collagen and hyaluronic acid, the latter being a space-filling,
water-holding
molecule. Collagen formation is facilitated by vitamins and amino acids in the
diet (vitamin C,
lysine, proline). Fibroblasts can be stimulated to produce hyaluronic acid by
estrogen, made
naturally in the body, and by estrogen-like molecules found in plants, called
phytoestrogens,
provided in the diet of by hyaluronic acid itself. Young females, by virtue of
the ability to
produce estrogen, exhibit thicker hair, smoother skin and more flexible
joints, due to the
abundance of hyaluronic acid. All of these being attributes of youthfulness.
[00100] The inability to regenerate hyaluronic acid results in tissues losing
their physical
integrity by virtue of loss of the space-filling properties of hyaluronic
acid. Without adequate
hyaluronic acid, a dehydrated state results and tissues shrink and shrivel up.
For example, skin
that is lacking hyaluronic acid will appear wrinkled and dry. Joint spaces
will lack the
cushioning and space-filling needed to prevent bone from rubbing on bone. The
eyes will
begin to shrink in size. Hair will thin due to the lack of hydration. These
are the most
prominent visible or cosmetic signs of aging.
[00101] In one embodiment, the present invention invention addresses both
cellular and
extracellular (connective tissue) aging, thus (a) preserving youthful function
of living cells by
removal of excess minerals, largely calcium and iron, from cells, this
facilitating autophagy
(cleanup of cellular debris, such as lipofuscin, via lysosomal enzymes) and
(b) invigorating and
preserving production of hyaluronan by stimulation of fibroblasts by HA,
phytoestrogens
(resveratrol, quercetin, genistein, are a few), to inhibition of degradation
of HA by provision of
metal chelators, such as phytic acid, ferulate, quercetin, resveratrol, etc.
[00102] In one embodiment, the present invention is a dietary supplement that
addresses both
cellular and non-cellular aging by its ability to:
(a) stimulate renewal of living cells from within via enzymatic degradation of
cellular debris by intracellular lysosomal bodies. This is facilitated by the
inclusion of metal (iron, copper, heavy metal) and calcium chelating
molecules within the formula. Lysosomes lose their ability to enzymatically
digest cellular debris with the progressive accumulation of iron, copper and
other metals, and the crystallization of calcium.
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(b) stimulate fibroblasts to produce hyaluronic acid at youthful levels again.
This
is accomplished by provision of orally-consumed molecules that stimulate
fibroblasts to produce hyaluronic acid.
(c) metal chelating molecules that help maintain youthful lysosomal function
are
identified as antioxidants, like vitamin E or vitamin C, lipoic acid, metal
chelators like IP6 phytate, quercetin, bioflavonoids or polyphenols,
resveratrol. Resveratrol works by its ability to stimulate production of heme
oxygenase, an enzyme that helps to control iron.
(d) molecules that inhibit crystallization of calcium are magnesium and IP6
phytate.
(e) orally consumed molecules that stimulate fibroblasts to produce hyaluronic
acid are hyaluronic acid, glucosamine, chondroitin, or estrogen-like molecules
such as genistein, lignans, hydroxytyrosol, or other molecules configured like
estrogen. Orally consumed HA stimulates greater HA and chondroitin
synthesis. Similarly, glucosamine stimulate fibroblasts to produce HA.
Alternatively, or additionally, glucosamine stimulates synovial production of
hyaluronic acid, which is primarily responsible for the lubricating and shock-
absorbing properties of synovial fluid" (McCarty, M.F. (1998) "Enhanced
Synovial Production Of Hyaluronic Acid May Explain Rapid Clinical
Response To High-Dose Glucosamine In Osteoarthritis," Medical Hypotheses
50:507-510, 1998).
(f) orally consumed molecules that stimulate production of collagen are
vitamin
C, proline and lysine.
[00103] In such embodiment, the present invention relates to a resveratrol and
hyaluronic
acid-containing dietary supplement that restores youthful function and
appearance to human
cells and tissue. The invention particularly pertains to such compositions
that additionally
comprise a chelator, and/or vitamin D. Most preferably, the composition will
comprise the
chelator phytic acid (inositol hexaphosphate; IP6). The compositions of the
present invention
synergistically enhance the specific activity of the resveratrol and/or
hyaluronic acid, and thus
the compositions of the present invention provide an enhancement of activity
above and beyond
that obtained with the components administered individually. In such
embodiment, the
invention relates to a method for restoring youthful function and appearance
to human cells and
tissues comprising the following steps:
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(a) stimulating renewal of living cells from within via enzymatic degradation
of
cellular debris by intracellular lysosomal bodies (preferably by providing a
metal chelating molecule that helps maintain youthful lysosomal function, such
molecules comprising antioxidants, such as vitamin E or vitamin C, lipoic
acid,
metal chelators like IP6 phytate, quercetin, bioflavonoids or polyphenols,
and/or resveratrol); and
(b) stimulating fibroblasts to produce hyaluronic acid (comprises providing
orally
consumed molecules that stimulate fibroblasts to produce hyaluronic acid, such
orally consumed molecules comprising, for example, hyaluronic acid,
glucosamine, chondroitin, and/or estrogen-like molecules such as genistein,
lignans, hydroxytyrosol, or other molecules configured like estrogen).
Preferably, such stimulation is achieved by the dietary administration of a
composition
comprising the stated compounds, more preferably in combination with an orally
consumable
molecule that stimulates production of collagen, such molecules comprising,
for example,
vitamin C, proline and/or lysine.
[00104] Without intending to be bound by any mechanism, when administered
together, the
four preferred components are believed to act in the following manner:
(a) Vitamin D: Vitamin D3 works as an agent that mimics the response to a
biological
stressor, solar radiation. In particular, vitamin D3 upregulates protective
genes
involved in activation of the immune system, particularly neutrophil count and
motility,
and aids in overcoming the decline in endogenous vitamin D3 production with
advancing age due to thickening of the skin, which reduces sun/skin production
of
vitamin D. Furthermore, vitamin D3 works synergistically to breakdown IP6 to
IP3,
thought to be a major active molecule. Resveratrol also works synergistically
to
sensitize cells to vitamin D3 (sensitizes the vitamin D receptor on the cell
surface).
Vitamin D serves to break down IP6 to IP3, which is its primary active form.
Vitamin
D is also believed to act as an immune system enhancing agent, boosting innate
immunity in humans. In this capacity, vitamin D has been shown experimentally
to
have important cancer-preventive and cancer-curing properties.
(b) Resveratrol: Resveratrol increases the sensitivity of the vitamin D
receptor on the
surface of cells, and thus is believed to act as an enhancing agent for
vitamin D and as
an anti-cancer agent. Resveratrol up-regulates the vitamin D receptor on the
surface of
cancer cells, and sensitizes cancer cells to vitamin D (Wietzke, J.A. et al.
(2003)
"Phytoestrogen Regulation Of A Vitamin D3 Receptor Promoter And 1,25-
Dihydroxyvitamin D3 Actions In Human Breast Cancer Cells," J. Steroid Biochem.
Molec. Biol. 84(2-3):149-157; Wietzke, J.A. et al. (2005) "Regulation Of The
Human
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Vitamin D3 Receptor Promoter In Breast Cancer Cells Is Mediated Through Spl
Sites," Molec. Cell. Endocrinol. 230(1-2): 59-68). Resveratrol is also
believed to be a
monoamine oxidase inhibitor (MAO Inhibitor).
(c) Hyaluronic acid: Hyaluronic acid is the water gelling molecule of the
human body
which serves as its scaffolding and hydrating agent. As aging progresses, less
Hyaluronic acid is produced, resulting in wrinkled skin, thinning hair,
unlubricated
joints. The chelators of the present composition also help to preserve
hyaluronic acid
in the body. The hyaluronic acid component and the mineral chelating
components
(e.g., resveratrol, quercetin, phytic acid IP6, ferulate) work as a total anti-
aging strategy
to maintain youthful function within cells and connective tissues. Hyaluronic
acid is
believed to have an affinity to cancer cells. It is believed to serve as a
delivery and
targeting (drug delivery agent) molecule in blood circulation and to address
aging of
the connective tissue. The collapse and loss of integrity of connective tissue
between
cells provides the signs of aging (e.g., skin wrinkling, hair thinning, joint
stiffness, loss
of stature, etc.). The addition of hyaluronic acid to the compositions of the
present
invention is believed to activate fibroblast cells in the human body to
produce
additional hyaluronic acid, thus serving to preserve connective tissue
(collagen) in a
youthful state (Yadav, A.K. et al. (2008) "An Insight On Hyaluronic Acid In
Drug
Targeting And Drug Delivery," J. Drug Target. 16(2):91-107; Liao, Y.H. et al.
(2005)
"Hyaluronan: Pharmaceutical Characterization And Drug Delivery," Drug Deliv.
12(6):327-342; Joddar, B. et al. (2006) "Elastogenic Effects Of Exogenous
Hyaluronan
Oligosaccharides On Vascular Smooth Muscle Cells," Biomaterials 27(33):5698-
5707;
Girish, K.S. et al. (2007) "The Magic Glue Hyaluronan And Its Eraser
Hyaluronidase:
A Biological Overview," Life Sci. 80(21):1921-1943).
(d) Phytic Acid: Phytic Acid, preferably in the form of rice bran, is believed
to act as an
iron and copper chelator and as an inhibitor of calcium cystallization. Phytic
Acid also
is believed to reduce the availability of metallic minerals that serve as
growth factors in
tumor cells. It is also believed to serve as a neutrophil priming and motility
agent.
Additionally, phytic acid has been found to be neuroprotective, and thus to
attenuate
the severity of conditions associated with neurodegenerative diseases
(especially
Parkinson's Disease, camptocormia, and Alzheimer's Disease) (Xu, Q. et al.
(Epub
2007 Dec 27) "Neuroprotective Effect Of The Natural Iron Chelator, Phytic Acid
In A
Cell Culture Model Of Parkinson's Disease," Toxicology 245(1-2):101-108). The
components of the compositions of the present invention are believed to
enhance such
neuroprotection.
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[00105] The iron chelator, quercetin, if present, is believed to serve to
increase immediate
bioavailability of resveratrol by permitting more passes through the liver
before it is
metabolized.
[00106] The individual components of the composition are believed to act
synergistically to
enhance the effect of, for example, resveratrol. Without intending to be
limited thereby, it is
proposed that the body's control or chelation of iron and calcium regulates
the rate of aging
after full growth has been achieved. During childhood growth all the iron and
calcium are
directed towards production of new bone and new red blood cells (hemoglobin).
The cessation
of childhood growth results in excess iron, copper and calcium, which then
progressively (a)
calcifies and (b) rusts tissues. The lysosomes begin to accumulate iron and
calcium, which
results in their dysfunction. The mitochondria begin to malfunction as they
also progressively
rust and calcify. The compositions of the present invention are believed to be
capable of
limiting or slowing the progressive rusting and calcification of cells and
cellular organelles to
thereby facilitate a slowing or reversal of the aging process. The chelation
is what controls the
genes. Genes are then favorably upregulated or downregulated. Resveratrol and
a copper
chelator are believed to act: (1) as controllers of calcium concentration via
upregulation of
osteocalcin, the hormone that helps retain calcium in bones and (2) as
controllers of iron
concentration via heme oxygenase, an antioxidant enzyme.
[00107] MAO inhibitors and iron chelators have been proposed as treatments for
Parkinson' s
disease (Youdim, M.B. et al. (2004) "Novel Bifunctional Drugs Targeting
Monoamine Oxidase
Inhibition And Iron Chelation As An Approach To Neuroprotection In Parkinson's
Disease And
Other Neurodegenerative Diseases," J. Neural. Transm. 111(10-11):1455-1471;
Yanez, M. et
al. (2006) "(-)-Trans-Epsilon-Viniferin, A Polyphenol Present In Wines, Is An
Inhibitor Of
Noradrenaline And 5-Hydroxytryptamine Uptake And Of Monoamine Oxidase
Activity," Eur. J.
Pharmacol. 542(1-3):54-60; Bureau, G. et al. (2008) "Resveratrol And
Quercetin, Two Natural
Polyphenols, Reduce Apoptotic Neuronal Cell Death Induced By
Neuroinflammation," J.
Neurosci. Res. 86(2):403-410; Singh, A. et al. (2003) "Quercetin Potentiates L-
Dopa Reversal
Of Drug-Induced Catalepsy In Rats: Possible COMT/MAO Inhibition," Pharmacol.
68(2):81-
88; Gao, X. et al. (2007) "Prospective Study Of Dietary Pattern And Risk Of
Parkinson
Disease," Am. J. Clin. Nutr. 86(5):1486-1494; Johnson, S. (2001) "Is
Parkinson's Disease The
Heterozygote Form Of Wilson's Disease: PD = 1/2 WD?," Med. Hypotheses
56(2):171-173).
The compositions of the present invention which contain the MAO inhibitor and
copper
chelator, resveratrol, the iron chelator and MAO inhibitor, quercetin, and the
broad metal
chelator, phytic acid are particularly preferred for the treatment of
neurodegenerative diseases
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(especially Parkinson's Disease, camptocormia, and Alzheimer's Disease) or in
the
amelioration of the symptoms of such diseases.
[00108] Having now generally described the invention, the same will be more
readily under-
stood through reference to the following examples, which are provided by way
of illustration
and are not intended to be limiting of the present invention unless specified.
Example 1
Comparative Effects of Resveratrol and the Compositions of the Present
Invention
[00109] In order to determine if the compositions of the present invention
were more
effective than resveratrol alone in mediating a resveratrol biological
activity, an analysis of
gene expression was conducted, comparing the modulation of gene expression
achieved by
calorie restriction to the modulation of gene expression achieved by the
compositions of the
present invention.
[00110] Accordingly, the ability of resveratrol alone and the resveratrol-
containing
compositions of the present invention to up-regulate survival/longevity genes
or down-regulate
genes whose expression enhances cellular damage was compared using the
expression profile
of a calorie restricted ("CR") animal as a positive control and the expression
profile of a
normally fed animal as a negative control. Male B6CHF1 mice (2 months of age)
were thus
either placed on a 40% calorie restricted diet, provided commercially obtained
trans-resveratrol
(Sigma Chemical; 1.25 mg/kg per day), provided a resveratrol-containing
composition of the
present invention (Longevinex ; Resveratrol Associates, LLC; 100 mg trans-
resveratrol
containing capsule per 80 kg human per day (i.e., 2.5 mg/kg per day of
resveratrol (1.25 mg/kg
per day trans-resveratrol) 0.31 mg/kg per day quercetin dihydrate, 0.94 mg/kg
per day rice bran
extract, 4.75 mg/kg per day rice bran oil and 0.70 mg/kg per day sunflower
lecithin)). The
mice were monitored until they had reached five months of age.
[00111] Body weight, serum glucose levels, serum insulin levels and lipid
peroxidation in
brain and muscle tissue were measured. The results showed that Longevinex did
not result in
an increase in weight that was distinguishable from control animals (Figure
1). Serum insulin
levels were found to be approximately the same as that observed in the calorie
restricted
animals (Figure 2). Serum glucose levels were found to be lower than that
observed in the
calorie restricted animals (Figure 3).
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Example 2
Comparative Effects of Resveratrol and the Compositions of the Present
Invention on Gene
Expression in Cardiac Tissue
[00112] The profile of expressed genes in the cardiac tissue of mice receiving
resveratrol or a
composition of the present invention (Longevinex ) was compared to that of
mice placed on a calorie
restricted diet and control mice. Gene expression was monitored using an
Affymetrix MG430 2.0
Array, containing 45,101 probe sets per array. In cases in which the array
represented the same gene
with multiple probes, the probe set with the highest signal intensity was
employed. Unknown genes
(including uncharacterized ESTs and cDNA sequences were not analyzed. Thus,
the array provided a
means for analyzing 20,341 genes having a single Entrez Gene ID. Analysis was
conducted
substantially as described by Lee, C.-K. et al. (2002) "Transcriptional
Profiles Associated With Aging
And Middle Age-Onset Caloric Restriction In Mouse Hearts," Proc. Natl. Acad.
Sci. (U.S.A.)
99:14988-14993. The mean of all arrays in a group were calculated. The means
of treated groups
were compared to the mean of the control group, and the statistical
significance of any differences
were determined using two-tailed t-tests (P < 0.01). The results of the
analysis are presented in Table
3 (CO, control; CR, calorie restricted; RES, resveratrol; LGX, Longevinex ;
FC, fold change. FC is
calculated as the mean of the treated group divided by the mean of the control
group, and this value is
then log-transformed (base 2) for statistical purposes. As an example, a gene
that is expressed at 100
in the control and 200 in a treated group would be have an Fc of 2 (i.e., a
twofold increase in
expression); a gene that is expressed at 100 in the control and 50 in the
treated group, would have an
Fc of -2 (i.e., a twofold decrease in expression).
[00113] Treatment of human umbilical vein epithelial cells with ferulic acid,
quercetin or resveratrol
has been reported to result in changes to gene expression of greater than 2-
fold down-regulation of 363
genes, and greater than 2-fold up-regulation of 233 genes of 10,000 genes
probed (Nicholson, S.K. et
al. (2008) "Effects Of Dietary Polyphenols On Gene Expression In Human
Vascular Endothelial
Cells," Proc. Nutr. Soc. 67(l):42-47). In contrast, Table 3 shows that 2,829
genes were found to
exhibit a statistically significant change in expression in treated vs.
control mice. Of these genes, 7%
were found to exhibit altered expression in mice that had been subjected to
only calorie restriction; 8%
were found to exhibit altered expression in mice subjected only to
resveratrol. Combining calorie
restriction with resveratrol administration failed to alter the expression of
any additional genes. In
contrast, administration of Longevinex was found to alter the expression of
61% of the 2,829 genes.
Administration of Longevinex to calorie restricted mice was found to alter
the expression of an
additional 2% of the genes. Administration of Longevinex to mice receiving
resveratrol
CA 02699908 2010-03-17
WO 2009/039195 PCT/US2008/076707
-49-
was found to alter the expression of an additional 21% of the genes. Thus,
Longevinex alone
or in combination with other regimens was found to affect 85% (2,406) of the
total genes
showing altered expression.
CA 02699908 2010-03-17
WO 2009/039195 PCT/US2008/076707
-50-
Table 3
CO CR RES LGX FC FC FC
Probe Set ID Treatment mean mean mean mean CR Res L x Entrez Info
1415670 at Lgx only 987 1139 1187 1378 1.15 1.20 1.40 Copg
1415671 at Res & Lgx 2454 2539 2030 2071 1.03 -1.21 -1.19 Atp6vOd1
1415672 at Res & L x 3213 2819 2637 22621-1.14 -1.22 -1.42 Gol a7
1415677 at Res & L x 706 747 933 934 1.06 1.32 1.32 Dhrsl
1415679 at Lgx only 4825 4129 3776 3154 -1.17 -1.28 -1.53 Psenen
1415684 at Lgx only 638 573 490 381 -1.11 -1.30 -1.67 At g5
1415696 at Res only 6629 7063 5491 5988 1.07 -1.21 -1.11 Sarla
1415700 a at Res & Lgx 5461 5179 3791, 2603 -1.05 -1.44 -2.10 Ssr3
1415704 a at Lgx only 5010 4472 3850 3285 -1.12 -1.30 -1.52 Cdv3
1415707 at Lgx only 1111 1317 1468 1535 1.19 1.32 1.38 Ana c2
1415714 a at Res & Lgx 4941 4632 2720 2379 -1.07 -1.82 -2.082610209M04Rik
1415723 at Res & L x 4272 3466 3385 3062 -1.23 -1.26 -1.40 EifS
1415733 a at Lgx only 13615 13963 9719 9991 1.03 -1.40 -1.36 1110019J04Rik
1415735 at Lgx only 2025 2617 3355 3642 1.29 1.66 1.80 Ddb1
1415736 at Res & L x 4957 3953 2536 1805 -1.25 -1.95 -2.75 PfdnS
1415738 at Res & Lgx 1914 1941 1575 1395 1.01 -1.22 -1.37 Txndcl2
1415742 at Lgx only 749 837 856 987 1.12 1.14 1.32Aupl
1415746 at Lgx only 726 949 1075 1501 1.31 1.48 2.07 Cic
1415749 a at L x onl 2368 2397 2111 1912 1.01 -1.12 -1.24 Rragc
1415754 at Lgx only 3512 3195 3099 2411 -1.10 -1.13 -1.46 Polr2f
1415755 a at Lgx only 2983 3602 3890 4068 1.21 1.30 1.36 Ube2vl
1415756 a at Res & Lgx 3581 3290 2710 2706 -1.09 -1.32 -1.32 Sna a
1415757 at Lgx only 901 1073 1189 1337 1.19 1.32 1.48 Gbf1
1415764 at L x onl 3381 3218 2545 24191-1.05 -1.33 -1.40 Zc3h 11 a
1415783 at Lgx only 4869 4728 4237 3960 -1.03 -1.15 -1.23 V s35
1415788 at Lgx only 1490 1572 1169 1046 1.05 -1.27 -1.42 Ublcpl
1415791 at Res & L x 2983 2870 2364 1805 -1.04 -1.26 -1.65 Rnf34
1415797 at Lgx only 319 488 522 805 1.53 1.64 2.53 Ddrl
1415802 at Res & Lgx 8566 8379 4763 4548 -1.02 -1.80 -1.88 Slcl6al
1415812 at Lgx only 31926 36029 41778 58920 1.13 1.31 1.85 Gsn
1415814 at CR only 1760 2239 1514 1433 1.27 -1.16 -1.23At 6vlb2
1415816 at Res only 5617 5279 4428 5553 -1.06 -1.27 -1.01 Cct7
1415818 at L x only 2554 2785 2838 3335 1.09 1.11 1.31 Anxa6
1415830 at Lgx only 586 494 424 3181-1.19 -1.38 -1.84 OrcSl
1415834 at Res only 579 703 419 430 1.211-1.38 -1.35 Dusp6
1415840 at Res & Lgx 1636 1461 974 856 -1.121-1.68 -1.91 ElovlS
1415850 at Res & L x 824 880 1129 1093 1.07 1.37 1.33 Rasa3
1415856 at Lgx only 148 168 172 242 1.14 1.16 1.63 Emb
1415875 at Res only 83 38 34 51 -2.19 -2.43 -1.63 30100031-21 Rik
1415876 a at Lgx only 13888 14344 16149 18965 1.03 1.16 1.37 Rps26
1415879 a at Lgx only 33385 37008 41034 49898 1.11 1.23 1.49 Rplp2
1415882 at Res only 20588 18774 17207 17741 -1.10 -1.20 -1.16 Ghitm
1415886 at All 637 966 1017 1132 1.51 1.60 1.78 Sh2d3c
1415901 at Lgx only 1435 1699 1682 1903 1.18 1.17 1.33 Plod3
1415907 at L x only 1656 1817 2329 2446 1.10 1.41 1.48 Ccnd3
1415909 at Res & L x 1788 1949 1414 1451 1.091-1.261 -1.23 Sti 1
CA 02699908 2010-03-17
WO 2009/039195 PCT/US2008/076707
-51-
Table 3
CO CR RES LGX FC FC FC
Probe Set ID Treatment mean mean mean mean CR Res L x Entrez Info
1415915 at Res & L x 2843 3059 3559 3668 1.08 1.25 1.29 Ddx1
1415930 a at Lgx only 14546 13685 14019 11677 -1.06 -1.04 -1.25 Ma l Ic3b
1415935 at Res & L x 1687 1988 2011 2446 1.18 1.19 1.45 Smoc2
1415947 at CR only 7499 6219 8373 7163 -1.21 1.12 -1.05 Cre l
1415951 at Lgx only 496 588 587 717 1.19 1.18 1.45 Fkbp 10
1415961 at Lgx only 2152 2177 2503 3192 1.01 1.16 1.48 ltm2c
1415966 a at L x onl 29789 33932 35207 35979 1.14 1.18 1.21 Ndufvl
1415971 at CR only 1825 1273 1649 1440 -1.43 -1.11 -1.27 Marcks
1415974 at Lgx only 1694 2075 2211 2392 1.22 1.31 1.41 Ma 2k2
1415977 at Lgx only 444 603 658 715 1.36 1.48 1.61 Isynal
1415987 at L x onl 8838 9568 10218 11109 1.08 1.16 1.26 Hdlbp
1415990 at CR & Lgx 27024 32941, 29714 35847 1.22 1.10 1.33 Vdac2
1415991 a at Res & L x 3051 3384 4293 4892 1.11 1.41 1.60 Klhdc3
1415996 at All 10650 22628 23188 27989 2.12 2.18 2.63 Txnip
1415998 at L x onl 33371 40497 35239 46095 1.21 1.06 1.38Vdacl
1416013 at Res & L x 926 1171 1314 1772 1.26 1.42 1.91 Pld3
1416014 at All 1518 981 801, 662 -1.551-1.90 -2.29 Abcel
1416016 at Res & Lgx 232 236 387 358 1.02 1.67 1.55 Ta l
1416019 at Res only 336 291 275 269 -1.15 -1.22 -1.25 Drl
1416027 at Res & L x 2414 2298 1834 1569 -1.05 -1.32 -1.54 Pdcd6
1416032 at Lgx only 1053 1425 1776 1638 1.35 1.69 1.56 Tmeml O9
1416046 a at L x only 4982 5500 3916 3426 1.10 -1.27 -1.45 Fuca2
1416048 at Res & L x 1089 1174 1589 1635 1.08 1.46 1.50 Phc2
1416050 a at Lgx only 903 1023 1209 1283 1.13 1.34 1.42 Scarbl
1416051 at Lgx only 128 165 178 252 1.28 1.39 1.97 C2
1416061 at Lgx only 1318 1255 1052 9641-1.05 -1.25 -1.37 Tbcl d15
1416064 a at Res only 12341 12004 9273 10433 -1.031-1.33 -1.18 Hs a5
1416069 at CR only 1055 1396 1197 1313 1.32 1.13 1.24 Pfkp
1416079 a at Lgx only 1323 1494 1456 1611 1.13 1.10 1.22Ar cla
1416082 at Res & L x 13983 13415 11321 10270 -1.04 -1.24 -1.36 Rabl
1416091 at Lgx only 1996 2372 2622 3315 1.19 1.31 1.66 Mtap4
1416106 at Lgx only 1108 939 1035 775 -1.181-1.07 -1.43 Ktil2
1416111 at CR & L x 368 212 288 138 -1.74 -1.28 -2.68 Cd83
1416112 at Lgx only 7587 9334 8583 12194 1.23 1.13 1.61 Cox8a
1416113 at Lgx only 1810 1965 2224 2559 1.09 1.23 1.41 Fkbp8
1416125 at Lgx only 550 764 772 809 1.39 1.40 1.47 Fkb 5
1416129 at Lgx only 1270 1118 1078 7341-1.14 -1.18 -1.73 Errfil
1416140 a at Lgx only 1672 1904 1977 1952 1.14 1.18 1.17 Dhx30
1416142 at L x only 614 690 511 333 1.12 -1.20 -1.85 Rps6
1416155 at Res & L x 3723 3890 2824 2551 1.041-1.32 -1.46 Hm b3
1416175 a at Res & Lgx 21409 19416 15845 13003 -1.10 -1.35 -1.65Vdac3
1416176 at Lgx only 2064 1801 1869 1358 -1.15 -1.10 -1.52 Hmgbl
1416177 at Res & Lgx 884 734 669 666 -1.20 -1.32 -1.33 Rbmxrt
1416181 at Res only 1982 1958 1504 1705 -1.01 -1.32 -1.16 Mesdc2
1416183 a at Lgx only 40384 48786 54318 64528 1.21 1.35 1.60 Ldhb
1416185 a at Lgx only 4447 4224 3331 2724 -1.05 -1.33 -1.63 Adh5
CA 02699908 2010-03-17
WO 2009/039195 PCT/US2008/076707
-52-
Table 3
CO CR RES LGX FC FC FC
Probe Set ID Treatment mean mean mean mean CR Res L x Entrez Info
1416186 at Lgx only 404 340 342 213 -1.19 -1.18 -1.90 Pnrc2
1416195 at Lgx only 1575 1576 1933 2022 1.00 1.23 1.28 RP23-136K12.4
1416209 at CR & L x 3673 4359 4108 4135 1.19 1.12 1.13 Gludl
1416210 at Lgx only 2605 2387 2225 2041 -1.09 -1.17 -1.28 lm 3
1416223 at Lgx only 629 633 838 882 1.01 1.33 1.40 Sh3b 5l
1416226 at Lgx only 1514 1558 2186 2127 1.03 1.44 1.40 Ar cl b
1416238 at Lgx only 982 1045 1322 1446 1.06 1.35 1.47 Tie1
1416240 at L x only 22627 18896 18958 17768 -1.201-1.19 -1.27 Psmb7
1416252 at Lgx only 1031 1322 1235 1464 1.28 1.20 1.42 Stk38
1416254 a at Lgx only 432 478 497 673 1.11 1.15 1.56 V s16
1416256 a at CR only 4550 5806 4704 5339 1.28 1.03 1.17Tubb5
1416259 at CR & Lgx 573 393 417 336 -1.46.-1.37 -1.71 Pex12
1416261 at Lgx only 328 394 350 470 1.20 1.07 1.43 Tmem19
1416268 at Lgx only 4666 4083 4613 3784 -1.14 -1.01 -1.23 Ets2
1416271 at CR & L x 3787 4661 4246 5035 1.23 1.12 1.33 Perp
1416272 at L x only 4874 4932 3921 3693 1.01 -1.24 -1.32 Ma 2k1i 1
1416280 at Lgx only 1640 1595 1340 12701-1.03 -1.22 -1.29 Sae2
1416283 at Res & L x 1026 1225 1415 1355 1.19 1.38 1.32 Gart
1416284 at Lgx only 5006 5498 6000 6739 1.10 1.20 1.35 Mr 128
1416292 at Res & L x 13464 12624 11145 11453 -1.07 -1.21 -1.18 Prdx3
1416294 at Lgx only 1274 1556 1654 2003 1.22 1.30 1.57 Scam 3
1416300 a at Lgx only 81172 93900 86598 106206 1.16 1.07 1.31 Slc25a3
1416312 at Res only 1570 1597 1351 1503 1.02 -1.16 -1.04 Rars
1416315 at L x only 1812 2063 2221 2496 1.14 1.23 1.38Abhd4
1416326 at Lgx only 8540 9522 10268 12292 1.11 1.20 1.44 Cri 1
1416329 at CR only 1231 933 1064 976 -1.32 -1.16 -1.26 C i 1
1416331 a at Lgx only 4998 5244 6828 7398 1.05 1.37 1.48 Nfe2ll
1416339 a at L x only 1730 1851 1929 2312 1.07 1.12 1.34 Prkcsh
1416340 a at Lgx only 1678 1836 2208 2386 1.09 1.32 1.42 Man2bl
1416350 at Lgx only 209 134 177 85 -1.56 -1.18 -2.46 K1f16
1416366 at Lgx only 27546 25654 21110 19836 -1.07 -1.30 -1.39 Ndufc2
1416368 at L x only 3559 3865 3913 4425 1.09 1.10 1.24 Gsta4
1416369 at Lgx only 728 542 558 4301-1.34 -1.30 -1.69 Hiatll
1416371 at Lgx only 934 773 973 1314 -1.21 1.04 1.41 A pod
1416384 a at Lgx only 3771 3990 4230 4569 1.06 1.12 1.21 Cope
1416393 at L x only 5020 5227 4128 2942 1.04 -1.22 -1.71 Em 1
1416405 at Lgx only 5254 5912 7260 10205 1.13 1.38 1.94 Bgn
1416411 at Lgx only 3752 3573 3504 3347 -1.05 -1.07 -1.12 Gstm2
1416412 at Res & Lgx 716 471 369 274 -1.52 -1.94 -2.61 Nsmaf
1416414 at L x only 461 561 703 739 1.22 1.52 1.60 Emilinl
1416417 a at Lgx only 29794 33340 35044 38096 1.12 1.18 1.28 Ndufb7
1416424 at Lgx only 3969 4305 4914 5377 1.08 1.24 1.35 M6 rb 1
1416425 at Lgx only 3908 4090 4560 4505 1.05 1.17 1.15 Pex19
1416427 at L x onl 14038 14608 14480 17881 1.04 1.03 1.27 Ccni
1416436 a at Res & L x 3463 3513 2761 2608 1.01 -1.25 -1.33 U cc
1416438 at Lgx only 1704 1946 2041 2300 1.14 1.20 1.35 Puf6O
CA 02699908 2010-03-17
WO 2009/039195 PCT/US2008/076707
-53-
Table 3
CO CR RES LGX FC FC FC
Probe Set ID Treatment mean mean mean mean CR Res L x Entrez Info
1416452 at Lgx only 5918 6059 6368 7090 1.02 1.08 1.20 Oat
1416455 a at Lgx only 49845 53641 55445 64019 1.08 1.11 1.28 Crab
1416457 at L x only 1208 1356 1592 1930 1.12 1.32 1.60 Ddah2
1416462 at Res & L x 3796 3321 2539 2621 -1.14 -1.49 -1.45 Ca rin1
1416478 a at Lgx only 49370 54196 49980 56965 1.10 1.01 1.15 Mdh2
1416479 a at Lgx only 3314 4024 3824 5065 1.21 1.15 1.53Tmeml4c
1416494 at L x only 24034 24945 28712 32059 1.04 1.19 1.33 Ndufs5
1416496 at CR & L x 9192 10747 9867 10827 1.17 1.07 1.18 Mrfa 1
1416498 at CR & L x 1234 1020 1151 968 -1.21 -1.07 -1.28 P is
1416502 a at Res & L x 1327 1624 1659 1918 1.22 1.25 1.45 Preb
1416506 at L x onl 5718 5208 4876 4228 -1.10 -1.17 -1.35 Psma6
1416510 at Lgx only 5555 6339 5912 6679 1.14 1.06 1.20 Mr l4
1416513 at Lgx only 1582 2144 2762 2762 1.35 1.75 1.75 Lamb2
