Th17-->Psoriasis --GlycoProtein (VSTM1-v2-) -->Microbiome --JaK-Stat -->GAB1 /GAB2 --LYN Tyrosine Kinase --Breast Cancer GENEs --HEM1 --> FAM83a FAM83b -- Metastatic 'switch' CCL25 & CCR9 -- KRAS & EGFR ->P53 -- BRCA1/2

[randall]

hi


New psor hit(s) on pubmed:


http://www.ncbi.nlm.nih.gov/pubmed/22962689
J Leukoc Biol. 2012 Sep 7.
Targeting the Th17 pathway in psoriasis.

Elloso MM, Gomez-Angelats M, Fourie AM.

Source
Janssen Research & Development, LLC, San Diego, California, USA.

Abstract
In recent years, the classic paradigm of Th1/Th2 CD4(+) T cell-
mediated immunity has evolved to include the IL-17A-producing Th17
subset, a distinct proinflammatory CD4(+) T cell lineage. Accumulating
evidence suggests that IL-17A and the Th17 pathway may play an
important role in the pathology of psoriasis and in other immune-
mediated inflammatory diseases. This review summarizes the preclinical
and clinical evidence implicating Th17 cells in psoriasis and the
therapeutic approaches, approved or under investigation, to target
this pathway in psoriasis.

PMID: 22962689


Let's find out who MM Elloso is?

Good idea!



24 hits - Elloso MM[Author]
http://www.ncbi.nlm.nih.gov/pubmed?term=Elloso%20MM%5BAuthor%5D

Elloso, MM (M Merle) - 8 hits -
http://lib.bioinfo.pl/auid:2385304
10 hits and citations
http://lib.bioinfo.pl/auth:Elloso,MM

EE Got them BONEs... !

And this company is part of J&J and that ain't half BAD. LOL

M. Merle Elloso
Associate Scientific Director at Janssen Research and Development, LLC
(Johnson & Johnson)
Greater Philadelphia Area | Pharmaceuticals
Current: Associate Scientific Director at Janssen Research and
Development, LLC (Johnson & Johnson) Past: Principal Research
Scientist at Centocor, Senior Research Scientist at Wyeth Research,
Postdoctoral Researcher at University of Pennsylvania Education:
University of Pennsylvania, Cinnaminson High School, Rutgers, The
State University of New Jersey-New Brunswick , University of Wisconsin-
Madison

http://www.janssenrnd.com/our-innovation/partnerships/janssen-labs-at-san-diego

http://en.wikipedia.org/wiki/Janssen_Pharmaceutica

That's odd. ON la jolla blvd where there ain't much big JJ company
wise?

Let's try this:

525 hits: Th17 + glycoprotein - pubmed
http://www.ncbi.nlm.nih.gov/pubmed?term=Th17%20glycoprotein

#1 of 525 is interesting:


http://www.ncbi.nlm.nih.gov/pubmed/22960280
Cell Immunol. 2012 Aug 16;278(1-2):136-142.
VSTM1-v2, a novel soluble glycoprotein, promotes the differentiation
and activation of Th17 cells.

Guo X, Zhang Y, Wang P, Li T, Fu W, Mo X, Shi T, Zhang Z, Chen Y, Ma
D, Han W.

Source
Peking University Center for Human Disease Genomics, Department of
Immunology, Key Laboratory of Medical Immunology, Ministry of Health,
School of Basic Medical Sciences, Peking University Health Science
Center, 38 Xueyuan Road, Beijing 100191, China.

Abstract
Cytokines are soluble proteins that mediate immune reactions and are
responsible for communication among immune cells. CD4(+) T cells are
the principle sources of cytokines of adaptive immunity. Cytokines
play critical roles in the differentiation and effector function of
CD4(+) T cells. They also play key roles in diseases, and some of them
have been developed into drugs in the forms of recombinant cytokines,
soluble receptors and neutralizing antibodies. Therefore, identifying
novel potential cytokines is necessary and beneficial for better
understanding immunology and enhancing human health. To find novel
potential cytokines, we carried out an integrated bioinformatics
analysis on the whole human genome. Cytokine candidates were selected
for cDNA cloning, sub-cloning, secretion verification, expression
profile analysis and functional study. Here, we report a novel soluble
protein, VSTM1-v2, which is a classical secretory glycoprotein mainly
expressed in immune tissues, and can promote the differentiation and
activation of Th17 cells.

PMID: 22960280

WELL so interesting there is only one hit of 525:

VSTM1-v2- one hit of 525
http://www.ncbi.nlm.nih.gov/pubmed?term=VSTM1-v2

And the above is that one hit. LOL

OK.

We have 46 hits of 525 with psoria*
http://www.ncbi.nlm.nih.gov/pubmed?term=Th17%20glycoprotein%20psoria*

#6 (PMID: 21968671 ) is how lps turns on CD70 which i covered: duh
https://groups.google.com/group/alt.support.skin-diseases.psoriasis/search?q=cd70+lps&start=0&


And still ONLY two hits: glycoprotein + Th17 + microbiota
http://www.ncbi.nlm.nih.gov/pubmed?term=glycoprotein%20Th17%20microbiota

And both have been posted in the p ng:

Loss of sex and age driven differences in the gut microbiome
characterize arthritis-susceptible 0401 mice but not arthritis-
resistant 0402 mice.
Gomez A, Luckey D, Yeoman CJ, Marietta EV, Berg Miller ME, Murray JA,
White BA, Taneja V.
PLoS One. 2012;7(4):e36095. Epub 2012 Apr 24.
PMID: 22553482

2.
The membrane-bound mucin Muc1 regulates T helper 17-cell responses and
colitis in mice.
Nishida A, Lau CW, Zhang M, Andoh A, Shi HN, Mizoguchi E, Mizoguchi A.
Gastroenterology. 2012 Apr;142(4):865-874.e2. Epub 2011 Dec 24.
PMID: 22202458

-----------

And 62 hits: Th17 + microbiota
http://www.ncbi.nlm.nih.gov/pubmed?term=Th17%20microbiota

=================

A new jak-stat to LOOK at:

http://www.ncbi.nlm.nih.gov/pubmed/22961000
Nat Genet. 2012 Sep 9. doi: 10.1038/ng.2395.
Dense fine-mapping study identifies new susceptibility loci for
primary biliary cirrhosis.

Liu JZ, Almarri MA, Gaffney DJ, Mells GF, Jostins L, Cordell HJ,
Ducker SJ, Day DB, Heneghan MA, Neuberger JM, Donaldson PT, Bathgate
AJ, Burroughs A, Davies MH, Jones DE, Alexander GJ, Barrett JC; The UK
Primary Biliary Cirrhosis (PBC) Consortium; The Wellcome Trust Case
Control Consortium 3, Sandford RN, Anderson CA.

Source
1] Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus,
Hinxton, Cambridge, UK. [2].

Abstract
We genotyped 2,861 cases of primary biliary cirrhosis (PBC) from the
UK PBC Consortium and 8,514 UK population controls across 196,524
variants within 186 known autoimmune risk loci. We identified 3 loci
newly associated with PBC (at P < 5 × 10(-8)), increasing the number
of known susceptibility loci to 25. The most associated variant at
19p12 is a low-frequency nonsynonymous SNP in TYK2, further
implicating JAK-STAT and cytokine signaling in disease pathogenesis.
An additional five loci contained nonsynonymous variants in high
linkage disequilibrium (LD; r(2) > 0.8) with the most associated
variant at the locus. We found multiple independent common, low-
frequency and rare variant association signals at five loci. Of the 26
independent non-human leukocyte antigen (HLA) signals tagged on the
Immunochip, 15 have SNPs in B-lymphoblastoid open chromatin regions in
high LD (r(2) > 0.8) with the most associated variant. This study
shows how data from dense fine-mapping arrays coupled with functional
genomic data can be used to identify candidate causal variants for
functional follow-up.