1416514 a at Lgx only 888 805 648 439 -1.10 -1.37 -2.02 Fscn1
1416517 at Lgx only 411 441 486 580 1.07 1.18 1.41 Pnpla6
1416524 at Lgx only 4034 4167 4527 5256 1.03 1.12 1.30 S o
1416540 at L x only 1017 1340 1386 1769 1.32 1.36 1.74 H s
1416547 at Lgx only 12925 12431 11457 10620 -1.04 -1.13 -1.22 Ndufb3
1416555 at Res & Lgx 2837 2868 2221 2008 1.01 -1.28 -1.41 Ei24
1416563 at Lgx only 1374 1532 1043 788 1.11 -1.32 -1.74 Ctps
1416576 at L x only 230 236 432 441 1.02 1.88 1.92 Socs3
1416587 a at Res & Lgx 372 605 623 822 1.63 1.68 2.21 Xrccl
1416595 at Lgx only 1722 1750 1272 1269 1.02 -1.35 -1.36 Mr s22
1416604 at Lgx only 55121 62820 59589 71198 1.14 1.08 1.29 Cycl
1416612 at L x only 424 520 635 826 1.23 1.50 1.95 C 1bl
1416621 at Res & L x 869 1007 1063 1287 1.16 1.22 1.48 LI l1
1416629 at Lgx only 412 524 548 620 1.27 1.33 1.50 Slc1 a5
1416634 at Res & Lgx 3167 2719 1899 1420.-1.16 -1.67 -2.235730536A07Rik
1416635 at Res & Lgx 4444 3643 3384 2684 -1.22 -1.31 -1.66 Sm dl3a
1416637 at Lgx only 525 603 661 780 1.15 1.26 1.49 Slc4a2
1416647 at Lgx only 5775 6096 7099 7557 1.06 1.23 1.31 Bckdha
1416648 at Lgx only 2599 3174 3890 4330 1.22 1.50 1.67 D nclhl
1416656 at L x only 1412 1659 1596 1864 1.18 1.13 1.32 Clicl
1416668 at Lgx only 10958 10417 8267 7237 -1.05 -1.33 -1.51 Ttc35
1416680 at Res & L x 2599 1810 1455 813 -1.44 -1.79 -3.20 Ube3a
1416683 at Lgx only 1687 2209 2493 2585 1.31 1.48 1.53 Plxnb2
1416690 at Res & L x 1379 1680 1929 1834 1.22 1.40 1.33 Gt b 2
1416699 at Res only 6446 6175 4968 5208 -1.04 -1.30 -1.24 1110008F13Rik
1416703 at Lgx only 2541 2311 2251 1680 -1.10 -1.13 -1.51 Ma k14
1416706 at Res only 408 412 258 254 1.01 -1.58 -1.61 Rpe
1416708 a at L x only 807 815 975 1044 1.01 1.21 1.29 Gramd l a
1416709 a at Res & L x 1287 1148 920 920 -1.12 -1.40 -1.40 N rn
1416713 at Lgx only 920 1162 1424 2002 1.26 1.55 2.18 T 3
1416730 at Lgx only 436 492 540 650 1.13 1.24 1.49 Rcl1
1416731 at Lgx only 1678 1349 1389 1118 -1.24 -1.21 -1.50 To 2b
1416737 at Lgx only 1600 2387 2293 2936 1.49 1.43 1.84 G s1
CA 02699908 2010-03-17
WO 2009/039195 PCT/US2008/076707
-54-
Table 3
CO CR RES LGX FC FC FC
Probe Set ID Treatment mean mean mean mean CR Res L x Entrez Info
1416740 at Lgx only 1068 1202 1516 1606 1.13 1.42 1.50 Col5al
1416749 at CR only 4558 5528 3766 3810 1.21 -1.21 -1.20 Htral
1416752 at L x onl 18842 22289 23077 26541 1.18 1.22 1.41 Ldb3
1416755 at CR & L x 1571 1157 1295 897 -1.36 -1.21 -1.75 Dnajbl
1416766 at Lgx only 2214 2261 2504 2834 1.02 1.13 1.28 Mosc2
1416791 a at Lgx only 1176 1162 1174 1630 -1.01 -1.00 1.39 Nxf1
1416805 at L x onl 1361 1327 1132 959 -1.03 -1.20 -1.42 1110032E23Rik
1416808 at Res & L x 2839 2486 1876 1518 -1.14 -1.51 -1.87 Nidl
1416819 at CR only 7318 8511 7739 8109 1.16 1.06 1.11 Cdc37
1416824 at Res & L x 6820 5799 4916 4447 -1.18 -1.39 -1.53 B230118H07Rik
1416832 at L x onl 179 250 238 315 1.40 1.33 1.76 Slc39a8
1416836 at Lgx only 2043 2339 2345 2519 1.15 1.15 1.23 Lrp 10
1416841 at Lgx only 761 651 582 4941-1.17 -1.31 -1.54 1110059E24Rik
1416842 at Lgx only 5799 5337 5053 4625 -1.09 -1.15 -1.25 Gstms
1416845 at Res & Lgx 253 365 392 412 1.44 1.55 1.63Tmem132a
1416867 at Res only 539 510 644 503 -1.06 1.19 -1.07 Betl
1416883 at Res & L x 3457 4227 5144 5330 1.22 1.49 1.54 CI tml
1416884 at Lgx only 1755 1451, 1259 10641-1.21 -1.39 -1.65 Cbx3
1416896 at Res only 354 336 521 404 -1.05 1.47 1.14 R s6ka1
1416903 at L x only 2268 2513 2807 2977 1.11 1.24 1.31 Nucb1
1416912 at L xonl 2816 2469 2287 1840 -1.14 -1.23 -1.536330407G11Rik
1416928 at Res & L x 295 289 197 136 -1.02 -1.50 -2.16 Rbm12
1416931 at Lgx only 695 726 597 533 1.05 -1.16 -1.30 Nif311
1416933 at Res & L x 1482 1837 2077 2466 1.24 1.40 1.66 Por
1416940 at Lgx only 9984 10810 10055 11650 1.08 1.01 1.17 Ppif
1416943 at Lgx only 1721 1477 1227 872 -1.16 -1.40 -1.97 Ube2el
1416953 at CR only 2136 3722 2891 2928 1.74 1.35 1.37 Ctf
1416963 at Res only 4471 4553 3878 4212 1.02 -1.15 -1.06 Ubacl
1416981 at Lgx only 926 912 1189 1623 -1.02 1.28 1.75 Foxo1
1416990 at Lgx only 926 985 1107 1231 1.06 1.19 1.33 Rxrb
1417000 at Lgx only 448 513 582 661, 1.14 1.30 1.48 Abtbl
1417006 at L x only 917 923 1024 1208 1.01 1.12 1.32 Commd4
1417007 a at Lgx only 2381 1901 1585 1243 -1.25 -1.50 -1.92 V s4b
1417008 at Lgx only 4995 5792 7236 8553 1.16 1.45 1.71 Crat
1417010 at Lgx only 1566 1338 1138 897,-1.17 -1.38 -1.75 Zf 238
1417018 at Lgx only 442 453 487 682 1.03 1.10 1.54 Efem 2
1417026 at L x only 1683 1749 1357 1217 1.04 -1.24 -1.38 Pfdnl
1417044 at Lgx only 959 1047 1076 1385 1.09 1.12 1.44 Lcmtl
1417049 at CR only 693 515 650 556 -1.34 -1.07 -1.25 Rhd
1417061 at All 1418 1003 1945 1761 -1.41 1.37 1.24 Slc40a1
1417065 at CR only 667 1043 914 758 1.56 1.37 1.14 Egrl
1417068 a at Res & L x 1030 1108 1271 1589 1.08 1.23 1.54 Pt nl
1417073 a at Lgx only 2797 2634 1839 1346 -1.06 -1.52 -2.08 Qk
1417075 at L x only 2020 1802 1853 15941-1.12 -1.09 -1.27 2010309E21 Rik
1417081 a at Lgx only 3594 4012 4252 4459 1.12 1.18 1.24 S n r2
1417082 at Lgx only 1946 1607 1455 1101 -1.211-1.341 -1.77 An 32b
CA 02699908 2010-03-17
WO 2009/039195 PCT/US2008/076707
-55-
Table 3
CO CR RES LGX FC FC FC
Probe Set ID Treatment mean mean mean mean CR Res L x Entrez Info
1417091 at Lgx only 520 510 358 207 -1.02 -1.45 -2.51 Chuk
1417105 at Lgx only 5064 4514 4396 4198 -1.12 -1.15 -1.21 Trappc2l
1417109 at Res & Lgx 1215 1681 1773 1883 1.38 1.46 1.55 Tina l
1417112 at Res & L x 3493 4015 4629 4787 1.15 1.33 1.37JArl2bp
1417124 at Lgx only 7386 6930 5048 4243 -1.07 -1.46 -1.74 Dstn
1417127 at Lgx only 53 106 136 186 2.01 2.58 3.52 Msxl
1417142 at Res & L x 852 935 1104 1181 1.10 1.30 1.394932442KO8Rik
1417146 at Res & Lgx 605 807 893 1039 1.33 1.48 1.722410018C20Rik
1417165 at Lgx only 2346 2465 2903 2874 1.05 1.24 1.23 Mbd2
1417168 a at Lgx only 2358 2585 3131 3801 1.10 1.33 1.61 Us p2
1417170 at Lgx only 1459 1405 1174 1121 -1.04 -1.24 -1.30 Lztfl1
1417174 at Res & L x 1039 958 738 798 -1.08 -1.41 -1.301810021J13Rik
1417177 at Lgx only 462 447 437 6281-1.03 -1.06 1.36 Galkl
1417180 at Res & L x 754 837 1024 1133 1.11 1.36 1.50 Pcsk7
1417185 at Lgx only 9497 9130 8221 7632 -1.04 -1.16 -1.24 Ly6a
1417190 at L x only 4733 4553 5431 6212 -1.04 1.15 1.31 Pbefl
1417191 at Lgx only 3776 3337 3338 2706 -1.13 -1.13 -1.40 Dnajb9
1417207 at Lgx only 80 144 149 248 1.79 1.86 3.09 Dv12
1417209 at L x only 1828 1950 2173 2377 1.07 1.19 1.30 Sertad2
1417226 at Lgx only 812 921 967 1224 1.13 1.19 1.51 Fbxw4
1417228 at L x only 535 649 639 835 1.21 1.19 1.56 Capnl
1417233 at Res & L x 2926 2760 2274 1898 -1.06 -1.29 -1.54 Chchd4
1417238 at Lgx only 767 878 883 1108 1.15 1.15 1.44 Ewsrl
1417239 at Lgx only 1936 1557 1139 998 -1.24 -1.70 -1.94 Cetn3
1417240 at Res & L x 1783 2528 2699 3377 1.42 1.51 1.89 Z x
1417241 at Res & Lgx 3699 3394 2641 1970 -1.09 -1.40 -1.881X83328
1417258 at Res & L x 4947 4979 3931 3307 1.01 -1.26 -1.50 Cct5
1417271 a at Lgx only 4442 4716 5165 6247 1.06 1.16 1.41 Eng
1417273 at Res & L x 8604 12748 23951 27986 1.48 2.78 3.25 Pdk4
1417285 a at Lgx only 32713 36339 37425 43067 1.11 1.14 1.32 Ndufas
1417291 at Res & Lgx 1425 1410 2175 2102 -1.01 1.53 1.47Tnfrsf1a
1417294 at L x only 1787 1927 2326 2186 1.08 1.30 1.22 Akr7a5
1417297 at All 145 259 295 450 1.79 2.03 3.10 ltr3
1417304 at Lgx only 198 308 367 470 1.56 1.85 2.37 Chrd
1417306 at Lgx only 427 464 581 668 1.09 1.36 1.56 T k2
1417307 at L x only 1236 1290 1344 1544 1.04 1.09 1.25 Dmd
1417308 at Lgx only 15382 20160 20634, 26200 1.31 1.34 1.70 Pkm2
1417311 at Lgx only 47051 55061 51583 64453 1.17 1.10 1.37 Crip2
1417312 at Lgx only 1316 1798 2877 4398 1.37 2.19 3.34 Dkk3
1417327 at L x only 3779 3050 2884 2338 -1.24 -1.31 -1.62 Cav2
1417334 at Lgx only 308 321, 400 466 1.04 1.30 1.51 Stk19
1417349 at Lgx only 3676 3837 3192 2742 1.04 -1.15 -1.34 Pldn
1417357 at Lgx only 1014 1076 1189 1373 1.06 1.17 1.35 Emd
1417367 at L x onl 11894 11153 11043 9572 -1.07 -1.08 -1.24 Ppp2ca
1417369 at Lgx only 2848 3279 3554 4089 1.15 1.25 1.44 Hsd17b4
1417373 a at CR & Res 57174 74618 40192 59746, 1.31 -1.42 1.04 Tuba4a
CA 02699908 2010-03-17
WO 2009/039195 PCT/US2008/076707
-56-
Table 3
CO CR RES LGX FC FC FC
Probe Set ID Treatment mean mean mean mean CR Res L x Entrez Info
1417382 at CR & Res 5433 4021 4266 4657 -1.35 -1.27 -1.17 Ent d5
1417389 at L x only 4932 5697 6811 9117 1.16 1.38 1.85 G cl
1417392 a at L x onl 386 416 569 884 1.08 1.47 2.29 Slc7a7
1417394 at Lgx only 1516 1224 998 705 -1.24 -1.52 -2.15 Klf4
1417397 at Lgx only 364 447 480 576 1.23 1.32 1.58 Slc9a1
1417398 at CR & L x 2047 1670 1999 1532 -1.23 -1.02 -1.34 Rras2
1417399 at L x onl 4367 4901 4815 5943 1.12 1.10 1.36 Gas6
1417402 at Lgx only 3863 4030 3439 3158 1.04 -1.12 -1.22 1190017012Rik
1417409 at Lgx only 1660 1563 1378 1058 -1.06 -1.20 -1.57 Jun
1417423 at All 1931 2829 3104 4003 1.47 1.61 2.07 Grina
1417433 at Res only 1695 1694 1291 1499 -1.00 -1.31 -1.13 Lypla2
1417437 at CR only 643 802 739 810 1.25 1.15 1.26 Xrcc6
1417441 at Lgx only 970 856 665 557 -1.131-1.46 -1.74 Dnajc12
1417446 at Res & Lgx 817 1066 1009 1405 1.31 1.24 1.72 SIc12a4
1417466 at Lgx only 22355 20101 19656 17738 -1.11 -1.14 -1.26 R s5
1417475 at L x only 541 682 670 846 1.26 1.24 1.57 At 13al
1417476 at Lgx only 1158 1444 1386 1454 1.25 1.20 1.26 Fbxw5
1417478 a at Res & L x 2285 1692 1323 979 -1.351-1.73 -2.34 P 2r3c
1417490 at Lgx only 17449 20356 20005 21458 1.17 1.15 1.23 Ctsb
1417493 at L x only 1896 1748 1628 1370 -1.09 -1.17 -1.38 Bmil
1417494 a at Lgx only 3168 2535 2703 2081 -1.25 -1.17 -1.52 Cp
1417503 at Lgx only 813 899 1044 1230 1.11 1.29 1.51 Rfc2
1417507 at Res only 303 313 206 250 1.04 -1.47 -1.21 Cyb561
1417516 at Res & L x 1417 1442 975 1093 1.02 -1.45 -1.30 Ddit3
1417533 a at Res & L x 3526 3994 5408 5733 1.13 1.53 1.63 It b5
1417536 at Lgx only 1523 1489 1327 1156 -1.02 -1.15 -1.32 Zmat2
1417544 a at Lgx only 1725 2092 2186 2613 1.21 1.27 1.52 Flot2
1417552 at L x only 368 330 315 219 -1.12 -1.17 -1.68 Fap
1417562 at Res & L x 5225 5748 7049 8132 1.10 1.35 1.56 Eif4eb 1
1417564 at Lgx only 1045 942 849 682 -1.11 -1.23 -1.53 Med7
1417574 at Lgx only 4249 4227 4829 5635 -1.01 1.14 1.33 Cxcl12
1417578 a at L x only 1318 1466 1614 1933 1.11 1.23 1.47 Gm a
1417581 at Lgx only 327 311 206 118 -1.05 -1.59 -2.77 Dhodh
1417588 at CR only 70 24 64 43 -2.88 -1.10 -1.62 Galnt3
1417590 at Res & L x 1193 1414 1657 1976 1.19 1.39 1.66 C 27a1
1417592 at L x only 1276 1544 1813 1967 1.21 1.42 1.54 Frapl
1417606 a at Lgx only 8113 8165 6538 5977 1.01 -1.24 -1.36 Calr
1417611 at Lgx only 410 483 562 660 1.18 1.37 1.61 Tmem37
1417614 at Lgx only 52366 62118 63982 71743 1.19 1.22 1.37 Ckm
1417626 at Lgx only 20898 23134 29205 31629 1.11 1.40 1.51 Pde4dip
1417629 at CR only 550 726 507 529 1.32 -1.08 -1.04 Prodh
1417631 at Res only 576 686 816 800 1.19 1.42 1.39 Mknk1
1417636 at Lgx only 357 496 550 864 1.39 1.54 2.42 Slc6a9
1417637 a at Lgx only 740 721 597 561 -1.031-1.24 -1.32 Hm 2Ob
1417659 at Res & Lgx 2296 1809 1478 837 -1.27 -1.55 -2.74 V s29
1417664 a at L x only 413 416 589 585 1.01 1.43 1.42 Ndr 3
CA 02699908 2010-03-17
WO 2009/039195 PCT/US2008/076707
-57-
Table 3
CO CR RES LGX FC FC FC
Probe Set ID Treatment mean mean mean mean CR Res L x Entrez Info
1417665 a at Lgx only 1641 1906 2136 2541 1.16 1.30 1.55 Cpsfl
1417669 at L xonl 1917 2203 2177 2365 1.15 1.14 1.23Abad12
1417673 at Res & L x 9046 10264 7598 7548 1.13 -1.19 -1.20 Grb14
1417680 at Lgx only 1039 914 800 514 -1.14 -1.30 -2.02 Kcna5
1417681 at L x only 2481 2417 2057 1755 -1.03 -1.21 -1.41 Nudt21
1417683 at Lgx only 3002 3170 2902 2615 1.06 -1.03 -1.15 Diablo
1417693 a at Lgx only 2110 2468 2597 3325 1.17 1.23 1.58 Gabl
1417712 at L x only 9771, 8265 8035 6481 -1.18 -1.22 -1.51 Eif2s2
1417715 a at Lgx only 37732 44662 43599 56266 1.18 1.16 1.49 Got2
1417722 at Lgx only 2172 2787 2703 3093 1.28 1.24 1.42 Pgls
1417724 at Lgx only 963 827 712 620 -1.17 -1.35 -1.55 Thoc4
1417727 at L x only 595 659 764 845 1.11 1.28 1.42 Sfrs9
1417728 at Lgx only 1083 1178 1375 1363 1.09 1.27 1.26 Mbd3
1417730 at Res & L x 759 785 1047 1112 1.03 1.38 1.47 Extl
1417762 a at Lgx only 15317 17412 16383 18728 1.14 1.07 1.22 R 18
1417775 at L x only 385 504 537 605 1.31 1.40 1.57 R o1-4
1417777 at Lgx only 300 380 359 417 1.27 1.20 1.39 Ltb4dh
1417778 at Lgx only 592 523 478 322 -1.13 -1.24 -1.84 Zf 35
1417791 a at Lgx only 752 638 524 553 -1.18 -1.43 -1.36 Zfml
1417807 at L x only 404 370 322 268 -1.09 -1.25 -1.51 2700038N03Rik
1417814 at CR only 1089 821 1021 931 -1.33 -1.07 -1.17 Plat 5
1417825 at Res & L x 10020 8920 8393 8135 -1.12 -1.19 -1.23 Esd
1417827 at Lgx only 1987 1887 1725 1334 -1.05 -1.15 -1.49 Nglyl
1417840 at L x only 655 635 537 4931-1.03 -1.22 -1.33 1500031 L02Rik
1417842 at CR only 735 604 602 618 -1.22 -1.22 -1.19 Caml
1417865 at Res only 1877 1747 1566 1714 -1.07 -1.20 -1.09 Tnfai 1
1417868 a at Lgx only 1651 1315 950 698 -1.26 -1.74 -2.36 Ctsz
1417889 at L x only 11804 10711 10232 8376 -1.10 -1.15 -1.41 A obec2
1417893 at Lgx only 350 308 313 275 -1.14 -1.12 -1.27 Sfxn3
1417912 at L x onl 4436 4290 4051 3653 -1.03 -1.10 -1.21 Tmem93
1417916 a at Lgx only 2557 2471 2075 1814 -1.03 -1.23 -1.41 Fxcl
1417928 at Lgx only 930 1019 1145 1635 1.10 1.23 1.76 Pdlim4
1417933 at Lgx only 1003 1029 1202 1834 1.03 1.20 1.83 I fb 6
1417936 at Res & Lgx 627 556 388 317 -1.13 -1.62 -1.98 Cc19
1417951 at Res & L x 39914 46728 50392 54619 1.17 1.26 1.37 Eno3
1417953 at Lgx only 721 903 916 1106 1.25 1.27 1.53 D6Wsu176e
1417963 at CR only 1666 1274 1799 1621 -1.31 1.08 -1.03 PIt
1417970 at Lgx only 2618 2363 2180 1814 -1.11 -1.20 -1.44 At 5s
1417974 at Lgx only 1516 1151 1001 799 -1.32 -1.51 -1.90 K na4
1417983 a at Lgx only 654 514 464 439 -1.271-1.41 -1.49 Ube2v2
1417985 at All 980 658 657 521 -1.49 -1.49 -1.88 Nrar
1418000 a at Lgx only 44199 45002 51725 57791 1.02 1.17 1.31 ltm2b
1418004 a at Lgx only 1596 1844 2175 2741 1.16 1.36 1.72 Tmeml76b
1418007 at Lgx only 559 548 518 370 -1.02 -1.08 -1.51 1810007M14Rik
1418025 at Res & L x 1814 1542, 1141 10351-1.181-1.591 -1.75 Bhlhb2
1418031 at Res & L x 433 559 602 614 1.29 1.39 1.42 M o9b
CA 02699908 2010-03-17
WO 2009/039195 PCT/US2008/076707
-58-
Table 3
CO CR RES LGX FC FC FC
Probe Set ID Treatment mean mean mean mean CR Res L x Entrez Info
1418048 at Lgx only 2291 1894 1822 1403 -1.21 -1.26 -1.63 1110059G10Rik
1418049 at Lgx only 564 707 732 893 1.25 1.30 1.58 Ltbp3
1418058 at L x onl 1896 1822 1556 15321-1.04 -1.22 -1.24 Eltdl
1418085 at Lgx only 119 169 209 189 1.42 1.76 1.59 Prkcz
1418090 at Lgx only 393 473 619 747 1.20 1.58 1.90 Plvap
1418093 a at Lgx only 180 168 242 294 -1.07 1.34 1.63 Ef
1418124 at Res & L x 3982 4177 4816 5241 1.05 1.21 1.32 Tmem85
1418128 at L x onl 2612 3481, 3429 3842 1.33 1.31 1.47 Adc 6
1418148 at Res & Lgx 1168 915 1700 1493 -1.28 1.46 1.28Abadl
1418181 at Lgx only 6615 7164 10513 10742 1.08 1.59 1.62 Pt 4a3
1418183 a at L x onl 2041 1857 1603 1381 -1.10 -1.27 -1.48 Pscd1
1418186 at Lgx only 1322 1528 1723 2106 1.16 1.30 1.59 Gsttl
1418187 at L x only 2289 2761 3034, 3198 1.21 1.33 1.40 Ram 2
1418209 a at Res & L x 3685 3274 2816 2402 -1.13 -1.31 -1.53 Pfn2
1418223 at Res & L x 2693 2594 2189 2015 -1.04 -1.23 -1.34 Sec11a
1418228 at Lgx only 3494 3467 2926 2282,-1.01 -1.19 -1.53 Nful
1418244 at Res & L x 3970 4253 2852 2563 1.07 -1.39 -1.55 Nat5
1418261 at All 412 712 724 860 1.73 1.76 2.09 S k
1418275 a at Lgx only 977 937 845 806 -1.04 -1.16 -1.21 Elf2
1418277 at Lgx only 5601 5071 4822 3833,-1.10 -1.16 -1.46 r p9
1418296 at Lgx only 743 895 936 1162 1.20 1.26 1.56 Fx d5
1418302 at Res & L x 1279 1585 1792 2129 1.24 1.40 1.66 P t2
1418306 at CR only 212 99 186 157 -2.15 -1.14 -1.35 Cr bbl
1418308 at Lgx only 312 316 235 144 1.02 -1.33 -2.17 Husl
1418310 a at CR only 27 74 31 71, 2.71 1.13 2.59 Rlbpl
1418325 at Res only 530 450 302 356 -1.18 -1.75 -1.49 Se hs2
1418327 at L x onl 6638 6594 5327 4629 -1.01 -1.25 -1.43 11100581-19Rik
1418328 at Lgx only 9663 10359 12241 14054 1.07 1.27 1.45 C tl b
1418364 a at Res & L x 6214 6280 8701 10097 1.01 1.40 1.62 Ftl1
1418373 at Res & Lgx 20321 25840 28141 36744 1.27 1.38 1.81 P am2
1418384 at L x onl 2697 2580 2446 2128 -1.05 -1.10 -1.27 A ool
1418394 a at All 1313 1651 1851 2002 1.26 1.41 1.52 Cd97
1418395 at Res only 2083 2050 2622 2487 -1.02 1.26 1.19 Slc47a1
1418421 at Lgx only 409 447 356 219 1.09 -1.15 -1.87 Bcl6b
1418427 at L x onl 4160 3689 3518 29311-1.131-1.18 -1.42 Kif5b
1418433 at Lgx only 2097 2223 2417 2813 1.06 1.15 1.34 Cab39
1418456 a at Lgx only 1322 1134 961 777 -1.17 -1.37 -1.70 Cxcl14
1418461 at Lgx only 137 207 161 226 1.52 1.18 1.65 Sh3d19
1418462 at Lgx only 938 943 764 665 1.01 -1.23 -1.41 Exosc9
1418464 at L x only 54 55 98 186 1.02 1.80 3.42 Matn4
1418467 at CR & Lgx 1961 2626 2477 2773 1.34 1.26 1.41 Smarcd3
1418479 at CR & Lgx 971 752 799 628 -1.29 -1.22 -1.55 V s54
1418483 a at Lgx only 801 694 755 588 -1.15 -1.06 -1.36 Ggtal
1418495 at Res only 310 349 161 194 1.13 -1.93 -1.60 Zc3h8
1418506 a at Res only 20857 23088 24680 25457 1.11 1.18 1.22 Prdx2
1418518 at L x only 701 821 854 1036 1.17 1.22 1.48 Furin
CA 02699908 2010-03-17
WO 2009/039195 PCT/US2008/076707
-59-
Table 3
CO CR RES LGX FC FC FC
Probe Set ID Treatment mean mean mean mean CR Res L x Entrez Info
1418528 a at Res & L x 4483 4424 3749 3167 -1.01 -1.20 -1.42 Dad1
1418530 at Lgx only 282 250 196 154 -1.13 -1.44 -1.84 Nu 160
1418532 at L x onl 180 202 332 354 1.12 1.85 1.97 Fzd2
1418551 at Lgx only 34184 47198 44002 56324 1.38 1.29 1.65 M b c3
1418560 at Lgx only 42487 47719 46215 55194 1.12 1.09 1.30 Pdhal
1418563 at Res & Lgx 1576 1497 1007 795 -1.05 -1.57 -1.98 Serbp 1
1418578 at L x onl 718 782 1230 1501 1.09 1.71 2.09 D ka
1418583 at Lgx only 4503 4409 3800 29641-1.02 -1.19 -1.52 Hint3
1418584 at Lgx only 2929 2748 2413 2257 -1.07 -1.21 -1.30 Ccnh
1418589 a at Res & Lgx 5966 5443 3817 3292 -1.10 -1.56 -1.81 Mlf1
1418593 at L x onl 967 1039 1128 1548 1.08 1.17 1.60 Taf6
1418595 at Lgx only 3838 4270 5239 5576 1.11 1.37 1.45S3-12
1418604 at CR only 118 179 95 148 1.51 -1.24 1.25 Av rl a
1418621 at Lgx only 6696 7127 7710 8254 1.06 1.15 1.23 Rab2
1418640 at Lgx only 445 396 366 260 -1.12 -1.22 -1.71 Sirtl
1418644 a at Res & L x 2290 2528 3079 3754 1.10 1.34 1.64 Stk11
1418646 at L x only 576 557 801 953 -1.03 1.39 1.65 Gna-rs1
1418649 at Res & Lgx 1817 1689 1010 1064 -1.08 -1.80 -1.71 Egln3
1418658 at Lgx only 3201 2867 2597 2170 -1.12 -1.23 -1.48 2410005016Rik
1418659 at Lgx only 655 451, 573 399 -1.45 -1.14 -1.64 Clock
1418665 at Res only 432 341 817 509 -1.27 1.89 1.18 lm a2
1418681 at Lgx only 167 97 90 44 -1.73 -1.85 -3.80 Alg 13
1418700 at Res only 2166 2223 2693 2292 1.03 1.24 1.06 Lias
1418703 at Res & L x 1788 1937 2728 2973 1.08 1.53 1.66 Rbms1
1418714 at L x only 176 149 306 402 -1.19 1.74 2.28 Dusp8
1418726 a at Lgx only 96588 107808 105192 136735 1.12 1.09 1.42 Tnnt2
1418739 at CR only 115 61 145 180 -1.88 1.26 1.56 S k2
1418749 at Lgx only 829 963 993 1502 1.16 1.20 1.81 Psd3
1418759 at CR only 65 25 85 74 -2.61 1.30 1.14 Pt n20
1418763 at Res only 1354 1349 1037 1054 -1.00 -1.31 -1.28 Nit2
1418773 at Lgx only 997 1127 1373 1342 1.13 1.38 1.35 Fads3
1418775 at Res & L x 1330 1611 1775 2047 1.21 1.33 1.54 A1837181
1418782 at L x only 1857 2604 2789 2699 1.40 1.50 1.45 Rxrg
1418817 at Lgx only 868 707 713 565 -1.23 -1.22 -1.54 Chm 1 b
1418835 at Lgx only 1187 1202 996 645 1.01 -1.19 -1.84 Phldal
1418838 at Lgx only 1243 1517 1333 1771 1.22 1.07 1.43Abcdl
1418840 at Lgx only 667 575 556 501 -1.16 -1.20 -1.33 Pdcd4
1418846 at CR only 103 199 99 162 1.93 -1.04 1.57A 4m1
1418847 at Lgx only 28 28 56 92 -1.04 1.95 3.24 Ar 2
1418861 at Res only 887 950 1409 1371 1.07 1.59 1.55 Pias4
1418863 at L x only 1860 2280 2226 2561 1.23 1.20 1.38 Gata4
1418869 a at Lgx only 678 738 805 954 1.09 1.19 1.41 Pusl
1418874 a at Lgx only 5030 5073 6091 6369 1.01 1.21 1.27 Psmd4
1418885 a at Res & L x 906 1107 1173 1863 1.22 1.30 2.06ldh3b
1418899 at Lgx only 1067 834 819 715 -1.28 -1.30 -1.49 Ufml
1418924 at L x only 89 173 226 307 1.95 2.54 3.45 Rassf7
CA 02699908 2010-03-17
WO 2009/039195 PCT/US2008/076707
-60-
Table 3
CO CR RES LGX FC FC FC
Probe Set ID Treatment mean mean mean mean CR Res L x Entrez Info
1418926 at Res & Lgx 3012 2659 2326 2255 -1.13 -1.29 -1.34 Zebl
1418928 a at L xonl 958 1057 1130 1663 1.10 1.18 1.742310038H17Rik
1418929 at L x onl 410 472 537 581 1.15 1.31 1.42 Ift57
1418933 at Res only 8 28 16 13 3.76 2.08 1.68 SIc1 a6
1418947 at CR only 247 343 289 319 1.39 1.17 1.29 Nek3
1418952 at Res & Lgx 9461 9278 12035 12244 -1.02 1.27 1.29 Txlnb
1418967 a at L x onl 302 261 219 209 -1.16 -1.38 -1.45 St7
1418968 at L only 2166 1884 1630 14731-1.15 -1.33 -1.47Rblccl
1418986 a at Lgx only 1097 1006 854 642 -1.09 -1.28 -1.71 Uxt
1418987 at Res only 161 117 260 269 -1.38 1.61 1.67 Plat 2d
1418988 at Res & L x 2768 2378 2028 1916 -1.16 -1.36 -1.44 Pex7
1418996 a at Lgx only 3436 3503 3043 2693 1.02 -1.13 -1.28 L rm5
1419013 at Res only 438 501 605 499 1.14 1.38 1.14 G atch1
1419026 at Lgx only 910 978 1211 1131 1.08 1.33 1.24 Daxx
1419037 at Lgx only 1248 1228 1010 1005 -1.02 -1.24 -1.24 Csnk2a1
1419062 at L x only 646 672 717 873, 1.04 1.11 1.35 Epb4.113
1419070 at CR only 274 536 312 423 1.96 1.14 1.54 C s1
1419072 at Lgx only 1253 1214 1154 1035 -1.03 -1.09 -1.21 Gstm7
1419074 at Lgx only 669 635 434 385 -1.05 -1.54 -1.74 Chac2
1419081 at Lgx only 620 617 514 392 -1.00 -1.21 -1.58 At 10
1419109 at Res & L x 19560 22347 25933 31691 1.14 1.33 1.62 Hrc
1419131 at CR only 10 65 30 43 6.52 2.99 4.25 F1 3b
1419144 at Lgx only 328 358 484 596 1.09 1.48 1.81 Cd163
1419158 a at CR only 760 935 726 788 1.23 -1.05 1.04 Hars2
1419164 at Res & L x 1598 1612 1126 698 1.01 -1.42 -2.29 Zf 260
1419169 at Lgx only 1118 1026 941 817 -1.09 -1.19 -1.37 Ma k6
1419170 at Lgx only 2926 2624 2049 1889 -1.12 -1.43 -1.55 Tmem157
1419174 at L xonl 1433 1234 1044 1065 -1.16 -1.37 -1.342410004B18Rik
1419182 at Lgx only 525 545 632 749 1.04 1.20 1.43 Sve 1
1419186 a at Res & L x 779 684 511, 470 -1.14 -1.52 -1.66 St8sia4
1419214 at Res only 146 199 310 284 1.36 2.12 1.94 Tnfrsfl la
1419238 at Lgx only 154 255 316 301 1.66 2.06 1.96 Abca7
1419258 at Lgx only 1711 1423 1294 1111 -1.20 -1.32 -1.54 Tcea1
1419272 at Res only 428 435 585 498 1.02 1.37 1.16 M d88
1419292 at Lgx only 3158 3740 4270 4656 1.18 1.35 1.47 Htra3
1419295 at Res only 209 211 411 276 1.01 1.96 1.32 Creb3ll
1419297 at CR only 149 66 122 147 -2.25 -1.22 -1.01 H2-Oa
1419302 at Res & L x 794 919 1108 1247 1.16 1.40 1.57 He l
1419333 at L x onl 392 461 414 572 1.18 1.06 1.46 1110008J03Rik
1419352 at Lgx only 1989 1829 1498 1340 -1.09 -1.33 -1.4817Rn6
1419354 at Lgx only 1196 1159 1578 1790 -1.03 1.32 1.50 Klf7
1419358 at Lgx only 207 323 185 348 1.56 -1.11 1.68 Sorcs2
1419366 at Res & Lgx 642 733 782 1009 1.14 1.22 1.57 Zmat5
1419375 at Res & L x 1257 1211 921 872 -1.04 -1.36 -1.44 Wb 4
1419398 a at Lgx only 10797 11078 10041 8759 1.03 -1.08 -1.23 Ree 5
1419415 a at CR only 1168 905 1009 964 -1.29 -1.16 -1.21 Rar
CA 02699908 2010-03-17
WO 2009/039195 PCT/US2008/076707
-61-
Table 3
CO CR RES LGX FC FC FC
Probe Set ID Treatment mean mean mean mean CR Res L x Entrez Info
1419428 a at Lgx only 1374 1692 1993 2038 1.23 1.45 1.48 Gaa
1419429 at Res & L x 79 137 161 223 1.74 2.04 2.83 Cntfr
1419452 at L x only 1034 914 835 680 -1.131-1.24 -1.52 Uchl5
1419455 at Lgx only 6361 6701 5697 5310 1.05 -1.12 -1.201ll Orb
1419470 at Res & L x 865 849 644 649 -1.02 -1.34 -1.33 Gnb4
1419477 at Res only 35 98 190 144 2.81 5.44 4.12 Clec2d
1419484 a at L x only 20734 22346 11461 5733 1.08 -1.81 -3.62 Gbas
1419491 at Res only 13 40 52 67 3.14 4.08 5.30 Defb1
1419495 at Lgx only 2055 1752 1771 1374 -1.17 -1.16 -1.50 lmm 21
1419499 at Lgx only 7940 7261 10653 11012 -1.09 1.34 1.39 G am
1419518 at All 7504 12289 3758 4518 1.64 -2.00 -1.66 Tuba8
1419527 at L x onl 403 437 548 829 1.08 1.36 2.06 Com
1419550 a at Lgx only 2491 2352 1855 1537 -1.06 -1.34 -1.62 Stk39
1419569 a at Res only 681 700 1171 1519 1.03 1.72 2.231s 20
1419584 at Lgx only 521 505 846 843 -1.03 1.62 1.62 Ttc28
1419609 at CR only 53 133 65 112 2.53 1.24 2.13 Ccr1
1419630 a at CR & L x 549 668 630 755 1.22 1.15 1.37Triml1
1419631 at Res & Lgx 119 146 218 228 1.23 1.84 1.92 Was
1419645 at Lgx only 463 390 335 288 -1.19 -1.38 -1.61 Cstf2
1419657 a at CR & Lgx 1163 874 858 623 -1.331-1.36 -1.87 SIc25a36
1419660 at Lgx only 4264 3723 4383 3253 -1.15 1.03 -1.31 1600012FO9Rik
1419687 at Lgx only 8909 9784 12046 13075 1.10 1.35 1.47 Macrodl
1419736 a at Res & L x 3408 3084 2455 1934 -1.10 -1.39 -1.76 Eif1a
1419762 at Res & Lgx 38 84 155 154 2.18 4.03 4.01 Ubd
1419787 a at Lgx only 312 385 461 581 1.24 1.48 1.86 Zf 628
1419824 a at Res & Lgx 455 428 270 228 -1.06 -1.69 -2.00 A230062G08Rik
1419952 at Lgx only 27 55 105 168 2.03 3.90 6.26 1700023D09Rik
1420099 at CR only 203 411, 349 286 2.02 1.72 1.40 D13Ertd787e
1420123 at Res & Lgx 3511 3401 5048 5686 -1.03 1.44 1.62 Tcta
1420183 at L x only 234 252 360 451 1.08 1.54 1.93 Lor
1420325 at Res only 57 130 144 132 2.26 2.52 2.30 Cram 11
1420329 at Lgx only 567 517 392 323 -1.10 -1.45 -1.764930455C21 Rik
1420339 at Res only 309 242 217 225 -1.28 -1.43 -1.37 LOC100047915
1420374 at Res & L x 758 989 1238 1240 1.31 1.63 1.64 Foxj2
1420375 at Res & L x 401 402 615 593 1.00 1.53 1.48 Kif3a
1420377 at Lgx only 89 105 134 173 1.18 1.50 1.94 St8sia2
1420387 at Res & L x 2021 2029 1347 1414 1.00 -1.50 -1.43 M v17
1420388 at Lgx only 160 221 219 350 1.38 1.37 2.19 Prss12
1420405 at L x onl 181 177 327 423 -1.02 1.81 2.34 SIcol a4
1420427 a at CR only 1499 1159 1676 1564 -1.29 1.12 1.04 Dhx32
1420497 a at Res only 446 471 707 611 1.06 1.58 1.37 Ceb z
1420502 at Lgx only 1203 971, 967 740 -1.24 -1.24 -1.63 Sall
1420507 a at Res & L x 787 742 523 391 -1.06 -1.50 -2.01 3110031B13Rik
1420513 at Res & L x 4347 3651 3096 26401-1.19 -1.40 -1.65 Efcab2
1420580 at Res only 108 171 205 173 1.59 1.90 1.60 49304291321 Rik
1420617 at CR & L x 1660 2030 1377 1316 1.221-1.21 -1.26 C eb4
CA 02699908 2010-03-17
WO 2009/039195 PCT/US2008/076707
-62-
Table 3
CO CR RES LGX FC FC FC
Probe Set ID Treatment mean mean mean mean CR Res L x Entrez Info
1420619 a at Lgx only 9782 11497 12736 14220 1.18 1.30 1.45 Aes
1420654 a at Lgx only 836 1010 530 414 1.21 -1.58 -2.02 Gbe1
1420657 at CR & L x 978 1762 1973 2727 1.80 2.02 2.79 Uc 3
1420684 at Lgx only 184 272 311 338 1.48 1.70 1.84 Acox3
1420693 at Lgx only 12144 13502 14705 16745 1.11 1.21 1.38 M om1
1420703 at Lgx only 230 242 309 412 1.05 1.34 1.79 Csf2ra
1420707 a at Res only 15 45 86 56 3.03 5.79 3.77 Traip
1420711 a at Res & L x 1740 1664 1104 1160 -1.051-1.58 -1.50 Pxm 3
1420715 a at Res only 264 353 394 398 1.34 1.49 1.51 P ar
1420727 a at Lgx only 834 685 683 642 -1.22 -1.22 -1.30 Tmlhe
1420770 at Lgx only 119 204 196 229 1.71 1.64 1.92 Klk1b24
1420812 at Res only 636 684 880 887 1.08 1.38 1.39 Hdac7a
1420815 at Res & L x 6531 5930 4529 3754 -1.10 -1.44 -1.74 Gdi2
1420829 a at Res & Lgx 1575 1422 1004 915 -1.11 -1.57 -1.72Ywhag
1420850 at Lgx only 811 697 641 504 -1.16 -1.27 -1.61 Crnkll
1420851 at Lgx only 742 595 613 560 -1.25 -1.21 -1.32 Pard6g
1420858 at L x only 4637 3856 3968 3017 -1.201-1.17, -1.54 Pkia
1420886 a at Res & Lgx 3739 3833 4963 5400 1.03 1.33 1.44 Xbp 1
1420890 at Res & L x 5214 4425 2406 1933 -1.18 -2.17 -2.70 Hccs
1420895 at Lgx only 917 770 710 650 -1.19 -1.29 -1.41 Tgfbrl
1420909 at L x only 2678 2641, 1885 13641-1.01 -1.42 -1.96 Ve fa
1420911 a at Lgx only 3466 3820 3678 4193 1.10 1.06 1.21 Mfge8
1420925 at Lgx only 72 124 151 175 1.71 2.08 2.42 Tub
1420960 at Res only 96 110 192 231 1.15 1.99 2.40 Fanc
1420965 a at Lgx only 874 1154 1487 1587 1.32 1.70 1.82 End
1420969 at L x only 466 483 535 830 1.04 1.15 1.78 Btbd14b
1420981 a at Lgx only 827 972 964 1187 1.18 1.17 1.44 Lmo4
1420990 at Res only 312 320 517 236 1.02 1.65 -1.32 Chdl
1420991 at L xonl 53384 52666 61602 72604 -1.01 1.15 1.36Ankrd1
1421019 at L x only 4065 3950 3600 3047 -1.03 -1.13 -1.33 1700021 F05Rik
1421025 at Lgx only 849 1055 1040 1273 1.24 1.22 1.50 A atl
1421027 a at Res & Lgx 1926 1835 1240 1194 -1.05 -1.55 -1.61 Mef2c
1421042 at Res only 445 458 615 583 1.03 1.38 1.31 Arhgef2
1421054 at Lgx only 720 688 568 4291-1.05 -1.27 -1.68 X o4
1421087 at CR & L x 659 948 669 1049 1.44 1.02 1.59 Per3
1421096 at Res & Lgx 343 231 143 153 -1.48 -2.39 -2.24 Tr cl
1421099 at Lgx only 201 206 279 348 1.03 1.39 1.74 Bhlhb3
1421140 a at Lgx only 966 1184 1048 1522 1.23 1.09 1.57 Foxpl
1421164 a at L x onl 790 1029 1101 1483 1.30 1.39 1.88 Arh ef1
1421174 at CR only 170 74 105 131 -2.29 -1.62 -1.30 Irf4
1421254 a at Res & L x 8190 8322 11932 11052 1.02 1.46 1.35 S c
1421265 a at Lgx only 2787 3702 3156 4067 1.33 1.13 1.46 Rbm38
1421287 a at Res & Lgx 1918 2165 2346 2394 1.13 1.22 1.25 Pecaml
1421292 a at L xonl 1159 1309 1372 1641 1.13 1.18 1.42A730008L03Rik
1421301 at Res & Lgx 25 50 65 79 2.01 2.64 3.20 Zic2
1421361 at Res only 7 12 14 17 1.71 1.97 2.36 Grkl
CA 02699908 2010-03-17
WO 2009/039195 PCT/US2008/076707
-63-
Table 3
CO CR RES LGX FC FC FC
Probe Set ID Treatment mean mean mean mean CR Res L x Entrez Info
1421373 at L x only 150 180 225 291 1.20 1.50 1.94 Cox4i2
1421374 a at Res & L x 22933 26328 30566 37711 1.15 1.33 1.64 Fx d 1
1421425 a at L x onl 16449 16822 17946 19197 1.02 1.09 1.17 Rcan2
1421444 at Res only 74 60 18 28 -1.23 -4.13 -2.61 P r
1421468 at Lgx only 901 957 947 1325 1.06 1.05 1.47 Kcnj3
1421530 a at Lgx only 27 71 53 97 2.66 1.98 3.62 Grm8
1421534 at L x onl 811 795 808 606 -1.02 -1.00 -1.34 Dfna5h
1421541 a at Lgx only 21 44 48 100 2.09 2.27 4.69 Mef2b
1421654 a at Lgx only 1679 1993 2038 2187 1.19 1.21 1.30 Lmna