PMID: 22961000

see:
http://cordis.europa.eu/fetch?CALLER=EN_NEWS&ACTION=D&SESSION=&RCN=35009
<snip>

14 hits: psoria* + jak STAT- pubmed
http://www.ncbi.nlm.nih.gov/pubmed?term=psoria*%20jak%20stat


http://en.wikipedia.org/wiki/JAK-STAT_signaling_pathway

203 hits: tyrosine + psoria* -pubmed
http://www.ncbi.nlm.nih.gov/pubmed?term=psoria*%20tyrosine


#1 of 203

http://www.ncbi.nlm.nih.gov/pubmed/22851227
Mol Cell Biochem. 2012 Oct;369(1-2):255-66. Epub 2012 Aug 1.
Participation of Gab1 and Gab2 in IL-22-mediated keratinocyte
proliferation, migration, and differentiation.

Zhu X, Li Z, Pan W, Qin L, Zhu G, Ke Y, Wu J, Bo P, Meng S.

Source
Department of Dermatology of Clinical Medical School, Yangzhou
University, Yangzhou, 225001, China.

Abstract
Interleukin-22 (IL-22) is one of the key mediators of keratinocyte
alterations in psoriasis. IL-22 inhibits keratinocyte differentiation
and induces the migration of human keratinocytes. Grb2-associated
binder 1 (Gab1) has been shown to mediate epidermal growth factor-
induced epidermal growth and differentiation via interaction with the
Src homology-2-containing protein-tyrosine phosphatase (Shp2). In this
investigation, we explore the role of Gab1 and Gab2 in IL-22-mediated
keratinocyte activities. We show that both Gab1 and Gab2 were tyrosine
phosphorylated in IL-22-stimulated HaCaT cells and human primary
epidermal keratinocytes and contributed to the activation of
Extracellular signal regulated kinase 1/2 (Erk1/2) through interaction
with Shp2. We further demonstrate that HaCaT cells infected with
adenoviruses expressing Shp2-binding-defective Gab1/2 mutants
exhibited decreased cell proliferation and migration, as well as
increased differentiation. Moreover, similar results were observed in
HaCaT cells infected with adenovirus-based small interfering RNAs
targeting Gab1 and/or Gab2. Altogether, these data underscore the
critical roles of Gab1 and Gab2 in IL-22-mediated HaCaT cell
proliferation, migration, and differentiation.

PMID: 22851227

#3 of 203

http://www.ncbi.nlm.nih.gov/pubmed/22805580
Functions of the Lyn tyrosine kinase in health and disease.
Ingley E.
Cell Commun Signal. 2012 Jul 17;10(1):21.

[...] Lyn is an important regulator of autoimmune diseases such as
asthma and psoriasis, due to its profound ability to influence immune
cell signaling.

PMID: 22805580
Free Article
http://www.biosignaling.com/content/10/1/21


http://en.wikipedia.org/wiki/LYN

10 hits: lyn - tyrosine - p ng
https://groups.google.com/group/alt.support.skin-diseases.psoriasis/search?q=Lyn+tyrosine+kinase&start=0&


http://www.ncbi.nlm.nih.gov/pubmed/19590497
The caspase-cleaved form of LYN mediates a psoriasis-like inflammatory
syndrome in mice.
Marchetti S, Gamas P, Belhacène N, Grosso S, Pradelli LA, Colosetti P,
Johansen C, Iversen L, Deckert M, Luciano F, Hofman P, Ortonne N,
Khemis A, Mari B, Ortonne JP, Ricci JE, Auberger P.
EMBO J. 2009 Aug 19;28(16):2449-60. Epub 2009 Jul 9.
PMID: 19590497
Free PMC Article
http://www.ncbi.nlm.nih.gov/pmc/articles/pmid/19590497/

357 hits : lyn + tyrosine + glycoprotein
http://www.ncbi.nlm.nih.gov/pubmed?term=lyn%20tyrosine%20glycoprotein

1467 without : glycoprotein
http://www.ncbi.nlm.nih.gov/pubmed?term=lyn%20tyrosine

http://www.ncbi.nlm.nih.gov/pubmed?term=lyn%20tyrosine%20microbiota


aaaaaaaaaaaaaaaaaahA


[...] From Shakespeare's Romeo and Juliet, 1592:

MERCUTIO:
I am hurt.
A plague o' both your houses! I am sped.
Is he gone, and hath nothing?
<snip>


http://www.shakespeare-online.com/biography/londondisease.html

[...] Shakespeare mentions plague in several plays, including The
Tempest (1.2.426), Timon of Athens (4.3.120), and King Lear:

But yet thou art my flesh, my blood, my daughter;
Or rather a disease that's in my flesh,
Which I must needs call mine: thou art a boil,
A plague-sore, an embossed carbuncle,
In my corrupted blood.
(2.4.242), Lear, describing his daughter, Goneril


Shakespeare also describes the act of searching out plague victims and
quarantining them in Romeo and Juliet (5.2.7). Incidentally, plague is
the indirect cause of the deaths of the star-cross'd lovers.

2. Smallpox
One of the worst outbreaks of smallpox occurred two years before
Shakespeare's birth, in 1562. Queen Elizabeth herself, then 29, was
attacked by the virus that causes high fever, vomiting, excessive
bleeding, and pus-filled scabs that leave deep pitted scars. Although
the Queen recovered she was rendered completely bald and forced to
wear an extra thick layer of make-up made from white lead and egg
whites.

3. Syphilis
Syphilis, one of the deadliest of all venereal diseases, spread
rapidly throughout Europe in the 15th century. A current theory on the
origin of the outbreak argues that Spaniards carried the disease home
from the Americas in 1493. Elizabethans had many names for this foul
malady; the most popular being the French pox, the Spanish sickness,
the great pox, and simply, the pox.
<snip>


A pox on your house for 3 generations?


That is the 2012 gustation?


http://en.wikipedia.org/wiki/Gustatory_system


FAT forks BEWARE!

Did grandMA screw YOU? oh wait? Might be the story after this one?
Or both?

http://www.eurekalert.org/pub_releases/2012-09/vt-bcr091012.php
Breast cancer risks acquired in pregnancy may pass to next 3
generations

Chemicals or foods that raise estrogen levels during pregnancy may
increase cancer risk in daughters, granddaughters, and even great-
granddaughters, according to scientists from Virginia Tech and
Georgetown University.

Pregnant rats on a diet supplemented with synthetic estrogen or with
fat, which increases estrogen levels, produce ensuing generations of
daughters that appear to be healthy, but harbor a greater than normal
risk for mammary cancer, the researchers report in today's Nature
Communications.

Although the findings have not yet been validated in humans, the study
shows that environmental damage may be passed from one generation to
the next not through genetic mutations, but through "epigenetic"
alterations that influence how genomic information is decoded.

The research also raises hope that people who may be especially
sensitive to carcinogens can be identified and novel prevention
strategies can be employed before cancer strikes.

"We have shown for the first time that altered DNA methylations
modulated by specific diet in normal development are heritable and
transgenerational," said Yue "Joseph" Wang, the Grant A. Dove
Professor of Electrical and Computer Engineering at Virginia Tech
Research Center – Arlington. "We also identified key methylation
alteration sites that may be involved or responsible for increased
breast cancer risk, which may serve as novel biomarkers for scientists
to develop novel and targeted prevention strategies."

The National Cancer Institute estimates that more than 226,000 women
and more than 2,000 men will develop breast cancer in 2012, and nearly
40,000 people will die of the disease.

Two thirds of breast cancers that occur in families have no known
genetic cause, according to Leena Hilakivi-Clarke, a professor of
oncology at Georgetown Lombardi Comprehensive Cancer Center. The study
shows what may be underlying the cancer are not genetic mutations, but
inherited effects of maternal intake of high-fat diets and exposure to
excess estrogen during pregnancy.

"It is becoming clear that the process of epigenetic signaling — which
genes are expressed and which genes are silenced — is being affected
by a mother's hormonal environment during pregnancy," said Hilakivi-
Clarke, who has studied the effects of maternal diet on offspring in
animals and humans for more than 20 years. "The early studies indicate
in a normal pregnancy a woman may have more than 20 different estrogen
levels, and the highest and the lowest all result in a healthy baby.
The challenge has been to understand how something in fetal
development can affect breast cancer risk more than 50 years later."

The study was led by Sonia de Assis, a postdoctoral researcher in
Hilakivi-Clarke's laboratory at the Georgetown Lombardi Comprehensive
Cancer Center at Georgetown University Medical Center.