1421657 a at Lgx only 586 697 816 882 1.19 1.39 1.51 Soxl7
1421712 at Res only 44 104 121 85 2.35 2.74 1.93 Sele
1421729 a at Res & L x 681 584 500 370 -1.17 -1.36 -1.84 Fert2
1421733 a at Res & L x 1129 1104 1432 1650 -1.02 1.27 1.46 T stl
1421743 a at Res & L x 9703 10330 11559 11327 1.06 1.19 1.17 Pcb 2
1421750 a at L x onl 2246 2231 1829 1446 -1.01 -1.23 -1.55 Vb 1
1421797 a at Lgx only 557 651 646 772 1.17 1.16 1.39 Snx12
1421808 at Res only 72 37 25 261-1.92 -2.88 -2.71 Defbs
1421810 at Lgx only 868 921 932 1143 1.06 1.07 1.32 Dgcr2
1421813 a at L x onl 18627 21854 22085 24924 1.17 1.19 1.34 Psap
1421820 a at Lgx only 2152 2587 2644 3110 1.20 1.23 1.45 Nf2
1421826 at Lgx only 702 623 580 445 -1.13 -1.21 -1.58 D114
1421861 at Lgx only 1285 1602 1652 1882 1.25 1.28 1.46 Clstnl
1421871 at L x onl 1104 837 695 549 -1.32 -1.59 -2.01 Sh3b rl
1421872 at Lgx only 911 910 719 556 -1.00 -1.27 -1.64 Rab24
1421880 at Res only 970 1061 1162 1121 1.09 1.20 1.16 Mtmrl
1421887 a at L x onl 10860 11944 14384 16154 1.10 1.32 1.49 A 12
1421894 a at L x onl 1285 1111 1077 8761-1.16 -1.19 -1.47 T 2
1421900 at Lgx only 704 851 937 1086 1.21 1.33 1.54 Eif2akl
1421910 at CR & Lgx 616 466 496 388 -1.32 -1.24 -1.58 Tcf20
1421929 at Res & L x 584 771 1070 1011 1.32 1.83 1.73 E ha4
1421960 at Lgx only 251 313 373 451 1.25 1.48 1.79 Adc 3
1421985 a at L x only 1206 1190 1259 970 -1.01 1.04 -1.24 Eif4e2
1422063 a at Res & Lgx 303 432 514 657 1.43 1.70 2.17 PexS
1422085 at Res only 89 141 178 209 1.58 2.00 2.34Tbx19
1422122 at Lgx only 45 52 102 145 1.15 2.26 3.23 Fcer2a
1422157 a at Res & L x 1891 1621, 1425 14081-1.17 -1.33 -1.34 It bl b 1
1422160 at Res & L x 194 137 98 86 -1.42 -1.99 -2.2411-12-T24
1422183 a at Res & Lgx 456 433 718 774 -1.05 1.57 1.70 Adral b
1422185 a at Lgx only 2280 2364 3023 3264 1.04 1.33 1.43 C b5r3
1422202 at All 187 261 266 299 1.39 1.42 1.60 Thrb
1422250 at Res only 74 95 175 109 1.29 2.36 1.47 Ma 3k2
1422253 at Res only 72 82 22 25 1.14 -3.30 -2.84 Coll Oa1
1422273 at CR only 17 64 65 79 3.66 3.75 4.54 Mrnp 1 b
1422303 a at Lgx only 115 142 161 192 1.24 1.40 1.67 Tnfrsfl8
1422325 at CR only 99 54 92 791- i - 85-1.08 -1.25 Ma ea5
1422349 at Res only 108 91 204, 1641-1.191 1.88 1.51 Ccr111
CA 02699908 2010-03-17
WO 2009/039195 PCT/US2008/076707
-64-
Table 3
CO CR RES LGX FC FC FC
Probe Set ID Treatment mean mean mean mean CR Res L x Entrez Info
1422368 at CR onl63 20 70 73 -3.19 1.12 1.17V1ra5
1422429 at Res & Lgx 3906 3945 3274 3064 1.01 -1.19 -1.27 Rnf14
1422431 at Res & L x 174 193 294 266 1.11 1.69 1.53 Ma eel
1422442 at Res & Lgx 2592 2482 1984 1860 -1.04 -1.31 -1.39Smul
1422443 at CR only 2188 2545 2408 2383 1.16 1.10 1.09 X n e l
1422470 at CR & L x 10633 8053 8886 6881 -1.32 -1.20 -1.55 Bni 3
1422476 at Lgx only 632 824 773 895 1.30 1.22 1.42 lfi30
1422479 at CR only 1246 1673 1146 1250 1.34 -1.09 1.OOAcss2
1422505 at Res & Lgx 2509 2529 2006 2084 1.01 -1.25 -1.20 Chracl
1422514 at Lgx only 811 912 1085 1253 1.12 1.34 1.54 Aeb l
1422521 at Lgx only 1147 1461 1635 2058 1.27 1.43 1.79 Dctn1
1422536 at L x onl 92593 100541 105298 145101 1.09 1.14 1.57 Tnni3
1422559 at Res & L x 2320 2134 1617 1469 -1.09 -1.44 -1.58 Ube2n
1422562 at Lgx only 4072 5149 5749 7406 1.26 1.41 1.82 Rrad
1422568 at Lgx only 4621 4163 3766 3704 -1.11 -1.23 -1.25 Ndell
1422579 at L x only 2795 2515 2100 1950 -1.11 -1.33 -1.43 Hs el
1422580 at L x onl 21473 23970 33904 66655 1.12 1.58 3.10 M y14
1422589 at Lgx only 1557 2101 1799 2359 1.35 1.16 1.51 Rab3a
1422594 at Res only 1164 1044 782 887 -1.12 -1.49 -1.31 5730470L24Rik
1422597 at L x only 1172 1880 1299 1581 1.60 1.11 1.35 rnp 15
1422598 at Lgx only 376 482 558 667 1.28 1.48 1.77 Cas 1
1422601 at Lgx only 678 602 614 451 -1.13 -1.11 -1.50 Ser inb9
1422622 at Lgx only 1987 2361 2556 2886 1.19 1.29 1.45 Nos3
1422624 at Res & Lgx 585 523 324 366 -1.12 -1.80 -1.60 Rev1
1422631 at CR only 459 290 354 311 -1.58 -1.30 -1.47Ahr
1422636 at Lgx only 484 476 356 311 -1.02 -1.36 -1.55 Dmtfl
1422647 at Lgx only 551 486 766 9451-1.13 1.39 1.72 Ringl
1422654 at Res & Lgx 6849 8679 9035 10593 1.27 1.32 1.55 S ca
1422656 at L x only 348 337 280 194 -1.03 -1.24 -1.79 Rasl2-9
1422669 at Res & Lgx 1326 1103 925 768 -1.20 -1.43 -1.72 Ebag9
1422678 at Lgx only 8205 10614 8228 11571 1.29 1.00 1.41 Dgat2
1422687 at Res only 342 422 540 502 1.23 1.58 1.47 Nras
1422704 at L x only 912 889 790 6921-1.03 -1.16 -1.32 Gyk
1422710 a at Lgx only 204 256 533 712 1.26 2.62 3.50 Cacna1 h
1422731 at Lgx only 1938 1979 1826 1508 1.02 -1.06 -1.29 Limdl
1422750 a at L x onl 12 15 16 26 1.27 1.32 2.13 Zm nd 10
1422754 at L x onl 5302 6134 5414 7120 1.16 1.02 1.34 Tmod 1
1422759 a at L x onl 716 910 1014 972 1.27 1.42 1.36 X o6
1422771 at L x onl 662 616 845 1033 -1.07 1.28 1.56 Smad6
1422794 at L x onl 2668 2498 2540 2197 -1.07 -1.05 -1.21 Cu13
1422797 at L x only 2497 2556 2816 3053 1.02 1.13 1.221Mapbpip
1422799 at Lgx only 1417 2232 2331 3007 1.58 1.64 2.12 Bat2
1422801 at Lgx only 1868 2054 2333 2401 1.10 1.25 1.29 G3bpl
1422811 at Lgx only 1842 1949 3745 4459 1.06 2.03 2.42 Slc27a1
1422819 at Lgx only 1868 1541 1669 1324 -1.21 -1.12 -1.41 Mr 136
1422820 at Res & L x 1160 1556 2287 3124 1.34 1.97 2.69 Li e
CA 02699908 2010-03-17
WO 2009/039195 PCT/US2008/076707
-65-
Table 3
CO CR RES LGX FC FC FC
Probe Set ID Treatment mean mean mean mean CR Res L x Entrez Info
1422845 at Res & L x 2601 2532 1767 1768 -1.03 -1.47 -1.47 Canx
1422855 at Lgx only 1072 1244 1287 1505 1.16 1.20 1.40 Cpsf3
1422858 at Res & Lgx 647 600 471 3851-1.08 -1.37 -1.68 Tri 4
1422869 at CR only 322 486 356 429 1.51 1.11 1.33 Mertk
1422880 at Res only 3821 4166 5178 4697 1.09 1.36 1.23S l
1422884 at Res & Lgx 2609 2458 1699 1360 -1.06 -1.54 -1.92 Snrpd3
1422888 at Res & Lgx 2451 2326 1824 1740 -1.05 -1.34 -1.41 Rnf5
1422895 at L x onl 1484 1345 1128 10851-1.10 -1.32 -1.37 Vam 4
1422904 at Lgx only 1644 2057 2434 3071 1.25 1.48 1.87 Fmo2
1422919 at Lgx only 1447 1561 1174 1081 1.08 -1.23 -1.34 Hrasls
1422927 at Lgx only 9559 8873 9036 7917 -1.08 -1.06 -1.21 Yipf7
1422975 at Lgx only 270 215 239 143 -1.25 -1.13 -1.88 Mme
1423025 a at Res & Lgx 4676 4201 3674 3128 -1.11 -1.27 -1.50 Schi 1
1423038 at CR only 739 613 619 676 -1.21 -1.19 -1.09 Stx6
1423044 at Lgx only 3560 3888 3058 2626 1.09 -1.16 -1.36 Prosc
1423047 at Lgx only 1895 2061 2077 2332 1.09 1.10 1.23 Tollip
1423049 a at L x only 87808 100652 95761 125022 1.15 1.09 1.42 T ml
1423067 at Lgx only 1021 1177 1166 1322 1.15 1.14 1.29 Cdk5ra 3
1423072 at Res & Lgx 9143 7426 14144 14099 -1.23 1.55 1.546720475J19Rik
1423073 at Res & L x 2730 2611 1976 1859 -1.05 -1.38 -1.47 Cm k
1423078 a at Res only 281 268 138 193 -1.05 -2.03 -1.45 Sc4mol
1423083 at Lgx only 829 634 640 576 -1.31 -1.30 -1.44 Rab33b
1423085 at L x onl 2081 2337 2335 2878 1.12 1.12 1.38 Efnb3
1423086 at Lgx only 581 574 944 865 -1.01 1.62 1.49 N cl
1423104 at Lgx only 1861 2159 1551 1285 1.16 -1.20 -1.45 Irs1
1423107 at Res & L x 13435 12780 18773 18511 -1.05 1.40 1.38 Ube2b
1423115 at Lgx only 1874 2293 2021 2497 1.22 1.08 1.33 St6 alnac6
1423116 at Lgx only 367 369 418 514 1.01 1.14 1.40 Dom3z
1423117 at Lgx only 1641 1974 2060 2325 1.20 1.26 1.42 Pum1
1423120 at Lgx only 1872 1820 2582 2866 -1.03 1.38 1.53 Ide
1423145 a at L x onl 67091 70639 67884 94069 1.05 1.01 1.40 Tcap
1423159 at Lgx only 8820 7770 8104 71851-1.14 -1.09 -1.23 DId
1423167 at Lgx only 2048 1950 1592 1289 -1.05 -1.29 -1.59 Mobkl3
1423185 a at Lgx only 1046 1030 1125 1433 -1.01 1.08 1.37 Ubapl
1423195 at L x only 770 772 644 545 1.001-1.20 -1.41 Had
1423210 a at Lgx only 15838 13912 13292 11593 -1.14 -1.19 -1.37 Nola3
1423238 at CR only 10141 11875 10734 10997 1.17 1.06 1.08It b1b 2
1423245 at Lgx only 2212 2559 2650 2839 1.16 1.20 1.28 Co s7a
1423247 at Res & Lgx 1654 1535 1377 1412 -1.08 -1.20 -1.17 Txndc4
1423283 at Res only 2245 2516 2704 2323 1.12 1.20 1.03 Pitpna
1423289 a at Lgx only 590 520 490 411 -1.14 -1.21 -1.44 1810029B16Rik
1423296 at Res & L x 4260 3917 3455 3149 -1.09 -1.23 -1.35 Psmd8
1423315 at Res only 239 239 393 245 -1.00 1.64 1.03 Bbc3
1423332 at Lgx only 7044 6555 6145 5521 -1.07 -1.15 -1.281Sdcbp
1423347 at Lgx only 1717 1446 1257 946 -1.19 -1.37 -1.81 Sec23a
1423362 at Lgx only 1116 1401 1546 2127 1.26 1.38 1.91 Sortl
CA 02699908 2010-03-17
WO 2009/039195 PCT/US2008/076707
-66-
Table 3
CO CR RES LGX FC FC FC
Probe Set ID Treatment mean mean mean mean CR Res L x Entrez Info
1423365 at Lgx only 220 341 321 487 1.55 1.46 2.22 Cacna1
1423368 at Res only 26862 24889 23668 24004 -1.08 -1.13 -1.12 La tm4a
1423369 at L x onl 512 450 400 2771-1.14 -1.28 -1.84 Fmrl
1423373 at Lgx only 1662 1543 1231 1041 -1.08 -1.35 -1.60 R 3O
1423383 a at Lgx only 3010 3451 3134 3991 1.15 1.04 1.33 Osbpl9
1423393 at Res & L x 9550 11356 12552 12982 1.19 1.31 1.36 Clic4
1423407 a at Res & L x 1285 1527 1976 2493 1.19 1.54 1.94 Fbin2
1423423 at Res & L x 3996 3941 3047 3212 -1.01 -1.31 -1.24 Pdia3
1423425 at Lgx only 639 706 761 947 1.10 1.19 1.48 1300012G16Rik
1423431 a at Res & L x 1593 1952 2320 2336 1.23 1.46 1.47 M bb 1 a
1423440 at L x only 631 546 529 467 -1.15 -1.19 -1.35 111000lAO7Rik
1423441 at L x onl 4060 3903 3850 34521-1.04 -1.05 -1.18 Tfb2m
1423448 at Res & L x 4469 4669 6840 6850 1.04 1.53 1.53 Rab l 1 b
1423449 a at Lgx only 1823 2337 2121 2533 1.28 1.16 1.39 Actn4
1423459 at Lgx only 3896 3424 3126 2505 -1.14 -1.25 -1.56 Co s2
1423474 at Res & Lgx 2213 2036 1686 1390 -1.09 -1.31 -1.59 To 1
1423485 at L x only 523 580 631 930 1.11 1.21 1.78 Rad5412
1423486 at Res & L x 4116 3309 2762 2491 -1.24 -1.49 -1.65 Cri t
1423490 at Lgx only 3791 3965 3044 2767 1.05 -1.25 -1.37 Fbxo3
1423494 at CR only 38 105 93 45 2.79 2.46 1.202310042E22Rik
1423512 at Lgx only 664 554 571 4941-1.20 -1.16 -1.35AW209491
1423529 at Lgx only 76 62 55 20 -1.22 -1.38 -3.78 G6 c2
1423535 at L x onl 4603 3572 3482 2393 -1.29 -1.32 -1.92 LOC100047794
1423557 at Res & Lgx 4123 4659 2949 2995 1.13 -1.40 -1.38 lfn r2
1423565 at Lgx only 6741 7261 5935 5619 1.08 -1.14 -1.20 Paics
1423577 at CR only 866 691 713 759 -1.25 -1.22 -1.14Ankrd32
1423588 at Res & L x 1204 1118 984 929 -1.08 -1.22 -1.30 Ar c4
1423599 a at Lgx only 741 579 555 467 -1.28 -1.33 -1.59 Pdcl
1423609 a at Lgx only 2102 2341 2391 3062 1.11 1.14 1.46 Mgatl
1423611 at CR only 736 949 973 1010 1.29 1.32 1.37 Ak 2
1423620 at L x onl 428 413 295 207 -1.04 -1.45 -2.07 Cen
1423629 at Lgx only 842 1015 1126 1457 1.21 1.34 1.73 Dnm2
1423642 at CR & Res 11579 15048 8041 9198 1.30 -1.44 -1.26 Tubb2c
1423643 at L x onl 1071 1196 843 821 1.12 -1.27 -1.30 Ddx39
1423647 a at Res only 344 396 605 457 1.15 1.76 1.33 Zdhhc3
1423648 at CR only 1771 2210 1681 1872 1.25 -1.05 1.06 Pdia6
1423657 at Res & L x 1515 1485 1236 1166 -1.02 -1.23 -1.30 Cdi t
1423662 at Res & Lgx 1443 1423 991, 902 -1.01 -1.46 -1.60 At 6a 2
1423663 at CR only 1057 1384 1080 1178 1.31 1.02 1.12 Flcn
1423667 at All 8373 7112 6577 5613 -1.18 -1.27 -1.49 Mat2a
1423669 at Lgx only 1075 1350 1555 2209 1.26 1.45 2.05 Coll a1
1423670 a at CR & Lgx 3169 3700 3314 3615 1.17 1.05 1.14 Sr r
1423676 at Lgx only 58661 62536 61203 80373 1.07 1.04 1.37 At 5h
1423685 at Lgx only 1108 1452 1375 1574 1.31 1.24 1.42 Aars
1423694 at CR only 1790 2077 2089 1818 1.16 1.17 1.02 Kctdl O
1423697 at Lgx only 6981 6288 6277 52481-1.11 -1.11 -1.33 Psmd6
CA 02699908 2010-03-17
WO 2009/039195 PCT/US2008/076707
-67-
Table 3
CO CR RES LGX FC FC FC
Probe Set ID Treatment mean mean mean mean CR Res L x Entrez Info
1423710 at Lgx only 9222 11179 10001 11429 1.21 1.08 1.24 Dlst
1423711 at Res & L x 2316 2307 1924 1627 -1.00 -1.20 -1.42 Ndufafl
1423725 at L x onl 985 705 674 7621-1.40 -1.46 -1.29 Pls3
1423734 at Lgx only 5006 5612 5707 6496 1.12 1.14 1.30 Racl
1423737 at Lgx only 24235 26450 27218 29730 1.09 1.12 1.23 Ndufs3
1423753 at CR only 1118 734 898 856 -1.52 -1.24 -1.31 Bambi
1423759 a at Res & Lgx 4031 3513 2876 2736 -1.15 -1.40 -1.47Tmco1
1423766 at Res & L x 1610 1380 1025 987 -1.17 -1.57 -1.63 Pakl i l
1423767 at L xonl 2146 2025 1774 1497 -1.06 -1.21 -1.432810410M20Rik
1423771 at Lgx only 815 750 811 1094 -1.09 -1.00 1.34 bp
1423773 at L x onl 4627 3985 3629 2816 -1.16 -1.28 -1.64 G b l
1423780 at Lgx only 10898 11906 12709 12518 1.09 1.17 1.15 Hibadh
1423785 at Lgx only 11606 13426 11821 15052 1.16 1.02 1.30 E lnl
1423790 at Lgx only 1487 1751 2032 2310 1.18 1.37 1.55 Dap
1423793 at Res & L x 936 1073 1319 1580 1.15 1.41 1.69 D2Ertd391 e
1423810 at CR only 1783 2180 1746 1816 1.22 -1.02 1.02 P met
1423822 a at Lgx only 730 653 569 5581-1.12 -1.28 -1.31 Tmem168
1423845 at Lgx only 460 477 805 739 1.04 1.75 1.61 Csdc2
1423847 at Res & L x 231 270 401 391 1.17 1.73 1.69 Nca d2
1423849 a at Lgx only 616 713 916 1030 1.16 1.49 1.67 Clk3
1423852 at Lgx only 50 52 68 154 1.03 1.36 3.07 Tmem46
1423857 at Res & Lgx 13121, 11472 8712 6533 -1.14 -1.51 -2.01 Mr l30
1423881 at L x onl 1929 2007 2122 2477 1.04 1.10 1.28 Sa s3
1423882 at Lgx only 933 840 739 618 -1.11 -1.26 -1.51 Rfwd3
1423883 at Lgx only 21573 22608 26023 29695 1.05 1.21 1.38Acsll
1423892 at CR only 3733 2926 4320 4066 -1.28 1.16 1.09A bbl
1423896 a at L x onl 7953 9503 10177 13002 1.19 1.28 1.63 Rnf187
1423907 a at Lgx only 21309 20866 21974 17327 -1.02 1.03 -1.23 Ndufs8
1423909 at Lgx only 670 657 729 1002 -1.02 1.09 1.50 Tmem176a
1423919 at Lgx only 445 348 353 351 -1.28 -1.26 -1.27 BC023882
1423927 at Res & Lgx 510 626 737 770 1.23 1.45 1.51 Slc35b2
1423939 a at Lgx only 6662 5968 5430 40271-1.12 -1.23 -1.65 Yifl a
1423947 at Res & L x 1479 1457 2188 2164 -1.01 1.48 1.46 1110008P14Rik
1423951 at Lgx only 936 768 718 654 -1.22 -1.30 -1.43 Tm2d3
1423958 a at Lgx only 1601 1398 1213 998 -1.15 -1.32 -1.60 Ttc33
1423960 at Res & L x 1368 1371 1946 2010 1.00 1.42 1.47 Mboat5
1423961 at Res & L x 1414 1142 839 602 -1.24 -1.69 -2.35 LOC100045629
1423967 at Lgx only 903 1044 1073 1359 1.16 1.19 1.51 Palm
1423969 at All 723 538 512 442 -1.34 -1.41 -1.64 Nu 37
1423972 at Lgx only 31981 34252 35126 43175 1.07 1.10 1.35 Etfa
1423973 a at L x only 644 716 819 1000 1.11 1.27 1.55 Arf3
1423978 at Lgx only 920 1504 1209 1467 1.64 1.31 1.59 Sbkl
1423991 at L x onl 392 425 448 564 1.08 1.14 1.44 No114
1423993 at Lgx only 4392 3844 3630 3056 -1.14 -1.21 -1.44 At 6vlf
1424000 a at Lgx only 20066 22495 23422 27778 1.12 1.17 1.38 R sl1
1424002 at Res & L x 2495 2175 1827 17851-1.151-1.371 -1.40 Pdcl3
CA 02699908 2010-03-17
WO 2009/039195 PCT/US2008/076707
-68-
Table 3
CO CR RES LGX FC FC FC
Probe Set ID Treatment mean mean mean mean CR Res L x Entrez Info
1424005 at Lgx only 3828 3557 3275 3040 -1.08 -1.17 -1.26 B230219D22Rik
1424010 at Lgx only 168 233 382 732 1.38 2.27 4.36 Mfap4
1424025 at Res & L x 5858 5688 4312 43831-1.03 -1.36 -1.34 BC013529
1424027 at Res only 619 902 924 853 1.46 1.49 1.38 Pxn
1424028 at Lgx only 874 861 614 481 -1.02 -1.42 -1.82 5830457010Rik
1424033 at Res & Lgx 935 735 479 332 -1.27 -1.95 -2.82 Sfrs7
1424036 at L x onl 1422 1354 1874 1752 -1.05 1.32 1.23 Pr f6
1424038 a at L only 2801 3278 3181 3602 1.17 1.14 1.292310044H10Rik
1424040 at Lgx only 5989 7521 7112 8135 1.26 1.19 1.36 Mta 7d 1
1424053 a at Res & Lgx 5291 5313 6583 6840 1.00 1.24 1.29 Tcf25
1424054 at Res & L x 1063 1467 1588 1882 1.38 1.49 1.77 Btbd2
1424058 at Lgx only 640 771 767 944 1.21 1.20 1.48 Prrcl
1424066 at Lgx only 990 1038 1084 1324 1.05 1.09 1.34 Dus3l
1424077 at Res only 654 544 493 479 -1.20 -1.33 -1.37 Gd d1
1424081 at Res & Lgx 380 271 291 277 -1.40 -1.31 -1.37 Pc f6
1424099 at L xonl 2023 1663 1332 1265 -1.22 -1.52 -1.602310016C16Rik
1424101 at Res & L x 874 934 533 583 1.071-1.64 -1.50 Hnr l
1424105 a at Lgx only 3516 2620 3158 2273 -1.34 -1.11 -1.55 Pttg 1
1424109 a at Res & L x 6904 7061 6174 6463 1.02 -1.12 -1.07 Glol
1424115 at CR & L x 1970 2313 2291 2496 1.17 1.16 1.27 P 5c
1424121 at Lgx only 986 890 677 523 -1.11 -1.46 -1.88 Commdl
1424126 at CR & Res 6092 9782 4437 5967 1.61 -1.37 -1.02 AIasl
1424134 at Lgx only 646 529 499 436 -1.22 -1.29 -1.48 Rs r 1
1424138 at L x onl 1703 1927 1979 2218 1.13 1.16 1.30 Rhbdfl
1424139 at Lgx only 5935 4960 4416 3478 -1.20 -1.34 -1.71 Rapla
1424140 at Res only 146 192 243 196 1.32 1.67 1.35 Gale
1424141 at Lgx only 2745 3324 3767 4195 1.21 1.37 1.53 Hectdl
1424147 at Res & Lgx 3868 4234 2946 2570 1.09 -1.31 -1.50 Ahsal
1424149 at CR only 435 531 523 573 1.22 1.20 1.32 Nsmce2
1424150 at Lgx only 438 540 561 688 1.23 1.28 1.57 Gd d5
1424151 at Res & Lgx 2327 2380 1795 1679 1.02 -1.30 -1.39 Jtv1
1424154 a at Lgx only 4155 3735 3761 3368 -1.11 -1.10 -1.231sca2
1424159 at Res & Lgx 618 578 459 454 -1.07 -1.34 -1.36 130001OM03Rik
1424160 at Lgx only 563 486 499 420 -1.16 -1.13 -1.34 AI 5
1424162 at CR only 115 37 144 125 -3.15 1.25 1.08 Trim29
1424163 at L x only 615 642 714, 803 1.04 1.16 1.31 Rmndsb
1424167 a at Lgx only 367 456 568 734 1.24 1.55 2.00 Pmml
1424175 at CR & Lgx 4138 5751 4597 7356 1.39 1.11 1.78 Tef
1424178 at L x only 8368 8313 7872 6995 -1.01 -1.06 -1.20 Tmem38a
1424179 at L x only 642 594 541 431 -1.08 -1.19 -1.49 Plekhjl
1424184 at Lgx only 33037 35163 37503 45711 1.06 1.14 1.38Acadvl
1424191 a at Lgx only 613 688 706 837 1.12 1.15 1.36 Tmem4l a
1424209 at Lgx only 1349 1298 1166 988 -1.04 -1.16 -1.37 Rars2
1424210 at Res & Lgx 892 764 657 670 -1.17 -1.36 -1.33 Erlinl
1424211 at CR & L x 1496 2374 1415 1975 1.59 -1.06 1.32 Slc25a33
1424216 a at Lgx only 1633 1442 1293 1181 -1.13 -1.26 -1.38 Papola
CA 02699908 2010-03-17
WO 2009/039195 PCT/US2008/076707
-69-
Table 3
CO CR RES LGX FC FC FC
Probe Set ID Treatment mean mean mean mean CR Res L x Entrez Info
1424223 at Lgx only 7099 8501 6040 6025 1.20 -1.18 -1.18 170002OC11 Rik
1424236 at Lgx only 741 789 838 950 1.06 1.13 1.28 Tbcl d1 Ob
1424237 at Res only 1047 1010 1262 11841-1.04 1.21 1.13 Zf 639
1424247 at Lgx only 543 591 600 802 1.09 1.10 1.48 Ercl
1424249 a at All 434 271 226 252 -1.60 -1.92 -1.72 Arha 9
1424255 at Res & Lgx 2458 2688 3230 3339 1.09 1.31 1.36 Supt5h
1424258 at Lgx only 955 696 690 604 -1.37 -1.38 -1.58 Polr2d
1424261 at Res & Lgx 1144 871 714 580 -1.311-1.60 -1.97 Zf 672
1424274 at Res & Lgx 1795 1574 1426 1084 -1.14 -1.26 -1.66Vdp
1424276 at Lgx only 410 338 308 258 -1.22 -1.33 -1.59 Snx16
1424280 at Res & L x 2125 1767 1658 1182 -1.20 -1.28 -1.80 Mos d l
1424303 at L x only 90 76 59 26 -1.19.-1.53 -3.47 De dc7
1424309 a at Res & L x 2945 2961 2220 1975 1.01 -1.33 -1.49 Mocs2
1424318 at Lgx only 2148 2040 1851 1802 -1.05 -1.16 -1.19 1110067D22Rik
1424321 at Lgx only 351 263 228 169 -1.34 -1.54 -2.07 Rfc4
1424324 at L x only 956 712 539 4031-1.34 -1.77 -2.37 Escol
1424346 at Lgx only 2287 1920 1820 1658 -1.19 -1.26 -1.38 Ppp6c
1424349 a at Res & L x 2326 1877 1516 1263 -1.24 -1.53 -1.84 L atl
1424356 a at Lgx only 770 697 694 603 -1.10 -1.11 -1.28 Metrnl
1424359 at L x only 1036 1229 2242 2519 1.19 2.16 2.43 O lah
1424361 at Lgx only 294 408 530 653 1.39 1.80 2.22 BC019943
1424372 at Res & L x 3282 2988 2215 2091 -1.10 -1.48 -1.57 Mr 132
1424374 at Lgx only 1936 1845 1535 1363 -1.05 -1.26 -1.42 Gima 4
1424377 at L x only 1007 971 895 801 -1.04 -1.12 -1.26 BC003885
1424380 at Lgx only 434 432 512 559 -1.01 1.18 1.29 V s37b
1424384 a at Lgx only 726 981 1007 1092 1.35 1.39 1.50 Znrf1
1424390 at Lgx only 597 493 481 472 -1.21 -1.24 -1.26 Null
1424391 at CR & L x 3544 3195 3213 2673 -1.11 -1.10 -1.33 Nrdl
1424403 a at L x onl 254 221 348 3761-1.15 1.37 1.48 Rufy3
1424406 at Lgx only 1180 1319 1489 1520 1.12 1.26 1.29 Bc12113
1424408 at Lgx only 3655 3925 4168 4751 1.07 1.14 1.30 Lims2
1424416 at Lgx only 2199 2535 2429 2712 1.15 1.10 1.23 Nkiras2
1424424 at Lgx only 1819 1642 1309 892 -1.11 -1.39 -2.04 Slc39a1
1424430 at Res only 647 598 475 466 -1.08 -1.36 -1.39 Mterfd2
1424433 at Res & L x 3043 3150 2599 2241 1.04 -1.17 -1.36 Msrb2
1424434 at Res & Lgx 2817 2667 2219 2042 -1.06 -1.27 -1.38 BC024814
1424447 at Lgx only 404 418 462 566 1.03 1.14 1.40 170003OK09Rik
1424461 at Res & Lgx 4865 4886 3994 3716 1.00 -1.22 -1.31 Dctn2
1424463 at Res & Lgx 1299 1043 945 877 -1.24 -1.37 -1.48221001OL05Rik
1424465 at Lgx only 957 881 710 583 -1.09 -1.35 -1.64 Ccdc58
1424467 at Lgx only 1725 2308 2228 2625 1.34 1.29 1.52 Phldbl
1424473 at Lgx only 911 823 725 502 -1.11 -1.26 -1.81 Polr2h
1424479 at Lgx only 39 46 64 119 1.18 1.64 3.02 Cst8
1424500 at L x onl 1020 947 744 637 -1.08 -1.37 -1.60 Utp6
1424505 at Lgx only 1309 1213 1172 895 -1.08 -1.12 -1.46 Rmndl
1424510 at Lgx only 783 733 627 574 -1.07 -1.25 -1.36 Nudt6
CA 02699908 2010-03-17
WO 2009/039195 PCT/US2008/076707
-70-
Table 3
CO CR RES LGX FC FC FC
Probe Set ID Treatment mean mean mean mean CR Res L x Entrez Info
1424517 at CR only 403 529 450 495 1.31 1.12 1.23 Ccdcl2
1424520 at Res only 687 597 550 610 -1.15 -1.25 -1.132010305A19Rik
1424526 a at L x onl 630 568 533 4391-1.11 -1.18 -1.43 T ds
1424527 at Lgx only 1547 1612 1940 2049 1.04 1.25 1.32 Ppp2r2d
1424531 a at Lgx only 1693 2053 2103 2408 1.21 1.24 1.42 Tcea3
1424539 at Res & Lgx 4074 4359 3294 2993 1.07 -1.24 -1.36 Ub14
1424541 at Res & Lgx 5299 4888 3970 2986 -1.08 -1.33 -1.77 Tmem70
1424545 at Res & Lgx 4029 3665 2845 2585 -1.10 -1.42 -1.56 80003965
1424553 at Lgx only 3262 3958 4239 4357 1.21 1.30 1.34 Hhatl
1424559 at Lgx only 301 268 241 157 -1.13 -1.25 -1.92 R a 2
1424562 a at L x onl <figref></figref># 112473 113888 167622 1.08 1.10 1.61 Slc25a4
1424564 at L x only 1274 1360 1557 1708 1.07 1.22 1.34 2410001 C21 Rik
1424572 a at Lgx only 1146 1213 1654 1775 1.06 1.44 1.5511-12afy
1424585 at Lgx only 895 932 1128 1160 1.04 1.26 1.30 Ranb 10
1424594 at L x onl 3378 3499 3621 4257 1.04 1.07 1.26 Lgals7
1424595 at Lgx only 1220 1320 1490 2039 1.08 1.22 1.67 F11 r
1424598 at Lgx only 2389 1604, 1838 14381-1.49 -1.30 -1.66 Ddx6
1424614 at Lgx only 2262 2581 3033 2935 1.14 1.34 1.30 Frag 1
1424635 at Lgx only 40976 41854 46791 54473 1.02 1.14 1.33 Eefl al
1424639 a at L x only 1837 2131 2120 2408 1.16 1.15 1.31 Hm cl
1424642 at Res & Lgx 839 793 585 514 -1.06 -1.43 -1.63 Thoc1
1424643 at Lgx only 361 461 466 524 1.28 1.29 1.45 Tcofl
1424644 at Lgx only 751 910 920 970 1.21 1.22 1.29 Tbcc
1424669 at Res & Lgx 1167 1216 852 883 1.04 -1.37 -1.32 Zfyve2l
1424682 at L x only 844 922 1107 1316 1.09 1.31 1.56 At bd1c
1424683 at Lgx only 15130 13625 13449 108061-1.11 -1.12 -1.40 1810015CO4Rik
1424686 at Lgx only 397 485 579 584 1.22 1.46 1.47 Heatr6
1424700 at Lgx only 1348 1564 1695 1953 1.16 1.26 1.45 Tmem38b
1424715 at All 1674 1255 2440 2317 -1.33 1.46 1.38 Retsat
1424720 at Lgx only 1275 1563 1533 1790 1.23 1.20 1.40 Mgat4b
1424727 at Lgx only 73 105 145 185 1.43 1.99 2.54 CcrS
1424728 at CR & L x 991 816 861 760 -1.21 -1.15 -1.30 BC011248
1424736 at Res & L x 18836 21343 24570 28063 1.13 1.30 1.49 Eef2
1424744 at Lgx only 318 193 275 639 -1.65 -1.16 2.01 Sds
1424745 at Lgx only 533 595 714 779 1.11 1.34 1.46 A xt2l2
1424746 at Res & Lgx 5066 5452 6046 7004 1.08 1.19 1.38 Kif1 c
1424749 at Res & Lgx 491 453 785 669 -1.08 1.60 1.36 Wdf 1
1424776 a at Lgx only 1323 1302 1746 1740 -1.02 1.32 1.32 Slc25a28
1424777 at Lgx only 572 536 703 792 -1.07 1.23 1.38 Wdr21
1424790 at Lgx only 1894 2211 3370 4182 1.17 1.78 2.21 Slc25a42
1424791 a at L x only 2967 3682 3547 3765 1.24 1.20 1.27 Bcam
1424795 a at Res only 62 70 170 154 1.13 2.74 2.48 1700001 O22Rik
1424819 a at Lgx only 557 580 605 719 1.04 1.09 1.29 Ric8
1424827 a at Lgx only 5109 5113 4471 3838 1.00 -1.14 -1.33 Csnklal
1424842 a at Lgx only 554 516 684 759 -1.07 1.24 1.37 Arh a 24
1424850 at L x only 392 341 315 2581-1.151-1.241 -1.52 Ma 3kl
CA 02699908 2010-03-17
WO 2009/039195 PCT/US2008/076707
-71-
Table 3
CO CR RES LGX FC FC FC
Probe Set ID Treatment mean mean mean mean CR Res L x Entrez Info
1424873 at Res & Lgx 906 801 637 641 -1.13 -1.42 -1.41 Rnf2
1424878 at CR & Lgx 255 508 463 632 1.99 1.82 2.48 Lrch4
1424898 at CR only 144 51 82 1141-2.84 -1.76 -1.27 SIcl Oat
1424912 at Lgx only 417 508 500 569 1.22 1.20 1.36 Slc25a17
1424918 at Res & Lgx 893 857 631 559 -1.04 -1.42 -1.60 Tbcl dl9
1424929 a at Lgx only 239 284 385 449 1.19 1.61 1.88 Trim26
1424942 a at CR only 55 147 154 55 2.69 2.81 1.00 M c
1424954 a at L x only 657 753 904 1030 1.15 1.38 1.57 Pi 5klc
1424956 at Lgx only 246 311 380 513 1.26 1.55 2.09 Ahdcl
1424978 at Res only 23 79 87 88 3.44 3.76 3.82 Odf4
1424988 at Lgx only 1652 1684 1806 2065 1.02 1.09 1.25 Mylip
1424990 at L x only 890 960 1037 1205 1.08 1.17 1.35Tmeml42a
1424996 at Lgx only 650 688 746 875 1.06 1.15 1.35 Cflar
1425024 at CR only 104 28 94 50 -3.79 -1.11 -2.09 E430018J23Rik
1425057 at Res only 88 164 237 176 1.85 2.68 1.98 Pbld
1425079 at CR only 40 118 72 60 2.96 1.79 1.51 Tm6sf2
1425114 at Res & Lgx 795 765 561 544 -1.04 -1.42 -1.46 Rbbp6
1425143 a at Lgx only 25337 27260 28070 34606 1.08 1.11 1.37 Ndufsl
1425158 at Res & Lgx 1320 1302 1751 1907 -1.01 1.33 1.44 Tbx20
1425164 a at L x only 265 328 383 483 1.24 1.44 1.82 Phkgl
1425189 a at Res & L x 3583 3540 2889 2383 -1.01 -1.24 -1.50 rp 115
1425214 at Lgx only 324 237 207 1331-1.37 -1.57 -2.44 P2r 6
1425225 at Lgx only 94 142 190 249 1.51 2.02 2.64 Fc r4
1425228 a at Lgx only 1536 1652 1255 1078 1.08 -1.22 -1.43 Dguok
1425243 at L x only 115 120 196 325 1.04 1.70 2.82 Cd207
1425257 at Lgx only 7 19 41 16 2.89 6.34 2.39 Acot5
1425270 at Res & L x 3017 2790 2111 19751-1.08 -1.43 -1.53 Kifl b
1425274 at Res & Lgx 4607 4976 3462 3212 1.08 -1.33 -1.43 As h
1425314 at Res only 27 57 96 118 2.10 3.57 4.36 G r98
1425332 at Lgx only 11194 12729 12529 16323 1.14 1.12 1.46 Zip 106
1425333 at Lgx only 410 538 624 856 1.31 1.52 2.09 Rab43
1425340 a at CR & L x 1281 1481 1447 1573 1.16 1.13 1.23 Pt ra
1425341 at Lgx only 2691 3341 3786 4027 1.24 1.41 1.50 Kcnk3
1425350 a at Res & L x 106 147 186 212 1.38 1.75 2.00 M ef2
1425455 a at Lgx only 4248 4028 3479 3392 -1.05 -1.22 -1.25 Churcl
1425480 at Res & L x 2113 2091 1616 1298 -1.011-1.31 -1.63 Cnot6l
1425492 at Res & Lgx 2530 2180 1751 1792 -1.16 -1.44 -1.41 Bm rl a
1425519 a at Res & L x 1769 1610 2963 2821 -1.10 1.67 1.59 Cd74
1425521 at Lgx only 337 279 205 188 -1.21 -1.64 -1.79 Paipl
1425558 at Res only 136 59 28 101 -2.32 -4.94 -1.34 Klc3
1425589 at Lgx only 148 111 123 381-1.34 -1.21 -3.88 Hsd17bl3
1425617 at L x only 243 296 355 486 1.22 1.46 1.99 Dhx9
1425639 at Lgx only 209 211 342 342 1.01 1.63 1.64 Centa2
1425646 at Lgx only 141 96 96 68 -1.46 -1.47 -2.08 BC016495
1425674 a at Lgx only 2104 1965 1606 1495 -1.07 -1.31 -1.41 Ssu72
1425677 a at Lgx only 11130 10594 9470 83781-1.05 -1.18 -1.33 Ankl
CA 02699908 2010-03-17
WO 2009/039195 PCT/US2008/076707
-72-
Table 3
CO CR RES LGX FC FC FC
Probe Set ID Treatment mean mean mean mean CR Res L x Entrez Info
1425682 a at Lgx only 518 419 373 288 -1.24 -1.39 -1.80 T rkb
1425702 a at Lgx only 574 571 734 946 -1.01 1.28 1.65 Enpp5
1425706 a at L x onl 371 337 391 2391-1.10 1.05 -1.55 Ddb2
1425718 a at Lgx only 33649 29835 25700 23101 -1.13 -1.31 -1.461vnslab
1425742 a at Lgx only 11487 11684 12973 13668 1.02 1.13 1.19 Tsc22d 1
1425753 a at Res only 701 793 434 484 1.13 -1.61 -1.45 Ung
1425760 a at L x onl 378 450 540 627 1.19 1.43 1.66 Pitpnml
1425764 a at Lgx only 2958 3344 3747 4049 1.13 1.27 1.37 Bcat2
1425780 a at Lgx only 1362 1035 1202 963 -1.32 -1.13 -1.41 Tmem167
1425792 a at Res & Lgx 599 793 1003 995 1.32 1.67 1.66 Rorc
1425795 a at Res & L x 2655 2581 1359 1207 -1.03 -1.95 -2.20 Ma 3k7
1425826 a at Lgx only 6893 8508 10213 13158 1.23 1.48 1.91 Sorbsl
1425894 at CR only 315 164 315 398 -1.92 1.00 1.26 Mr rf
1425895 a at Lgx only 2855 3457 3880 4028 1.21 1.36 1.41 Idl
1425904 at Res only 34 52 104 62 1.53 3.06 1.82 Satb2
1425930 a at Lgx only 698 638 680 5631-1.09 -1.03 -1.24 MIx
1425933 a at Res & Lgx 1038 1091 859 854 1.05 -1.21 -1.21 Nt5c2
1425940 a at Lgx only 184 208 306 319 1.13 1.66 1.73 Ssb 3
1425978 at Res & L x 1850 1652 1140 1026 -1.12 -1.62 -1.80 M ocd
1425993 a at Res & L x 1379 1079 897 848 -1.28 -1.54 -1.63 Hs 110
1426000 at Lgx only 164 196 167 317 1.19 1.02 1.93 Oxtr
1426016 a at L x only 55 65 130 164 1.18 2.39 3.00 Tro
1426068 at Lgx only 935 868 767 692 -1.08 -1.22 -1.35 Slc7a4
1426089 a at L x onl 1823 1590 1565 1314 -1.15 -1.17 -1.39 80003331
1426100 a at Lgx only 218 225 310 338 1.03 1.42 1.55 Tk2
1426114 at Res & Lgx 5491 5041 29756 25956 -1.09 5.42 4.73 Hnrpab
1426118 a at Lgx only 1454 1702 1714 1820 1.17 1.18 1.25 Tomm40
1426179 a at Lgx only 910 1026 1204 1351 1.13 1.32 1.48 Tws 1
1426187 a at Lgx only 1603 1568 1266 1056 -1.02 -1.27 -1.52 Haxl
1426195 a at Lgx only 29737 32186 35405 39796 1.08 1.19 1.34 Cst3
1426235 a at Res & L x 2374 2866 5732 6147 1.21 2.41 2.59 Glul
1426241 a at Lgx only 771 982 908 1062 1.27 1.18 1.38 Scmh 1
1426249 at Res & Lgx 1302 1459 1804 2108 1.12 1.39 1.62Adrbkl
1426254 at Lgx only 1276 1145 917 731 -1.12 -1.39 -1.75 Tm2d 1
1426257 a at Res & Lgx 1948 2192 2318 2595 1.13 1.19 1.33 Sars
1426263 at Lgx only 1203 1175 1108 911 -1.02 -1.09 -1.32 Cad m4
1426269 at Res & L x 684 560 450 371 -1.22 -1.52 -1.85 S bll
1426277 at Lgx only 386 336 445 519 -1.15 1.15 1.34 C730025P13Rik
1426279 at L xonl 770 726 591 516 -1.06 -1.30 -1.495830415L20Rik
1426285 at L x only 2453 2580 2755 3223 1.05 1.12 1.31 Lama2
1426286 at Lgx only 335 275 211 119 -1.22 -1.59 -2.81 Noc3l
1426297 at Lgx only 466 452 754 680 -1.03 1.62 1.46 Tcfe2a
1426307 at Res & L x 1936 1817 1474 1311 -1.07 -1.31 -1.48 C b5r4
1426337 a at CR & L x 32 84 49 110 2.64 1.55 3.45 Tead4
1426344 at Lgx only 475 506 511 653 1.07 1.08 1.38 Glel1
1426347 at CR only 783 635 743 686 -1.231-1.051 -1.142010321M09Rik
CA 02699908 2010-03-17
WO 2009/039195 PCT/US2008/076707
-73-
Table 3
CO CR RES LGX FC FC FC
Probe Set ID Treatment mean mean mean mean CR Res L x Entrez Info
1426353 at Lgx only 1157 1203 1210 1377 1.04 1.05 1.19 Stat6