Virginia Tech researchers developed mathematical models and machine-
learning techniques to analyze the changes in DNA methylation status
in the descending daughters to understand how increased cancer risk is
transmitted without genetic mutation.

DNA methylation is a key process in normal development, allowing cells
with the same genome to perform different functions by adding chemical
groups to DNA to turn some genes on and some genes off.

Wang's group found that the descendants with increased risk had
several hundred common DNA regions that were methylated differently
than in a control group, providing statistically convincing evidence
that breast cancer risk can be transmitted via epigenetic means.

"Ultimately, it may be possible to undo or prevent this harmful
methylation and decrease the risk of breast cancer." Wang said. "A
next step will be to study the timing of the intervention and the
impacts of the methylation as it occurs in the early, middle or end of
the pregnancy. The promising news is pharmacologic or other
interventions may be able to reverse the harmful exposure."
###
<snip>


OMG - GRANDma DID screw YOU?


OK so what does the funky diet (fats- omega-6 or transFATS) do to
fam83a or b?


http://www.genengnews.com/gen-news-highlights/breast-cancer-drug-resistance-linked-to-gene-family/81247183/


Two related proteins have been implicated in the mechanisms that allow
breast cancer, and potentially other tumor types, to resist therapy
with tyrosine kinase inhibitors (TKIs). FAM83A and FAM83B have been
identified by separate research groups reporting in parallel in the
Journal of Clinical Investigation. Both teams say that if their
findings can be validated, the proteins may represent promising new
therapeutic targets.
http://www.genengnews.com/keyword/breast-cancer/52

Researchers at Case Western Reserve University used a validation-based
insertional mutagenesis (VBIM) strategy to generate libraries of HEM1
immortalized human mammary epithelieal cells (HMECs) that carried
unique, single genetic alterations, as a means to identify genes that
promoted anchorage-independent growth (AIG, a hallmark of transformed
cells), and tumorigenicity, and then carried out further cell-based
assays to see which of the identified genes could promote tumor growth
independently of RAS.
http://www.genengnews.com/keyword/case-western-reserve-university/1895

Expression of FAM83B was found to promote AIG and tumorigenesis, in
naïve HME1 cells, and FAM83B-expressing cells were also shown to be
capable of forming tumors in immunodeficient mice, confirming its
function as a transforming oncogene. Interestingly, when the
researchers looked at public microarray data they found that FAM83B
expression was elevated in human breast cancer and a range of other
solid tumors, relative to normal tissue. In fact, high FAM83B
expression levels were associated with specific cancer subtypes, with
increased tumor grade, and with decreased overall survival. For
example, increased expression of FAM83B was significantly associated
with estrogen receptor– (ER-) and progesterone receptor–negative (PR-
negative) breast tumors, with higher grade and poor outcome.

Further in vitro assays showed that FAM83B binds with a downstream RAS
effector, CRAF, and that this binding resulted in markedly increased
MAPK and mTOR signaling, and reduced sensitivity to EGFR-TKIs.
Effectively, write Mark W. Jackson, M.D., Rocky Cipriano, M.D., and
colleagues, tumors with elevated FAM83B display self-sufficient growth
signaling. Importantly, knocking out FAM83B inhibited the
proliferation and malignant phenotype of tumor-derived cells or RAS-
transformed HMECs.

The authors say targeting FAM38B therapeutically may increase the
sensitivity of breast cancer to EGFR-TKI therapy. “Approximately 30%
of breast cancers overexpress EGFR, which correlates with loss of
estrogen responsiveness and poor prognosis, yet TKIs have thus far had
low clinical value for breast cancer patients,” they point out. “Given
the requirement for FAM83B as an activator of CRAF/MAPK in EGFR and
RAS signaling, the levels of FAM83B and FAM83A may be important to
consider when determining which patients receive TKI treatment … Our
observation that cancer cells harboring mutant RAS were sensitive to
FAM83B ablation lays the foundation for future studies aimed at
identifying novel therapies capable of targeting FAM83B.” The Case
Western-led researchers describe their findings in a paper titled
"FAM83B mediates EGFR- and RAS-driven oncogenic transformation."

A Lawrence Berkeley National Laboratory-led team of researchers
reporting in the same issue of JCI performed a screen of human breast
cancer cell lines to identify genes that make cancer cells resistant
to EGFR TKIs. Top of the list of candidates was FAM38A, which had
coincidentally previously been identified as highly expressed in lung
cancer. The researchers then used an FAM38A antibody to look at the
expression of the protein in human breast tissues, and found that,
while normal tissue didn’t produce the FAM38A, it was highly expressed
in malignant tissue. Notably, the protein was also expressed in every
breast cancer cell line they looked at and was particularly elevated
in those that were more resistant to EGFR-TKI treatment. “Indeed,
breast cancer patients exhibiting high levels of FAM83A expression had
significantly lower survival than did patients with low levels of
FAM83A,” note lead author Mina J. Bissell, Ph.D., et al. And when
breast cancer cells were treated with an shRNA that blocked FAM38A
expression, the cells became less proliferative and more sensitive to
EGFR-TKI treatment. Conversely, FAM83A overexpression led to elevated
invasiveness.

Mechanistically, FAM83A was shown to interact with and cause
phosphorylation of CRAF and PI3K, upstream of MAPK and downstream of
EGFR. This finding correlates well with the mechanism reported for
FAM38B by the Case Western team, the Berkeley researchers point out.
“Their and our studies have identified a family of breast cancer–
associated genes or a possible family of oncogenes and support the
contention that FAM83A and FAM83B (and possibly other family members)
are involved in therapeutic resistance in breast cancer and other
cancer types,” Dr. Bissell, et al., state. “Our findings suggest the
importance of FAM83 family members as potential drug targets for
therapy as well as for sensitization to EGFR-TKIs.”
<snip>


Let's kick cancer of the breast and everywhere ELSE to the CURB
already?


Hey!


I'm GAME...

R u?

Their FAM83A or B and LOL (the above says FAM38b missprint?) pubmed:

http://www.ncbi.nlm.nih.gov/pubmed/22886299
J Clin Invest. 2012 Sep 4;122(9):3048-51. doi: 10.1172/JCI64412. Epub
2012 Aug 13.
FAM83A and FAM83B: candidate oncogenes and TKI resistance mediators.

Grant S.

Abstract
The growth and survival of tumor cells can depend upon the expression
of a single oncogene, and therapeutically targeting this oncogene
addiction has already proven to be an effective approach in fighting
cancer. However, it is also clear that cancer cells can adapt and
become resistant to therapy through compensatory activation of
downstream pathways that relieve the cell of its addicted phenotype.
In this issue of the JCI, two groups - Lee et al. and Cipriano et al.
- identify two related candidate oncogenes that might both contribute
to therapeutic resistance to tyrosine kinase inhibitors (TKIs). If
validated, this information could help to identify new targets for
therapeutic interventions in breast cancer and possibly other cancers
and may also assist in the development of strategies designed to
overcome resistance to currently available TKIs.

PMID: 22886299
PMCID: PMC3428099 [Available on 2013/1/1]
<i can hardly WAIT>


Whoops there is a fam38b but i still think it's a miss print:
http://www.genecards.org/cgi-bin/carddisp.pl?gene=PIEZO2

And six hits on pubmed: fam38b for some piezo dealy bob?
http://www.ncbi.nlm.nih.gov/pubmed?term=fam38b

Piezo2 (Fam38B)
http://www.ncbi.nlm.nih.gov/pubmed/20813920
pmid # 20813920

OK so while it was a miss print it's still a real deal. LOL

attack on us official.. killed in cairo or ben GAZHI? Yikes.


What?

Todays 911 and these guys are picking a fight?

Are they crazy?

Is obama?


Will the TWAIN meet? LOL

BAck to fam83a and B and not 38.... LOL


---------

http://www.ncbi.nlm.nih.gov/pubmed/22886303
J Clin Invest. 2012 Sep 4;122(9):3211-20. doi: 10.1172/JCI60498. Epub
2012 Aug 13.
FAM83A confers EGFR-TKI resistance in breast cancer cells and in mice.