1426380 at Lgx only 4215 4149 4647 5122 -1.02 1.10 1.22 Eif4b
1426386 at Res & L x 1464 1483 1190 993 1.01 -1.23 -1.47 R l7l l
1426390 a at Lgx only 22906 23329 19114 18319 1.02 -1.20 -1.25 Arfl
1426398 at Lgx only 989 893 750 661 -1.11 -1.32 -1.50 Ube2w
1426400 a at Res & L x 9253 10079 10609 11708 1.09 1.15 1.27 Ca nsl
1426406 at Res & Lgx 2553 2947 3706 4584 1.15 1.45 1.80 Setd8
1426416 a at Res & Lgx 1595 1370 1005 953 -1.161-1.59 -1.67 Yi f4
1426423 at Res & L x 820 1004 1130 1251 1.22 1.38 1.53 Shmt2
1426436 at Lgx only 760 764 675 568 1.00 -1.13 -1.34 Tmem159
1426440 at Lgx only 2254 2820 2177 2947 1.25 -1.04 1.31 Dhrs7
1426444 at Res only 314 254 467 460 -1.24 1.48 1.46 Rhbdd2
1426445 at Lgx only 1978 2219 2502 2536 1.12 1.26 1.28 Cta e5
1426446 at L xonl 312 312 438 458 1.00 1.40 1.476430548M08Rik
1426452 a at Lgx only 202 256 129 77 1.26 -1.57 -2.64 Rab30
1426455 at L x only 402 394 369 274 -1.02 -1.09 -1.47 Sdcca 1 O
1426457 at Lgx only 9329 9212 7693 68761-1.01 -1.21 -1.361SImap
1426468 at Res only 1223 1032 910 976 -1.18 -1.34 -1.250610037L13Rik
1426477 at Lgx only 1012 893 905 676 -1.13 -1.12 -1.50 Rasal
1426480 at L x only 2278 2147 2786 3030 -1.06 1.22 1.33 Sbds
1426481 at Res & L x 1112 1028 1505 1624 -1.08 1.35 1.46 Klhl22
1426482 at Lgx only 3505 2977 2762 2410 -1.18 -1.27 -1.45 Prkrir
1426495 at Lgx only 348 251 218 208 -1.39 -1.59 -1.68 2410042D21 Rik
1426539 at Lgx only 295 365 390 465 1.24 1.32 1.58 Us 11
1426567 a at Res only 434 445 254 264 1.02 -1.71 -1.64 P lcl
1426586 at Lgx only 17315 21329 19691 21472 1.23 1.14 1.24 Slc25a11
1426596 a at All 539 412 417 219 -1.31 -1.29 -2.46Smnl
1426607 at Lgx only 304 267 198 175 -1.14 -1.54 -1.73 EG633640
1426613 a at Lgx only 1480 1201 1246 838 -1.23 -1.19 -1.77 Snr b2
1426614 at Lgx only 741 922 870 1015 1.25 1.18 1.37 Prkcbpl
1426624 a at Res & Lgx 2908 3005 4008 4108 1.03 1.38 1.41 Ypel3
1426629 at Lgx only 450 528 534 613 1.17 1.19 1.36 Dhx8
1426643 at Lgx only 959 1059 1176 1265 1.10 1.23 1.32 EI 3
1426646 at Lgx only 3289 3191 2689 2507 -1.03 -1.22 -1.31913001 1J15Rik
1426648 at L x onl 3467 4510 4856 5396 1.30 1.40 1.56 Ma ka k2
1426670 at Res & L x 701 789 1130 1113 1.13 1.61 1.59 A rn
1426671 a at Lgx only 1307 1327 1062 766 1.02 -1.23 -1.71 Rbm39
1426675 at Lgx only 1376 1180 884 626 -1.17 -1.56 -2.20 Tomm7Oa
1426681 at Lgx only 284 309 369 440 1.09 1.30 1.55 Unk
1426682 at L x only 1328 1222 1113 852 -1.09 -1.19 -1.56 LOC100046343
1426688 at Lgx only 30012 35064 33818 42859 1.17 1.13 1.43 Sdha
1426690 a at Res & Lgx 1211 1395 1784 2490 1.15 1.47 2.06 Srebf1
1426691 at Lgx only 818 960 944 1189 1.17 1.15 1.45 Ta 1
1426700 a at Lgx only 310 327 417 406 1.06 1.35 1.31 Us 52
1426717 at Res & L x 1834 1766 1219 10921-1.04 -1.50 -1.68 Ni a2
1426718 at Res & Lgx 972 829 713 7261-1.17 -1.36 -1.34 Skiv212
CA 02699908 2010-03-17
WO 2009/039195 PCT/US2008/076707
-74-
Table 3
CO CR RES LGX FC FC FC
Probe Set ID Treatment mean mean mean mean CR Res L x Entrez Info
1426731 at Lgx only 15714 18402 19327 23750 1.17 1.23 1.51 Des
1426741 a at Lgx only 1254 1098 1044 860 -1.14 -1.20 -1.46 Fastkd2
1426743 at L x onl 3106 3174 2664 2485 1.02 -1.17 -1.25 A l2
1426752 at Res only 1165 945 826 990 -1.23 -1.41 -1.18 Phf17
1426760 at Res & L x 1194 1065 823 781 -1.12 -1.45 -1.53 I o8
1426773 at Lgx only 6830 8123 9064 9354 1.19 1.33 1.37 Mfn1
1426774 at Res & L x 607 595 485 347 -1.02 -1.25 -1.75 Par 12
1426794 at L x onl 934 1249 1207 1600 1.34 1.29 1.71 Ptprs
1426799 at Lgx only 826 683 610 489 -1.21 -1.35 -1.69 Rab8b
1426819 at Lgx only 9939 6798 6585 3448 -1.46 -1.51 -2.88 LOC100048439
1426820 at Lgx only 5084 5617 5406 6361 1.10 1.06 1.25 2610507811 Rik
1426830 a at L x only 3633 3395 3097 2585 -1.071-1.17 -1.41 Ahc l l
1426833 at Lgx only 846 870 1103 1089 1.03 1.30 1.29 Eif4g3
1426854 a at Lgx only 4159 4032 3462 3261 -1.03 -1.20 -1.28 Set
1426857 a at Lgx only 5854 4850 5610 4740 -1.21 -1.04 -1.23 Hsdl2
1426866 at Lgx only 571 766 674 802 1.34 1.18 1.41 Chst14
1426886 at Res & L x 872 844 723 633 -1.03 -1.21 -1.38 Cln5
1426895 at Res & Lgx 897 707 604 450 -1.27 -1.48 -1.99 Zf 191
1426898 at Res only 391 401 533 528 1.03 1.36 1.35 Ma 3k7i 1
1426900 at Lgx only 986 807 644 600 -1.22 -1.53 -1.64 Jmjdl c
1426948 at Res & Lgx 3583 4241 4782 5859 1.18 1.33 1.64 T pr
1426952 at Lgx only 524 503 478 259 -1.04 -1.10 -2.02 Arh a 18
1426964 at Lgx only 1856 1813 1314 1265 -1.02 -1.41 -1.47 3110003A17Rik
1426965 at Lgx only 402 405 499 568 1.01 1.24 1.41 Rap2a
1426969 at Res & Lgx 551 378 376 287 -1.461-1.46 -1.92 Trim23
1426976 at Lgx only 3711 3721 4100 4747 1.00 1.10 1.28 Us 47
1426979 at Lgx only 993 1192 1354 1332 1.20 1.36 1.341MIxip
1426982 at Res & Lgx 535 607 880 853 1.13 1.65 1.59 Flywchl
1426984 at Res & L x 291 540 554 854 1.86 1.91 2.9423100671310Rik
1426992 at Res & Lgx 1745 1757 1076 1052 1.01 -1.62 -1.66 X rl
1427028 at L x onl 556 635 615 891 1.14 1.11 1.60 Lgr6
1427039 at Lgx only 1834 2329 2407 2983 1.27 1.31 1.63 E n1
1427040 at Lgx only 1252 987 952 855 -1.27 -1.31 -1.46 Mdfic
1427045 at L x onl 778 817 1248 1424, 1.05 1.60 1.83 S n o
1427051 at Res & Lgx 454 548 673 770 1.21 1.48 1.70Tnks1b 1
1427058 at Res only 8484 8530 6619 7155 1.01 -1.28 -1.19 Eif4al
1427073 at Res only 1956 2206 1536 1648 1.13 -1.27 -1.19 Lacel
1427084 a at Lgx only 686 606 508 463 -1.13 -1.35 -1.48 Ma 4k5
1427099 at Res only 320 486 646 461, 1.52 2.02 1.44 Maz
1427117 at Lgx only 619 616 790 979 -1.01 1.28 1.58 Mtmr3
1427120 at Lgx only 835 688 573 468 -1.21 -1.46 -1.78 Zf 26
1427129 a at Lgx only 1545 1252 1132 930 -1.23 -1.36 -1.66 Hnrpr
1427132 at Lgx only 348 463 524 564 1.33 1.51 1.62 Sbf2
1427139 at Lgx only 795 940 925 1054 1.18 1.16 1.33 Adamtsl O
1427144 at Res & Lgx 1131 1047 680 637 -1.08 -1.66 -1.78 Hnr ll
1427146 at Res & Lgx 673 839 1204 1613 1.25 1.79 2.40 A1790298
CA 02699908 2010-03-17
WO 2009/039195 PCT/US2008/076707
-75-
Table 3
CO CR RES LGX FC FC FC
Probe Set ID Treatment mean mean mean mean CR Res L x Entrez Info
1427165 at Res & L x 1308 1233 814 792 -1.06 -1.61 -1.651113ra1
1427166 a at Lgx only 1401 1747 2035 2399 1.25 1.45 1.71 Spg7
1427170 at All 74 25 24 131-2.94 -3.10 -5.66 Psma8
1427197 at L x only 496 530 403 303 1.07 -1.23 -1.64 Atr
1427201 at Lgx only 551 457 565 769 -1.20 1.03 1.40 Mustnl
1427228 at Lgx only 2099 2379 3387 3964 1.13 1.61 1.89 Palld
1427239 at CR & Lgx 552 808 637 680 1.46 1.15 1.231ft122
1427240 at Lgx only 815 1013 1033 1520 1.24 1.27 1.86 Dock6
1427241 at L x only 610 547 387 384 -1.12 -1.58 -1.59 Papolg
1427260 a at Res & Lgx 2978 2624 2355 1823 -1.13 -1.26 -1.63 Tpm3
1427266 at All 1181 848 784 732 -1.39 -1.51 -1.61 Pbrml
1427296 at Res & L x 4758 5054 3684 3677 1.061-1.29 -1.29 BC010304
1427312 at L x only 12654 14384 15939 18697 1.14 1.26 1.48 Cm a5
1427314 at Res & Lgx 2995 2439 2188 1689 -1.23 -1.37 -1.77 Tmed7
1427319 at CR & Lgx 694 468 551 427 -1.48 -1.26 -1.63A230046K03Rik
1427342 at Res & Lgx 802 683 597 4991-1.18 -1.35 -1.61 Fastkdl
1427395 a at L x only 74 37 30 33 -2.00 -2.51 -2.27Aldh1a3
1427418 a at Lgx only 1864 1555 1250 796 -1.20 -1.49 -2.34 Hif1 a
1427432 a at Lgx only 2372 2225 1569 1292 -1.07 -1.51 -1.84 Sfrs10
1427447 a at Res & Lgx 1080 1415 1561 1854 1.31 1.44 1.72 Triobp
1427490 at Lgx only 356 348 274 2361-1.02 -1.30 -1.51 Abcb7
1427529 at Res only 151 90 67 82 -1.68 -2.25 -1.84 Fzd9
1427555 at L x onl 35 64 76 96 1.85 2.18 2.76 M112
1427557 at Lgx only 180 201 256 281 1.11 1.42 1.56 AI 12
1427604 a at Lgx only 871 1023 1176 1356 1.17 1.35 1.56 At 9a
1427661 a at Res & Lgx 382 474 594 597 1.24 1.56 1.56 Tssc4
1427689 a at L x onl 1261 1266 1376 1652 1.00 1.09 1.31 Tnipl
1427720 a at Lgx only 2747 2851 3040 3415 1.04 1.11 1.24 Rrpl
1427728 at CR only 34 97 56 57 2.88 1.65 1.68 Chrng
1427735 a at CR & Res 8359 12700 12493 12108 1.52 1.49 1.45Acta1
1427873 at L x only 17 54 56 110 3.19 3.31 6.50 Defcrl5
1427874 at Lgx only 1399 1574 1815 1899 1.13 1.30 1.36 Zf 313
1427876 at Lgx only 1630 1676 1431 1226 1.03 -1.14 -1.33 Zc3h 15
1427886 at L x onl 969 755 581 374 -1.28.-1.67 -2.59 Porn 121
1427888 a at CR & Lgx 5357 6838 6596 7987 1.28 1.23 1.49 Spna2
1427894 at Lgx only 472 396 538 682 -1.19 1.14 1.44 Vasn
1427898 at Lgx only 822 714 616 515 -1.15 -1.33 -1.60 Rnf6
1427901 at Lgx only 3381 3126 2782 21281-1.08 -1.22 -1.59 Mrpsl8c
1427903 at Res & Lgx 5849 5774 4732 4224 -1.01 -1.24 -1.38 Ph tl
1427913 at Lgx only 2402 2230 1819 1452 -1.08 -1.32 -1.65 Rwdd1
1427918 a at Lgx only 7544 7921 8074 9445 1.05 1.07 1.25 Rhog
1427929 a at Lgx only 610 746 507 763 1.22 -1.20 1.25 Pdxk
1427943 at Lgx only 6234 5441 5157 39291-1.15 -1.21 -1.59 Ac 2
1427947 at CR only 493 623 501 547 1.26 1.02 1.11 BC028440
1427955 a at Lgx only 6984 7396 5948 4819 1.06 -1.17 -1.45 Debt
1427971 at L x only 957 802 781 608 -1.19 -1.22 -1.57 Cdc73
CA 02699908 2010-03-17
WO 2009/039195 PCT/US2008/076707
-76-
Table 3
CO CR RES LGX FC FC FC
Probe Set ID Treatment mean mean mean mean CR Res L x Entrez Info
1427983 at Lgx only 514 395 447 362 -1.30 -1.15 -1.42 Suhw3
1427990 at Lgx only 355 290 266 214 -1.22 -1.34 -1.66 Us 45
1427996 at L x onl 850 752 733 6051-1.13 -1.16 -1.41 BC028528
1427997 at Res & L x 3311 2612 2104 1880 -1.27 -1.57 -1.76 1110007MO4Rik
1428029 a at Res & L x 4750 5138 6149 6341 1.08 1.29 1.33 H2afv
1428061 at Res & Lgx 945 762 578 474 -1.24 -1.64 -1.99 Hatt
1428064 at L x onl 545 548 561 729 1.01 1.03 1.34 Centd2
1428071 at Lgx only 1332 1392 1595 1813 1.04 1.20 1.36 1110038D17Rik
1428083 at CR & L x 11028 17747 12934 18091 1.61 1.17 1.642310043N10Rik
1428084 at Lgx only 1028 928 751 646 -1.11 -1.37 -1.59 Krrl
1428100 at L x onl 710 679 484 450 -1.05 -1.47 -1.58 Sfrs1
1428103 at CR & Lgx 1072 830 813 700 -1.29.-1.32 -1.53AdamlO
1428124 at Lgx only 422 302 322 263 -1.40 -1.31 -1.60 Gtf2el
1428128 at Res & L x 1502 1659 2529 2521 1.10 1.68 1.684921506J03Rik
1428134 at Lgx only 16660 18474 18163 20707 1.11 1.09 1.24 Co q9
1428143 a at Res & Lgx 6354 8097 11246 12003 1.27 1.77 1.89 Pnpla2
1428158 at Res & Lgx 1535 1812 2043 2286 1.18 1.33 1.49 Akt1 sl
1428160 at Lgx only 2716 2030 1757 1025 -1.34 -1.55 -2.65 Ndufabl
1428173 at Lgx only 437 537 595 762 1.23 1.36 1.74 Em12
1428179 at L x only 43162 47906 48747 57849 1.11 1.13 1.34 Ndufv2
1428182 at Lgx only 840 966 980 1096 1.15 1.17 1.30 Prpsap 1
1428198 at Lgx only 360 322 266 2171-1.12 -1.36 -1.66Adal
1428201 at CR only 2131 2525 2452 2729 1.19 1.15 1.282310036022Rik
1428206 at Res only 104 76 36 108 -1.38 -2.90 1.04 Ccdc69
1428213 at Res & L x 2496 2367 1629 1372 -1.05 -1.53 -1.82 Nsmce4a
1428230 at CR only 963 819 985 833 -1.18 1.02 -1.16 Prkcn
1428235 at L x onl 19980 23234 20415 24655 1.16 1.02 1.23 Sdhd
1428236 at Lgx only 556 408 377 306 -1.36 -1.48 -1.81 Acbds
1428244 at Lgx only 821 1001 1063 1344 1.22 1.29 1.64 Larpl
1428250 at Lgx only 150 122 155 259 -1.23 1.03 1.73 G per
1428251 at L x onl 464 397 316 330 -1.17 -1.47 -1.40 Smchdl
1428253 at Res & L x 1966 1803 1418 1374 -1.09 -1.39 -1.43 Chm 2b
1428256 at Res & Lgx 2199 1822 1588 1576 -1.21 -1.39 -1.40 2310047H23Rik
1428260 at Res & Lgx 200 180 123 107 -1.11 -1.62 -1.88 S 3a
1428277 at L x onl 2436 2410 1959 1529 -1.01 -1.24 -1.59 Otud6b
1428282 at Lgx only 1073 922 1060 7571-1.16 -1.01 -1.42 Tbce
1428299 at Res & L x 1060 1010 682 653 -1.05 -1.55 -1.62 D rkla
1428307 at Lgx only 1160 1032 931 745 -1.12 -1.24 -1.56 Zdhhcl 3
1428316 a at Res & L x 6077 4954 4136 3051 -1.23 -1.47 -1.99 Fundc2
1428332 at CR & Lgx 2444 3279 2758 3376 1.34 1.13 1.38 Pik3ipl
1428335 a at Lgx only 810 785 691 580 -1.031-1.17 -1.40 Scfdl
1428357 at Res only 190 206 336 219 1.08 1.77 1.152610019F03Rik
1428365 a at Lgx only 2043 2396 2896 3413 1.17 1.42 1.67 Lonpl
1428366 at All 798 646 577 485 -1.23 -1.38 -1.651600027N09Rik
1428370 at CR only 128 228 179 125 1.78 1.40 -1.03 1500011 B03Rik
1428380 at Res & L x 2352 2151 1639 13941-1.091-1.441 -1.6910610007C21 Rik
CA 02699908 2010-03-17
WO 2009/039195 PCT/US2008/076707
-77-
Table 3
CO CR RES LGX FC FC FC
Probe Set ID Treatment mean mean mean mean CR Res L x Entrez Info
1428382 at Lgx only 964 1129 1473 1531 1.17 1.53 1.59 Smarcc2
1428391 at Lgx only 267 295 348 432 1.10 1.30 1.62 Rab3ill
1428395 at L x onl 487 508 647 727 1.04 1.33 1.49 Smurfl
1428405 at Lgx only 9641 10670 11324 12596 1.11 1.17 1.31 Hcfc1 rl
1428412 at Lgx only 2036 2091 2325 2629 1.03 1.14 1.29 Tm9sf3
1428421 a at Lgx only 2913 2410 2394 2019 -1.21 -1.22 -1.44 Glod4
1428423 at L x onl 1714 1643 1657 1494 -1.041-1.03 -1.15 Pc f3
1428427 at CR only 92 36 39 101 -2.53 -2.37 1.10 Fbxl2
1428431 at Res & Lgx 1390 1453 1755 1963 1.04 1.26 1.41 2310047A01 Rik
1428436 at Res & L x 1165 1047 815 839 -1.11 -1.43 -1.39 Lsm14a
1428440 at L x only 8819 10649 10766 12943 1.21 1.22 1.47 Slc25a12
1428441 at L x only 2992 2477 1975 1655 -1.21 -1.51 -1.81 Cisd2
1428443 a at L x onl 732 902 816 1006 1.23 1.11 1.37 Rap 1 gap
1428465 at Lgx only 6696 7010 5690 4717 1.05 -1.18 -1.42 Tmem147
1428468 at All 950 768 805 688 -1.24 -1.18 -1.3813110043021 Rik
1428476 a at Lgx only 441 575 672 824 1.30 1.52 1.87 Elac2
1428494 a at Lgx only 3176 3065 2853 2679 -1.04 -1.11 -1.19 Polr2i
1428495 at Res & Lgx 2251 1796 1512 1278 -1.25 -1.49 -1.76 2410003K15Rik
1428503 a at L x onl 2042 1913 1596 1490 -1.07 -1.28 -1.37 Nkirasl
1428505 at L x only 4503 4374 3908 2889.-1.03 -1.15 -1.56 Ccdc90b
1428507 at Lgx only 1620 1610 1433 1331 -1.01 -1.13 -1.22 Hdhd2
1428508 at Lgx only 415 458 547 572 1.10 1.32 1.38 Tbcl d2b
1428510 at Lgx only 331 473 485 525 1.43 1.46 1.58 Lphnl
1428515 at L x only 845 790 736 569 -1.07 -1.15 -1.48 2410012H22Rik
1428519 at Lgx only 3006 3200 2041 1928 1.06 -1.47 -1.56 2610528E23Rik
1428540 at Lgx only 162 219 253 370 1.35 1.56 2.28 3321401 G04Rik
1428544 at Res & Lgx 1458 1331 1205 1043 -1.10 -1.21 -1.40 06100071-01 Rik
1428549 at L x only 404 587 708 973 1.45 1.75 2.41 Ccdc3
1428551 at All 518 361 300 223 -1.44 -1.72 -2.32 Trmt11
1428552 at Res & Lgx 2497 2020 1544 1257 -1.24 -1.62 -1.992610001J05Rik
1428554 a at Lgx only 2768 2661 2626 2233 -1.04 -1.05 -1.24 1810035L17Rik
1428564 at L x only 417 459 555 738 1.10 1.33 1.77 Zf 579
1428580 at Lgx only 1441 1418 1326 1067 -1.02 -1.09 -1.35 Blvra
1428585 at L xonl 720 831 840 1309 1.15 1.17 1.82Actn1
1428587 at Res & Lgx 2171 2060 1437 1374 -1.05 -1.51 -1.58 Tmem41 b
1428589 at Lgx only 7082 6392 5436 4990 -1.11 -1.30 -1.42 Mr 141
1428593 at Res only 436 336 287 244 -1.30 -1.52 -1.79 1700029F09Rik
1428594 at Lgx only 1864 1998 1599 1255 1.07 -1.17 -1.48 Garnll
1428598 at All 663 946 941 976 1.43 1.42 1.47 Tbcl d7
1428613 at Res only 548 583 786 754 1.06 1.43 1.38 Ldhd
1428615 at CR only 1077 892 1088 1153 -1.21 1.01 1.07 P2r 5
1428617 at Res & Lgx 1207 1018 969 859 -1.19 -1.25 -1.41 Hcfc2
1428626 at Lgx only 750 726 685 550 -1.03 -1.09 -1.36 L smd2
1428651 at CR & Lgx 5284 4538 5141 4573 -1.16 -1.03 -1.16 K1h124
1428652 at Res & Lgx 341 312 224 199 -1.09 -1.53 -1.72 061001 OF05Rik
1428668 at Lgx only 921 942 1096 1235 1.02 1.19 1.34Acbd3
CA 02699908 2010-03-17
WO 2009/039195 PCT/US2008/076707
-78-
Table 3
CO CR RES LGX FC FC FC
Probe Set ID Treatment mean mean mean mean CR Res L x Entrez Info
1428682 at CR only 181 79 159 142 -2.29 -1.14 -1.27 Zc3h6
1428691 at Lgx only 1373 1505 1521 1856 1.10 1.11 1.35 Chd2
1428697 at L x onl 1082 1076 1176 13981-1.01 1.09 1.29 D 8
1428707 at Lgx only 2825 3531 3687 4608 1.25 1.31 1.63 Ptms
1428715 at Res & Lgx 561 444 367 278 -1.26 -1.53 -2.022810423A18Rik
1428722 at L x only 59642 62216 62442 77221 1.04 1.05 1.29 Ckmt2
1428723 at L xonl 404 425 515 657 1.05 1.27 1.622310047M1ORik
1428728 at CR only 232 387 266 290 1.67 1.15 1.25 Ddx51
1428731 at Lgx only 946 1052 960 1147 1.11 1.01 1.21 Us 54
1428748 at Lgx only 426 369 313 221 -1.16 -1.36 -1.93 5830428H23Rik
1428749 at Res & Lgx 631 573 372 387 -1.10 -1.69 -1.63 Dmxl2
1428758 at CR & Res 2386 1678 1803 1967 -1.42 -1.32 -1.21 Tmem86a
1428767 at Lgx only 347 345 449 482 -1.00 1.30 1.39 Gsdmdcl
1428769 at Res only 568 531 411 491 -1.07 -1.38 -1.16 Tatdn3
1428782 a at Res & Lgx 40904 44865 48798 54806 1.10 1.19 1.34 U crcl
1428786 at Res only 261 274 406 363 1.05 1.55 1.39 Ncka 11
1428789 at CR only 425 281 383 383 -1.51 -1.11 -1.11 Ralgps2
1428791 at Lgx only 2024 2245 2339 2646 1.11 1.16 1.31 Ube2h
1428807 at L x onl 24 19 27 66 -1.30 1.10 2.72 Pab c3
1428810 at Lgx only 1298 1336 1428 1643 1.03 1.10 1.27 2700097009Rik
1428812 at Res only 600 608 802 795 1.01 1.34 1.33 170004OL02Rik
1428829 at CR & L x 827 624 677 551 -1.32 -1.22 -1.50 6820401 H01 Rik
1428831 at L xonl 626 553 446 354 -1.13 -1.40 -1.776230429P13Rik
1428835 at Lgx only 1354 1406 2031 2409, 1.04 1.50 1.78 M h14
1428845 at Res & L x 2313 2038 1791 1813 -1.14 -1.29 -1.28 Bclafl
1428848 a at Lgx only 2317 2709 2961 3010 1.17 1.28 1.30 Macf1
1428884 at L x onl 1347 1481 1302 1707 1.10 -1.03 1.27 Tmem57
1428890 at Lgx only 1103 993 869 687 -1.11 -1.27 -1.61 Fem1 c
1428897 at Res & L x 1192 1158 601 686 -1.03 -1.98 -1.74,2610029101 Rik
1428899 at Res & L x 6189 6125 4734 4774 -1.01 -1.31 -1.30 Tmem182
1428914 at Res & L x 1933 2302 2457 2903 1.19 1.27 1.50 2310014D11 Rik
1428919 at Res & Lgx 753 645 488 360 -1.17 -1.54 -2.09 Fgfrlop
1428926 at L x only 1791 2110 2525 2734 1.18 1.41 1.53 1110003008Rik
1428945 at Res only 511 424 286 365 -1.21 -1.79 -1.40 Ube112
1428949 at L x onl 1079 913 908 601 -1.18 -1.19 -1.80 X of
1428982 at Res & L x 465 367 261 211 -1.27 -1.78 -2.20 Atad2b
1428998 at Lgx only 1201 1404 1356 1719 1.17 1.13 1.43 Phf3
1429001 at Res only 370 340 478 410 -1.09 1.29 1.11 Pir
1429024 at L x onl 3812 4605 4484 5982 1.21 1.18 1.57 Rbm2O
1429028 at Lgx only 460 366 348 309 -1.26 -1.32 -1.49 Dockl 1
1429034 at Lgx only 277 217 197 144,-1.28 -1.41 -1.93 Eme2
1429042 at Res & Lgx 583 493 381 355 -1.18 -1.53 -1.642010200016Rik
1429057 at Res & L x 412 390 249 239 -1.06 -1.65 -1.73 Nar 11
1429070 at Lgx only 166 214 221 297 1.29 1.33 1.794933440H19Rik
1429085 at Lgx only 3041 3379 3563 3775 1.11 1.17 1.24 Vezfl
1429103 at Res & Lgx 4218 4035 2877 26231-1.051-1.47 -1.61 Tomm22
CA 02699908 2010-03-17
WO 2009/039195 PCT/US2008/076707
-79-
Table 3
CO CR RES LGX FC FC FC
Probe Set ID Treatment mean mean mean mean CR Res L x Entrez Info
1429107 at Lgx only 2462 2746 3278 3325 1.12 1.33 1.35 Zf 650
1429119 at Lgx only 962 917 756 744 -1.05 -1.27 -1.29 lahl
1429121 at L x onl 375 263 322 1701-1.43 -1.16 -2.20 4921 51 7NO4Rik
1429137 at L xonl 193 143 138 92 -1.36 -1.40 -2.09281042202ORik
1429144 at Res only 14307 13184 10505 13791 -1.09 -1.36 -1.04 Prei4
1429146 at L xonl 1179 1070 980 860 -1.10 -1.20 -1.37 6620401 M08Rik
1429155 at Res onl996 805 760 789 -1.24 -1.31 -1.264933411K20Rik
1429160 at Res & L x 684 523 484 470 -1.31 -1.41 -1.45 Mtif3
1429183 at Lgx only 4351 3822 4249 3307 -1.14 -1.02 -1.32 Pk p2
1429186 a at Lgx only 1223 1135 973 934 -1.08 -1.26 -1.31 Cdadcl
1429188 at L x onl 1122 1148 907 855 1.02 -1.24 -1.31 Cox11
1429194 at Lgx only 546 487 456 3941-1.12 -1.20 -1.39 Ti d2
1429196 at Lgx only 1381 1472 2063 2670 1.07 1.49 1.93 Raba 11
1429206 at Lgx only 3457 4642 4046 4930 1.34 1.17 1.43 Rhobtbl
1429209 at CR only 179 101 118 196 -1.78 -1.52 1.09 Co123a1
1429223 a at Res & L x 2792 2374 2100 1610 -1.18 -1.33 -1.73 Hfe2
1429243 at Res & L x 597 537 380 369 -1.11 -1.57 -1.62 1110054005Rik
1429253 at Lgx only 562 445 513 371 -1.26 -1.10 -1.52 Zm m4
1429264 at L x onl 496 426 359 315 -1.16 -1.38 -1.58 C0300441311 Rik
1429278 at Res only 1094 1016 863 869 -1.08 -1.27 -1.26 Nubpl
1429281 at Res & L x 323 264 201 185 -1.22 -1.60 -1.75 2610008E11 Rik
1429300 at Lgx only 742 943 806 1172 1.27 1.09 1.58 Ankrd9
1429321 at L x onl 284 215 514 719 -1.32 1.81 2.53 Rnf149
1429328 at Lgx only 5245 4514 4643 3961 -1.16 -1.13 -1.32 Nsfll c
1429335 at L x onl 320 284 287 200 -1.13 -1.12 -1.60 Sna cl
1429352 at CR only 291 116 140 150 -2.52 -2.08 -1.95 Mocos
1429362 a at Res & Lgx 1201 1528 1807 2347 1.27 1.50 1.95 Sf3b2
1429364 at Lgx only 108 72 103 47 -1.511-1.05, -2.304930579G24Rik
1429367 at L x only 693 717 798 936 1.03 1.15 1.35 Wi i2
1429375 at L x onl 1484 1372 1276 913 -1.08 -1.16 -1.63 Ana cl O
1429395 at Lgx only 138 142 96 54 1.02 -1.45 -2.55 Gstcd
1429400 at Lgx only 189 176 206 314.-1.07 1.09 1.66 ClcnS
1429407 at Lgx only 188 211 333 337 1.12 1.77 1.79 Pexl 1 c
1429413 at Res & L x 292 246 187 156 -1.18 -1.56 -1.88 C pm
1429425 at Res & L x 3510 3354 2840 2532 -1.05 -1.24 -1.39 Rnf139
1429454 at Res & L x 1848 1764 1340 1334 -1.05 -1.38 -1.38 Ga vdl
1429460 at CR only 15 60 60 28 4.09 4.13 1.89 G r115
1429486 at CR only 1047 1648 912 1004 1.57 -1.15 -1.04 Pfkfb2
1429487 at Lgx only 1134 1266 1668 1601 1.12 1.47 1.41 P 1 rl2a
1429505 at CR & Lgx 2791 1949 2450 1714 -1.43 -1.14 -1.63 2310076G1 3Rik
1429514 at Lgx only 4969 4087 4128 2951 -1.22 -1.20 -1.68 P a 2b
1429521 at Lgx only 323 250 235 1531-1.29 -1.37 -2.12 Alkbh8
1429532 at Res only 865 998 1089 938 1.15 1.26 1.08 Morc2a
1429534 a at Lgx only 10910 12210 12327 12968 1.12 1.13 1.19 lmmt
1429553 at Lgx only 151, 181, 260 574 1.20 1.73 3.81 Cilp2
1429556 at Lgx only 2326 2174 1662 1363 -1.07 -1.40 -1.71 2610024B07Rik
CA 02699908 2010-03-17
WO 2009/039195 PCT/US2008/076707
-80-
Table 3
CO CR RES LGX FC FC FC
Probe Set ID Treatment mean mean mean mean CR Res L x Entrez Info
1429570 at Res only 126 63 36 102 -2.00 -3.45 -1.24 Mlkl
1429621 at Lgx only 839 1173 1240 1343 1.40 1.48 1.60 Cand2
1429648 at L x onl 637 552 475 461 -1.15 -1.34 -1.38 Slc35a3
1429681 a at Lgx only 21171 22951 25817 28204 1.08 1.22 1.33 G sn2
1429698 at Res & Lgx 163 155 82 89 -1.05 -1.99 -1.83 Mterf
1429710 at Res & Lgx 839 763 558 459 -1.10 -1.51 -1.83 Styx
1429723 at Res & Lgx 2893 2604 1673 1495 -1.11 -1.73 -1.946330409N04Rik
1429764 at CR only 2988 2220 3256 2552 -1.35 1.09 -1.17 1500005K14Rik
1429771 at Lgx only 927 823 776 635 -1.13 -1.19 -1.46131100731-101 Rik
1429783 at Res & L x 13193 13213 10275 9645 1.00 -1.28 -1.37 Pdlim5
1429819 at L x onl 393 378 337 275 -1.04 -1.17 -1.43 Nmnatl
1429836 at CR only 142 251 216 269 1.78 1.53 1.90 U c l2
1429860 at CR only 43 117 154 113 2.69 3.56 2.61 LOC677447
1429888 a at Lgx only 4996 5288 5443 6090 1.06 1.09 1.22 Hs b2
1429915 at L x onl 56 63 79 116 1.12 1.42 2.084930426L09Rik
1429918 at CR only 433 297 409 4161-1.46 -1.06 -1.04Arh a 20
1429961 at CR & Lgx 308 198 313 200 -1.55 1.02 -1.541700021C14Rik
1429990 at Lgx only 114 138 174 186 1.21 1.52 1.63 Hyal4
1430000 at CR only 71 24 62 56 -2.92 -1.16 -1.27 B230117O15Rik
1430045 at CR & Res 416 259 269 292 -1.61 -1.55 -1.42 Tsnax
1430078 a at L x onl 284 264 259 1541-1.07 -1.09 -1.85 O 1
1430089 at L xonl 355 291 227 142 -1.22 -1.57 -2.505830469G19Rik
1430095 at Lgx only 90 95 135 240 1.06 1.50 2.66 D930020B18Rik
1430123 a at Lgx only 13843 13323 16691 18357 -1.04 1.21 1.33Akrla4
1430137 at Res only 148 166 220 222 1.12 1.49 1.51 LOC100043489
1430170 at Res only 162 131 69 89 -1.24 -2.35 -1.82 BbslO
1430224 at Res only 101 97 238 112 -1.03 2.36 1.12 Wfdc3
1430253 at Lgx only 114 159 173 252 1.40 1.52 2.22 2900006811 Rik
1430292 a at Res & Lgx 3466 3219 2398 2125 -1.08 -1.45 -1.63 1810030N24Rik
1430309 at Res & Lgx 1747 1890 2535 2577 1.08 1.45 1.47 Nipbl
1430378 at Res & L x 205 160 103 72 -1.28 -2.00 -2.85 2900011 G08Rik
1430388 a at Lgx only 1818 2657 2347 2718 1.46 1.29 1.49 Sulf2
1430474 a at Res & L x 8337 8097 5357 5222 -1.031-1.56 -1.60 Mtch2
1430518 at L only 85 28 55 171-3.02 -1.56 -5.035430402E10Rik
1430519 a at Lgx only 939 787 784 667 -1.19 -1.20 -1.41 Cnot7
1430527 a at Res & L x 2831 2873 3201 3440 1.01 1.13 1.22 Rnf167
1430544 at Lgx only 259 358 390 468 1.39 1.51 1.81 5830404H04Rik
1430656 a at Res & Lgx 3948 3401 2556 2175 -1.161-1.54 -1.82 Asnsdl
1430676 at CR & L x 26 92 89 122 3.52 3.39 4.65 Col19a1
1430685 at Res only 17 41 35 64 2.38 2.07 3.786330503C03Rik
1430736 at L xonl 176 135 173 48 -1.31 -1.02 -3.709030411M15Rik
1430768 at L xonl 206 134 121 101 -1.54 -1.70 -2.0395300181-114Rik
1430770 at Res & L x 56 28 13 121-1.97 -4.28 -4.68 3110080E11 Rik
1430781 at Lgx only 164 131 118 78 -1.26 -1.39 -2.11 Ak7
1430799 at Res & L x 68 35 14 18 -1.91 -4.91 -3.765830432E09Rik
1430818 at CR only 37 121 118 66 3.27 3.20 1.78 Tmcl
CA 02699908 2010-03-17
WO 2009/039195 PCT/US2008/076707
-81-
Table 3
CO CR RES LGX FC FC FC
Probe Set ID Treatment mean mean mean mean CR Res L x Entrez Info
1430835 at CR only 112 29 98 107 -3.85 -1.14 -1.05 Ccdcl25
1430883 at CR only 103 36 71 54 -2.83 -1.44 -1.894933402CO5Rik
1430910 at CR only 173 44 108 1261-3.91 -1.60 -1.374930544LO4Rik
1430999 a at Res & Lgx 840 643 415 329 -1.31 -2.02 -2.55 Scoc
1431043 at Lgx only 596 596 738 893 -1.00 1.24 1.50 Kbtbd5
1431255 at CR only 604 385 610 572 -1.57 1.01 -1.06 Calr3
1431287 at CR only 71 140 68 62 1.97 -1.05 -1.15 Pcml
1431293 a at Res & L x 2705 1856 1662 1146 -1.46 -1.63 -2.36 Cldnd1
1431302 a at CR & L x 4139 2946 3637 2685 -1.41 -1.14 -1.54 Nudt7
1431322 at Lgx only 704 836 854 982 1.19 1.21 1.40 I sf3
1431415 a at L x onl 681 643 595 493 -1.06 -1.14 -1.38 Tb ll
1431428 a at Lgx only 1082 1202 1304 1403 1.11 1.21 1.30 Nosip
1431429 a at L x onl 858 839 1095 1129 -1.02 1.28 1.32 Arl4a
1431473 at Lgx only 18 7 25 81 -2.53 1.36 4.43 5330423111 Rik
1431498 at Res only 94 120 187 171 1.28 1.99 1.829530097N15Rik
1431551 at Lgx only 62 105 104 164 1.69 1.68 2.64 2610028D06Rik
1431561 a at Res only 485 676 690 684 1.39 1.42 1.41 Dhx34
1431587 at Res only 70 55 24 53 -1.28 -2.90 -1.32 Ccdc7
1431610 at Res only 49 101 141 107 2.05 2.87 2.185330439A09Rik
1431618 a at CR & Res 325 230 221 179 -1.41 -1.47 -1.82 D14Ertd581e
1431619 a at Lgx only 3465 3627 4405 4627 1.05 1.27 1.34 Dtnbpl
1431679 at Res only 49 89 165 104 1.80 3.35 2.11 2510042H12Rik
1431746 a at L x onl 3679 3526 2924 2509 -1.04 -1.26 -1.47 Ubelc
1431785 at Lgx only 175 194 145 90 1.11 -1.20 -1.94 Rnaset2a
1431796 at L x only 31 106 75 91 3.40 2.40 2.93 2810430111 Rik
1431804 a at Res & Lgx 690 548 337 2791-1.26 -2.04 -2.47 S p3
1431822 a at Res & Lgx 3622 3320 2534 2374 -1.09 -1.43 -1.53Azi2
1431827 a at L x onl 896 797 717 590 -1.12 -1.25 -1.52 Tlk2
1431853 at CR only 92 40 75 92 -2.33 -1.22 1.004933413C19Rik
1431893 a at Res & Lgx 638 758 379 436 1.19 -1.68 -1.46 Pdssl
1431900 a at CR only 32 90 31 85 2.79 -1.06 2.64 Foxa3
1431934 at L x only 72 109 81 157 1.51 1.13 2.184930505020Rik
1431986 at Res only 197 193 296 133 -1.02 1.50 -1.484933421A08Rik
1431998 at CR only 69 14 61 59 -4.95 -1.14 -1.164930432L08Rik
1432000 a at Lgx only 342 378 448 482, 1.11 1.31 1.41 Dedd
1432016 a at CR only 31956 37162 31250 32250 1.16 -1.02 1.01 ldh3a
1432057 a at Lgx only 662 743 770 911 1.12 1.16 1.38 Prdms
1432073 at Res & L x 3205 3584 2249 2107 1.12 -1.43 -1.52 1700113122Rik
1432122 at Lgx only 128 89 121 44.-1.44 -1.05 -2.91 Lrrc44
1432158 a at Res & Lgx 2091 1924 1569 1489 -1.09 -1.33 -1.40 Tra c2
1432207 a at Lgx only 454 448 459 350 -1.01 1.01 -1.30 Toel
1432248 at Lgx only 31 74 52 105 2.36 1.66 3.36 5430402P08Rik
1432271 a at Res & L x 1856 1636 1172 967 -1.13 -1.58 -1.92 Dcunld5
1432348 at L x only 59 61 97 183 1.03 1.63 3.094930524007Rik
1432369 at CR & Res 60 139 152 155 2.30 2.52 2.57 3010027C24Rik
1432420 a at Lgx only 1929 1605, 1516 1137 -1.20 -1.27 -1.70 23100021-09Rik
CA 02699908 2010-03-17
WO 2009/039195 PCT/US2008/076707
-82-
Table 3
CO CR RES LGX FC FC FC
Probe Set ID Treatment mean mean mean mean CR Res L x Entrez Info
1432444 a at Lgx only 1027 964 956 784 -1.07 -1.08 -1.31 Eapp
1432457 at Res only 99 147 183 188 1.48 1.85 1.904930448F12Rik
1432466 a at L x only 9714 10651 13047 18186 1.10 1.34 1.87 A oe
1432533 a at Lgx only 372 420 476 655 1.13 1.28 1.76 Slc35a2
1432543 a at Res only 510 488 700 806 -1.04 1.37 1.58 Klf13
1432560 at Res only 52 58 122 70 1.13 2.37 1.35 1700127DO6Rik
1432590 at CR only 156 51 107 119 -3.09 -1.46 -1.314930573021 Rik
1432625 at Res only 32 59 123 62 1.81 3.78 1.905830487K18Rik
1432626 at L x only 132 227 247 311 1.72 1.87 2.36 5730507A11 Rik
1432648 at Res only 67 77 17 67 1.16 -4.01 1.01 4930466F19Rik
1432662 at Res only 37 77 112 109 2.11 3.05 2.97 0610042E11 Rik
1432735 at Lgx only 256 258 314 474 1.01 1.23 1.86117000171-101 Rik
1432930 at Res only 200 222 294 287 1.11 1.47 1.434930453009Rik
1433048 at CR onl185 107 139 196 -1.74 -1.33 1.064933428L01Rik
1433132 at CR only 86 27 80 127 -3.21 -1.07 1.47 Edaradd
1433148 at CR only 226 484 386 319 2.14 1.71 1.41 4930513N2ORik
1433164 at Res only 54 99 180 154 1.82 3.31 2.834930570E01 Rik
1433207 at L xonl 57 67 66 136 1.17 1.14 2.375033430J17Rik
1433241 at L xonl 142 102 87 51 -1.39 -1.63 -2.799430013L17Rik
1433253 at L x only 40 88 74 128 2.21 1.86 3.24 5033423K11 Rik
1433314 at L x onl 77 51 77 21 -1.52 1.00 -3.654930486A15Rik
1433442 at Lgx only 2641 2244 1952 16941-1.18 -1.35 -1.56 Klh19
1433464 at Lgx only 1806 2481 2178 2563 1.37 1.21 1.42 I ol3
1433503 at Res & Lgx 5903 5778 4609 4467 -1.02 -1.28 -1.32 Zadhl
1433504 at Lgx only 18431 20243 22647 25548 1.10 1.23 1.39 Pygb
1433514 at Lgx only 1169 1037 957 909 -1.13 -1.22 -1.29 Etnk1
1433518 at L x onl 529 567 612 674 1.07 1.16 1.27 Lcmt2
1433519 at Lgx only 2411 2000 2022 1774 -1.21 -1.19 -1.36 Nucksl
1433520 at Lgx only 1068 1427 1464 1816 1.34 1.37 1.70 Scap
1433521 at Res & L x 1059 954 812 613 -1.11 -1.31 -1.73Ankrdl3c
1433522 at Lgx only 465 508 536 616 1.09 1.15 1.32 Pskh1
1433528 at L x only 1899 1634 1420 1242 -1.16 -1.34 -1.53 Gtf2a2
1433537 at Lgx only 1183 1089 1042 737 -1.09 -1.14 -1.604833408C14Rik
1433539 at Res & L x 2660 2213 1775 1485 -1.20 -1.50 -1.79 Commd3
1433544 at Lgx only 1808 1547 1540 1070 -1.17 -1.17 -1.69 Als2cr2
1433555 at L x only 416 379 412 237 -1.10 -1.01 -1.75 Eafl
1433556 at Res & L x 138 182 263 232 1.32 1.90 1.68 Cental