Lee SY, Meier R, Furuta S, Lenburg ME, Kenny PA, Xu R, Bissell MJ.

Abstract
Breast cancers commonly become resistant to EGFR-tyrosine kinase
inhibitors (EGFR-TKIs); however, the mechanisms of this resistance
remain largely unknown. We hypothesized that resistance may originate,
at least in part, from molecular alterations that activate signaling
downstream of EGFR. Using a screen to measure reversion of malignant
cells into phenotypically nonmalignant cells in 3D gels, we identified
FAM83A as a candidate cancer-associated gene capable of conferring
resistance to EGFR-TKIs. FAM83A overexpression in cancer cells
increased proliferation and invasion and imparted EGFR-TKI resistance
both in cultured cells and in animals. Tumor cells that survived EGFR-
TKI treatment in vivo had upregulated FAM83A levels. Additionally,
FAM83A overexpression dramatically increased the number and size of
transformed foci in cultured cells and anchorage-independent growth in
soft agar. Conversely, FAM83A depletion in cancer cells caused
reversion of the malignant phenotype, delayed tumor growth in mice,
and rendered cells more sensitive to EGFR-TKI. Analyses of published
clinical data revealed a correlation between high FAM83A expression
and breast cancer patients' poor prognosis. We found that FAM83A
interacted with and caused phosphorylation of c-RAF and PI3K p85,
upstream of MAPK and downstream of EGFR. These data provide an
additional mechanism by which tumor cells can become EGFR-TKI
resistant.

PMID: 22886303
Free PMC Article


------------------more colon cancer please?


Yes, yes, yes!

http://www.news.cornell.edu/stories/Sept12/cancerSwitch.html
Sept. 10, 2012
Metastatic 'switch' sheds new light on colon cancer

By Anne Ju

What kills cancer patients often isn't the primary tumor; it's when
the tumor metastasizes -- or spreads the cancer to other areas of the
body.

Focusing on colorectal cancer, a leading cause of cancer death
worldwide, a multidisciplinary research team has shed new light on how
these cancer cells metastasize by identifying a key chemical signaling
factor that triggers the process.

What's more, they have engineered a low-cost, surgery-free genetic
"switch" that turns metastatic behavior of colorectal cancer cells on
and off, allowing for easy, repeatable study of this process.

The research is detailed in the Journal of Clinical Investigation,
published Sept. 4, and was led by Huanhuan Joyce Chen, a graduate
student under Xiling Shen, assistant professor of electrical and
computer engineering and a field member of biomedical engineering.
Shen is a co-author with Steven Lipkin, associate professor of
medicine at Weill Cornell Medical College. The work was also
highlighted online by the company Qiagen.

The researchers found that particular signaling mechanisms called
chemokines induce metastasis of colorectal cancer cells. Chemokines
are "motility factors" because they help cells move throughout the
body. They are known, for example, to be important in the body's
immunoresponse, which requires immune cells to travel quickly to areas
of inflammation or infection.

The researchers established a link between a particular chemokine
receptor, called CCR9, and its ligand chemokine CCL25, to the
metastatic behavior of colorectal cancer cells. Normal expression of
these chemokines keeps the cancer cells in the gut, but once the cells
lose CCR9 expression, they can spread. In other words, cancer cells
hijack the signaling mechanism.

This discovery in itself, Shen said, could form the basis for targeted
anti-metastatic therapies.

A barrier to cancer research, however, is the lack of good animal
models to test therapies, Shen said, and human clinical trials often
fail as a result.

So Chen used her engineering background to take things a step further:
She made a mouse with a CCL25 and CCR-9 metastatic "switch" that could
be turned on and off after cancer cells were injected into the mouse.
At first, the cells expressed the CCR9 receptor, and the tumor only
formed in the gut. Turning off the switch made the cells lose the
signaling mechanism, and metastasis occurred.

This switch could eliminate the traditional way scientists study
metastasis: expensive, low-throughput surgical implantation of
metastasized cancer cells. With the switch, metastasis can be studied
and repeated by a simple injection of colorectal cancer cells.