1433561 at Lgx only 660 543 419 307 -1.22 -1.58 -2.15 Centb2
1433575 at Lgx only 3214 2986 2497 1537 -1.08 -1.29 -2.09 Sox4
1433585 at L x only 1024 898 841 6441-1.14 -1.22 -1.59 Tn of
1433597 at Res & Lgx 3769 3787 2160 1597 1.00 -1.75 -2.369430010003Rik
1433599 at Lgx only 331 323 351 222 -1.03 1.06 -1.49 Bazl a
1433645 at Lgx only 1238 1288 985 887 1.04 -1.26 -1.40 Slc44a1
1433648 at Lgx only 3984 3473 3149 2552 -1.15 -1.26 -1.56 S a 9
1433656 a at Lgx only 1182 1107 1036 879 -1.07 -1.14 -1.34 Gn13
1433664 at Res & Lgx 664 522 428 3771-1.271-1.55 -1.76 Ube2 2
CA 02699908 2010-03-17
WO 2009/039195 PCT/US2008/076707
-83-
Table 3
CO CR RES LGX FC FC FC
Probe Set ID Treatment mean mean mean mean CR Res L x Entrez Info
1433676 at Res & Lgx 12728 12400 8809 8342 -1.03 -1.44 -1.53 Wnkl
1433682 at Lgx only 618 849 914 1124 1.37 1.48 1.82 Arh ef17
1433686 at L x onl 489 533 546 724 1.09 1.12 1.48 Cabin 1
1433691 at Res & L x 10244 10216 6379 5292 -1.00 -1.61 -1.94 P lr3c
1433698 a at Res & Lgx 2618 2633 2921 3059 1.01 1.12 1.17 Txnl4
1433700 at Res & Lgx 1009 844 673 749 -1.19 -1.50 -1.354933433P14Rik
1433705 at L x onl 300 269 253 170 -1.11 -1.19 -1.77 Zf 213
1433712 at Lgx only 362 437 443 538 1.20 1.22 1.48 AW555464
1433717 at All 1355 1876 1743 2058 1.38 1.29 1.52 D19Wsu162e
1433718 a at Lgx only 862 744 773 554 -1.16 -1.12 -1.56 LOC100047028
1433722 at L x onl 1946 2601 2972 3714 1.34 1.53 1.91 Aka 13
1433725 at Res & L x 840 1078 1085 1123 1.28 1.29 1.34 Acvr1 b
1433727 at Lgx only 79 101 90 160 1.28 1.15 2.03 BC038479
1433733 a at Lgx only 179 226 163 115 1.26 -1.10 -1.55 Cryl
1433738 at Res & Lgx 1127 966 802 666 -1.17 -1.40 -1.69 Pa d5
1433741 at Lgx only 877 693 635 628 -1.26 -1.38 -1.40 Cd38
1433746 at L x onl 484 409 361 2751-1.18 -1.34 -1.76Wdr3
1433751 at Lgx only 580 428 435 248 -1.36 -1.33 -2.34 Slc39a10
1433760 a at Lgx only 732 943 926 1027 1.29 1.26 1.40 Rhbdd3
1433765 at Lgx only 521 587 784 834 1.13 1.50 1.60 Ube2o
1433770 at Lgx only 4705 4826 3514 3354 1.03 -1.34 -1.40 Dpysl2
1433772 at Res & Lgx 820 636 421, 437 -1.29 -1.95 -1.87 Stch
1433790 at CR only 350 155 281 350 -2.261-1.25 -1.00 Troap
1433794 at Lgx only 1506 1268 1106 881 -1.19 -1.36 -1.71 Setx
1433799 at Lgx only 877 735 582 537 -1.19 -1.51 -1.63 Rdhl3
1433808 at L x only 912 1110 1207 1392 1.22 1.32 1.53 D330001 F17Rik
1433811 at Res & Lgx 1795 2006 2548 2534 1.12 1.42 1.41 M11t6
1433847 at Lgx only 747 626 504 348 -1.19 -1.48 -2.15 D330017J2ORik
1433868 at Lgx only 702 663 569 482 -1.06 -1.23 -1.46 Btbd3
1433875 at Lgx only 1471 1304 1208 1141 -1.13 -1.22 -1.294732418C07Rik
1433883 at Lgx only 3597 3657 2717 2316 1.02 -1.32 -1.55 T m4
1433891 at Res & L x 1002 916 685 639 -1.091-1.46 -1.57 L r4
1433897 at Res & Lgx 1769 1483 1048 773 -1.19 -1.69 -2.29 A1597468
1433898 at Lgx only 236 213, 201 140 -1.11 -1.18 -1.69AV025504
1433910 at Lgx only 1523 1421 1465 1231 -1.07 -1.04 -1.24 Zcchc6
1433914 at Res & Lgx 589 442 369 340 -1.33 -1.60 -1.73 A1747699
1433918 at Res & Lgx 1665 1645 1006 852 -1.01 -1.65 -1.95 At 4d
1433922 at Res & L x 1341, 1190 903 781 -1.13 -1.48 -1.72 Rab35
1433926 at Res & Lgx 1929 1830 1548 1580 -1.05 -1.25 -1.22 Dyncl 1i2
1433931 at Lgx only 1207 1431 1706 2152 1.18 1.41 1.78 0030046101 Rik
1433952 at Res & Lgx 1764 2403 2540 2663 1.36 1.44 1.51 Tufm
1433953 at Lgx only 1145 1007 993 868 -1.14 -1.15 -1.32 Zf 277
1433979 at L x onl 1885 2263 1938 2261 1.20 1.03 1.20 Rbms2
1433986 at Lgx only 2432 2354 2145 2176 -1.03 -1.13 -1.12 BC024659
1434001 at Res & Lgx 591 503 394 398 -1.17 -1.50 -1.48 Ttc9c
1434008 at Lgx only 1391 940 1006 8851-1.48 -1.38 -1.57 Scn4b
CA 02699908 2010-03-17
WO 2009/039195 PCT/US2008/076707
-84-
Table 3
CO CR RES LGX FC FC FC
Probe Set ID Treatment mean mean mean mean CR Res L x Entrez Info
1434009 at Res & Lgx 624 786 1028 1225 1.26 1.65 1.96 Grlfl
1434018 at Lgx only 996 1035 1127 1368 1.04 1.13 1.37 BC043098
1434059 at L x onl 519 522 671 756 1.00 1.29 1.46 B230312A22Rik
1434064 at Res & Lgx 474 589 715 770 1.24 1.51 1.62Tmem142c
1434066 at L x only 807 953 1127 1361 1.18 1.40 1.69 Gtf3cl
1434067 at Res only 21 38 74 62 1.83 3.54 2.96A1662270
1434072 at L x onl 893 774 728 646 -1.15 -1.23 -1.38 Smcr7
1434075 at Res & Lgx 1023 923 673 623 -1.11 -1.52 -1.64 BC030336
1434082 at Lgx only 1059 957 940 850 -1.11 -1.13 -1.25 Pctk2
1434084 at Lgx only 536 417 380 265 -1.28 -1.41 -2.02 5730601 F06Rik
1434088 at L x onl 814 957 921 1043 1.18 1.13 1.28 Zkscan17
1434096 at Lgx only 760 778 873 1035 1.02 1.15 1.36 Slc4a4
1434105 at Lgx only 1682 1795 2023 2368 1.07 1.20 1.41 E m2ai 1
1434115 at Lgx only 3429 4304 3972 4713 1.26 1.16 1.37 Cdh 13
1434131 at L x onl 1087 1126 1252 1367 1.04 1.15 1.26 Rufyl
1434135 at Lgx only 634 615 511 451 -1.03 -1.24 -1.40 B3galnt2
1434138 at Lgx only 910 747 789 6851-1.22 -1.15 -1.33 Prune
1434140 at CR only 1207 1781 1342 1311 1.48 1.11 1.09 Mcf2l
1434153 at CR & L x 845 1513 953 1127 1.79 1.13 1.33 Shb
1434174 at Res only 619 536 463 444 -1.16 -1.34 -1.40 L smd3
1434200 at Res & L x 604 514 322 304 -1.17 -1.88 -1.99 BC010981
1434205 at Res & L x 3650 3118 2521 16211-1.17 -1.45 -2.25 P 2r5c
1434234 at L x onl 23 72 52 115 3.07 2.22 4.92 Zf 341
1434238 at Lgx only 417 408 282 247 -1.02 -1.48 -1.69 Taf2
1434248 at Res only 842 810 1061 848 -1.04 1.26 1.01 Prkch
1434268 at Lgx only 761 830 965 1097 1.09 1.27 1.44 Adar
1434271 at Res & L x 520 568 711 747 1.09 1.37 1.44 Gba2
1434273 at Lgx only 11070 12667 12227 13559 1.14 1.10 1.22 BC034069
1434277 a at CR only 774 1200 842 881 1.55 1.09 1.14Y el2
1434278 at Lgx only 1459 881, 1015 473 -1.66 -1.44 -3.09 Mtml
1434281 at Lgx only 1018 999 812 698 -1.021-1.25 -1.46 1500034JOl Rik
1434283 at Res & L x 893 1206 1278 1477 1.35 1.43 1.65 L0C100044968
1434284 at Res & Lgx 829 710 613 588 -1.17 -1.35 -1.41 Bd 1
1434296 at Lgx only 291 265 237 224 -1.10 -1.23 -1.30 BC049349
1434303 at Lgx only 1077 1189 2323 2458 1.10 2.16 2.28 Ra hl
1434320 at Lgx only 512 413 369 377 -1.241-1.39 -1.36 Gtf3c4
1434328 at L x only 2487 2492 2004 1703 1.00 -1.24 -1.46 R 115
1434339 at Res & L x 966 835 676 499 -1.16 -1.43 -1.94 Fnb l l
1434344 at Lgx only 1331 1208 1085 944 -1.10 -1.23 -1.41 Gpkow
1434354 at Lgx only 3473 3028 2675 2382 -1.15 -1.30 -1.46 Maob
1434356 a at L x only 6321 5829 5156 47461-1.08 -1.23 -1.33 Psmas
1434372 at L xonl 2170 1834 1771 1504 -1.18 -1.23 -1.44AW112010
1434378 a at Lgx only 952 996 1039 1163 1.05 1.09 1.22 Mxd4
1434387 at Lgx only 2313 2828 3081 3362 1.22 1.33 1.45 ltf 3
1434392 at Res & L x 1484 1245 1133 925 -1.19 -1.31 -1.61 Us 34
1434402 at Lgx only 683 631 619 4321-1.08 -1.10 -1.58 Samd8
CA 02699908 2010-03-17
WO 2009/039195 PCT/US2008/076707
-85-
Table 3
CO CR RES LGX FC FC FC
Probe Set ID Treatment mean mean mean mean CR Res L x Entrez Info
1434405 at Res & Lgx 1119 991 685 678 -1.13 -1.63 -1.65 Fnipl
1434422 at CR & Lgx 232 140 152 120 -1.66 -1.53 -1.94 AI428479
1434441 at L x only 1752 1522 1369 1299 -1.151-1.28 -1.35 1110018J18Rik
1434442 at CR onl391 549 429 449 1.40 1.10 1.15Stbd1
1434461 at Res & L x 1215 1185 926 822 -1.03 -1.31 -1.48 Zf 715
1434487 at Lgx only 1586 1697 2179 2499 1.07 1.37 1.58 Mef2d
1434493 at L x only 158 164 101 106 1.03 -1.57 -1.50 1810022KO9Rik
1434511 at Lgx only 1331 1195 1108 9201-1.11 -1.20 -1.45 Phkb
1434516 at L x onl 1502 1422, 1254 1162 -1.06 -1.20 -1.29 Pstk
1434518 at Res & L x 918 972 1104 1186 1.06 1.20 1.29 Phka2
1434558 at Lgx only 280 256 227 155 -1.09 -1.23 -1.81 Wdr47
1434565 at Res & Lgx 1072 1078 773 729 1.01 -1.39 -1.47 Cgrrfl
1434586 a at L x only 2001, 1938 1529 1209 -1.031-1.31 -1.66 Ptdss2
1434597 at Lgx only 2702 3318 3044 3746 1.23 1.13 1.39 Lar 5
1434604 at Lgx only 1414 1229 1298 1039 -1.15 -1.09 -1.36 Eif5b
1434610 at Res & Lgx 2684 3974 4970 6496 1.48 1.85 2.42 Pled
1434613 at L x only 2786 2883 1811 1538 1.03 -1.54 -1.81 1810013L24Rik
1434625 at Lgx only 882 647 703 609 -1.36 -1.25 -1.454930432021 Rik
1434642 at Res & L x 3093 2964 4527 4450 -1.04 1.46 1.44 Hsdl7bl 1
1434647 at Lgx only 754 584 603 458 -1.29 -1.25 -1.65 E flam
1434648 a at L x only 900 688 589 361 -1.31 -1.53 -2.50 Ccm2
1434655 at Lgx only 206 244 274 363 1.18 1.33 1.76 Foxk1
1434665 at Lgx only 1767 1845 1861 2289 1.04 1.05 1.30 A a
1434671 at Lgx only 1246 959 1311 840 -1.30 1.05 -1.48 B230337E12Rik
1434672 at L x only 1613 1191 1046 779 -1.35 -1.54 -2.07 G r22
1434714 at Lgx only 227 243 341 399 1.07 1.50 1.76 Erollb
1434736 at Lgx only 894 1036 1010 1326 1.16 1.13 1.48 Hlf
1434765 at Lgx only 788 738 602 509 -1.07 -1.31 -1.55 E 300
1434775 at L x only 573 537 690 773 -1.07 1.20 1.35 Pard3
1434791 at Lgx only 746 909 934 1128 1.22 1.25 1.51 Atp6vOa2
1434792 at L xonl 639 423 604 401 -1.51 -1.06 -1.602010320M18Rik
1434805 at Lgx only 439 529 521 670 1.20 1.19 1.53 Mlltl
1434822 at L x only 1213 1095 1009 970 -1.11 -1.20 -1.25 Pphlnl
1434824 at Lgx only 1740 2163, 2205 2627 1.24 1.27 1.51 Baz1 b
1434826 at Lgx only 548 525 447 344 -1.04 -1.23 -1.59 Rfesd
1434835 at Lgx only 1066 952 926 824 -1.12 -1.15 -1.29 Wa al
1434838 at L x only 4161 4913 5731 5398 1.18 1.38 1.30 Kcng2
1434864 at Res & Lgx 690 688 467 358 -1.00 -1.48 -1.93 Nipal
1434891 at Lgx only 949 1098 1092 1555 1.16 1.15 1.64 Ptgfrn
1434896 at Res & Lgx 968 863 618 562 -1.12 -1.57 -1.72 Zf 422-rs1
1434900 at L x only 265 301 367 406 1.13 1.38 1.53 Mkl1
1434904 at Res & Lgx 462 569 661 898 1.23 1.43 1.94 Hive p2
1434909 at Res & L x 2412 2355 1922 1743 -1.02 -1.26 -1.38 Rra d
1434916 at L x onl 470 406 406 314 -1.16 -1.16 -1.50 Vkorcl l l
1434927 at Lgx only 38292 44321 50306 62045 1.16 1.31 1.62 Hs b7
1434930 at Lgx only 665 821 984 1031 1.23 1.48 1.55 T cn 1
CA 02699908 2010-03-17
WO 2009/039195 PCT/US2008/076707
-86-
Table 3
CO CR RES LGX FC FC FC
Probe Set ID Treatment mean mean mean mean CR Res L x Entrez Info
1434934 at Res & Lgx 4033 3850 2890 2753 -1.05 -1.40 -1.46At af1
1434936 at Lgx only 374 413 491 592 1.10 1.31 1.58 Hirip3
1434942 at Res & Lgx 901 696 666 528 -1.301-1.35 -1.71 Esf1
1434944 at Lgx only 6233 7918 9727 9182 1.27 1.56 1.47 Dm k
1434967 at Res & Lgx 535 436 358 324 -1.23 -1.49 -1.65 Zswim6
1434978 at Lgx only 1957 2176 1745 1353 1.11 -1.12 -1.454933403FO5Rik
1434981 at Res only 109 143 215 123 1.31 1.97 1.12 E130303BO6Rik
1434997 at Lgx only 592 529 618 756 -1.12 1.04 1.28 Cdc216
1435016 at Lgx only 3394 3426 2781 2210 1.01 -1.22 -1.54 Trak2
1435017 at Lgx only 3573 4157 4007 4259 1.16 1.12 1.19 Me113
1435018 at Lgx only 872 1011 949 1112 1.16 1.09 1.28 5930434B04Rik
1435032 at L x only 747 869 992 1031 1.16 1.33 1.38 Gol bl
1435091 at Lgx only 591 460 474, 418 -1.291-1.25 -1.41 Zfp568
1435117 a at Lgx only 460 552 597 615 1.20 1.30 1.34 Rbj
1435135 at Res & Lgx 6817 7003 9784 10952 1.03 1.44 1.61 Aadacll
1435153 at L x only 764 784 688 591 1.03 -1.11 -1.29 Btbd6
1435169 at CR only 1062 1377 1382 1273 1.30 1.30 1.20 A930001 N09Rik
1435180 at Lgx only 460 729 770 1246 1.58 1.67 2.71 Podn
1435183 at All 452 596 827 928 1.32 1.83 2.05 Tbkb 1
1435224 at L x only 1147 1340 1495 1677 1.17 1.30 1.46 Crebbp
1435242 at Res & Lgx 596 524 452 456 -1.14 -1.32 -1.31 Pdssb
1435248 a at Lgx only 793 736 625 445 -1.08 -1.27 -1.78 Btafl
1435250 at Res & Lgx 509 498 329 263 -1.02 -1.55 -1.93lnts8
1435261 at Res & Lgx 2639 2800 3398 4623 1.06 1.29 1.754732416N19Rik
1435295 at Res only 394 484 605 566 1.23 1.54 1.44 Dopeyl
1435340 at L x onl 409 634 611 728 1.55 1.49 1.78 Jmjd2a
1435349 at Lgx only 646 526 503 317 -1.23 -1.28 -2.04 Nr 2
1435351 at CR only 601 471 619 512 -1.28 1.03 -1.182310026E23Rik
1435360 at Lgx only 1234 1322 1550 1828 1.07 1.26 1.48 Zf 651
1435377 at Res & Lgx 561 417 320 302 -1.34 -1.75 -1.862410002022Rik
1435378 at L x onl 977 1013 1221 1341 1.04 1.25 1.37 2210020M01 Rik
1435386 at Lgx only 966 1325 1564 2231, 1.37 1.62 2.31 Vwf
1435437 at Lgx only 1823 1595, 1637 1411 -1.14 -1.11 -1.29 Setd7
1435441 at Res only 366 339 487 474 -1.08 1.33 1.29Ablim2
1435442 at Res & Lgx 1660 1466 1220 1214 -1.131-1.36 -1.37Wdsofl
1435443 at Lgx only 715 866 940 998 1.21 1.31 1.40 Eya3
1435461 at Res & Lgx 2568 2130 1753 1415 -1.21 -1.46 -1.81 Ma i3
1435490 at CR only 110 246 176 195 2.23 1.60 1.77 Hk3
1435505 at Res only 1051 1219 1346 1482 1.16 1.28 1.41 Dmwd
1435524 at L xonl 1085 1246 1347 1415 1.15 1.24 1.302010109N14Rik
1435526 at Lgx only 566 469 430 359 -1.21 -1.32 -1.58 Tort ai 2
1435527 at Lgx only 1442 1796 2081 2372 1.24 1.44 1.64 Nfic
1435529 at Res & L x 949 677 595 504 -1.401-1.60 -1.880TTMUSG00000016644
1435543 at L x only 986 868 772 684 -1.14 -1.28 -1.44 LOC100048863
11143 at Lgx only 1442 1468 1270 1189 1.02 -1.14 -1.21 ENSMUSG00000075401
CA 02699908 2010-03-17
WO 2009/039195 PCT/US2008/076707
-87-
Table 3
CO CR RES LGX FC FC FC
Probe Set ID Treatment mean mean mean mean CR Res L x Entrez Info
1435548 at Lgx only 726 703 596 466 -1.03 -1.22 -1.56 Mrs2l
1435549 at Lgx only 434 440 504 549 1.01 1.16 1.26 Tr m4
1435554 at Res & Lgx 1663 1372 1080 9221-1.21 -1.54 -1.80 Tmcc3
1435556 at Lgx only 530 463 373 373 -1.15 -1.42 -1.42 Zf 597
1435589 at Res & L x 510 650 831 1114 1.27 1.63 2.18 Ccdc85b
1435641 at Res & Lgx 437 400 308 300 -1.09 -1.42 -1.459530018107Rik
1435655 at Lgx only 248 223 189 131 -1.11 -1.31 -1.89 Snora65
1435674 at L x only 361 478 368 510 1.33 1.02 1.41 Rhobtb2
1435679 at Lgx only 1778 1866 1603 1228 1.05 -1.11 -1.45 Optn
1435693 at CR only 348 448 320 452 1.29 -1.09 1.30 Mall
1435695 a at L xonl 876 756 620 449 -1.16 -1.41 -1.95A030007L17Rik
1435743 at Res & Lgx 987 808 671 634 -1.22 -1.47 -1.56 K1h123
1435754 at Res & L x 1015 818 741 7141-1.24 -1.37 -1.42 Z 11 b
1435768 at Lgx only 919 909 725 632 -1.01 -1.27 -1.46 Arid4b
1435774 at L x onl 487 394 360 292 -1.24 -1.35 -1.67 AV024533
1435777 at Lgx only 1189 995 853 715 -1.19 -1.39 -1.66 E0300181\111 Rik
1435782 at Lgx only 166 244 291 295 1.47 1.75 1.78 LOC668206
1435808 at Res & Lgx 579 704 924 1015 1.22 1.60 1.75A230051G13Rik
1435813 at L x onl 2373 3193 3181 3356 1.35 1.34 1.41 Mypn
1435864 a at Res & L x 2251 2148 1526 1411 -1.05 -1.48 -1.59 1810063B05Rik
1435874 at L x onl 1005 1045, 939 727 1.04 -1.07 -1.38 Prkab2
1435900 at Res & Lgx 775 768 643 518 -1.01 -1.20 -1.49 Zbtb43
1435912 at Lgx only 670 587 579 4751-1.14 -1.16 -1.41 Ubxd7
1435947 at L xonl 647 572 495 456 -1.13 -1.31 -1.422810455D13Rik
1436014 a at CR only 449 349 494 518 -1.28 1.10 1.16 Rusc1
1436026 at Lgx only 476 418 620 736 -1.14 1.30 1.54 Zf 703
1436033 at Lgx only 879 984 1031 1238, 1.12 1.17 1.41 BC031353
1436041 at CR & L x 1831 1425 1788 1414 -1.28 -1.02 -1.29 L0C100046086
1436045 at L x only 381 321 282 216 -1.19 -1.35 -1.76 Ts al O
1436059 at Res & Lgx 254 366 397 446 1.44 1.56 1.75 Rfxl
1436075 at Lgx only 280 256 422 622 -1.09 1.51 2.22 Sfr 5
1436081 a at Lgx only 1053 1205 1255 1434 1.14 1.19 1.36 Zf 414
1436112 at Res only 158 196 325 246 1.24 2.06 1.55 All 18078
1436113 a at Res only 2773 2845 2148 2176 1.03 -1.29 -1.27 St13
1436121 a at Lgx only 1870 1812 1483 1122 -1.03 -1.26 -1.67 Nsmcel
1436122 at Res only 242 299 396 310 1.24 1.64 1.28 Zf 667
1436157 at L x only 1826 1496 1478 1265 -1.22 -1.24 -1.44 Ccarl
1436188 a at CR only 7033 11508 7677 9091 1.64 1.09 1.29 Ndr 4
1436208 at CR & Lgx 551 716 663 794 1.30 1.20 1.44Asbl
1436214 at L x onl 567 465 395 293 -1.22 -1.44 -1.93 1110028C15Rik
1436215 at Lgx only 642 508 549 4331-1.26 -1.17 -1.48 I mk
1436233 at Lgx only 1039 871 997 736 -1.19 -1.04 -1.41 Btnl9
1436240 at Lgx only 382 383 308 256 1.00 -1.24 -1.49 Sost
1436243 at L x onl 2945 3472 2166 1917 1.18 -1.36 -1.54 Frmds
1436275 at Lgx only 5589 6926 4236 4096 1.241-1.32 -1.36 Kcni 2
1436299 at Res & L x 1490 1306 1113 8771-1.14 -1.34 -1.70 GIs
CA 02699908 2010-03-17
WO 2009/039195 PCT/US2008/076707
-88-
Table 3
CO CR RES LGX FC FC FC
Probe Set ID Treatment mean mean mean mean CR Res L x Entrez Info
1436310 at Lgx only 199 301 245 313 1.51 1.23 1.57 Gemin5
1436332 at Lgx only 32378 38509 38078 46348 1.19 1.18 1.43 Hs b6
1436339 at L x onl 6840 6976 10138 9417 1.02 1.48 1.38 1810058124Rik
1436342 a at Lgx only 1693 1473 1337 1170 -1.15 -1.27 -1.45 D19Ertd721e
1436367 at Lgx only 3325 3749 4038 4164 1.13 1.21 1.25 C130094E24
1436377 at Res only 595 716 830 810 1.20 1.40 1.36 G r137
1436408 at L x onl 88 45 76 29 -1.95 -1.16 -3.02 Rprml
1436425 at L xonl 182 121 125 1261-1.50 -1.45 -1.45Ankrd38
1436446 at Res & L x 675 568 441 416 -1.19 -1.53 -1.6212310007011 Rik
1436505 at CR only 722 511 816 739 -1.41 1.13 1.02 Ppig
1436511 at Res & L x 675 634 510 460 -1.06 -1.32 -1.47 BC031781
1436521 at L x only 995 1371 1104 1496 1.38 1.11 1.50 Slc36a2
1436537 at CR only 624 518 554 573 -1.20 -1.13 -1.09 Zf 629
1436538 at Res & L x 425 320 201 116 -1.33 -2.12 -3.68Ankrd37
1436546 at Res & L x 1262 1105 994 881 -1.14 -1.27 -1.43 Lix11
1436547 at CR only 380 285, 282 3521-1.33 -1.34 -1.08 Dgke
1436562 at Lgx only 579 545 498 363 -1.06 -1.16 -1.59 Ddx58
1436584 at Res & Lgx 825 721 541 545 -1.15 -1.53 -1.51 S r 2
1436594 at Lgx only 180 124 152 103 -1.45 -1.18 -1.74 Zf 719
1436609 a at L x only 4537 4960 5297 5655 1.09 1.17 1.25 Lr a l
1436650 at CR & L x 729 1049 944 1072 1.44 1.30 1.47 Fili 1
1436665 a at Lgx only 3944 5547 5624 7673 1.41 1.43 1.95 Ltbp4
1436739 at Lgx only 2627 2725 2561 2047 1.04 -1.03 -1.28 A trl a
1436747 at L x only 2419 2508 2836 3129 1.04 1.17 1.29 1110014KO8Rik
1436797 a at Lgx only 1519 1814 1790 2289, 1.19 1.18 1.51 Surf4
1436809 a at All 1520 2518 2464 2994 1.66 1.62 1.97 Sin1
1436817 at Lgx only 1182 1030 929 752 -1.15 -1.27 -1.57 Exoc5
1436842 at Res & Lgx 3911 3696 2482 2369 -1.06 -1.58 -1.65 B230380D07Rik
1436844 at Lgx only 536 431 451 371 -1.24 -1.19 -1.44AW046287
1436865 at CR only 308 173 311 209 -1.78 1.01 -1.47 Slc26a11
1436867 at CR only 23230 28014 23888 25409 1.21 1.03 1.09 Srl
1436883 at L x only 558 425 421 399 -1.31 -1.32 -1.40 Mbtps2
1436918 at Lgx only 857 823 801 562 -1.04 -1.07 -1.53 LOC100044376
1436947 a at L x onl 4903 4267, 3399 27031-1.15 -1.44 -1.81 Txnll
1436984 at Lgx only 752 734 574 497 -1.02 -1.31 -1.51 Abi2
1436985 at Res & Lgx 1800 1660 1487 1422 -1.08 -1.21 -1.27 Zfp644
1436999 at Res only 619 512 464 480 -1.21 -1.33 -1.295033414K04Rik
1437026 at Lgx only 472 457 287 194 -1.03 -1.65 -2.44 BC057893
1437069 at Lgx only 1632 1471 1282 9721-1.11 -1.27 -1.68 Osbpl8
1437077 at Res & L x 2086 1987 1493 1649 -1.051-1.401 -1.26 Dcunld2
1437092 at Res & L x 535 440 282 286 -1.22 -1.90 -1.87 LOC100048376
1437111 at Lgx only 474 441 430 320 -1.08 -1.10 -1.48 Zc3h 12c
1437136 at Res only 60 130 240 141 2.17 4.00 2.355830436119Rik
1437143 a at All 4498 3397 2547 1894 -1.32 -1.77 -2.38 Txndcl
1437148 at CR & Lgx 7652 9004 8835 9409 1.18 1.15 1.23 Arpc2
1437149 at Lgx only 2370 2826 3182 3347 1.19 1.34 1.41 Slc6a6
CA 02699908 2010-03-17
WO 2009/039195 PCT/US2008/076707
-89-
Table 3
CO CR RES LGX FC FC FC
Probe Set ID Treatment mean mean mean mean CR Res L x Entrez Info
1437151 at Lgx only 1757 1972 2085 2237 1.12 1.19 1.27 Us 22
1437216 at Lgx only 363 289 295 210 -1.25 -1.23 -1.73 Ccdc88a
1437236 a at L x onl 449 348 371 3021-1.29 -1.21 -1.49 Zf 110
1437241 at CR only 760 1025 755 926 1.35 -1.01 1.22 Klf11
1437283 at Lgx only 376 462 480 662 1.23 1.28 1.76 Tn o2
1437287 at Res & L x 2217 1647 1611 1014 -1.35 -1.38 -2.19 1110020G09Rik
1437290 at L x onl 1027 946 711 722 -1.09 -1.44 -1.42 Im adl
1437354 at Res & L x 1278 1069 925 8111-1.20 -1.38 -1.58 C230091 D08Rik
1437382 at Lgx only 1211 1154 1069 922 -1.05 -1.13 -1.31 Acvr2a
1437394 at Lgx only 343 383 446 567 1.12 1.30 1.65 Cent g2
1437397 at Res & L x 277 210 181 160 -1.32 -1.53 -1.73 Prlr
1437398 a at All 781 1052 1289 1566 1.35 1.65 2.01 Aldh9al
1437403 at L x only 41, 70 69 98 1.72 1.69 2.41 Samds
1437405 a at Lgx only 5956 7647 8743 11879 1.28 1.47 1.99 I fb 4
1437426 at Lgx only 275 200 273 162 -1.37 -1.01 -1.70 Wac
1437432 a at Res only 220 153 98 165,-1.44 -2.25 -1.33 Trim12
1437442 at Res & L x 1223 963 774 621 -1.27 -1.58 -1.97 Pcdh7
1437449 at Lgx only 727 595 602 560 -1.22 -1.21 -1.30 Rsadl
1437482 at Res & Lgx 7128 6639 4396 3270 -1.07 -1.62 -2.18 Srd5a2l2
1437484 at Res & L x 321 372 527 541 1.16 1.64 1.68 Zbtb5
1437513 a at L x only 5779 5896 6781 7125 1.02 1.17 1.23 Serinc1
1437533 at Res & L x 2000 1894 1502 1237 -1.06 -1.33 -1.62 Birc4
1437537 at Res & L x 249 339 340 398 1.36 1.36 1.60 Cas 9
1437704 at Res & Lgx 194 157 376 378 -1.23 1.93 1.942900024010Rik
1437729 at Lgx only 1474 1094 793 4121-1.35 -1.86 -3.58 Rp127a
1437740 at Lgx only 763 1122 1005 1343 1.47 1.32 1.76 Plekhm2
1437741 at Lgx only 2327 2390 1778 1560 1.03 -1.31 -1.49 Rab2l
1437785 at L x only 474 397 463 337 -1.191-1.03 -1.41 Adamts9
1437869 at Res & L x 14570 13664 11826 11731 -1.07 -1.23 -1.243222402P14Rik
1437875 at Lgx only 2753 2607 2485 2181 -1.06 -1.11 -1.26 Bicd2
1437900 at Lgx only 566 564 505 437 -1.00 -1.12 -1.304930523C07Rik
1437917 at L x only 370 334 293 223 -1.11 -1.26 -1.65 D530037H12Rik
1438024 at Res & Lgx 3610 3226 2484 2237 -1.12 -1.45 -1.61 Ccdc90a
1438026 at Lgx only 623 498 498 393 -1.25 -1.25 -1.58 Zf 560
1438045 at Lgx only 737 678 702 495 -1.09 -1.05 -1.49 Eeal
1438047 at Res & L x 1053 1176 1296 1256 1.12 1.23 1.19 Zf 384
1438062 at CR only 588 372 440 434 -1.58 -1.34 -1.364832420A03Rik
1438077 at Lgx only 18 38 17 62 2.11 -1.09 3.42 Nlr 4a
1438097 at Lgx only 611 574 490 391 -1.06 -1.25 -1.56 Rab20
1438169 a at L x only 747 494 424 347 -1.51 -1.76 -2.15 Frmd4b
1438195 at Lgx only 2915 3104 2321 2279 1.06 -1.26 -1.28 G d1I
1438208 at Res only 286 277 424 361 -1.03 1.48 1.26 Taok2
1438213 at L xonl 15 30 39 79 2.00 2.61 5.30A830018L16Rik
1438229 at Res only 843 887 609 701 1.05 -1.38 -1.20 P t1 b
1438238 at Lgx only 231 217 198 106 -1.07 -1.17 -2.18 2010315B03Rik
1438241 at Lgx only 525 593 734 837 1.13 1.40 1.59 R ma
CA 02699908 2010-03-17
WO 2009/039195 PCT/US2008/076707
-90-
Table 3
CO CR RES LGX FC FC FC
Probe Set ID Treatment mean mean mean mean CR Res L x Entrez Info
1438258 at CR & Res 3530 2388 4783 3703 -1.48 1.35 1.05 Vldlr
1438340 at L x only 219 117 157 125 -1.86 -1.40 -1.75 A930006D11 Rik
1438349 at L x onl 195 145 121 751-1.34 -1.61 -2.60 BC043476
1438400 at Lgx only 1226 1403 1426 1614 1.14 1.16 1.3214632411131 2Rik
1438416 at Lgx only 1855 2525 2386 2992 1.36 1.29 1.61 Med16
1438422 at Res & Lgx 1011 996 736 664 -1.01 -1.37 -1.52 Lrrc20
1438444 at L x only 9 29 35 26 3.33 3.99 3.02 S inkl0
1438510 a at L x onl 910 841, 730 5351-1.08 -1.25 -1.70 Hars
1438512 at Res only 68 151 177 104 2.21 2.59 1.52 BC048679
1438532 at Lgx only 292 307 310 176 1.05 1.06 -1.66 Hmcnl
1438610 a at Lgx only 887 695 489 435 -1.28 -1.82 -2.04 Cr z
1438658 a at All 1738 1228 1017 715 -1.421-1.71 -2.43 Ed 3
1438673 at Lgx only 759 586 535 411 -1.29 -1.42 -1.85 Slc4a7
1438676 at CR & Lgx 499 296 432 285 -1.68 -1.16 -1.75 Mpa2l
1438678 at Lgx only 3261 2863 2608 2178 -1.14 -1.25 -1.50 1500011 K16Rik
1438691 at Res only 664 655 437 488 -1.01 -1.52 -1.36 Zzefl
1438693 at Res & L x 311 353 461 515 1.14 1.48 1.66Tmem110
1438895 at Res only 571 519 762 647 -1.10 1.33 1.13A430102J17Rik
1438908 at Lgx only 246 204 303 415 -1.21 1.23 1.69 Ma 3k12
1438909 at Lgx only 51 62 76 173 1.23 1.49 3.41 Sccpdh
1438910 a at L x only 3956 3657 4466 5068 -1.08 1.13 1.28 Stom
1439008 at Lgx only 251 272 389 478 1.09 1.55 1.91 Zfp319
1439010 at L x onl 1107 987 790 675 -1.12 -1.40 -1.64 Larp4
1439024 at CR only 297 211 222 198 -1.41 -1.34 -1.50 Bag4
1439029 at Lgx only 629 843 709 1038 1.34 1.13 1.65 Gpt2
OTTMUSG-
1439055 at L x onl 13 23 23 25 1.76 1.80 1.89 00000001305
1439078 at Lgx only 188 135 137 90 -1.39 -1.37 -2.08 Klhl4
1439143 at CR & Lgx 411 604 540 582 1.47 1.32 1.42A930018M24Rik
1439153 at Lgx only 917 1123 739 645 1.22 -1.24 -1.42 lbrdc2
1439189 at CR only 592 915 521 472 1.54 -1.14 -1.25 D630023B12Rik
1439244 a at Lgx only 2004 1777 2537 31751-1.13 1.27 1.58 Tnrc6a
1439266 a at Res & Lgx 524 404 272 229 -1.30 -1.93 -2.29 Polr3k
1439364 a at Lgx only 1881 2097 2565 2782 1.11 1.36 1.48 Mm 2
1439397 at All 322 190 197 172 -1.69 -1.63 -1.88 Fmnl
1439460 a at All 2411 1816 1398 1125 -1.331-1.73 -2.14 Zf 289
1439483 at Res only 47 63 129 96 1.33 2.71 2.02A1506816
1439488 at Lgx only 427 660 693 889 1.55 1.62 2.08 Dotl 1
1439509 at Res only 161 198 257 226 1.22 1.59 1.402900008C10Rik
1439529 at Res & L x 293 347 451 554 1.18 1.54 1.89A430110N23Rik
1439675 at Res only 1299 1589 964 977 1.22 -1.35 -1.334933429D07Rik
1439793 at Lgx only 539 391 382 304 -1.38 -1.41 -1.77 Gja3
1439797 at Lgx only 324 388 353 514 1.20 1.09 1.59 Ppard
1439815 at Lgx only 1354 1602 1962 2028 1.18 1.45 1.50 Heatrsb
1439821 at Res onl 147 79 51 75 -1.86 -2.91 -1.96 Lr 2b
1440018 at Lgx only 32 47 70 136 1.48 2.21 4.30 A330043J 11 Rik
1440096 at Lgx only 360 318 281 177 -1.13 -1.28 -2.03 Ecm2
CA 02699908 2010-03-17
WO 2009/039195 PCT/US2008/076707
-91-
Table 3
CO CR RES LGX FC FC FC
Probe Set ID Treatment mean mean mean mean CR Res L x Entrez Info
1440143 at Lgx only 141 181 180 383 1.28 1.28 2.71 Pigz
1440232 at Res only 47 67 145 121 1.41 3.07 2.55 EG622645
1440234 at L x onl 1187 1250 1054 915 1.05 -1.13 -1.30 1810012P15Rik
1440279 at Lgx only 326 267 247 189 -1.22 -1.32 -1.73 Txndc10
1440335 at Lgx only 2118 2238 2120 1677 1.06 1.00 -1.26 LOC100046468
1440478 at Res only 176 92 68 123 -1.90 -2.57 -1.43 LOC100047601
1440480 at L xonl 60 174 203 293 2.89 3.38 4.87AB182283
1440520 a at CR only 147 330 264 161 2.24 1.79 1.09 1700051A21 Rik
1440537 at Res only 313 264 495 395 -1.19 1.58 1.26 Kcnv2
1440542 at Res only 82 53 18 48 -1.54 -4.45 -1.72 7420416P09Rik
1440561 at L x onl 65 85 111 158 1.30 1.70 2.43 C87259
1440739 at CR only 524 357 538 4431-1.47 1.03 -1.18 Ve fc
1440781 at CR only 133 48 101 60 -2.75 -1.32 -2.21 B830007DO8Rik
1440831 at Res only 1257 1218 923 944 -1.03 -1.36 -1.33 Bach1
1440838 at Lgx only 431 523 579 624 1.21 1.34 1.45 A1852064
1440841 at Lgx only 745 669 622 529 -1.11 -1.20 -1.41 BB217526
1440849 at CR only 660 558 616 573 -1.18 -1.07 -1.1 5 633041 7GO4Rik
1440874 at CR only 311 151 297 337 -2.06 -1.05 1.08 Slco5al
1440908 at L x onl 346 365 317 547 1.06 -1.09 1.58 D030063E12
1440934 at Lgx only 102 101 173 224 -1.00 1.70 2.20 AW742931
1440969 at All 199 103 102 67 -1.93 -1.94 -2.95 BC030308
1441001 at L x onl 52 82 140 150 1.59 2.70 2.91 A1225934
1441075 at Lgx only 317 274 260 171 -1.16 -1.22 -1.86 Nostrin
1441081 a at Lgx only 202 199 256 320 -1.02 1.27 1.58 1110038B12Rik
ENSMUSG-
1441139 at CR only 2413 2791 2076 2479 1.16 -1.16 1.0300000071543
1441174 a at Res & L x 123 85 72 87 -1.44 -1.71 -1.41 Lmin
1441229 at Res & L x 174 114 73 70 -1.52 -2.36 -2.48 D230019N24Rik
1441266 at Res & Lgx 812 636 542 457 -1.28 -1.50 -1.78 Strn3
1441320 a at Res & Lgx 602 634 812 873 1.05 1.35 1.45 A1413194
1441438 at CR only 269 183 277 225 -1.47 1.03 -1.20 G c6
1441536 at L x only 18 44 32 86 2.39 1.74 4.68 Hm csl
1441590 at Lgx only 1067 1051 1373 1614 -1.01 1.29 1.51 Kcnjs
1441970 at Lgx only 419 391 340 3021-1.07 -1.23 -1.39 E43001ON07Rik
1441987 at Res & L x 585 488 465 395 -1.201-1.26 -1.48 Mbd5
1442002 at L x only 348 254 303 186 -1.37 -1.15 -1.87 7030402D04Rik
1442027 at Lgx only 1531 1126 1055 790 -1.36 -1.45 -1.94 Nbeall
1442050 at Res & Lgx 328 298 521 618 -1.10 1.59 1.88 Zfp608
1442064 at Res & Lgx 84 144 242 284 1.71 2.88 3.37 AW556556
1442090 at Res only 33 77 108 83 2.30 3.24 2.478030463A06Rik
1442174 at L x only 360 314 499 581 -1.15 1.39 1.61 Ts an18
1442186 at Res & L x 215 323 448 443 1.50 2.09 2.06 LOC100045002
1442362 at Res & L x 165 113 51 64 -1.45 -3.22 -2.59 Gm104
1442434 at Res only 466 588 765 673 1.26 1.64 1.44 D8Ertd82e
1442659 at Lgx only 332 320 312 473 -1.04 -1.07 1.42 Pcdh9
1442695 at Lgx only 49 67 48 156 1.35 -1.03 3.15 0030007101 Rik
1442732 at CR only 380 683 596 574 1.80 1.57 1.51 Hadhb
CA 02699908 2010-03-17
WO 2009/039195 PCT/US2008/076707
-92-
Table 3
CO CR RES LGX FC FC FC
Probe Set ID Treatment mean mean mean mean CR Res L x Entrez Info
1442757 at CR & Res 432 288 287 372 -1.50 -1.50 -1.16 Lrchl
1442867 at Res only 135 148 262 224 1.10 1.94 1.65 Me fl 1
1442926 at L x onl 10 49 42 75 5.07 4.40 7.80 1700011 B04Rik
1443103 at CR only 69 23 45 45 -2.98 -1.53 -1.53 D830046C22Rik
1443416 at Lgx only 197 253 192 328 1.28 -1.03 1.66 C79741
1443483 at Lgx only 59 59 64 17 1.01 1.08 -3.39 Xlr5a
1443632 at CR only 10172 12920 10060 11150 1.271-1.01 1.10 Obscn
1443682 at Res only 259 192 424 371 -1.35 1.64 1.43 A1662476
1443854 at Lgx only 405 288 380 192 -1.41 -1.07 -2.11 Hand2
1443856 at Lgx only 726 687 651 538 -1.06 -1.11 -1.35 Rabepl
1443896 at L x onl 748 888 896 1033 1.19 1.20 1.38 Tbcl d5
1443932 at Res & L x 2283 1935 1827 1552 -1.18 -1.25 -1.47 Klhdcl
1443935 at Res only 401 429 494 464 1.07 1.23 1.16 BC032203
1444041 at Lgx only 146 127 94 62 -1.15 -1.55 -2.35 AU041133
ENSMUSG-
1444112 at L x only 1457 1326 1343 1080 -1.10 -1.09 -1.35 00000074466
1444217 at Lgx only 212 168 299 382 -1.26 1.41 1.80 Mr 138
1444254 at CR only 84 28 74 105 -2.95 -1.12 1.26 Tns4
1444294 at Lgx only 127 204 249 265 1.61 1.97 2.104930551A22Rik
1444370 at CR only 46 16 60, 24 -2.80 1.31 -1.91 C77058
1444456 at Lgx only 245 268 240 176 1.091-1.02 -1.39 9030425P06Rik
1444494 at All 2200 1830 1616 1601 -1.20 -1.36 -1.37 Kbtbdl0
1444537 at Lgx only 219 296 347 346 1.35 1.59 1.58 A1429363
1444684 at L xonl 50 23 43 16 -2.18 -1.15 -3.188030475D13Rik
1444766 at Lgx only 107 102 101 31 -1.04 -1.06 -3.48 Atxn7ll
1445191 at CR only 187 125 201 197 -1.50 1.08 1.05 Exdll
1445459 at Lgx only 50 100 93 186 2.00 1.87 3.72 Sstr5
1446062 at Res only 58 100 121 102 1.74 2.10 1.77 B830028B13Rik
1446214 at CR only 18 68 77 45 3.67 4.16 2.45 D430018E03Rik
1446678 at L x only 37 60 62 121, 1.62 1.68 3.26 D14Ertdl6e
1446781 at CR only 95 21 55 68 -4.54 -1.73 -1.39 D8Ertd54e
1446812 at Res & Lgx 890 716 584 552 -1.24 -1.52 -1.61 LOC100040515
1446842 at CR only 68 13 26 27 -5.38 -2.60 -2.47 D4Ertd571 e
1447035 at L x only 41 91 109 139 2.21 2.63 3.36 A230091 C14Rik
1447095 at Lgx only 109 130 166 195 1.19 1.52 1.79 C86942
1447923 at Lgx only 781 678 544 448 -1.15 -1.44 -1.74 1810026B05Rik
1447967 at Res only 256 260 440 360 1.01 1.72 1.41 Tmem69
1447981 at CR only 68 13 66 56 -5.40 -1.03 -1.21 C78441
1448091 at CR & Lgx 18 85 41 75 4.74 2.28 4.20 D15Ertd5Oe
1448100 at Res & Lgx 4461 4342 3733 3467 -1.03 -1.20 -1.2948334391-19Rik
1448116 at Res & Lgx 3337 3991 4522 5277 1.20 1.35 1.58 Ube 1x
1448122 at CR & Lgx 8342 9257 8220 9546 1.11 -1.01 1.14 Tcpl
1448143 at Lgx only 6719 7951 7830 8811 1.18 1.17 1.31 Aldh2
1448145 at Lgx only 304 323 454 535 1.06 1.50 1.76 Ww 2
1448148 at Res & L x 1666 2147 2587 3224 1.29 1.55 1.94 Grn
1448153 at Lgx only 60488 68353 63338 84246 1.13 1.05 1.39 Coxsa
111448154 at L x only 19344 22511 19920 25912 1.16 1.03 1.34 Ndrg2
CA 02699908 2010-03-17
WO 2009/039195 PCT/US2008/076707
-93-
Table 3
CO CR RES LGX FC FC FC
Probe Set ID Treatment mean mean mean mean CR Res L x Entrez Info
1448163 at Lgx only 798 1050 981 1240 1.32 1.23 1.55 Gnpdal
1448167 at Lgx only 684 808 806 1130 1.18 1.18 1.65 Ifn rl
1448174 at L x onl 1875 1928 2181 2232 1.03 1.16 1.19 Cull
1448181 at CR only 1549 2211 1745 1742 1.43 1.13 1.12 Klf15
1448185 at Lgx only 5495 7055 5636 8302 1.28 1.03 1.51 Herpudl
1448188 at Lgx only 5526 6650 8466 12288 1.20 1.53 2.22 Uc 2
1448189 a at L x onl 2277 2853 3180 3351 1.25 1.40 1.47 Flii
1448196 at Res & L x 3368 2651 2008 1537 -1.27 -1.68 -2.19 Mat2b
1448198 a at Lgx only 38229 43229 40539 48367 1.13 1.06 1.27 Ndufb8
1448199 at Res only 679 631 507 543 -1.08 -1.34 -1.25 Ankrd10
1448206 at L x onl 6419 7041 7577 10844 1.10 1.18 1.69 Psma2
1448208 at Lgx only 632 474 499 3481-1.34 -1.27 -1.82 Smad 1
1448209 a at Lgx only 246 316 363 502 1.29 1.48 2.04 Slc22al 7
1448212 at Lgx only 1004 973 746 707 -1.03 -1.35 -1.42 Tnfsfsi 1
1448221 at CR only 4042 4996 4086 4247 1.24 1.01 1.05 Batt a
1448224 at Lgx only 1460 1359 1117 995 -1.07 -1.31 -1.47 Tfam
1448225 at Lgx only 498 691 692 796 1.39 1.39 1.60 Gpaal
1448240 at Lgx only 1199 1319 1410 1668 1.10 1.18 1.39 Mbtpsl
1448242 at L x onl 1162 1336 1617 1835 1.15 1.39 1.58 Sec61 a1
1448244 at Lgx only 1573 1505 1192 813 -1.05 -1.32 -1.93 Lyplal
1448252 a at Lgx only 7588 7012 6014 5451 -1.08 -1.26 -1.39 Eeflb2
1448258 a at Lgx only 6413 6297 5305 4246 -1.02 -1.21 -1.51 Spcsl
1448269 a at Res & L x 613 517 374 350 -1.19 -1.64 -1.75 Klhll3
1448276 at L x onl 1808 2156 1862 2730 1.19 1.03 1.51 Tspan4
1448284 a at Lgx only 37586 40364 44938 56730 1.07 1.20 1.51 Ndufcl
1448287 at Lgx only 4436 4040 3639 28301-1.10 -1.22 -1.57 Rpol-3
1448304 a at Res & L x 3053 2867 2183 1770 -1.06 -1.40 -1.72 Rab6
1448313 at Lgx only 2609 2807 3061 3302 1.08 1.17 1.27 T 1
1448325 at Res & L x 757 893 1112 1080 1.18 1.47 1.43 M d116
1448327 at Lgx only 30728 36837 37776 43889 1.20 1.23 1.43 Actn2
1448330 at Res & L x 7365 8521 9720 11395 1.16 1.32 1.55 Gstml
1448336 at Lgx only 1711 1622 1611 1433 -1.05 -1.06 -1.19 Drgl
1448339 at Res & Lgx 4104 3995 2913 2634 -1.03 -1.41 -1.56 Tmem30a
1448341 a at Lgx only 321 317 503 653 -1.01 1.57 2.04 Stxb 2
1448345 at Lgx only 1081 1303 1204 1435 1.21 1.11 1.33 Tomm34
1448346 at CR only 2920 2207 2287 2450 -1.321-1.28 -1.19 Cfl1
1448351 at L xonl 1035 1248 1300 1665 1.21 1.26 1.61 Coro 1b
1448356 at Lgx only 2083 1903 1705 1572 -1.09 -1.22 -1.32 Ube2d2
1448362 at Lgx only 1772 2097 2189 2519 1.18 1.24 1.42 Dnajc7
1448363 at Res & Lgx 2486 2740 3232 3785 1.10 1.30 1.52 Ya 1
1448365 at Res & L x 1790 1723 1184 1227 -1.04 -1.51 -1.46 Exosc7
1448379 at Res only 647 563 413 518 -1.15 -1.57 -1.25 Potla
1448380 at Res & L x 1020 1208 1439 1659 1.19 1.41 1.63 Lgals3bp
1448388 a at L x only 2505 2405 1802 1158 -1.041-1.39 -2.16 1110002BO5Rik
1448402 at Lgx only 1415 1869 2287 2869 1.32 1.62 2.03 Tln 1
1448412 a at Lgx only 3472 4076 4244 4721 1.17 1.22 1.36 Tsc22d4
CA 02699908 2010-03-17
WO 2009/039195 PCT/US2008/076707
-94-
Table 3
CO CR RES LGX FC FC FC
Probe Set ID Treatment mean mean mean mean CR Res L x Entrez Info
1448415 a at Lgx only 387 438 593 653 1.13 1.53 1.69 Sema3b
1448416 at Lgx only 16601 20394 19345 31156 1.23 1.17 1.88 Mgp
1448417 at L x only 1000 1181 1301 1299 1.18 1.30 1.30 Ninjl
1448429 at Res & L x 3339 3198 2421 1974 -1.04 -1.38 -1.69 G
1448430 a at CR & Lgx 8516 10720 9639 10638 1.26 1.13 1.25 Naca
1448432 at Lgx only 369 514 544 661 1.40 1.48 1.79 Plcdl
1448438 at L x only 2204 1814 1971 1577 -1.22 -1.12 -1.40 Der12
1448463 at L x onl 4645 4072 3480 3091,-1.14 -1.33 -1.504933434E2ORik
1448467 a at Lgx only 1218 1447 1612 1817 1.19 1.32 1.49 Ehb 111
1448476 at CR & L x 5612 6609 6127 7217 1.18 1.09 1.29 Nap 114
1448480 at Res & Lgx 1000 728 556 360 -1.37 -1.80 -2.78 Nip7
1448484 at Res & L x 5744 5110 3530 3419 -1.121-1.63 -1.68Amdl
1448488 at CR & L x 831, 1036 919 1013 1.25 1.11 1.22 Mr s5
1448492 a at Res & Lgx 4733 4441 3842 3020 -1.07 -1.23 -1.57 Psmd12
1448493 at CR & Lgx 9202 6905 8442 6228 -1.33 -1.09 -1.48 Paip2
1448495 at Lgx only 723 911 890 1046 1.26 1.23 1.45 Tsta3
1448498 at L x only 793 1061, 951 1228 1.34 1.20 1.55 Rps6ka4
1448505 at Res & L x 1738 1400 1033 860 -1.24 -1.68 -2.02 C 1 d
1448508 at Lgx only 237 284 322 442 1.20 1.36 1.86 Traf3i 2
1448517 at Lgx only 2047 2144 1562 1376 1.05 -1.31 -1.49 Timm22
1448527 at Lgx only 1955 1753 1345 1338 -1.12 -1.45 -1.46 PdcdlO
1448533 at Res & Lgx 3076 2967 2613 2263 -1.04 -1.18 -1.36 Tbcb
1448535 at Lgx only 306 250 237 154 -1.22 -1.29 -1.98 El p4
1448536 at Lgx only 4579 4812 3261 2727 1.05 -1.40 -1.68 Lsm3
1448537 at Res & L x 2417 2026 1762 1591 -1.19 -1.37 -1.52 Ttcl
1448543 at Res & Lgx 1715 1494 908 822 -1.15 -1.89 -2.09 SImo2
1448548 at Lgx only 1328 1385 1288 1631 1.04 -1.03 1.23 Tul 4
1448549 a at Res only 1179 1068 850 1106 -1.10 -1.39 -1.07 D a tl
1448559 at Lgx only 5131 5547 6227 7143 1.08 1.21 1.39 Flotl
1448564 at Res only 511 609 713 573 1.19 1.40 1.12 Cibl
1448565 at Lgx only 2831 2386 2740 1942 -1.19 -1.03 -1.46 P 1 rl 1
1448567 at Lgx only 590 668 763 806 1.13 1.29 1.37 Tmeml 15
1448568 a at CR only 688 524 629 533 -1.31 -1.09 -1.29 Slc20a1
1448570 at L x only 1666 1576 1258 948 -1.06 -1.32 -1.76 Gmfb
1448579 at Lgx only 2689 2976 3392 3692 1.11 1.26 1.37 GI 1
1448585 at Res only 751 809 578 655 1.08 -1.30 -1.15 Gtf2h4
1448591 at CR only 1010 720 1099 736 -1.40 1.09 -1.37 Ctss
1448613 at L x only 1206 1308 1426 1969 1.08 1.18 1.63 Ecml
1448615 at Res & L x 769 858 1028 1113 1.12 1.34 1.45 Ccs
1448621 a at Res & L x 7092 7555 5213 5291 1.07 -1.36 -1.34Sm dl
1448623 at Lgx only 1699 1287 1178 807 -1.32 -1.44 -2.11 Tmem123
1448625 at Res & L x 1612 1957 2268 2558 1.21 1.41 1.59 Gol a2
1448637 at Lgx only 1033 1248 1507 1924 1.21 1.46 1.86 Med25
1448638 at Res only 68 79 140 150 1.17 2.06 2.21 Mtbp
1448644 at Lgx only 1286 1471 1597 1684 1.14 1.24 1.31 Pefl
1448645 at Lgx only 2239 2328 1993 1844 1.04 -1.12 -1.21 Ms131
CA 02699908 2010-03-17
WO 2009/039195 PCT/US2008/076707
-95-
Table 3
CO CR RES LGX FC FC FC
Probe Set ID Treatment mean mean mean mean CR Res L x Entrez Info
1448649 at Lgx only 540 500 484 392 -1.08 -1.12 -1.38 Enpep
1448684 at Res & L x 4396 3940 3485 3517 -1.12 -1.26 -1.25 P 1 r2
1448696 at Res only 95 115 47 40 1.20 -2.03 -2.37 He h
1448700 at Lgx only 4037 3143 2765 2331 -1.28 -1.46 -1.73 G0s2
1448717 at CR only 889 671 980 830 -1.32 1.10 -1.07 Gcdh
1448720 at Lgx only 342 284 279 229 -1.21 -1.23 -1.49 Lrrc40
1448724 at Res only 4162 4532 2682 2820 1.09 -1.55 -1.48 Cish
1448727 at L x only 269 370 398 484 1.37 1.48 1.80 Tle6
1448729 a at CR & L x 1559 1304 1446 1143 -1.20 -1.08 -1.3639329
1448737 at Lgx only 4695 4240 4264 3613 -1.11 -1.10 -1.30 Ts an7
1448760 at Lgx only 643 554 539 457 -1.16 -1.19 -1.41 Zfp68
1448762 at Res & L x 1357 1116 910 676 -1.22.-1.49 -2.01 Rad17
1448769 at Lgx only 2415 2426 2058 1875 1.00 -1.17 -1.29 Slc35b1
1448770 a at Lgx only 6679 6835 5272 3909 1.02 -1.27 -1.71 Atpifl
1448771 a at Lgx only 49028 51355 54395 64994 1.05 1.11 1.33 Fthl
1448788 at Res & L x 1474 1445 1194 1065 -1.02 -1.24 -1.38 Cd200
1448792 a at Res only 137 80 49 1448 -1.711-2.79 10.55 C 2f2
1448797 at Res & Lgx 945 842 674 584 -1.12 -1.40 -1.62 Elk3
1448809 at Res & L x 2605 2313 1681 1641 -1.13 -1.55 -1.59 Csel l
1448810 at Res & L x 397 445 638 701 1.12 1.61 1.77 Gne
1448826 at L x only 95590 115497 118388 173815 1.21 1.24 1.82 Myh6
1448830 at Lgx only 5138 4291 4152 3187 -1.201-1.24 -1.61 Duspl
1448835 at Res & Lgx 5346 5044 3924 3656 -1.06 -1.36 -1.46 E2f6
1448838 at Lgx only 386 350 281 214 -1.10 -1.37 -1.81 To ors
1448840 at Lgx only 461 474 456 753 1.03 -1.01 1.63 Tmubl
1448844 at L x only 1373 1278 1179 983 -1.07 -1.17 -1.40 C b5b
1448853 at Lgx only 5831 5559 4659 4095 -1.05 -1.25 -1.42 Synj2bp
1448856 a at Res & L x 2552 2477 2140 2204 -1.03 -1.19 -1.16 Msra
1448860 at Res only 17 35 50 64 2.14 3.02 3.84 Rem2
1448864 at Lgx only 3508 4978 4574 4515 1.42 1.30 1.29 Snrk
1448867 at L x onl 2465 2370 1926 1977 -1.04 -1.28 -1.25 Tmem9b
1448883 at Lgx only 986 1264 880 1339 1.28 -1.12 1.36 Lg mn
1448884 at Lgx only 742 688 554 408 -1.08 -1.34 -1.82 Gtf2e2
1448885 at CR only 299 214 340 415 -1.40 1.14 1.39 Rap2b
1448893 at L x onl 851 1373 1459 1947 1.61 1.71 2.29 Ncor2
1448894 at Lgx only 832 852 961 1170 1.02 1.15 1.41 Akr1 b8
1448900 at L x onl 4895 4713, 4330 3890 -1.04 -1.13 -1.26 D16H22S680E
1448903 at Lgx only 7279 5973 5176 3901 -1.22 -1.41 -1.8739340
1448917 at Lgx only 1574 1229 1326 1221 -1.28 -1.19 -1.29 Med30
1448918 at Lgx only 1286 1478 1757 1991, 1.15 1.37 1.55 Slco3al
1448943 at Lgx only 4428 4185 3289 2623 -1.06 -1.35 -1.69 Nrpl
1448947 at L xonl 2361 2309 1900 1544 -1.02 -1.24 -1.532810004N23Rik
1448948 at L x onl 1247 1146 1163 1058 -1.09 -1.07 -1.18 Ra 1a 1
1448956 at Lgx only 3964 4452 6177 9601 1.12 1.56 2.42 Stard10
1448960 at L x only 1075 1032 1164 1411 -1.04 1.08 1.31 Cxxc5
1448970 at Lgx only 3836 3551 3364 2960 -1.08 -1.14 -1.30 Slc25a46
CA 02699908 2010-03-17
WO 2009/039195 PCT/US2008/076707
-96-
Table 3
CO CR RES LGX FC FC FC
Probe Set ID Treatment mean mean mean mean CR Res L x Entrez Info
1448971 at Lgx only 389 353 307 236 -1.10 -1.26 -1.65 2410022LO5Rik
1448987 at Lgx only 43424 51619 52391 80140 1.19 1.21 1.85 Acadl
1448993 at Res & Lgx 2740 2404 1834 15171-1.14 -1.49 -1.81 At g3
1449014 at Res only 881 843 642 705 -1.05 -1.37 -1.25 Lactb
1449025 at Lgx only 548 576 657 774 1.05 1.20 1.41 lfit3
1449026 at Res & Lgx 503 552 779 792 1.10 1.55 1.57 Ifnarl
1449042 at L x onl 936 870 1132 1241 -1.08 1.21 1.33 Ctcf
1449044 at Lgx only 1437 1195 953 8011-1.20 -1.51 -1.79 Eeflel
1449045 at Lgx only 952 1152 1135 1427 1.21 1.19 1.50 Af 3ll
1449046 a at Lgx only 1537 1426 1431 1340 -1.08 -1.07 -1.15 Josd2
1449058 at Lgx only 143 148 92 232 1.04 -1.55 1.63 Glil
1449062 at L x only 347 452 475 608 1.30 1.37 1.75 Khk
1449063 at Res only 1262 1084 930 1007 -1.16 -1.36 -1.25 Sec22b
1449071 at Lgx only 25977 29211 40937 73543 1.12 1.58 2.83 M l7
1449072 a at Lgx only 1737 1759 1601 1044 1.01 -1.09 -1.66 N6amt2
1449078 at Res & L x 1395 1028 1025 751 -1.36 -1.36 -1.86 St3 al6
1449080 at All 447 289 283 232 -1.55 -1.58 -1.93 Hdac2
1449088 at Lgx only 1611 1389 2284 2373 -1.16 1.42 1.47 Fb 2
1449096 at Lgx only 1028 1107 863 714 1.08 -1.19 -1.44 Ccdcl27
1449106 at L x only 16622 17727 24198 34324 1.07 1.46 2.07 G x3
1449108 at Lgx only 7575 7320 6088 49141-1.03 -1.24 -1.54 Fdxl
1449113 at Res only 848 830 647 687 -1.02 -1.31 -1.23 G b l l l
1449123 at Lgx only 84 43 111 29 -1.96 1.32 -2.93 ltih3
1449124 at Res & L x 310 370 480 455 1.19 1.55 1.47 R I1
1449125 at Lgx only 202 143 142 96 -1.42 -1.43 -2.11 Tnfaip8ll
1449138 at L x onl 3517 3750 4329 4360 1.07 1.23 1.24 Sf3b1
1449140 at Lgx only 273 266 217 136 -1.03 -1.26 -2.00 Nudcd2
1449145 a at Lgx only 11453 13083 13559 16570 1.14 1.18 1.45 Cavl
1449151 at Lgx only 508 569 665 675 1.12 1.31 1.33 Pctk3
1449187 at Lgx only 529 457 392 333 -1.16 -1.35 -1.59 Pd fa
1449217 at L x onl 230 198 132 111 -1.16 -1.74 -2.07 Cas 8a 2
1449256 a at Lgx only 2956 2919 3638 3430 -1.01 1.23 1.16 Rabl 1 a
1449269 at Lgx only 168 147 139 61 -1.15 -1.21 -2.75 F5
1449281 at Lgx only 1873 2466 2400 2905 1.32 1.28 1.55 Nrtn
1449298 a at Lgx only 237 268 246 322 1.13 1.04 1.36 Pdela
1449300 at L x only 553 544 493 380 -1.02 -1.12 -1.46 Cttnbp2nl
1449304 at L xonl 463 404 649 649 -1.15 1.40 1.402310061J03Rik
1449333 at Lgx only 549 662 682 852 1.21 1.24 1.55 Sf3a1
1449335 at L x only 5926 8089 8111 11301 1.37 1.37 1.91 Tim 3
1449338 at L x only 3319 3175 3019 2290 -1.05 -1.10 -1.45 DlOErtd64le
1449345 at Res only 139 99 60 69 -1.40 -2.32 -2.02 Ccdc34
1449348 at Lgx only 2011 1876 1690 1475 -1.07 -1.19 -1.36 M 6
1449354 at Res & L x 959 1115 1378 1597 1.16 1.44 1.67 Zrsrl
1449355 a at L x only 676 967 976 975 1.43 1.44 1.44 E sl5I1
1449356 at Lgx only 1478 999 1176 608 -1.48 -1.26 -2.43 Asb5
1449357 at Res & Lgx 286 192 172 175 -1.49 -1.67 -1.642310030G06Rik
CA 02699908 2010-03-17
WO 2009/039195 PCT/US2008/076707
-97-
Table 3
CO CR RES LGX FC FC FC
Probe Set ID Treatment mean mean mean mean CR Res L x Entrez Info
1449363 at Res only 306 165 208 182 -1.86 -1.47 -1.68Atf3
1449368 at Lgx only 25201 21347 33485 36603 -1.18 1.33 1.45 Dcn
1449372 at Res only 1022 867 1303 12251-1.18 1.27 1.20 Dnajc3a
1449388 at Lgx only 707 620 583 439 -1.14 -1.21 -1.61 Thbs4
1449396 at Lgx only 250 389 302 405 1.56 1.21 1.62 Aoc3
1449398 at Lgx only 8560 9487 11462 12020 1.11 1.34 1.40 R p131
1449400 at Lgx only 22 43 45 102 1.93 2.04 4.58 Cs1
1449408 at L x only 3014 3550 3724 3878 1.18 1.24 1.29Jam2
1449491 at Lgx only 1509 1650 1845 1973 1.09 1.22 1.31 Card10
1449505 at Res & L x 2070 2142 1758 1736 1.03 -1.18 -1.19 K nal
1449511 a at Lgx only 661 691 781 854 1.05 1.18 1.29 Ssb 4
1449514 at CR only 2473 1904 2807 2301 -1.30 1.14 -1.07 Grk5
1449547 at Res & Lgx 2990 2491 1986 1510 -1.20 -1.51 -1.98Asb14
1449551 at Lgx only 1623 1886 1869 1988 1.16 1.15 1.22 M of c
1449553 at CR & L x 868 640 1034 1201 -1.36 1.19 1.382610200G18Rik
1449566 at L x only 2519 2746 3461 3832 1.09 1.37 1.52 Nkx2-5
1449575 a at Res & L x 13795 15659 17129 18543 1.14 1.24 1.34 Gst 1
1449588 at Lgx only 588 491 438 385 -1.20 -1.34 -1.53Abca4
1449592 at CR only 1101 791 1255 1092 -1.39 1.14 -1.01 Tcf15
1449813 at Res only 276 352 86 217 1.27 -3.22 -1.27 Zf 30
1449818 at CR only 1563 2002 1765 1942 1.28 1.13 1.24 Abcb4
1449842 at Res & Lgx 718 590 533 420 -1.22 -1.35 -1.71 1810059G22Rik
1449845 a at Lgx only 745 860 974 1211 1.16 1.31 1.63 Ephb4
1449849 a at Lgx only 371 465 477 508 1.26 1.29 1.37 Fbx16
1449851 at L x only 442 679 726 810, 1.54 1.64 1.83 Pert
1449852 a at CR only 6223 8480 5751 5735 1.36 -1.08 -1.09 Ehd4
1449860 at Lgx only 730 574 585 447 -1.27 -1.25 -1.63 Hi d1b
1449872 at Lgx only 1222 1194 1026 765 -1.02 -1.19 -1.60 Hs b3
1449935 a at CR only 3719 4445 4158 4213 1.20 1.12 1.13 Dnaja3
1449942 a at L x onl 2010 2379 2324 2472 1.18 1.16 1.2311k
1449944 a at Res only 767 785 647 741 1.02 -1.19 -1.03 Sec61 a2
1449964 a at Lgx only 2099 2072 3263 3012 -1.01 1.55 1.43 Mlycd
1449969 at Lgx only 1482 1463 1356 1042 -1.01 -1.09 -1.42 Tmod4
1450016 at Lgx only 26432 25470 23049 19945 -1.04 -1.15 -1.33 Ccngl
1450023 at L x onl 732 879 873 1230 1.20 1.19 1.68 Gt b 1
1450031 at Lgx only 1227 1176 1239 982 -1.04 1.01 -1.25 Aff4
1450054 at Lgx only 2952 3635 3914 4173 1.23 1.33 1.41 Add1
1450067 a at Res & Lgx 2875 2957 2406 2199 1.03 -1.19 -1.31 1810034K20Rik
1450086 at Lgx only 172 236 254 316 1.37 1.48 1.84 Gmebl
1450095 a at L x only 387 339 395 207 -1.14 1.02 -1.87 Ac 1
1450122 at Lgx only 539 488 473 337 -1.11 -1.14 -1.60 Pt r
1450123 at Lgx only 11629 13643 15609 19737 1.17 1.34 1.70 Ryr2
1450138 a at Lgx only 3319 3219 2766 2714 -1.03 -1.20 -1.22 Ser inb6a
1450180 a at L x onl 38 71, 80 181 1.85 2.09 4.70 Rara
1450195 at Lgx only 35 102 106 144 2.91 3.04 4.11 Ndst4
1450199 a at Lgx only 795 979 986 1080 1.23 1.24 1.36 Stabl
CA 02699908 2010-03-17
WO 2009/039195 PCT/US2008/076707
-98-
Table 3
CO CR RES LGX FC FC FC
Probe Set ID Treatment mean mean mean mean CR Res L x Entrez Info
1450203 at Lgx only 5141 5970 4705 4331 1.16 -1.09 -1.19 Sm d 1
1450308 a at Res & Lgx 373 389 657 764 1.04 1.76 2.05 Xrn1
1450355 a at Res only 432 329 314 351 -1.31 -1.38 -1.23 Ca
1450361 at CR only 129 52 132 65 -2.47 1.02 -1.99 Pro 1
1450376 at Lgx only 2003 2127 2276 2577 1.06 1.14 1.29 Mxi1
1450377 at Lgx only 165 219 246 321 1.33 1.49 1.94 LOC640441
1450395 at L x onl 1580 1719 1822 2403 1.09 1.15 1.52 Slc22a5
1450405 at Res & L x 725 643 354, 320 -1.13 -2.05 -2.27 Mr 119
1450409 a at Lgx only 1748 1899 2253 2570 1.09 1.29 1.474930570O03Rik
1450415 at CR only 56 17 56 44 -3.33 -1.01 -1.29 Pde6a
1450424 a at CR only 188 296 252 253 1.58 1.34 1118bp
1450431 a at Res & L x 11524 12897 16998 18939 1.12 1.48 1.64 Nedd4
1450435 at Lgx only 277 284 353 397 1.03 1.27 1.44 L1 cam
1450449 a at L xonl 3983 4570 4434 5830 1.15 1.11 1.46 2900002H 1 6Rik
1450490 at Lgx only 417 575 570 646 1.38 1.37 1.55 Kcna7
1450519 a at Lgx only 4324 5666 5682 6518 1.31 1.31 1.51 Prkaca
1450531 at CR only 102 24 54 78 -4.30 -1.90 -1.30 1-12-131
1450584 at Res only 25 69 107 61 2.76 4.32 2.45 Hoxd11
1450623 at Lgx only 3269 3884 4094 4247 1.19 1.25 1.30 Gnb2
1450627 at Res & L x 10383 11098 8410 8645 1.07 -1.23 -1.20 Ank
1450649 at Lgx only 1489 966 883 760 -1.54 -1.69 -1.96 Gn 1O
1450650 at Lgx only 987 1096 1732 1739 1.11 1.76 1.76 M ol0
1450662 at L x onl 584 632 750 830 1.08 1.28 1.42 Tesk1
1450664 at CR & Lgx 1309 969 977 814 -1.35 -1.34 -1.61 Gab pa
1450670 at Lgx only 884 1083 1043 1276 1.22 1.18 1.44 Dbh
1450672 a at Lgx only 892 966 977 1154 1.08 1.10 1.29 Trexl
1450678 at CR only 384 292 365 338 -1.32 -1.05 -1.141t b2
1450690 at L x onl 1537 1178 953 774 -1.30 -1.61 -1.98 Ranbp2
1450691 at Res only 621 793 919 894, 1.28 1.48 1.44 Caskin2
1450700 at Res & L x 1859 1642 1543 1404 -1.13 -1.20 -1.32 Cdc42e 3
1450706 a at Lgx only 2959 2743 2744 2114 -1.08 -1.08 -1.40 Arl3
1450714 at Res & Lgx 2451 2021, 1702 1453 -1.21 -1.44 -1.69Azin1
1450729 at Lgx only 637 561 625 508 -1.14 -1.02 -1.25 Hs2st1
1450735 at Res & L x 2114 2019 1724 14631-1.05 -1.23 -1.45 Pno1
1450738 at L x onl 938 886 1089 1210 -1.06 1.16 1.29 Kif21 a
1450740 a at Res & L x 4235 4039 3546 3025 -1.05 -1.19 -1.40 Ma ref
1450744 at Lgx only 488 355 297 213 -1.38 -1.65 -2.29 E112
1450759 at Res only 852 857 1146 1021 1.01 1.35 1.20 Bmp6
1450791 at L x onl 15042 15107 14450 8913 1.00 -1.04 -1.69 Nppb
1450798 at L x only 819 1305 1266 1651 1.59 1.54 2.01 Tnxb
1450801 at Res & Lgx 37 93 146 227 2.53 3.98 6.20 Adam21
1450816 at Res only 384 341 301 362 -1.13 -1.27 -1.06 Polg2
1450839 at Res only 1123 1002 829 1015 -1.12 -1.35 -1.11 DOH4S114
1450840 a at L x only 50799 56471 65223 75285 1.11 1.28 1.48 R p139
1450842 a at CR & L x 2062 1704 1758 1347 -1.21 -1.17 -1.53 en pa
1450857 a at Lgx only 2960 3430 3914 4745 1.16 1.32 1.60 Co11 a2
CA 02699908 2010-03-17
WO 2009/039195 PCT/US2008/076707
-99-
Table 3
CO CR RES LGX FC FC FC
Probe Set ID Treatment mean mean mean mean CR Res L x Entrez Info
1450866 a at Lgx only 3015 3253 3652 3857 1.08 1.21 1.28 Mr 117
1450878 at Lgx only 2049 1928 1635 1368 -1.06 -1.25 -1.50 Sri
1450879 at L x onl 610 710 716 993 1.16 1.17 1.63 At 9b
1450883 a at CR only 31708 23985 32717 30704 -1.32 1.03 -1.03 Cd36
1450890 a at Lgx only 948 726 729 585 -1.31 -1.30 -1.62Abil
1450891 at Lgx only 5718 5089 4197 3750 -1.12 -1.36 -1.53 Sr 19
1450894 a at Res & Lgx 2906 3585 3746 3815 1.23 1.29 1.31 A 2ml
1450897 at Lgx only 1688 1363 1427 11651-1.24 -1.18 -1.45 Arh a 5
1450903 at Lgx only 1020 958 834 627 -1.06 -1.22 -1.63 Rad23b
1450927 at Lgx only 514 591 685 712 1.15 1.33 1.39 Lztrl
1450934 at Res & L x 22353 18933 16228 15963 -1.18 -1.38 -1.40 Eif4a2
1450948 a at Lgx only 827 736 541 458.-1.12 -1.53 -1.81 Mrpll
1450953 at Res & L x 2794 2661 2247 2084 -1.05 -1.24 -1.34 Ciao1
1450957 a at Lgx only 14361 13299 20795 20648 -1.08 1.45 1.44 S stm1
1450958 at Lgx only 5954 4641 4404 4138 -1.28 -1.35 -1.44 Tm4sf1
1450965 at Res & Lgx 1995 2296 2538 3135 1.15 1.27 1.57 Tex261
1450966 at L x only 927 836 863 6791-1.111-1.07 -1.37 Crot
1450968 at Lgx only 39927 41899 42555 55205 1.05 1.07 1.38 U crfsl
1450970 at Lgx only 25949 32719 31690 36332 1.26 1.22 1.40 Gott
1450971 at Res & L x 551 827 965 1069 1.50 1.75 1.94 Gadd45b
1450974 at Res & L x 776 1077 1180 1212 1.39 1.52 1.56 Tim 4
1450994 at Lgx only 2773 2136 2256 1821 -1.30 -1.23 -1.52 Rockl
1451002 at L x onl 54266 62734 61354 75692 1.16 1.13 1.39Aco2
1451006 at Lgx only 1143 1483 1634 1746 1.30 1.43 1.53 Xdh
1451010 at L x onl 656 786 728 858 1.20 1.11 1.31 Noll 1
1451017 at Lgx only 1586 1728 1871 2173 1.09 1.18 1.37 Er ic3
1451019 at Lgx only 1338 1281 1678 2014 -1.04 1.25 1.51 Ctsf
1451022 at Lgx only 545 506 713 8521-1.08 1.31 1.56 Lrp6
1451025 at Lgx only 2443 2161 1929 1347 -1.13 -1.27 -1.81 Ar11
1451050 at Lgx only 3147 2948 2847 2290 -1.07 -1.11 -1.37 Nt5c3
1451051 a at L x onl 837 1040 1137 1455 1.24 1.36 1.74 Sc l l
1451067 at Lgx only 3259 4112 4448 4416 1.26 1.37 1.36 S to
1451070 at Lgx only 2031 2545 2472 3265 1.25 1.22 1.61 Gdil
1451074 at Res & L x 4210 3824 3180 2816 -1.10 -1.32 -1.49 Rnf13
1451096 at L x onl 29178 32946 32150 36689 1.13 1.10 1.26 Ndufs2
1451099 at Lgx only 535 685 718 838 1.28 1.34 1.57 Mbc2
1451104 a at CR & L x 1056 1430 1492 1790 1.35 1.41 1.69 Snr 70
1451118 a at L xonl 790 918 855 1042 1.16 1.08 1.322410018C17Rik
1451119 a at L x onl 2418 2685 3222 3877 1.11 1.33 1.60 Fblnl
1451121 a at Res & L x 1112 1325 1636 1783 1.19 1.47 1.60 Gltscr2
1451126 at Lgx only 4627 4444 5283 55891-1.04 1.14 1.21 Mafl
1451134 a at Res & L x 1207 953 612 601 -1.27 -1.97 -2.01 Tm2d2
1451144 at All 1442 1150 986 886 -1.25 -1.46 -1.63 Bxdc2
1451159 at Res & L x 4282 5561 6247 8339 1.30 1.46 1.95Arh ef12
1451168 a at Res & L x 4732 5809 6829 7722 1.23 1.44 1.63 Arh dia
1451177 at Res & L x 6681 6017 4465 40801-1.11 -1.50 -1.64 Dnajb4
CA 02699908 2010-03-17
WO 2009/039195 PCT/US2008/076707
-100-
Table 3
CO CR RES LGX FC FC FC
Probe Set ID Treatment mean mean mean mean CR Res L x Entrez Info
1451187 at Lgx only 4203 4110 3516 3225 -1.02 -1.20 -1.30 0610037PO5Rik
1451204 at Res only 2057 1633 1312 1410 -1.26 -1.57 -1.46 Scara5
1451217 a at L x onl 6459 5713 5401 43881-1.13 -1.20 -1.47 Imm l l
1451219 at Lgx only 915 777 738 662 -1.18 -1.24 -1.38 Ormdll
1451223 a at Lgx only 2697 2588 2232 1739 -1.04 -1.21 -1.55 Btf314
1451225 at Lgx only 6229 6428 6944 7210 1.03 1.11 1.16 Pt nl 1
1451226 at L x onl 1149 1523 1685 2053 1.32 1.47 1.79 Pex6
1451232 at Lgx only 6475 6003 4860 43461-1.08 -1.33 -1.49 Cd151
1451244 a at Lgx only 1155 1068 902 915 -1.08 -1.28 -1.26 Zf 422
1451245 at Lgx only 1838 1659 1561 1417 -1.11 -1.18 -1.30 Lrrc3b
1451248 at Res & L x 1477 1443 1184 1086 -1.02 -1.25 -1.36 Prmt7
1451254 at Res & L x 1081, 1005 719 681 -1.08 -1.50 lkbkap
1451269 at Lgx only 1025 970 886 831 -1.06 -1.16 -1.23 Pdzdl1
1451272 a at Res & L x 1518 1300 972 856 -1.171-1.56 -1.77 Ube2f
1451274 at Lgx only 18853 24930 23212 26074 1.32 1.23 1.38 Ogdh
1451281 at Res onl182 134 126 176 -1.36 -1.44 -1.03Zscan12
1451284 at Lgx only 824 1042 937 1011 1.26 1.14 1.23 Yi f3
1451285 at Lgx only 1415 1654 1921 2284 1.17 1.36 1.61 Fus
1451290 at Lgx only 19210 20375 21862 26463 1.06 1.14 1.38 Map 1lc3a
1451291 at CR only 985 1221 1225 1080 1.24 1.24 1.10 Obfc2b
1451293 at CR only 334 573 472 317 1.71 1.41 -1.05 Rrp9
1451295 a at Res & L x 645 582 1919 1477 -1.11 2.98 2.29 Chd4
1451297 at Res only 17 25 80 44 1.45 4.66 2.55 Gulo
1451298 at L x only 536 562 684 976 1.05 1.28 1.82 Plekhh3
1451312 at Lgx only 31762 35863 37350 45671 1.13 1.18 1.44 Ndufs7
1451316 a at Res & L x 5859 5369 3411 3242 -1.09 -1.72 -1.81 Picalm
1451343 at Lgx only 832 752 752 595.-1.11 -1.11 -1.40 V s36
1451344 at L x only 284 314 447 534 1.11 1.57 1.88 Tmeml 19
1451349 at Lgx only 129 111 75 50 -1.16 -1.73 -2.56 BC020077
1451364 at Res & L x 1068 1040 814 549 -1.03 -1.31 -1.94 Polr3 l
1451369 at Lgx only 1208 1284 1405 1759 1.06 1.16 1.46 Commds
1451381 at L x only 3059 2545 2352 20421-1.20 -1.30 -1.50 181002OD17Rik
1451382 at Res & L x 247 447 470 562 1.81 1.90 2.28 Chad
1451388 a at L x onl 1122 1092 1224 1351 -1.03 1.09 1.20 At 11b
1451405 at Lgx only 3973 4289 5228 5041 1.08 1.32 1.27 Pcca
1451415 at CR only 1529 2052 1641 1570 1.34 1.07 1.031181001101 ORik
1451420 at Res & L x 2878 2478 2242 2325 -1.16 -1.28 -1.24 Ccdc47
1451427 a at Lgx only 1907 2012 2224 2426 1.05 1.17 1.27 E f17
1451448 a at L x only 1765 1548 1206 984 -1.14 -1.46 -1.79 1110005AO3Rik
1451453 at Lgx only 246 248 265 336 1.01 1.08 1.36 Da k2
1451455 at Res only 273 220 478 3741-1.24 1.75 1.37 Thnsl2
1451462 a at Lgx only 1261 1287 1200 958 1.02 -1.05 -1.32 lfnar2
1451465 at Lgx only 1407 1531 1643 1908 1.09 1.17 1.36 Ub17
1451471 at Lgx only 421 391 360 290 -1.08 -1.17 -1.45 Ears2
1451488 at Lgx only 7929 9254 9001 10760 1.17 1.14 1.36 1110028AO7Rik
1451502 at CR only 160 305 224, 282 1.90 1.40 1.76 Plat 10
CA 02699908 2010-03-17
WO 2009/039195 PCT/US2008/076707
-101-
Table 3
CO CR RES LGX FC FC FC
Probe Set ID Treatment mean mean mean mean CR Res L x Entrez Info
1451508 at Lgx only 1347 1314 1107 988 -1.02 -1.22 -1.36 Larp2
1451523 a at Lgx only 1126 879 1016 827 -1.28 -1.11 -1.36 Mif4gd
1451538 at L x onl 135 123 153 2421-1.10 1.13 1.78 Sox9
1451553 at Lgx only 713 650 619 510 -1.10 -1.15 -1.40 Art5
1451561 at Res & L x 450 622 809 978 1.38 1.80 2.18 Prrl2
1451583 a at Res & L x 69 119 158 261 1.72 2.29 3.78 BC025076
1451604 a at L x onl 658 716 707 849 1.09 1.07 1.29 Acvrl1
1451622 at Lgx only 2006 2187 2476 2643 1.09 1.23 1.32 Lmbrd1
1451663 a at Lgx only 743 755 847 912 1.02 1.14 1.23 Trim3
1451665 a at Res & Lgx 5435 4923 4504 4166 -1.10 -1.21 -1.30A 4s1
1451674 at L x onl 114 131 180 195 1.15 1.57 1.70 Slc12a5
1451678 at Res & L x 2482 2409 1553 1507 -1.03 -1.60 -1.65 Narf
1451700 a at Res & L x 2076 2271 2807 2740 1.09 1.35 1.3211100071-15Rik
1451728 at Lgx only 792 823 931 1122 1.04 1.17 1.42Wdr13
1451741 a at Lgx only 732 614 585 518 -1.19 -1.25 -1.41 Cdk7
1451742 a at Lgx only 14534 14261 12397 114261-1.02 -1.17 -1.27 Ugp2
1451782 a at L x only 2095 2186 2027 2552 1.04 -1.03 1.22 Slc29a1
1451789 a at CR only 651 1037 851 972 1.59 1.31 1.49 R k
1451803 a at Lgx only 6764 8556 8339 9104 1.26 1.23 1.35 Ve fb
1451820 at Lgx only 131 214 241 536 1.64 1.84 4.10 Dirasl
1451839 a at CR only 890 1444 1029 1071 1.62 1.16 1.20 Pde7a
1451854 a at Lgx only 383 572 575 694 1.49 1.50 1.81 Shroom3
1451857 a at Lgx only 194 239 319 373 1.23 1.64 1.92 Notum
ENSMUSG-
1451883 at Res & Lgx 401 497 932 825 1.24 2.32 2.06 00000074670
1451902 at Lgx only 572 427 446 344 -1.34 -1.28 -1.66 Zf 758
1451911 a at Lgx only 784 928 1055 1218 1.18 1.35 1.55 Ace
1451974 at Lgx only 3494 3897 3875 4394 1.12 1.11 1.26 Osbpl2
1451984 at Res & L x 1996 1833 1480 1574 -1.09 -1.35 -1.27 Hnr ull
1452012 a at Lgx only 688 561 589 4331-1.23 -1.17 -1.59 Exoscl
1452024 a at Lgx only 972 977 1305 1295 1.00 1.34 1.33 Ldbl
1452043 at L xonl 638 593 728 510 -1.07 1.14 -1.252310011J03Rik
1452047 at Res & L x 2343 2094 1524 1383 -1.12 -1.54 -1.69 Cacybp
1452057 at Lgx only 1040 1024 1176 1469 -1.02 1.13 1.41 Actr1 b
1452058 a at Res & L x 8691 8360 5764 57281-1.04 -1.51 -1.52 Rnfl 1
1452072 at Res & Lgx 1185 937 765 822 -1.27 -1.55 -1.44 Myctl
1452080 a at L x only 1213 1057 971 775 -1.15 -1.25 -1.57 Dcunldl
1452088 at Res only 153 231 81 127 1.51 -1.89 -1.21 Zbed3
1452091 a at CR & Lgx 852 1127 962 1169 1.32 1.13 1.37 Rbm28
1452110 at Lgx only 459 361 351 3271-1.27 -1.31 -1.41 Mtrr
1452130 at Res & Lgx 1764 1802 966 869 1.02 -1.83 -2.03 Txndcl4
1452140 at Res & L x 867 934 1137 1294 1.08 1.31 1.49 Tbcl d20
1452141 a at L x onl 25419 26171 28265 32953 1.03 1.11 1.30 Seppl
1452143 at All 21772 24259 24942 27902 1.11 1.15 1.28 S nb2
1452145 at L x onl 524 698, 748 1076 1.33 1.43 2.06 H6 pd
1452152 at Lgx only 2710 2333 2165 17851-1.161-1.25 -1.52 Clintl
1452155 a at Res & L x 3205 3897 4271 4549 1.22 1.33 1.42 Ddx17
CA 02699908 2010-03-17
WO 2009/039195 PCT/US2008/076707
-102-
Table 3
CO CR RES LGX FC FC FC
Probe Set ID Treatment mean mean mean mean CR Res L x Entrez Info
1452156 a at Lgx only 4703 5715 5941 7648 1.22 1.26 1.63 Nisch
1452159 at Res & L x 1379 1311 1056 977 -1.05 -1.31 -1.41 2310001A20Rik
1452173 at L x onl 26826 30831 34012 38315 1.15 1.27 1.43 Hadha
1452174 at Res & Lgx 500 634 880 1000 1.27 1.76 2.00 Srebf2
1452202 at Lgx only 1135 1145 1336 1475 1.01 1.18 1.30 Pde2a
1452203 at All 2414 1686 1491 1035 -1.43 -1.62 -2.33 Obfc2a
1452208 at L x onl 485 620 638 696 1.28 1.31 1.43 Prdm4
1452213 at Res & Lgx 1320 1264 1036 845 -1.04 -1.27 -1.56 Tex2
1452214 at Lgx only 1513 1185 1126 850 -1.28 -1.34 -1.78 Skil
1452221 a at Lgx only 1063 1125 1281 1393 1.06 1.20 1.31 Cxxcl
1452222 at L x onl 1656 1643 1732 2090 -1.01 1.05 1.26 Utrn
1452225 at Lgx only 1335 1061 1047 10001-1.26 -1.28 -1.33 2010106G01 Rik
1452250 a at Lgx only 2260 2785 2667 3592 1.23 1.18 1.59 Col6a2
1452262 at Lgx only 708 642 550 557 -1.10 -1.29 -1.27 Grpel2
1452286 at Res & Lgx 6581 4659 2979 2444 -1.41 -2.21 -2.69 Slain2
1452291 at Lgx only 564 461 566 360 -1.22 1.00 -1.57 Centdl
1452292 at L only 1094 1334 1435 1847 1.22 1.31 1.69A 2b1
1452296 at Lgx only 237 266 412 579 1.12 1.74 2.45 Slit3
1452308 a at L xonl 4905 5839 6466 6497 1.19 1.32 1.32At 1a2
1452309 at Lgx only 721 839 763 1132 1.16 1.06 1.57 Cgnll
1452318 a at Res & L x 536 385 278 289 -1.39 -1.93 -1.86 Hs al b
1452319 at CR only 283 194 251 220 -1.46 -1.13 -1.28 Zf 82
1452327 at Lgx only 904 1190 1305 1397 1.32 1.44 1.55 I sect
1452329 at Res & L x 265 311 451 486 1.17 1.71 1.84 Plekhnl
1452330 a at L x only 2664 2991 3519 4501, 1.12 1.32 1.69 Mxra8
1452333 at Res & L x 475 512 815 822 1.08 1.71 1.73 Smarca2
1452335 at Res & L x 485 467 382 319 -1.04 -1.27 -1.52 Mfsd8
1452339 at Lgx only 320 425 415 535 1.33 1.30 1.67 Adamts7
1452374 at L x only 756 605 602 553 -1.25 -1.26 -1.37 Zf 322a
1452375 at Lgx only 1059 1280 1336 1441 1.21 1.26 1.36 AIdh4al
1452395 at Res & L x 550 421 386 2951-1.31 -1.42 -1.87 Med19
1452398 at Lgx only 1052 998 837 640 -1.051-1.26 -1.64 PIcel
1452401 at Lgx only 1940 1839 1632 1573 -1.05 -1.19 -1.23Wtap
1452411 at L x only 261, 364 308 474 1.40 1.18 1.82 Lrrcl
1452432 at Lgx only 2342 2445 2339 1802 1.04 -1.00 -1.30 Tf i
1452446 a at Lgx only 1260 1260 1436 1569 1.00 1.14 1.25 Tmub2
1452462 a at Lgx only 342 469 538 591 1.37 1.58 1.73 Ban p
1452469 a at Res & Lgx 1833 2687 2690 3184 1.47 1.47 1.74 Smtn
1452472 at Lgx only 128 142 189 242 1.11 1.47 1.89 Rt 3
1452499 a at Res only 705 659 530 573 -1.07 -1.33 -1.23 Kif2a
ENSMUSG-
1452502 at L x only 190 121 131 88 -1.56 -1.45 -2.15 00000050599
1452509 at CR only 114 33 80 89 -3.44 -1.44 -1.29 Us 9
1452587 at Lgx only 3962 3990 3352 3268 1.01 -1.18 -1.21 Actr2
1452596 at Lgx only 4654 3854 3014 2105 -1.21 -1.54 -2.21 Polr2k
1452601 a at Lgx only 978 969, 1221 1242,-1.01 1.25 1.27Acbd6
1452607 at L x only 978 917 707 5871-1.07 -1.38 -1.67 2610030H06Rik
CA 02699908 2010-03-17
WO 2009/039195 PCT/US2008/076707
-103-
Table 3
CO CR RES LGX FC FC FC
Probe Set ID Treatment mean mean mean mean CR Res L x Entrez Info
1452608 at Res & Lgx 727 527 412 452 -1.38 -1.76 -1.61 Mycbp
1452625 at Lgx only 772 766 950 1078 -1.01 1.23 1.40 Kctd2
1452653 at L x only 1121 1286 1501 1804 1.15 1.34 1.61 Slc25a22
1452657 at L xonl 1898 1692 1530 1326 -1.12 -1.24 -1.43A 1s2
1452661 at Res & Lgx 4325 6173 1466 1666 1.43 -2.95 -2.60 Tfrc
1452689 at Res only 1202 1315 1457 1353 1.09 1.21 1.13 Zf 512
1452694 at L x onl 1776 1941 2134 2382 1.09 1.20 1.34 Ih kl
1452698 at Lgx only 1101 1252 1139 1500 1.14 1.04 1.36 Tsfm
1452709 at Res & Lgx 590 680 819 833 1.15 1.39 1.41 Poldip3
1452714 at Lgx only 872 1040 976 1284 1.19 1.12 1.47 Tancl
1452737 at L xonl 1487 1388 1103 899 -1.07 -1.35 -1.652810008M24Rik
1452745 at Lgx only 788 1066 1236 1408 1.35 1.57 1.79 1810044A24Rik
1452749 at Lgx only 1136 1094 893 738 -1.04 -1.27 -1.54 Pa dl
1452753 at Res only 837 908 529 625 1.08 -1.58 -1.34 Foxk2
1452761 a at L x onl 485 513 599 1042 1.06 1.24 2.15 8430436014Rik
1452767 at Lgx only 2638 2966 3499 3821 1.12 1.33 1.45 Rrb 1
1452776 a at Res only 663 841 1073 970 1.27 1.62 1.46 Nubl
1452813 a at Res & L x 2436 2172 1960 1741 -1.12 -1.24 -1.40Tmeml88
1452843 at Res & Lgx 3451 4038 4593 5346 1.17 1.33 1.55116st
1452844 at Res only 751 823 1059 1074 1.10 1.41 1.43 Pou6fl
1452856 at Res only 739 644 536 657 -1.15 -1.38 -1.13 Crebzf
1452866 at CR & Res 2752 2260 2177 2385 -1.22 -1.26 -1.15 Nars
1452867 at Lgx only 2212 1946 1780 1556 -1.14 -1.24 -1.42 Col4a3bp
1452871 at Lgx only 416 352 302 259 -1.18 -1.38 -1.61 Neill
1452874 at Lgx only 2271 2311 2091 1836 1.02 -1.09 -1.24 2510003E04Rik
1452877 at L xonl 2296 2197 1472 1361 -1.05 -1.56 -1.692700029M09Rik
1452885 at L x onl 1428 1377 2182 2172 -1.04 1.53 1.52 Sfrs2ip
1452897 at CR & Lgx 696 543 615 531 -1.28 -1.13 -1.31 Cdc215
1452901 at Lgx only 1170 1145 777 693,-1.02 -1.50 -1.69 Crebl
1452913 at Lgx only 2974 3092 3677 4408 1.04 1.24 1.48 Pcp4ll
1452918 at Res & L x 829 733 480 371 -1.131-1.73 -2.23 D19Ertd737e
1452920 a at Lgx only 1190 1193 1012 760 1.00 -1.18 -1.57 P il2
1452952 at Res & L x 922 773 689 632 -1.19 -1.34 -1.46 9030418K01 Rik
1452953 at Res & Lgx 992 827 679 580 -1.20 -1.46 -1.71 Faml8b
1452960 at L x onl 245 207 208 1631-1.18 -1.18 -1.51 Scyl3
1452965 at Res only 29 40 111 84 1.36 3.79 2.86Ankrd13d
1452972 at Lgx only 1013 814 912 729 -1.25 -1.11 -1.39 Ttc32
1452977 at Lgx only 531 595 622 751 1.12 1.17 1.42 Zhx3
1452985 at Lgx only 878 899 1344 1287 1.02 1.53 1.47 Uaca
1452999 at L x only 842 889 680 565 1.06 -1.24 -1.49 Smndcl
1453007 at CR only 283 386 348 337 1.36 1.23 1.19 3110082117Rik
1453013 at Res & Lgx 382 472 620 612 1.23 1.62 1.60 Zf 740
1453014 a at Lgx only 1817 2542 2796 3042 1.40 1.54 1.67 Sec31 a
1453023 at L x only 617 600 801 808 -1.03 1.30 1.31 Ankhdl
1453028 at Lgx only 215 210 184 94 -1.03 -1.17 -2.294631424J17Rik
1453039 at Lgx only 590 726 780 855 1.23 1.32 1.45 Zf 335
CA 02699908 2010-03-17
WO 2009/039195 PCT/US2008/076707
-104-
Table 3
CO CR RES LGX FC FC FC
Probe Set ID Treatment mean mean mean mean CR Res L x Entrez Info
1453058 at Lgx only 174 168 136 55 -1.04 -1.28 -3.18 Wdr5b
1453059 at Lgx only 8551 8336 7741 7324 -1.03 -1.10 -1.17 2310046AO6Rik
1453062 at CR only 223 400 295 433 1.80 1.33 1.95A930026122Rik
1453097 a at Lgx only 1577 1678 1749 2148 1.06 1.11 1.36 Ubtf
1453119 at Res & L x 559 481 365 290 -1.16 -1.53 -1.92Otud1
1453129 a at Lgx only 557 617 773 837 1.11 1.39 1.50 R s12
1453137 at Lgx only 1023 1022 916 767 -1.00 -1.12 -1.33 Fbxo30
1453149 at L x only 290 191 219 111 -1.52 -1.33 -2.61 Slc25a32
1453154 at CR only 79 24 84 44 -3.27 1.06 -1.78 1700029M20Rik
1453155 at Lgx only 2675 2692 2995 3076 1.01 1.12 1.15 Tmem50a
1453160 at Lgx only 738 596 734 458 -1.24 -1.01 -1.61 Med13
1453180 at Res only 782 784 635 639 1.00 -1.23 -1.23 65304041\121 Rik
1453187 at All 605 410 365 248 -1.48 -1.66 -2.44 Ociad2
1453191 at Lgx only 374 503 391 738 1.34 1.04 1.97 Co127a1
1453196 a at Res & L x 254 340 389 411 1.34 1.53 1.62 0as12
1453206 at Res & L x 890 1145 1255 1633 1.29 1.41 1.84Acad9
1453212 at L x only 319 237 226 141 -1.34 -1.41 -2.27 Zf 383
1453224 at Res & L x 809 940 1461 1631 1.16 1.81 2.02 Zfands
1453257 at Lgx only 853 753 660 637 -1.13 -1.29 -1.34 A at5
1453271 at Res & L x 1296 1098 939 900 -1.18 -1.38 -1.44 Phf14
1453296 at CR only 113 32 90 1341-3.51 -1.25 1.19 Tmeml O3
1453312 at Lgx only 790 818 632 503 1.04 -1.25 -1.57 I wdl
1453377 at Res & Lgx 606 603 406 399 -1.00 -1.49 -1.52 Sh2d4a
1453391 at CR only 28 75 84 70 2.64 2.97 2.47 S eer7- sl
1453399 at Res & Lgx 607 726 1159 1232 1.20 1.91 2.03 Ccnt2
1453412 a at CR only 2089 2711 2591, 2801 1.30 1.24 1.34 Sec1411
1453486 a at Lgx only 1455 1240 1142 1034 -1.17 -1.27 -1.41 Scube2
1453494 at Res only 98 79 44 66 -1.23 -2.21 -1.49 4921 51 3H07Rik
1453502 at L x only 77 79 94 27 1.02 1.22 -2.82 2210408121 Rik
1453552 at CR & Lgx 1567 1069 1454 9801-1.47 -1.08 -1.602310014F07Rik
1453572 a at Lgx only 2411 2727 2793 3149 1.13 1.16 1.31 PI 2
1453592 at Lgx only 3846 3055 3329 2431 -1.26 -1.16 -1.58 Lrrc39
1453673 at L x only 76 65 94 172 -1.18 1.24 2.26 LOC100046982
1453728 a at Lgx only 3261 3568 2905 2627 1.09 -1.12 -1.24 Mr sl7
1453729 a at L x onl 41216 43763 46983 55549 1.06 1.14 1.35 R 137
1453731 a at Lgx only 3325 2887 2681 2049 -1.15 -1.24 -1.62 Tmem77
1453739 at Res & Lgx 450 425 316 266 -1.06 -1.42 -1.69Tmem126b
1453740 a at Lgx only 2063 2311 2547 2926 1.12 1.24 1.42 Ccnl2
1453761 at Res only 74 144 179, 199 1.95 2.43 2.71 Phf6
1453795 at Lgx only 1896 2038 2175 2434 1.08 1.15 1.28 Fahd2a
1453804 a at Lgx only 804 758 637 604 -1.06 -1.26 -1.33 Orc4l
1453821 at Res only 642 596 1039 923 -1.08 1.62 1.44 N6amtl
1453850 at L x onl 43 35 37 131 -1.24 -1.19 3.01 1500002101 Rik
1453851 a at Lgx only 352 496 457 640 1.41 1.30 1.82 Gadd45
1453865 a at Res & L x 869 969 1199 1124 1.12 1.38 1.29 Otud5
1453866 a at Lgx only 43 74 75 126 1.71 1.73 2.91 Xk
CA 02699908 2010-03-17
WO 2009/039195 PCT/US2008/076707
-105-
Table 3
CO CR RES LGX FC FC FC
Probe Set ID Treatment mean mean mean mean CR Res L x Entrez Info
1453898 at CR only 501 793 335 384 1.58 -1.49 -1.30 Itb1b 3
1453913 a at Lgx only 849 962 1213 1299 1.13 1.43 1.53 Ta 2
1453976 at CR only 143 76 125 134 -1.891-1.15 -1.074432414FO5Rik
1453983 a at Lgx only 927 804 894 635 -1.15 -1.04 -1.46 MettlOd
1454017 at Res & Lgx 25 38 74 84 1.54 3.00 3.41 4921509007Rik
1454020 at Lgx only 51 52 75 163 1.04 1.49 3.21 4930554H23Rik
1454021 a at CR only 1143 1359 1194 1279 1.19 1.04 1.12 Exoscl0
1454023 a at Lgx only 385 503 469 613 1.31 1.22 1.59 D1 Bw 1363e
1454034 a at Lgx only 569 709 792 894 1.25 1.39 1.57 Us 21
1454047 a at CR only 276 183 203 229 -1.51 -1.36 -1.202410017P07Rik
1454074 a at Res & L x 1611 1425 1123 9001-1.13 -1.43 -1.79 Rsrc2
1454092 a at Res only 593 635 442 463 1.07 -1.34 -1.28 Gtf2h3
1454109 a at Res & Lgx 591, 481 406 366 -1.23 -1.46 -1.61 Jmjd6
1454116 a at Lgx only 1801 1594 1238 1086 -1.13 -1.46 -1.66 Mterfdl
1454189 at Lgx only 73 110 141 142 1.51 1.93 1.944930557J02Rik
1454206 a at L xonl 392 464 580 728 1.18 1.48 1.86Adam15
1454214 a at L x onl 746 743 637 541 -1.00 -1.17 -1.38 2410019A14Rik
1454236 a at Res only 269 286 159 248 1.06 -1.69 -1.08 P 4r11
1454395 at Lgx only 439 558 623 761 1.27 1.42 1.734632404M16Rik
1454455 at L xonl 72 65 114 167 -1.10 1.59 2.336530413G14Rik
1454466 at CR only 80 13 67 52 -6.28 -1.18 -1.544933407118Rik
1454606 at Lgx only 1497 1775 1754 1897 1.19 1.17 1.27 4933426M1 1 Rik
1454611 a at Res only 4696 4347 3422 3420 -1.08 -1.37 -1.37 Calml
1454612 at Lgx only 610 597 535 4371-1.02 -1.14 -1.40 Mex3c
1454613 at Lgx only 978 1329 1415 1720 1.36 1.45 1.76 Dpysl3
1454619 at L x only 1392 1555 1880 2331 1.12 1.35 1.67 Tmeml 12b
1454626 at Lgx only 3655 3568 2821 2614 -1.02 -1.30 -1.40 Cltc
1454631 at L x only 639 592 552 433 -1.081-1.16 -1.48 Gtf2al
1454638 a at Lgx only 1004 949 703 592 -1.06 -1.43 -1.70 Pah
1454644 at L xonl 470 566 617 705 1.20 1.31 1.50 6330569M22Rik
1454645 at Res & L x 3953 5231 5398 6226 1.32 1.37 1.57 M rnl
1454646 at Res only 5976 6134 4613 4866 1.03 -1.30 -1.23 Tc 1112
1454647 at Lgx only 3249 2669 2518 21121-1.22 -1.29 -1.54 Acadl1
1454654 at Lgx only 1244 1418 1330 1645 1.14 1.07 1.32 Dirc2
1454658 at Res only 790 826 1079 882 1.05 1.37 1.12 llvbl
1454666 at Lgx only 2164 1836 1500 1233 -1.18 -1.44 -1.76 LOC100046855
1454670 at L x only 1041 1359 1101 1577 1.31 1.06 1.51 Rere
1454679 at Lgx only 374 407 335 481 1.09 -1.12 1.29 D8Ertd457e
1454682 at L xonl 1062 918 870 788 -1.16 -1.22 -1.35A430005L14Rik
1454693 at Lgx only 512 617 534 706 1.20 1.04 1.38 Hdac4
1454697 at L x only 1244 1274 1567 1632 1.02 1.26 1.31 Tlocl
1454704 at Lgx only 8488 8673 9500 10160 1.02 1.12 1.20 Scarb2
1454706 at Res & L x 841 933 1147 1655 1.11 1.36 1.97 Uvra
1454709 at CR only 1558 1256 1428 1353 -1.24 -1.09 -1.15 Tmem64
1454718 at CR only 405 601 518 565 1.48 1.28 1.40 Nagpa
1454723 at L x only 553 511 424 378 -1.08 -1.31 -1.46 1110033M05Rik
CA 02699908 2010-03-17
WO 2009/039195 PCT/US2008/076707
-106-
Table 3
CO CR RES LGX FC FC FC
Probe Set ID Treatment mean mean mean mean CR Res L x Entrez Info
1454727 at Lgx only 1394 1215 977 798 -1.15 -1.43 -1.75 Afa 111
1454730 at All 769 590 524 464 -1.30 -1.47 -1.66 Taptl
1454733 at Res only 911 985 1221 1082 1.08 1.34 1.19 Nodl
1454739 at Res & L x 644 552 440 462 -1.17 -1.46 -1.39 Cdc27
1454745 at Lgx only 3289 3105 2800 2804 -1.06 -1.17 -1.17 Arh a 29
1454749 at Lgx only 684 403 1251 1482 -1.70 1.83 2.17 Pcnt
1454753 at L x onl 1587 2106 2105 2294 1.33 1.33 1.45 Rn e ll
1454759 at Lgx only 438 629 684 820 1.43 1.56 1.87 Gitl
1454780 at Res & Lgx 369 411 559 501 1.12 1.52 1.36 Galntl4
1454797 at Res & Lgx 1016 1208 1395 1607 1.19 1.37 1.58 Tmem55b
1454801 at L x onl 432 318 409 291 -1.36 -1.06 -1.48 Ankrd28
1454813 at Lgx only 14224 13070 12391 10412 -1.09 -1.15 -1.37 Ccdc72
1454820 at Res & L x 41 115 186 231 2.83 4.59 5.68 BC037034
1454834 at Lgx only 2775 2711 2558 2415 -1.02 -1.08 -1.15 Nfib
1454848 at Lgx only 465 542 638 645 1.16 1.37 1.39 P 1 rl2c
1454861 at Lgx only 629 688 770 967 1.09 1.22 1.54 Txlna
1454868 at L x only 1589 2148 2178 2607 1.35 1.37 1.64 D4Ertd429e
1454887 at Lgx only 747 899 852 1049 1.20 1.14 1.41 Pak2
1454888 at Res & Lgx 1357 1167 902 903 -1.16 -1.50 -1.50 Pfdn4
1454892 at Lgx only 2663 2785 3279 3697 1.05 1.23 1.39 Pitpnb
1454894 at Lgx only 1514 1552 1292 1165 1.03 -1.17 -1.30 LOC100045522
1454895 at Res & L x 580 737 920 969 1.27 1.59 1.67 C basc3
1454906 at Res & Lgx 1336 1248 925 804 -1.07 -1.44 -1.66 Rarb
1454914 at Lgx only 1116 1031 928 845 -1.08 -1.20 -1.32 2610101 N1 ORik
1454915 at Res & L x 351, 379 517 591 1.08 1.47 1.68 Raba a 2
1454921 at Lgx only 2860 2668 2533 1763 -1.071-1.13 -1.62 Gm561
1454922 at Res & Lgx 927 893 748 601 -1.04 -1.24 -1.54Wdr92
1454928 at Lgx only 431 638 710 848 1.48 1.65 1.97 Safb
1454930 at CR only 902 684 840 692 -1.32 -1.07 -1.30 Tbce1
1454934 at CR only 783 941 754 809 1.20 -1.04 1.03 P m1f
1454937 at L x onl 411 351 295 228 -1.17 -1.39 -1.80 B630005N14Rik
1454938 at Lgx only 1417 1321 1222 1011 -1.07 -1.16 -1.40 Snxl3
1454955 at Lgx only 6741 6181 6145 5319 -1.09 -1.10 -1.271 o7
1454960 at L x onl 737 915 886 1114 1.24 1.20 1.51 Smad3
1454964 at CR only 4312 5102 4189 4991 1.18 -1.03 1.16 BC021395
1454977 at Lgx only 235 290 342 395 1.23 1.46 1.68 AU020772
1454979 at Lgx only 940 990 1118 1206 1.05 1.19 1.28 Diapl
1454980 at Lgx only 2726 3305 3169 3859 1.21 1.16 1.424930402E16Rik
1454985 at L x only 374 389 391 531 1.04 1.05 1.42 D030051 N19Rik
1454991 at Res & Lgx 1439 1242 1003 894 -1.16 -1.43 -1.61 Slc7al
1454997 at CR only 2397 3094 2233 2451 1.29 -1.07 1.02 Msrb3
1455014 at Res & Lgx 1453 1054 833 759 -1.38 -1.75 -1.91 AV009015
1455018 at Lgx only 1301 1669 1774 2383 1.28 1.36 1.83 Lmtk2
1455025 at Res only 1073 1005 788 8491-1.07 -1.36 -1.26 Pa r9
1455051 at L x only 500 578 720 851 1.16 1.44 1.70 Rnf31
1455061 a at Lgx only 19692 20976 24991 27704 1.07 1.27 1.41 Acaa2
CA 02699908 2010-03-17
WO 2009/039195 PCT/US2008/076707
-107-
Table 3
CO CR RES LGX FC FC FC
Probe Set ID Treatment mean mean mean mean CR Res L x Entrez Info
1455081 at Lgx only 393 471 526 526 1.20 1.34 1.34 Txnl4b
1455082 at Lgx only 455 375 356 312 -1.21 -1.28 -1.46 Cblb
1455090 at L x onl 2902 3308 2931 3642 1.14 1.01 1.26 An tl2
1455105 at Lgx only 1072 1049 833 740 -1.02 -1.29 -1.45 Pt nl2
1455118 at Res & L x 1938 1850 1436 1478 -1.05 -1.35 -1.31 D9Ertd4O2e
1455131 at Lgx only 2218 2140 2041 1890 -1.04 -1.09 -1.17 Opa3
1455142 at L x onl 409 403 306 230 -1.02 -1.34 -1.78 Socs4
1455143 at Res & L x 326 441 617 772 1.35 1.89 2.36 NI n2
1455152 at Res & Lgx 2267 2135 1838 1619 -1.06 -1.23 -1.40 AI462493
1455153 at Lgx only 505 453 471 342 -1.11 -1.07 -1.47 Zf 236
1455155 at L x onl 1223 1091 976 862 -1.12 -1.25 -1.42 Lsm14b
1455157 a at Res & L x 788 737 1180 1481,-1.07 1.50 1.88 BC039210
1455159 at Lgx only 527 455 447 310 -1.16 -1.18 -1.70 A ll
1455164 at Lgx only 1752 2160 2211 2588 1.23 1.26 1.48 Cdgap
1455166 at Res & Lgx 1049 897 812 763 -1.17 -1.29 -1.37 Arl5b
1455188 at Res only 445 474 263 378 1.06 -1.69 -1.18 Ephbl
1455197 at Res only 89, 155 200 137 1.74 2.24 1.54 Rnd1
1455204 at Res & Lgx 1784 1576 1400 1239 -1.13 -1.27 -1.44 Pitpncl
1455205 a at Lgx only 1304 1651 1627 1812 1.27 1.25 1.39 Us 19
1455207 at L x only 687 606 578 507 -1.13 -1.19 -1.36 2410017P09Rik
1455210 at Lgx only 573 682 716 811, 1.19 1.25 1.42 Zhx2
1455226 at Res & Lgx 980 1142 1530 1869 1.17 1.56 1.91 Spnbl
1455244 at Res & L x 3049 2993 2023 1746 -1.02 -1.51 -1.75 Daam1
1455267 at Lgx only 1101 1050 793 685 -1.05 -1.39 -1.61 Esrrg
1455268 at Res & L x 575 477 313 321 -1.20 -1.84 -1.79 D h3
1455285 at Res & Lgx 760 771 569 445 1.01 -1.34 -1.71 Slc3lal
1455288 at Res & L x 1136 1274 1630 1957 1.12 1.43 1.72 1110036003Rik
1455293 at Lgx only 249 208, 259 124 -1.20 1.04 -2.02 Leo1
1455296 at L x only 784 1049 929, 1119 1.34 1.19 1.43 LOC100047385
1455300 at Res & L x 629 510 389 317 -1.23 -1.62 -1.98 E130014J05Rik
1455307 at Lgx only 487 544 697 794 1.12 1.43 1.63 BC037112
1455309 at Res & Lgx 761, 829 1263 1387 1.09 1.66 1.82 Tmem l 6f
1455312 at L x only 785 972 944 1067 1.24 1.20 1.36 Phc3
1455320 at CR & Lgx 3658 2918 2870 27931-1.25 -1.27 -1.31 A1480535
1455340 at Res & L x 576 384 329 275 -1.50 -1.75 -2.09 D030011 010Rik
1455349 at Lgx only 697 526 549 463 -1.32 -1.27 -1.50 L0C100048397
1455353 at L x only 968 809 836 782 -1.20 -1.16 -1.24 Tmccl
1455356 at Lgx only 320 299 499 662 -1.07 1.56 2.07 Camsa 1
1455387 at Res & L x 1358 1115 995 7581-1.22 -1.36 -1.79 Nufi 2
1455390 at Lgx only 1575 1427 1439 1118 -1.10 -1.09 -1.41 Alkbh6
1455434 a at Res & Lgx 6402 5782 5247 4407 -1.11 -1.22 -1.45 Ktn1
1455442 at Res & Lgx 74 104 176 197 1.41 2.37 2.67 Slc6a19
1455450 at Lgx only 1232 1200 1327 1592 -1.03 1.08 1.29 Pt n3
1455456 a at Lgx only 1242 1516 1332 1587 1.22 1.07 1.28 Timm5O
1455462 at Res & Lgx 218 251 334 356 1.15 1.53 1.63 Adc 2
1455479 a at Res & L x 12338 12135 7678 6396 -1.021-1.611 -1.93 Ube2d3
CA 02699908 2010-03-17
WO 2009/039195 PCT/US2008/076707
-108-
Table 3
CO CR RES LGX FC FC FC
Probe Set ID Treatment mean mean mean mean CR Res L x Entrez Info
1455482 at All 516 724 797 1018 1.40 1.54 1.97 A 2a2
1455491 at Res & L x 1099 1208 811 846 1.10 -1.36 -1.30 Hnr h3
1455506 at L x onl 5998 5890 8637 94041-1.02 1.44 1.57 Slc25a34
1455508 at Lgx only 354 367 312 217 1.04 -1.14 -1.63 A530082C11 Rik
1455538 at L xonl 942 726 609 472 -1.30 -1.55 -2.006330403M23Rik
1455585 at Lgx only 601 526 486 404 -1.14 -1.24 -1.49 Rnf168
1455587 at Res only 11 16 20 21 1.39 1.75 1.82 BC030183
1455588 at Res & Lgx 1065 816 578 556 -1.30 -1.84 -1.91 L rm4
1455655 a at Res & L x 1506 1115 925 831 -1.35 -1.63 -1.81 Tardb
1455688 at Lgx only 951 817 745 702 -1.16 -1.28 -1.35 Ddr2
1455689 at L x only 270 358 391 488 1.33 1.45 1.81 Fzd10
1455700 at Res & L x 1328 1183 811 6641-1.12 -1.64 -2.00 Mterfd3
1455702 at Lgx only 584 734 962 803 1.26 1.65 1.37Wdr22
1455733 at Res & Lgx 135 216 228 227 1.60 1.69 1.68 Taok3
1455734 at CR & L x 1289 881 1118 921 -1.46 -1.15 -1.40 Crbn
1455741 a at Res & L x 1206 1346 1718 2034 1.12 1.42 1.69 Ecel
1455750 at Res & Lgx 1072 1041 733 717 -1.03 -1.46 -1.50 A230067G21 Rik
1455757 at Res & Lgx 522 526 371 305 1.01 -1.41 -1.71 D3Ertd254e
1455794 at L x onl 566 625 809 1034 1.10 1.43 1.83 Smtnl2
1455832 a at Res only 420 352 325 287 -1.19 -1.29 -1.46 Umps
1455854 a at Res & Lgx 470 513 771 829 1.09 1.64 1.76Sshl
1455870 at Lgx only 2176 2652 2908 3503 1.22 1.34 1.61 Aka p2
1455873 a at L x onl 271 383 402 483 1.41 1.48 1.78 V s18
1455884 at Lgx only 508 747 821 851 1.47 1.62 1.67 Dpp9
1455914 at Lgx only 168 138 101 93 -1.22 -1.66 -1.81 A1987944
1455915 at CR only 191, 132 150 138 -1.44 -1.27 -1.38 Galnt4
1455922 at L x onl 1213 1256 1440 1560 1.04 1.19 1.29 Raba a 1
1455936 a at CR & Lgx 1540 2056 1827 2200 1.33 1.19 1.43 Rb ms
1455944 at Lgx only 153 127 219 289 -1.21 1.43 1.88 Zf 516
1455945 at Lgx only 192 166 136 117 -1.16 -1.41 -1.65 Zf 817
1456046 at Lgx only 3587 3017 2786 2266 -1.19 -1.29 -1.58 Cd93
1456058 at L x only 807 745 690 598 -1.08 -1.17 -1.35 Rbm27
1456059 at Lgx only 4664 4475 3594 3214 -1.04 -1.30 -1.45 Psmdl 1
1456061 at Res & L x 740 574 371 2581-1.29 -1.99 -2.87 Gima 8
1456065 at CR only 128 49 171 119 -2.60 1.33 -1.07 Ubash3a
1456092 at Lgx only 86 52 58 26 -1.67 -1.49 -3.35 Kctd7
1456099 at Res only 128 174 254 207 1.35 1.98 1.61 D930017JO3Rik
1456161 at L xonl 403 283 297 279 -1.42 -1.36 -1.440610040B10Rik
1456169 at Res only 128 171 178 144 1.34 1.39 1.13 EG226654
1456210 at Lgx only 150 178 101 68 1.18 -1.48 -2.21 5430407P10Rik
1456241 a at Lgx only 3667 3705 4635 4984 1.01 1.26 1.361810073N04Rik
1456257 at Res only 495 565 327 409 1.14 -1.51 -1.21 C130065N1ORik
1456315 a at Res & L x 5639 5549 3253 27161-1.02 -1.73 -2.08 Ptla
1456398 at Lgx only 1951 1675 1544 1204 -1.16 -1.26 -1.62 Tu 1
1456487 at Lgx only 270 438 425 592 1.62 1.57 2.19 Adc 1
1456599 at CR only 106 165 118 109 1.55 1.11 1.03 Nxt2
CA 02699908 2010-03-17
WO 2009/039195 PCT/US2008/076707
-109-
Table 3
CO CR RES LGX FC FC FC
Probe Set ID Treatment mean mean mean mean CR Res L x Entrez Info
1456604 a at Lgx only 2365 2051 1676 1367 -1.15 -1.41 -1.73 Pcmtl
1456611 at Lgx only 462 581 505 608 1.26 1.09 1.31 D430015BO1Rik
1456625 at L x onl 192 140 145 1261-1.37 -1.33 -1.52 Aasdh t
1456643 at Lgx only 386 308 278 233 -1.25 -1.39 -1.65 9230114K14Rik
1456659 at Lgx only 319 363 307 153 1.14 -1.04 -2.08 LOC552902
1456727 a at Res & L x 2775 2975 4693 5107 1.07 1.69 1.84 Csnkld
1456768 a at L x onl 1333 1602 1733 2588 1.20 1.30 1.94 Mmrn2
1456774 at Lgx only 324 594 806 961, 1.83 2.49 2.97 P 1 rl 31
1456777 at CR & L x 38 14 75 13 -2.79 1.95 -3.02 M am
1456827 at Lgx only 196 148 119 61 -1.33 -1.64 -3.22 AA987161
1456836 at CR only 151 39 112 115 -3.85 -1.34 -1.31 ltk
1456871 a at Res only 1810 1658 2405 2210 -1.09 1.33 1.22 Phf2Ol1
1456888 at Lgx only 252 244 313 371 -1.03 1.24 1.47 Pfkfb4
1456896 at Res only 473 464 642 654 -1.02 1.36 1.386720462K09Rik
1456914 at L x onl 239 197 190 142 -1.21 -1.26 -1.69 Slc16a4
1457058 at Lgx only 245 319 349 556 1.31 1.43 2.27 Adamts2
1457111 at Res only 267 251 189 227 -1.07 -1.41 -1.18AA415038
1457276 at Res only 149 225 240 200 1.51 1.61 1.35 Snfllk2
1457285 at Lgx only 1194 1178 764 664 -1.01 -1.56 -1.80 Zf 187
1457334 at All 286 516 618 643 1.80 2.16 2.25 C130057MO5Rik
1457401 at L x only 63 89 114 167 1.41 1.81 2.64 Dnahc9
1457448 at CR only 154 79 90 117 -1.94 -1.71 -1.32 Pnplal
1457501 at Res only 20 78 111 63 3.99 5.68 3.23 RP23-233B9.8
1457508 at Res & Lgx 400 281 286 239 -1.42 -1.40 -1.67 C430003N24Rik
1457557 at Lgx only 81 31 72 23 -2.59 -1.13 -3.55 A330076H08Rik
1457626 at Res only 58 84 135 152 1.44 2.31 2.59 D3Wsu106e
1457671 at Lgx only 767 700 555 483 -1.10 -1.38 -1.59 93301201-111 Rik
1457681 at L x only 1108 992 1385 1651 -1.12 1.25 1.49 2610301 F02Rik
1457707 at Res & Lgx 55 71 153 177 1.29 2.78 3.21 ctp
2
1457745 at Res only 361 391 519 505 1.08 1.44 1.40 G r4
1457747 at Res only 8 14, 30 35, 1.77 3.81 4.349330109K16Rik
1457801 at CR only 268 388 343 329 1.45 1.28 1.239930024M15Rik
1458058 at Lgx only 149 104 122 59 -1.44 -1.21 -2.53 7030407E18Rik
1458190 at Res only 120 146 291 240 1.21 2.41 2.00Arh a 4
1458311 at Res only 249 304 433 381 1.22 1.74 1.53 Us 36
1458353 at Res only 162 269 340 244 1.66 2.10 1.51 Nwdl
1458438 at Lgx only 240 181 180 118 -1.33 -1.34 -2.03 Ccdcl22
1458455 at Lgx only 566 438 512 358 -1.29 -1.11 -1.58 Abra
1458461 at Res only 12 21 40 20 1.66 3.22 1.57 E330021 D16Rik
1458478 at Res only 65 48 12 53 -1.36 -5.63 -1.23 923011 0F11 Rik
1458482 at Lgx only 1340 1453 1156 1017 1.08 -1.16 -1.32 Tnni3k
1458624 at Res & Lgx 1590 1831 2206 2675 1.15 1.39 1.68 Rbm24
1458780 at Res only 20 68 74 55 3.33 3.61 2.70 D8Ertd620e
1458863 at Res only 152 101 37 851-1.50 -4.15 -1.796330415G19Rik
1459108 a at Res & Lgx 219 259 328 445 1.18 1.50 2.03 Yeats2
1459220 at Lgx only 138 217 222 276 1.57 1.61 2.00 C78651
CA 02699908 2010-03-17
WO 2009/039195 PCT/US2008/076707
-110-
Table 3
CO CR RES LGX FC FC FC
Probe Set ID Treatment mean mean mean mean CR Res L x Entrez Info
1459363 at Lgx only 312 405 407 506 1.30 1.31 1.62 Atxn2
1459578 at Res only 54 61 155 88 1.12 2.85 1.62AA407175
1460033 at CR only 74 180 125 105 2.42 1.69 1.42 CO30002C11 Rik
1460053 at CR only 242 144 218 221 -1.68 -1.11 -1.1 O Sm d4
1460113 at CR only 104 187 144 134 1.80 1.38 1.29 B930093H17Rik
1460165 at Res & L x 9064 9043 7129 6522 -1.00 -1.27 -1.39 P Ica
1460167 at L x onl 988 1120 1063 1253 1.13 1.08 1.27 AIdh7al
1460169 a at Lgx only 2453 3136 3555 4351, 1.28 1.45 1.77 Pctkl
1460177 at Res & L x 1301 1575 1640 1671 1.21 1.26 1.28 Cnd 2
1460184 at Lgx only 36182 38955 42606 49147 1.08 1.18 1.36 Hadh
1460189 at Res & Lgx 4600 3988 3323 2755 -1.15 -1.38 -1.67Wdr23
1460194 at Lgx only 12145 13386 14000 14613 1.10 1.15 1.20 Phyh
1460196 at Lgx only 1079 1068 1158 1385 -1.01 1.07 1.28 Cbrl
1460210 at Lgx only 683 848 775 1026 1.24 1.13 1.50 Pkd1
1460214 at CR only 27 97 92 108 3.67 3.46 4.07 Pc p4
1460216 at L x only 5275 5712 6310 7377 1.08 1.20 1.40 Acads
1460230 at Lgx only 106 114 120 192 1.07 1.13 1.81 Syn2
1460239 at Lgx only 3477 3308 3484 3037 -1.05 1.00 -1.15 Ts anl3
1460251 at Lgx only 464 467 407 262 1.01 -1.14 -1.77 Fas
1460254 at Res & L x 1563 1408 1168 924 -1.11 -1.34 -1.69 1810049H 1 3Rik
1460271 at CR only 157 66 118 1251-2.38 -1.33 -1.26 Trem3
1460276 a at L x only 822 886 967 1097 1.08 1.18 1.33 G r175
1460321 at CR only 129 52 117 105 -2.48 -1.10 -1.23 Cntn4
1460326 at Res & Lgx 1395 1325 1867 1690 -1.05 1.34 1.21 Pik3ca
1460328 at Res & Lgx 619 628 880 862 1.01 1.42 1.39 Brd3
1460329 at Res only 713 637 458 5041-1.12 -1.56 -1.42 LOC675709
1460330 at Lgx only 1601 1521 1413 1219 -1.05 -1.13 -1.31 Anxa3
1460331 at Res & Lgx 5861 5156 4527 4030 -1.14 -1.29 -1.45 Tm9sf2
1460336 at Lgx only 2689 2686 4293 5218 -1.00 1.60 1.94 P ar cl a
1460337 at CR only 4383 5948 3663 4114 1.36 -1.20 -1.07 Sh3kb l
1460344 at L xonl 1002 1085 1313 1398 1.08 1.31 1.402310033F14Rik
1460396 at Lgx only 483 621 790 817 1.29 1.63 1.69 Ddx54
1460409 at L x only 1345 1292 1713 2001 -1.04 1.27 1.49 C tl a
1460412 at CR only 58 20 45 57 -2.84 -1.30 -1.03 1600015H2ORik
1460420 a at Lgx only 634 820 934 1142 1.29 1.47 1.80 Egfr
1460428 at L x only 919 958 1120 1123 1.04 1.22 1.22Ankrdl3a
1460432 a at Lgx only 12140 9937 10609 8730 -1.22 -1.14 -1.39 Eif3e
1460433 at L x onl 662 763 813 1034 1.15 1.23 1.56 Ent d6
1460435 at Lgx only 573 713 699 935 1.25 1.22 1.63 1500002020Rik
1460444 at L xonl 329 323 411 491 -1.02 1.25 1.49Arrbl
1460500 at Lgx only 313 176 158 981-1.78 -1.98 -3.20 5033421 C21 Rik
1460510 a at Res & Lgx 3505 3184 2702 2908 -1.10 -1.30 -1.21 Co lOb
1460539 at Res only 68 139 141 153 2.04 2.07 2.254933404K13Rik
1460547 a at Res & Lgx 4912 3450 2670 1733 -1.42 -1.84 -2.84 Hnrpk
1460552 at Lgx only 2039 2109 2286 2886 1.03 1.12 1.42 Ascc3l l
1460557 at Lgx only 1577 1866 1401, 1297 1.18 -1.13 -1.22 Su v3ll
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Table 3
CO CR RES LGX FC FC FC
Probe Set ID Treatment mean mean mean mean CR Res L x Entrez Info
1460559 at Lgx only 2459 2747 3020 4193 1.12 1.23 1.71 Ankrd25
1460570 at Lgx only 90 123 168 176 1.36 1.87 1.95 Pgbd5
1460573 at Res & L x 838 611 460 341 -1.37 -1.82 -2.46 AI848100
1460576 at Res & L x 1390 1299 1107 878 -1.07 -1.26 -1.58 LOC100047539
1460580 at Lgx only 950 1086 1029 1226 1.14 1.08 1.29 Pcnx
1460586 at Lgx only 802 890 990 1316 1.11 1.23 1.64 Me f8
1460603 at Res only 703 632 490 590 -1.11 -1.43 -1.19 Samd91
1460607 at CR only 43 102 138 99 2.38 3.21 2.30 I sf11
1460610 at Lgx only 191 208 233 328 1.09 1.22 1.72 A bl5
1460614 at Lgx only 331 289 291 199 -1.14 -1.14 -1.66 LOC100045020
1460624 at Res & Lgx 363 266 217 198 -1.36 -1.67 -1.836330564D18Rik
1460643 at L x only 270 360 304 400 1.34 1.13 1.48 Ell
1460644 at Lgx only 2028 2060 2523 2936 1.02 1.24 1.45 Bckdk
1460645 at Res & L x 1384 1178 880 926 -1.17 -1.57 -1.49 Chordcl
1460648 at Lgx only 1100 1245 1478 1574 1.13 1.34 1.43 Nr2f6
1460674 at L x only 477 623 657 970 1.31 1.38 2.04 Pa r7
1460675 at Lgx only 412 429 642 729 1.04 1.56 1.77 lgsf8
1460695 a at Lgx only 2491 2664 2132 1926 1.07 -1.17 -1.2912010111101 Rik
1460704 at Lgx only 664 756 815 930 1.14 1.23 1.40 Rfng
1460716 a at L x only 2287 2216 2090 1679 -1.03 -1.09 -1.36 Cbfb
1460720 at Res & Lgx 1749, 2092 2554 2716 1.20 1.46 1.55 Trpc4ap
1460732 a at Lgx only 495 527 571, 770 1.06 1.15 1.56 Ppl
FFX-b-ActinMur
M12481 3 at Res & Lgx 37967 41791 48255 54572 1.10 1.27 1.44 Actb
FFX-GapdhMur
M32599 M at Lx only 90974, 104691 98912 122441, 1.15 1.09 1.35 Ga dh
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[00114] Several genes of particular interest showed expression patterns
indicating that
compounds of the present invention (Longevinex ) up-regulated
survival/longevity genes or
down-regulate genes whose expression enhances cellular damage to a greater
extent than
resveratrol:
(A) The sirtuin family of genes, and in particular Sirtuin 1, are thought to
be critical
mediators of extended lifespans (Boily, G. et al. (2008) "SirTi Regulates
Energy
Metabolism And Response To Caloric Restriction In Mice," PLoS ONE 3(3):e1759;
Huang, J. et al. (2008) "SIRTI Overexpression Antagonizes Cellular Senescence
with
Activated ERK/S6k1 Signaling in Human Diploid Fibroblasts," PLoS ONE
3(3):e1710). Whereas mice receiving resveratrol showed only a 1.22 fold
decrease in
expression and mice subjected to a calorie restricted diet showed only a 1.12
fold
reduction in Sirtuin 1 expression, expression of Sirtuin 1 was found to be
decreased
1.71 fold in mice receiving Longevinex .
(B) Pgc-la (peroxisome proliferative activated receptor, gamma, coactivator 1
alpha;
ppargcla) is a transcriptional co-factor that controls energy metabolism and
mitochondrial biogenesis; its expression is increased in skeletal muscle
tissue upon
long-term calorie restriction (Conley, K.E. et al. (2007) "Mitochondrial
Dysfunction
and Age," Curr. Opin. Clin. Nutr. Metab. Care. 10(6):688-692; Wu, Z. et al.
(2007)
"Targeting PGC-1 Alpha To Control Energy Homeostasis," Expert Opin. Ther.
Targets
11(10):1329-1338). Whereas mice receiving resveratrol showed only a 1.6 fold
increase in expression and mice subjected to a calorie restricted diet showed
no
increase in Pgc-la expression, mice receiving Longevinex showed a 1.94 fold
increase in Pgc-la expression.
(C) Uncoupling protein-3 is believed to be a target of Pgc-la and to play a
role in fatty acid
metabolism; its expression is increased in cardiac tissue upon long-term
calorie
restriction (Bezaire, V. et al. (Epub 2007 Jan 3) "Uncoupling Protein-3: Clues
In An
Ongoing Mitochondrial Mystery," FASEB J. 21(2):312-324; Chan, C.B. et al.
(2006)
"Uncoupling Proteins: Role In Insulin Resistance And Insulin Insufficiency,"
Curr.
Diabetes Rev. 2(3):271-283). Whereas mice receiving resveratrol showed only a
2.02
fold increase in expression and mice subjected to a calorie restricted diet
showed only a
1.8 fold increase in uncoupling protein-3 expression, mice receiving
Longevinex
showed a 2.79 fold increase in uncoupling protein-3 expression.
(D) Pyruvate dehydrogenase kinase 4 coordinates fuel selection during fasting
to promote
fatty acid metabolism (Sugden, M.C. et al. (2006) "Mechanisms Underlying
Regulation
Of The Expression And Activities Of The Mammalian Pyruvate Dehydrogenase
Kinases," Arch. Physiol. Biochem. 112(3):139-149; Pilegaard, H. et al. (2004)
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"Transcriptional Regulation Of Pyruvate Dehydrogenase Kinase 4 In Skeletal
Muscle
During And After Exercise," Proc. Nutr. Soc. 63(2):221-226; Sugden, M.C.
(2003)
"PDK4: A factor in fatness?," Obes. Res. 11(2):167-169). It is a target of Pgc-
la and
is induced in multiple tissues by long-term calorie restriction. Whereas mice
receiving
resveratrol showed only a 2.78 fold increase in expression and mice subjected
to a
calorie restricted diet showed only a 1.48 fold increase in pyruvate
dehydrogenase
kinase 4 expression, mice receiving Longevinex showed a 3.25 fold increase in
pyruvate dehydrogenase kinase 4 expression.
[00115] Analysis of the genes up-regulated or down-regulated by a compound of
the present
invention (Longevinex ) revealed that oxidative phosphorylation genes, which
are involved in
mitochondrial ATP production, were markedly up-regulated (Table 4).
Table 4
FC CR FC RES FCLGX Gene
1.11 1.14 1.32 Ndufa5
-1.00 -1.20 -1.42 Ndufafl
-1.04 -1.13 -1.22 Ndufb3
1.13 1.06 1.27 Ndufb8
1.12 1.18 1.28 Ndufb7
-1.34 -1.55 -2.65 Ndufab
1.07 1.20 1.51 Ndufcl
-1.07 -1.30 -1.39 Ndufc2
1.08 1.11 1.37 Ndufsl
1.13 1.10 1.26 Ndufs2
1.09 1.12 1.23 Ndufs3
1.04 1.19 1.33 Ndufs5
1.13 1.18 1.44 Ndufs7
-1.02 1.03 -1.23 Ndufs8
1.14 1.18 1.21 Ndufvl
1.11 1.13 1.34 Ndufv2
1.17 1.13 1.43 Sdha
1.16 1.02 1.23 Sdhd
1.46 1.29 1.49 Sulf2
1.01 -1.25 -1.33 U cc
1.10 1.19 1.34 U crcl
1.05 1.07 1.38 U crfsl
1.20 1.50 1.94 Cox4i2
1.13 1.05 1.39 Cox5a
1.23 1.13 1.61 Cox8a
Example 4
Biochemical Pathways Affected by the Compositions of the Present Invention
[00116] Recent research has suggested that complex traits are emergent
properties of
molecular networks that are modulated by complex genetic loci and
environmental
factors.Chen, Y. et at. (Epub 2008 Mar 16) "Variations In DNA Elucidate
Molecular Networks
That Cause Disease," Nature 452(7186):429-435).
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[00117] Indeed, research within the last decade has revealed that most chronic
illnesses such
as cancer, cardiovascular and pulmonary diseases, neurological diseases,
diabetes, and
autoimmune diseases exhibit dysregulation of multiple cell signaling pathways
(Harikumar,
K.B. et al. (Epub February 15, 2008) "Resveratrol.= A Multitargeted Agent For
Age-Associated
Chronic Diseases," Cell Cycle. 2008:7(8)). The compounds of the present
invention were
therefore evaluated for their effect on the expression of biochemical pathways
and were found
to affect the expression of genes involved in 220 biological processes (P <
0.05) by (Table 5).
Table 5
Changed Number
GO ID Biological Processes Treatment by LT-CR of Genes CR RES LGX
in Series
GO:0051128 Regulation Of Cellular Component CR only 0.0277 51 5 - -
Organization And Biogenesis
GO:0001558 Regulation Of Cell Growth CR only - 74 5 - -
GO:0006820 Anion Transport CR only - 155 6 - -
GO:0008361 Regulation Of Cell Size CR only - 102 6 - -
GO:0016049 Cell Growth CR only - 90 5 - -
GO:0030217 T Cell Differentiation CR only - 55 3 - -
GO:0030595 Leukocyte Chemotaxis CR only - 18 2 - -
GO:0045580 Regulation Of T Cell Differentiation CR only - 15 2 - -
GO:0045792 Negative Regulation Of Cell Size CR only - 16 2 - -
GO:0048705 Skeletal Morphogenesis CR only - 20 2 - -
GO:0051246 Regulation Of Protein Metabolic Process CR only - 204 8 - -
GO:0033554 Cellular Response To Stress RES only 0.0074 14 - 3 -
GO:0006888 ER To Golgi Vesicle-Mediated Transport RES only 0.0284 16 - 3 -
GO:0000723 Telomere Maintenance RES only - 17 - 3 -
GO:0001958 Endochondral Ossification RES only - 8 - 2 -
GO:0006281 DNA Repair RES only - 178 - 13 -
GO:0006353 Transcription Termination RES only - 6 - 2 -
GO:0006446 Regulation Of Translational Initiation RES only - 20 - 4 -
GO:0006596 Polyamine Biosynthetic Process RES only - 5 - 2 -
GO:0006625 Protein Targeting To Peroxisome RES only - 5 - 2 -
GO:0006825 Copper Ion Transport RES only - 9 - 3 -
GO:0006919 Caspase Activation RES only - 16 - 3 -
GO:0006974 Response To DNA Damage Stimulus RES only - 217 - 15 -
GO:0006983 ER Overload Response RES only - 5 - 2 -
GO:0007017 Microtubule-Based Process RES only - 155 - 12 -
GO:0007091 Mitotic Metaphase/Anaphase Transition RES only - 8 - 2 -
GO:0007143 Female Meiosis RES only - 8 - 2 -
GO:0008299 Isoprenoid Biosynthetic Process RES only - 19 - 3 -
GO:0045351 Interferon Type I Biosynthetic Process RES only - 6 - 2 -
GO:0045577 Regulation Of B Cell Differentiation RES only - 8 - 2 -
GO:0046330 Positive Regulation Of INK Cascade RES only - 8 - 2 -
GO:0048193 Golgi Vesicle Transport RES only - 37 - 6 -
GO:0050673 Epithelial Cell Proliferation RES only - 30 - 4 -
GO:0006119 Oxidative Phosphorylation LGX only 0.0001 39 - - 10
GO:0042773 ATP Synthesis Coupled Electron LGX only 0.0019 11 - - 5
Transport
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Table 5
Changed Number
GO ID Biological Processes Treatment by LT-CR of Genes CR RES LGX
in Series
60:0030036 Actin Cytoskeleton Organization And LGX only 0.0024 146 - - 34
Biogenesis
GO:0006629 Lipid Metabolic Process LGX only 0.0146 535 - - 89
GO:0044255 Cellular Lipid Metabolic Process LGX only 0.0147 459 - - 80
GO:0001701 In Utero Embryonic Development LGX only 0.0195 101 - - 19
GO:0040008 Regulation Of Growth LGX only 0.0242 135 - - 23
60:0000375 RNA Splicing, Via Transesterification LGX only 0.0251 39 - - 10
Reactions
GO:0000398 Nuclear Mina Splicing, Via Spliceosome LGX only 0.0251 39 - - 10
GO:0006366 Transcription From RNA Polymerase II LGX only 0.0264 392 - - 72
Promoter
60:0006357 Regulation Of Transcription From RNA LGX only 0.0276 351 - - 59
Polymerase II Promoter
GO:0016044 Membrane Organization And Biogenesis LGX only 0.0292 209 - - 34
GO:0006066 Alcohol Metabolic Process LGX only 0.0299 222 - - 41
GO:0065002 Intracellular Protein Transport Across A LGX only 0.0372 59 - - 16
Membrane
GO:0006099 Tricarboxylic Acid Cycle LGX only 0.0396 23 - - 7
GO:0009060 Aerobic Respiration LGX only 0.0396 24 - - 7
GO:0044265 Cellular Macromolecule Catabolic LGX only 0.0417 201 - - 41
Process
GO:0006006 Glucose Metabolic Process LGX only 0.0441 83 - - 16
GO:0045333 Cellular Respiration LGX only 0.0484 28 - - 8
60:0000038 Very-Long-Chain Fatty Acid Metabolic LGX only - 5 - - 3
Process
GO:0000059 Protein Import Into Nucleus, Docking LGX only - 15 - - 7
GO:0000186 Activation Of MAPKK Activity LGX only - 10 - - 5
GO:0001525 Angiogenesis LGX only - 124 - - 26
GO:0001568 Blood Vessel Development LGX only - 188 - - 42
GO:0001570 Vasculogenesis LGX only - 27 - - 8
GO:0001839 Neural Plate Morphogenesis LGX only - 40 - - 9
GO:0001841 Neural Tube Formation LGX only - 39 - - 9
GO:0001843 Neural Tube Closure LGX only - 29 - - 7
GO:0001935 Endothelial Cell Proliferation LGX only - 8 - - 4
GO:0002026 Cardiac Inotropy LGX only - 10 - - 4
GO:0003007 Heart Morphogenesis LGX only - 32 - - 8
GO:0005978 Glycogen Biosynthetic Process LGX only - 11 - - 5
GO:0006007 Glucose Catabolic Process LGX only - 44 - - 11
GO:0006098 Pentose-Phosphate Shunt LGX only - 7 - - 3
GO:0006118 Electron Transport LGX only - 303 - - 65
60:0006120 Mitochondrial Electron Transport, LGX only - 6 - - 5
NADH To Ubiquinone
GO:0006171 Camp Biosynthetic Process LGX only - 14 - - 5
GO:0006259 DNA Metabolic Process LGX only - 524 - - 77
GO:0006323 DNA Packaging LGX only - 209 - - 37
60:0006325 Establishment And/Or Maintenance Of LGX only - 203 - - 34
Chromatin Architecture
GO:0006333 Chromatin Assembly Or Disassembly LGX only - 80 - - 15
GO:0006352 Transcription Initiation LGX only - 27 - - 7
GO:0006354 RNA Elongation LGX only - 5 - - 3
GO:0006367 Transcription Initiation From RNA LGX only - I1 - - 5
Polymerase II Promoter
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Table 5
Changed Number
GO ID Biological Processes Treatment by LT-CR of Genes CR RES LGX
in Series
GO:0006396 RNA Processing LGX only - 319 - - 63
GO:0006397 Mina Processing LGX only - 213 - - 43
GO:0006414 Translational Elongation LGX only - 19 - - 6
GO:0006461 Protein Complex Assembly LGX only - 122 - - 28
GO:0006468 Protein Amino Acid Phosphorylation LGX only - 545 - - 83
GO:0006470 Protein Amino Acid Dephosphorylation LGX only - 99 - - 18
GO:0006473 Protein Amino Acid Acetylation LGX only - 12 - - 4
GO:0006508 Proteolysis LGX only - 545 - - 85
GO:0006520 Amino Acid Metabolic Process LGX only - 198 - - 34
GO:0006606 Protein Import Into Nucleus LGX only - 53 - - 13
GO:0006612 Protein Targeting To Membrane LGX only - 15 - - 5
GO:0006631 Fatty Acid Metabolic Process LGX only - 142 - - 35
GO:0006635 Fatty Acid Beta-Oxidation LGX only - 13 - - 6
GO:0006638 Neutral Lipid Metabolic Process LGX only - 21 - - 6
GO:0006641 Triacylglycerol Metabolic Process LGX only - 17 - - 6
GO:0006662 Glycerol Ether Metabolic Process LGX only - 23 - - 6
GO:0006766 Vitamin Metabolic Process LGX only - 57 - - 14
GO:0006807 Nitrogen Compound Metabolic Process LGX only - 315 - - 49
GO:0006869 Lipid Transport LGX only - 67 - - 16
GO:0006913 Nucleocytoplasmic Transport LGX only - 89 - - 23
GO:0006914 Autophagy LGX only - 21 - - 8
GO:0007031 Peroxisome Organization And LGX only - 22 - - 7
Biogenesis
GO:0007182 Common-Partner SMAD Protein LGX only - 8 - - 4
Phosphorylation
GO:0007190 Adenylate Cyclase Activation LGX only - 12 - - 4
GO:0007242 Intracellular Signaling Cascade LGX only - 915 - - 133
GO:0007369 Gastrulation LGX only - 55 - - 13
GO:0007498 Mesoderm Development LGX only - 44 - - 13
GO:0007507 Heart Development LGX only - 158 - - 39
GO:0007512 Adult Heart Development LGX only - 9 - - 4
GO:0007517 Muscle Development LGX only - 105 - - 19
GO:0008016 Regulation Of Heart Contraction LGX only - 27 - - 9
GO:0008286 Insulin Receptor Signaling Pathway LGX only - 24 - - 7
GO:0009308 Amine Metabolic Process LGX only - 294 - - 46
GO:0009653 Anatomical Structure Morphogenesis LGX only - 993 - - 143
GO:0009790 Embryonic Development LGX only - 387 - - 61
GO:0009792 Embryonic Development Ending In Birth LGX only - 190 - - 32
Or Egg Hatching
GO:0010003 Gastrulation (Sensu Mammalia) LGX only - 17 - - 6
GO:0015804 Neutral Amino Acid Transport LGX only - 6 - - 3
GO:0015908 Fatty Acid Transport LGX only - 6 - - 3
GO:0016071 Mina Metabolic Process LGX only - 240 - - 45
GO:0016192 Vesicle-Mediated Transport LGX only - 365 - - 61
GO:0016310 Phosphorylation LGX only - 601 - - 95
GO:0016311 Dephosphorylation LGX only - 111 - - 20
GO:0016481 Negative Regulation Of Transcription LGX only - 223 - - 40
GO:0016485 Protein Processing LGX only - 58 - - 14
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Table 5
Changed Number
GO ID Biological Processes Treatment by LT-CR of Genes CR RES LGX
in Series
GO:0016540 Protein Autoprocessing LGX only - 30 - - 9
GO:0016567 Protein Ubiquitination LGX only - 36 - - 9
GO:0016568 Chromatin Modification LGX only - 152 - - 27
GO:0016574 Histone Ubiquitination LGX only - 5 - - 3
GO:0019395 Fatty Acid Oxidation LGX only - 20 - - 8
GO:0019752 Carboxylic Acid Metabolic Process LGX only - 403 - - 78
GO:0030163 Protein Catabolic Process LGX only - 162 - - 31
GO:0030239 Myofibril Assembly LGX only - 12 - - 5
GO:0030323 Respiratory Tube Development LGX only - 58 - - 12
GO:0030324 Lung Development LGX only - 57 - - 12
GO:0030855 Epithelial Cell Differentiation LGX only - 34 - - 8
60:0030856 Regulation Of Epithelial Cell LGX only - 7 - - 3
Differentiation
60:0030865 Cortical Cytoskeleton Organization And LGX only - 10 - - 5
Biogenesis
60:0031032 Actomyosin Structure Organization And LGX only - 16 - - 5
Biogenesis
GO:0032147 Activation Of Protein Kinase Activity LGX only - 28 - - 8
GO:0035051 Cardiac Cell Differentiation LGX only - 13 - - 6
GO:0035239 Tube Morphogenesis LGX only - 128 - - 25
GO:0035295 Tube Development LGX only - 174 - - 36
GO:0042254 Ribosome Biogenesis And Assembly LGX only - 97 - - 18
GO:0042692 Muscle Cell Differentiation LGX only - 58 - - 14
GO:0043009 Chordate Embryonic Development LGX only - 187 - - 32
GO:0043087 Regulation Of Gtpase Activity LGX only - 59 - - 12
GO:0043623 Cellular Protein Complex Assembly LGX only - 39 - - 11
GO:0043631 RNA Polyadenylation LGX only - 11 - - 4
GO:0044257 Cellular Protein Catabolic Process LGX only - 116 - - 27
GO:0045214 Sarcomere Organization LGX only - 9 - - 4
60:0045761 Regulation Of Adenylate Cyclase LGX only - 16 - - 5
Activity
GO:0045893 Positive Regulation Of Transcription, LGX only - 225 - - 44
DNA-Dependent
GO:0045944 Positive Regulation Of Transcription LGX only - 186 - - 34
From RNA Polymerase II Promoter
GO:0046058 Camp Metabolic Process LGX only - 17 - - 5
GO:0046777 Protein Amino Acid LGX only - 29 - - 9
Autophosphorylation
GO:0048276 Gastrulation (Sensu Vertebrata) LGX only - 24 - - 7
GO:0048514 Blood Vessel Morphogenesis LGX only - 160 - - 36
GO:0048646 Anatomical Structure Formation LGX only - 171 - - 34
GO:0050658 RNA Transport LGX only - 48 - - 11
GO:0051028 Mina Transport LGX only - 45 - - 11
GO:0051146 Striated Muscle Cell Differentiation LGX only - 26 - - 11
GO:0051170 Nuclear Import LGX only - 54 - - 13
GO:0055001 Muscle Cell Development LGX only - 13 - - 5
GO:0055002 Striated Muscle Cell Development LGX only - 12 - - 5
GO:0055007 Cardiac Muscle Cell Differentiation LGX only - 9 - - 6
60:0055012 Ventricular Cardiac Muscle Cell LGX only - 6 - - 4
Differentiation
GO:0051016 Barbed-End Actin Filament Capping CR & RES 0.0487 17 2 3 -
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Table 5
Changed Number
GO ID Biological Processes Treatment by LT-CR of Genes CR RES LGX
in Series
GO:0030029 Actin Filament-Based Process CR & LGX 0.0049 157 6 - 37
GO:0006084 Acetyl-Coa Metabolic Process CR & LGX 0.0068 33 3 - 11
GO:0045941 Positive Regulation Of Transcription CR & LGX 0.0119 267 8 - 48
GO:0006915 Apoptosis CR & LGX 0.0172 537 14 - 84
GO:0012501 Programmed Cell Death CR & LGX 0.0198 544 14 - 84
GO:0046356 Acetyl-Coa Catabolic Process CR & LGX 0.0396 24 2 - 8
GO:0008219 Cell Death CR & LGX 0.0410 564 14 - 84
GO:0006364 Rrna Processing CR & LGX - 50 3 - 11
GO:0006519 Amino Acid And Derivative Metabolic CR & LGX - 253 8 - 41
Process
GO:0006796 Phosphate Metabolic Process CR & LGX - 714 17 - 114
GO:0006839 Mitochondrial Transport CR & LGX - 20 2 - 9
GO:0007005 Mitochondrion Organization And CR & LGX - 58 4 - 19
Biogenesis
GO:0007167 Enzyme Linked Receptor Protein CR & LGX - 252 9 - 46
Signaling Pathway
GO:0007179 Transforming Growth Factor Beta CR & LGX - 42 3 - 11
Receptor Signaling Pathway
GO:0009056 Catabolic Process CR & LGX - 474 13 - 79
GO:0016265 Death CR & LGX - 564 14 - 84
GO:0030833 Regulation Of Actin Filament CR & LGX - 10 2 - 4
Polymerization
GO:0008104 Protein Localization RES & LGX 0.0007 663 - 38 127
GO:0015031 Protein Transport RES & LGX 0.0011 581 - 38 121
GO:0045184 Establishment Of Protein Localization RES & LGX 0.0028 610 - 38 123
GO:0006886 Intracellular Protein Transport RES & LGX 0.0098 357 - 26 75
GO:0006605 Protein Targeting RES & LGX 0.0099 161 - 12 34
GO:0044249 Cellular Biosynthetic Process RES & LGX 0.0107 710 - 45 117
GO:0009058 Biosynthetic Process RES & LGX 0.0120 979 - 60 155
GO:0006412 Translation RES & LGX 0.0364 338 - 25 62
GO:0044262 Cellular Carbohydrate Metabolic Process RES & LGX 0.0471 221 - 18
49
GO:0005975 Carbohydrate Metabolic Process RES & LGX - 316 - 21 60
GO:0005976 Polysaccharide Metabolic Process RES & LGX - 42 - 9 15
GO:0005977 Glycogen Metabolic Process RES & LGX - 31 - 7 13
GO:0006091 Generation Of Precursor Metabolites RES & LGX - 390 - 24 88
And Energy
GO:0006112 Energy Reserve Metabolic Process RES & LGX - 35 - 7 13
GO:0006413 Translational Initiation RES & LGX - 40 - 6 9
GO:0006511 Ubiquitin-Dependent Protein Catabolic RES & LGX - 109 - 9 27
Process
GO:0006512 Ubiquitin Cycle RES & LGX - 356 - 27 79
Transmembrane Receptor Protein
GO:0007178 Serine/Threonine Kinase Signaling RES & LGX - 75 - 7 19
Pathway
GO:0007264 Small Gtpase Mediated Signal RES & LGX - 320 - 22 62
Transduction
GO:0008380 RNA Splicing RES & LGX - 162 - 12 30
GO:0009059 Macromolecule Biosynthetic Process RES & LGX - 525 - 35 90
GO:0019941 Modification-Dependent Protein RES & LGX - 111 - 9 27
Catabolic Process
60:0043085 Positive Regulation Of Enzyme Activity RES & LGX - 40 - 5 11
GO:0043280 Positive Regulation Of Caspase Activity RES & LGX - 17 - 3 5
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Table 5
Changed Number
GO ID Biological Processes Treatment by LT-CR of Genes CR RES LGX
in Series
GO:0043281 Regulation Of Caspase Activity RES & LGX - 27 - 5 8
GO:0045454 Cell Redox Homeostasis RES & LGX - 40 - 6 9
GO:0050790 Regulation Of Catalytic Activity RES & LGX - 241 - 21 53
GO:0008064 Regulation Of Actin Polymerization All 0.0139 30 5 4 9
And/Or Depolymerization
GO:0030832 Regulation Of Actin Filament Length All 0.0139 31 5 4 9
GO:0046907 Intracellular Transport All 0.0287 523 16 43 113
GO:0008154 Actin Polymerization And/Or All 0.0414 39 5 6 12
De of merization
GO:0051649 Establishment Of Cellular Localization All 0.0467 653 17 45 125
GO:0006457 Protein Folding All - 124 6 13 34
GO:0006996 Organelle Organization And Biogenesis All - 897 27 53 158
GO:0007010 Cytoskeleton Organization And All - 403 12 26 70
Biogenesis
GO:0007018 Microtubule-Based Movement All - 72 4 9 14
GO:0030041 Actin Filament Polymerization All - 17 2 =6~
1 GO:0051258 Protein Polymerization All - 32 6 [00118] Calorie restriction
affected genes associated with 5% of these processes,
administration of resveratrol affected genes associated with 10% of these
processes.
Compounds of the present invention (e.g., Longevinex ) were found to affect
85% of these
processes. Administration of resveratrol to calorie restricted mice failed to
affect any genes in
any of these processes. Administration of Longevinex to calorie restricted
mice was found to
affect genes associated with 8% of these processes. Administration of both
resveratrol and
Longevinex was found to affect genes associated with 12% of these processes.
Table 6
shows the modulation of the genes of the oxidative phosphorylation pathway
(GO:0006119)
caused by calorie restriction (CR), resveratrol alone (Res), or the
compositions of the present
invention (LGX).
Table 6
Modulation Of The Genes Of The Oxidative Phosphorylation Pathway
(GO:0006119)
Gene Fold Change
CR Res LGX
Atp6vOdl 1.03 -1.21 -1.19
Atp6vlb2 1.27 -1.16 -1.23
Ndufvl 1.14 1.18 1.21
Ndufc2 -1.07 -1.30 -1.39
Atp6vld 1.13 -1.09 -1.05
Ndufs3 1.09 1.12 1.23
Atp6vlf -1.14 -1.21 -1.44
Ndufs7 1.13 1.18 1.44
U crh 1.05 -1.40 -1.34
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Table 6
Modulation Of The Genes Of The Oxidative Phosphorylation Pathway
(GO:0006119)
Gene Fold Change
CR Res LGX
Atp5j 1.07 -1.00 1.24
C c1 1.14 1.08 1.29
At 5b 1.10 1.01 1.27
Atp5k 1.05 1.02 1.24
Atp5al 1.09 1.02 1.29
At 5h 1.07 1.04 1.37
1110020P15Rik 1.06 1.09 1.26
Ndufsl 1.08 1.11 1.37
Atp5fl 1.09 1.08 1.19
Uqcr 1.03 1.10 1.30
Atp6vla -1.04 -1.18 -1.35
Ndufb9 1.07 1.07 1.25
Atp6vlh -1.17 -1.19 -1.11
U crb -1.09 -1.00 -1.22
Msh2 1.05 -1.03 -1.15
Atp6vlcl -1.10 -1.07 -1.06
Atp6vlc2 2.17 1.42 -1.00
Atp6vOd2 1.04 1.65 1.21
Atp7a -1.13 -1.18 -1.29
At 5cl -1.16 -1.28 -1.16
At 5 l 1.26 -1.58 -1.17
Atp6vlel 1.05 -1.42 -1.42
Atp6vle2 1.11 1.28 1.30
Ndufa7 -1.07 -1.14 -1.07
Atp5g3 1.06 -1.11 -1.01
[00119] Table 7 shows the modulation of the genes of the glucose metabolism
pathway
(GO:0006006) caused by calorie restriction (CR), resveratrol alone (Res), or
the compositions
of the present invention (LGX).
Table 7
Modulation Of The Genes Of The Glucose Metabolism Pathway
(GO:0006006)
Gene Fold Change
CR Res LGX
Pgam2 1.27 1.38 1.81
Pkm2 1.31 1.34 1.70
Pis 1.28 1.24 1.42
Eno3 1.17 1.26 1.37
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Table 7
Modulation Of The Genes Of The Glucose Metabolism Pathway
(GO:0006006)
Gene Fold Change
CR Res LGX
Atf3 -1.86 -1.47 -1.68
Pdk4 1.48 2.78 3.25
H6 pd 1.33 1.43 2.06
Pcx 1.40 1.33 1.60
Fbp2 -1.16 1.42 1.47
Pfkp 1.32 1.13 1.24
Pik3ca -1.05 1.34 1.21
Hibadh 1.09 1.17 1.15
Sds -1.65 -1.16 2.01
Hk3 2.23 1.60 1.77
Hkdcl 2.64 2.10 1.68
Ldhb 1.21 1.35 1.60
Mdh1 1.07 1.08 1.41
Ogdh 1.32 1.23 1.38
Gapdh 1.15 1.09 1.35
Pdhal 1.12 1.09 1.30
Tit 1.15 1.06 1.24
Mdh2 1.10 1.01 1.15
Pgm211 1.19 1.31 1.11
Pdk1 -1.01 1.01 -1.18
Hk1 1.12 -1.24 -1.34
Prkaal -1.08 1.17 -1.38
Ma k14 -1.10 -1.13 -1.51
Pckl 1.68 2.36 4.03
Aldoartl 2.17 2.37 3.08
G6 d2 1.93 1.37 2.90
Ldhal6b 1.15 1.45 2.73
Ldhc 1.94 2.25 2.44
Gpdl 1.83 1.51 2.41
Adi o 1.74 1.24 2.14
Eno2 -1.19 1.32 1.86
Aktl 1.11 1.66 1.73
Bpgm -1.28 1.35 1.57
Pdha2 1.78 -1.03 1.57
Npylr 1.11 1.37 1.53
Gapdhs 1.35 1.62 1.50
G6pdx 1.30 1.00 1.38
Adpgk -1.02 1.24 1.37
Insl 1.19 1.49 1.37
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Table 7
Modulation Of The Genes Of The Glucose Metabolism Pathway
(GO:0006006)
Gene Fold Change
CR Res LGX
Aldoc -1.32 1.14 1.32
Pdk2 1.11 1.11 1.24
Aldob -1.06 1.24 1.21
Pdk3 -2.02 -1.04 1.21
P m1 1.05 1.14 1.21
Fbpl -1.50 -1.25 1.20
S1c2a8 1.11 1.30 1.19
Gpd2 1.48 -1.41 1.17
Gck 1.16 1.26 1.16
Pgd 1.20 -1.05 1.16
Dcxr 1.05 1.08 1.14
R pia 1.04 1.06 1.12
Tnf -1.16 -1.73 1.11
Atf4 -1.06 1.07 1.10
Nr3cl 1.14 -1.14 1.10
Taldol 1.12 1.04 1.08
Pgaml 1.15 1.01 1.07
Aldoart2 -1.05 1.16 1.05
Ldha 1.10 -1.03 1.04
Lrrc16 1.00 -1.10 1.03
Pgm2 1.11 1.09 1.03
P1km 1.13 1.07 1.02
Pgk2 -1.79 1.29 -1.01
6430537H07Rik -1.26 -1.73 -1.04
Pck2 1.06 -1.09 -1.05
Bad 1.05 1.10 -1.07
Dial 1.05 -1.09 -1.07
Dhtkdl -1.45 -1.32 -1.08
Pflcl 1.19 -1.15 -1.11
Car5a -2.59 1.19 -1.14
Pdx1 -3.03 -1.37 -1.14
Cacnala -1.31 1.03 -1.21
Acn9 -1.04 -1.08 -1.22
Fabps 1.14 -1.13 -1.26
Para 1.14 -1.06 -1.28
Uevld -1.01 -1.12 -1.28
Pgm3 1.13 -1.09 -1.29
Ganc -1.26 1.08 -1.30
Lep -1.57 -1.96 -1.43
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Table 7
Modulation Of The Genes Of The Glucose Metabolism Pathway
(GO:0006006)
Gene Fold Change
CR Res LGX
Pklr 1.12 -1.08 -1.47
G6 c 1.42 -1.62 -1.71
1 Onecutl -1.32 -2.13 -2.05 11
[00120] Table 8 shows the modulation of the genes of the tricarboxylic acid
metabolism
pathway (GO:0006099) caused by calorie restriction (CR), resveratrol alone
(Res), or the
compositions of the present invention (LGX).
Table 8
Modulation Of The Genes Of The Tricarboxylic Acid Metabolism
Pathway (GO 0006099)
Gene Fold Change
CR Res LGX
Idh3b 1.22 1.30 2.06
Cs 1.22 1.07 1.46
Sdhd 1.16 1.02 1.23
Sdha 1.17 1.13 1.43
Sdhb 1.08 1.13 1.42
Mdhl 1.07 1.08 1.41
Aco2 1.16 1.13 1.39
Idh2 1.12 1.21 1.36
2610507B11Rik 1.10 1.06 1.25
Dist 1.21 1.08 1.24
Fhl -1.01 1.05 1.18
Mdh2 1.10 1.01 1.15
Idh3a 1.16 -1.02 1.01
Sdhc -1.01 -1.06 -1.20
Suclg2 -1.03 -1.00 -1.25
Polr3h -1.19 -1.20 -1.34
Sucla2 1.01 -1.01 1.05
Sucl 1 1.08 -1.07 1.00
Mdh1b -1.23 -1.20 -1.00
AtpSg3 1.06 -1.11 -1.01
Idh3g 1.02 -1.06 -1.02
Acol 1.00 -1.01 -1.05
[00121] Table 9 shows the modulation of the genes of the fatty acid metabolism
pathway
(GO:000663 1) caused by calorie restriction (CR), resveratrol alone (Res), or
the compositions
of the present invention (LGX).
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Table 9
Modulation Of The Genes Of The Fatty Acid Metabolism Pathway
(GO:0006631)
Gene Fold Change
CR Res LGX
Ucp3 1.80 2.02 2.79
Pex5 1.43 1.70 2.17
Syk 1.73 1.76 2.09
Tnxb 1.59 1.54 2.01
Acox3 1.48 1.70 1.84
Scap 1.34 1.37 1.70
Hadhb 1.80 1.57 1.51
Pex7 -1.16 -1.36 -1.44
S1c27a1 1.06 2.03 2.42
Prkar2b 1.95 2.01 2.24
Acadl 1.19 1.21 1.85
Crat 1.16 1.45 1.71
Tnfrsfl a -1.01 1.53 1.47
Cavl 1.14 1.18 1.45
Cptlb 1.07 1.27 1.45
Hsdl7b4 1.15 1.25 1.44
Acaa2 1.07 1.27 1.41
Gam -1.09 1.34 1.39
Hadh 1.08 1.18 1.36
Fads3 1.13 1.38 1.35
L la2 -1.00 -1.31 -1.13
Acs16 -1.15 -1.23 -1.26
Elov15 -1.12 -1.68 -1.91
Aasdh -1.06 -1.69 -2.00
Qk -1.06 -1.52 -2.08
Acox2 1.17 1.01 2.52
Acot5 2.89 6.34 2.39
Ptgis 1.16 1.17 1.66
Ppard 1.20 1.09 1.59
Acsf3 1.28 1.17 1.57
Cptla -1.04 1.27 1.49
Hadha 1.15 1.27 1.43
Mlycd -1.01 1.55 1.43
Acads 1.08 1.20 1.40
Acadvl 1.06 1.14 1.3 8
Acsll 1.05 1.21 1.38
Apoa2 1.24 1.29 1.34
Agpat6 1.15 1.15 1.32
Echdc2 1.06 1.19 1.32
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Table 9
Modulation Of The Genes Of The Fatty Acid Metabolism Pathway
(GO:0006631)
Gene Fold Change
CR Res LGX
Echl 1.00 1.06 1.30
Dci 1.06 1.13 1.24
Tit 1.15 1.06 1.24
Mecr -1.04 1.09 1.21
Phyh 1.10 1.15 1.20
Ltc4s 1.46 -1.05 1.19
Elovll -1.03 1.15 1.18
Scp2 -1.02 1.06 1.16
Acot7 1.20 1.03 1.06
Ptges2 1.20 1.04 -1.03
Echsl 1.07 1.01 -1.09
Mcat 1.04 1.01 -1.15
Acs13 -1.91 -2.10 -1.17
2010111101Rik 1.07 -1.17 -1.29
Acs14 -1.34 -1.20 -1.35
Crot -1.11 -1.07 -1.37
Prkaal -1.08 1.17 -1.38
Prkab2 1.04 -1.07 -1.38
Mapk14 -1.10 -1.13 -1.51
Lyplal -1.05 -1.32 -1.93
Ndufabl -1.34 -1.55 -2.65
Scdl 2.18 1.67 3.27
Fasn 2.54 1.54 3.10
Agt 1.42 1.57 2.50
Baat 2.33 2.78 2.42
Elov16 2.36 1.27 2.38
Alox8 1.27 1.12 2.31
LcnS 1.58 1.74 2.30
Acot4 1.58 1.65 2.24
Acsm3 -1.03 1.12 2.21
Adipoq 1.74 1.24 2.14
Mlstdl -1.18 1.29 1.78
S1c27a3 1.31 1.84 1.65
Acsbgl 1.64 2.24 1.62
Acot12 -1.09 -1.16 1.59
Acot2 -1.35 2.13 1.58
Abat -1.16 1.03 1.56
Lta4h 1.38 1.68 1.49 -J~
Elovl3 -1.12 1.11 1.47
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Table 9
Modulation Of The Genes Of The Fatty Acid Metabolism Pathway
(GO:0006631)
Gene Fold Change
CR Res LGX
Acsml 1.27 1.25 1.43
Alox15 1.12 1.10 1.43
L la3 1.31 1.42 1.41
S1c27a2 -1.52 -1.96 1.41
Elov17 1.41 1.20 1.39
Fads2 1.10 1.15 1.39
Ptgs 1 1.18 1.26 1.37
Brcal -1.08 1.29 1.36
Pt s2 1.01 1.25 1.35
Scd2 1.19 -1.03 1.33
Aacs 1.35 -1.12 1.32
AloxS 1.18 1.22 1.32
Fadsl 1.19 1.27 1.28
Ces3 -1.16 1.06 1.23
Pdpn -1.14 -1.04 1.22
Aloxe3 -1.14 1.00 1.21
Ggtlal -1.03 1.15 1.20
S1c27a4 1.23 1.25 1.20
Acs15 1.19 1.04 1.19
Acotl1 1.22 -1.08 1.18
Aloxl2e -2.02 -2.10 1.18
AldhSal 1.25 1.15 1.17
Adipor2 -1.16 1.11 1.15
Hao3 -1.71 -4.04 1.13
O1ah 1.33 -1.02 1.11
Myo5a 1.21 1.09 1.09
T 1 -1.43 -1.18 1.09
Acot8 1.05 -1.05 1.08
Acsm5 -1.38 1.14 1.08
Hnfl a 1.20 1.81 1.06
Fcerla 1.55 1.73 1.05
Fa2h -1.27 1.18 1.04
Prkag2 -1.05 -1.16 1.03
Alox12 1.04 1.08 1.02
Prkabl -1.12 1.04 1.02
Ehhadh -1.02 1.12 1.00
Peer -1.01 -1.03 1.00
Degsl 1.02 -1.16 -1.00
Scd3 -1.37 1.36 -1.01
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Table 9
Modulation Of The Genes Of The Fatty Acid Metabolism Pathway
(GO:0006631)
Gene Fold Change
CR Res LGX
Acadm -1.02 -1.10 -1.02
Pccb 1.01 -1.01 -1.02
Prkagl 1.09 -1.14 -1.02
Acoxl -1.06 1.06 -1.03
Cpt2 -1.14 1.01 -1.03
Tbxasl 1.00 -1.06 -1.03
Pex13 -1.05 -1.03 -1.04
C1 tnf2 -1.23 -1.02 -1.05
S1c27a5 -1.57 -1.03 -1.05
Ptges3 -1.08 -1.03 -1.07
Acoxl -1.85 -1.39 -1.08
Alox5ap 1.07 -1.08 -1.09
Ankrd23 1.06 1.23 -1.09
Adiporl 1.08 1.03 -1.10
C b5 -1.10 -1.21 -1.10
Ptgds -1.29 1.05 -1.10
Ptgds2 -1.77 -1.02 -1.12
Acsm2 -1.33 1.06 -1.19
Cptlc -1.69 1.29 -1.22
Ncfl -1.16 1.07 -1.25
Para 1.14 -1.06 -1.28
Elov14 1.00 1.45 -1.29
Mlstd2 -1.20 -1.19 -1.29
Oxsm -1.02 1.04 -1.29
Plp1 -1.03 1.06 -1.29
Cryll -1.44 -1.14 -1.31
Prkaa2 -1.17 -1.22 -1.31
Elov12 -1.91 -1.31 -1.34
Rn e 1.13 -1.07 -1.36
Acsbg2 -1.55 -1.14 -1.37
Ptges -1.05 -1.30 -1.38
Prkag3 -1.24 1.34 -1.45
Hpgd 1.17 -1.14 -2.59
[00122] A study of the expression of 20,341 genes in cardiac tissue revealed
that 2,829 genes
exhibited statistically significant differences in expression (P<0.01). Of
these, 7%
(approximately 189 genes) exhibited altered expression in animals subjected
only to calorie
reduced diets; 8% (approximately 226 genes) exhibited altered expression in
animals receiving
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only resveratrol; no additional genes exhibited altered expression in animals
that received
resveratrol and which were subjected to calorie reduced diets. In contrast,
61% of the 20,341
genes (approximately 1,729 genes) exhibited altered expression in animals
receiving only
compounds of the present invention (e.g., Longevinex ); an additional 2% of
the genes
(approximately 56 genes) exhibited altered expression in animals that had
received compounds
of the present invention (e.g., Longevinex ) and which had been subjected to
calorie reduced
diets; an additional 21% of the genes (approximately 594 genes) exhibited
altered expression in
animals that had received compounds of the present invention (e.g., Longevinex
) and
resveratrol; an additional 1% of the genes (approximately 28 genes) exhibited
altered
expression in animals that had received compounds of the present invention
(e.g.,
Longevinex ), resveratrol and which had been subjected to calorie reduced
diets.
[00123] The above data demonstrates that compounds of the present invention
(e.g.,
Longevinex ) were effective in modulating gene expression in hear tissue to an
extent
surpassing even that of calorie restriction. Similar effects have been
observed in non-heart
tissue. A study of the expression of 20,341 genes in brain tissue revealed
that 3,572 genes
exhibited statistically significant differences in expression (P<0.01). Of
these, 124 genes
exhibited altered expression in animals subjected only to calorie reduced
diets; 424 genes
exhibited altered expression in animals receiving only resveratrol; 10 genes
exhibited altered
expression in animals that received resveratrol and which were subjected to
calorie reduced
diets. In contrast, 2,560 genes exhibited altered expression in animals
receiving only
compounds of the present invention (e.g., Longevinex ); 19 additional genes
exhibited altered
expression in animals that had received compounds of the present invention
(e.g.,
Longevinex ) and which had been subjected to calorie reduced diets; 430
additional genes
exhibited altered expression in animals that had received compounds of the
present invention
(e.g., Longevinex ) and resveratrol; 5 additional genes exhibited altered
expression in animals
that had received compounds of the present invention (e.g., Longevinex ),
resveratrol and
which had been subjected to calorie reduced diets.
Example 4
Model Mechanism of Action of the Compositions of the Present Invention
[00124] The compounds of the present invention were thus found to greatly
exceed the
modulation of gene expression observed upon calorie restriction and to alter
the expression of
genes in key patyhways of lipid metabolism, glucose metabolism, oxidative
phosphorylation,
the Kreb's cycle, ATP synthesis and fatty acid R oxidation. In summary, the
compounds of the
present invention were found to have a greater specific activity than
resveratrol alone, both in
terms of the number of genes and the number of different biochemical pathways
affected. The
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results are significant since calorie restriction (CR) is considered the
unequivocal method of
prolonging life in all forms of life. Generally, reduction of 50% of caloric
intake doubles the lifespan
of any organism. The above-described experiments demonstrate that the
compositions of the present
invention exert a more powerful influence over genome expression than
resveratrol or CR, and marks
the first time any technology has been shown to exceed the effects of CR.
Furthermore, the
compositions of the present invention were found to influence genome
expression at an earlier stage of
life than CR (which requires a life-long adherence to a CR diet to
differentiate genes).
[00125] Without intending to be bound by any mechanism of action, the above
results suggest that
the compounds of the present invention act by enhancing the activity of the
forkhead Foxo l (daf-16,
dFoxO) transcription factor (Figure 5). Studies in model organisms has shown
that Foxol mediates
lifespan expression by enhancing gene expression. Insulin/IGF-1 signaling
phosphorylates Foxol,
thereby causing it to be excluded from the nucleus and downregulating its
actions. The compounds of
the present invention decrease insulin and IGF-1 signaling thereby decreasing
Foxol phosphorylation.
Consistent with this model are the observations that the insulin receptor
signaling pathway (e.g.,
GO:008286; genes Ide, Igfbp4, and Igfbp6) is affected by the compounds of the
present invention.
Expression of Foxol is increased by 1.75 fold. The compounds of the present
invention mediate
decreased glycolysis and increased gluconeogenesis (e.g., GO:0006006),
enhanced Pgc-la expression
(thereby leading to stimulation of Pdk4 expression (e.g., a 1.94 fold increase
in Ppargcla and a 3.25
fold increase in Pdk4), increased expression of lipid metabolism genes (e.g.,
a 2.79 fold increase in
Ucp3, 1.49 fold increase in Cpt 1 a, and a 1.45 fold increase in Cpt 1 b).
Lipid and fatty acid metabolism
genes GO:0006629 and GO:0006635 are uniquely affected by the compounds of the
present invention.
The compounds of the present invention thus exert a more pronounced favorable
effect on key
processes affected by calorie restriction and resveratrol (e.g., chromatin
remodeling, transcription from
RNA polymerase II promoter, and the ubiquitin cycle. Genes GO:0006333 and
GO:0006367 are
uniquely affected by the compounds of the present invention; Gene GO:0006512
is affected by
resveratrol and Longevinex . Thus, in sum, a proposed mechanism of action is
that the compositions
of the present invention deliver resveratrol to cells, where it passes through
cell walls, enters the
cytoplasm, and facilitates the translocation of Foxol gene into the cell
nucleus, which produces the
longevity effects.
[00126] While the invention has been described in connection with specific
embodiments thereof, it
will be
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understood that it is capable of further modifications and this application is
intended to cover
any variations, uses, or adaptations of the invention following, in general,
the principles of the
invention and including such departures from the present disclosure as come
within known or
customary practice within the art to which the invention pertains and as may
be applied to the
essential features hereinbefore set forth.