The work was supported by the National Science Foundation and the
Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for
Computational Biomedicine, the Coffrin Center for Biomedical
Information at Weill Cornell, and a donation by philanthropist Matthew
Bell.
<snip>

Their abstract:

http://www.ncbi.nlm.nih.gov/pubmed/22863617
J Clin Invest. 2012 Sep 4;122(9):3184-96. doi: 10.1172/JCI62110. Epub
2012 Aug 6.
Chemokine 25-induced signaling suppresses colon cancer invasion and
metastasis.

Chen HJ, Edwards R, Tucci S, Bu P, Milsom J, Lee S, Edelmann W, Gümüs
ZH, Shen X, Lipkin S.

Abstract
Chemotactic cytokines (chemokines) can help regulate tumor cell
invasion and metastasis. Here, we show that chemokine 25 (CCL25) and
its cognate receptor chemokine receptor 9 (CCR9) inhibit colorectal
cancer (CRC) invasion and metastasis. We found that CCR9 protein
expression levels were highest in colon adenomas and progressively
decreased in invasive and metastatic CRCs. CCR9 was expressed in both
primary tumor cell cultures and colon-cancer-initiating cell (CCIC)
lines derived from early-stage CRCs but not from metastatic CRC. CCL25
stimulated cell proliferation by activating AKT signaling. In vivo,
systemically injected CCR9+ early-stage CCICs led to the formation of
orthotopic gastrointestinal xenograft tumors. Blocking CCR9 signaling
inhibited CRC tumor formation in the native gastrointestinal CCL25+
microenvironment, while increasing extraintestinal tumor incidence.
NOTCH signaling, which promotes CRC metastasis, increased
extraintestinal tumor frequency by stimulating CCR9 proteasomal
degradation. Overall, these data indicate that CCL25 and CCR9 regulate
CRC progression and invasion and further demonstrate an appropriate in
vivo experimental system to study CRC progression in the native colon
microenvironment.

PMID: 22863617
Free PMC Article
http://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22863617/


What took these folks so LONG?

This is back in 2007 for CCL25 + CCR9 :

http://www.ncbi.nlm.nih.gov/pubmed/17551016
Proc Natl Acad Sci U S A. 2007 Jun 12;104(24):10122-7. Epub 2007 Jun
5.
Differential homing mechanisms regulate regionalized effector
CD8alphabeta+ T cell accumulation within the small intestine.

Stenstad H, Svensson M, Cucak H, Kotarsky K, Agace WW.

Source
Immunology Section, Lund University, BMC I-13, S-221 84 Lund, Sweden.

Abstract
The CC chemokine receptor (CCR)9 is expressed on the majority of small
intestinal, but few colonic, T cells, whereas its ligand CCL25 is
constitutively expressed by small intestinal epithelial cells. As
such, CCR9/CCL25 have been proposed to play a central role in
regulating small intestinal but not colonic immune responses and thus
to organize regionalized immunity within the intestinal mucosa. Here,
we demonstrate that CCL25 is expressed at reduced levels by epithelial
cells in the distal compared with proximal small intestine, which
correlated with less efficient CCR9-dependent effector CD8alphabeta+ T
cell entry into the ileal epithelium. In vitro-generated alpha4beta7+
effector CD8alphabeta+ T cell entry into the lamina propria was less
dependent on CCR9 than entry into the epithelium along the entire
length of the small intestine and in particular in the ileum. CCR9-
independent alpha4beta7+ effector CD8alphabeta+ T cell entry was
pertussis toxin-sensitive, suggesting a role for additional Galpha(I)-
linked G protein-coupled receptors. Finally, in vivo-primed effector
CD8alphabeta+ T cells displayed regionalized differences in their
entry to the small intestinal epithelium with enhanced CCR9-
independent entry to the ileum. These results highlight a hitherto
underappreciated compartmentalization of immune responses within the
small intestine and have direct implications for targeting strategies
aimed at regulating T cell localization to the small intestinal
mucosa.

PMID: 17551016
Free PMC Article
http://www.ncbi.nlm.nih.gov/pmc/articles/pmid/17551016/


And this one confirms:

http://www.ncbi.nlm.nih.gov/pubmed/22539284
Eur J Immunol. 2012 May;42(5):1097-101. doi: 10.1002/eji.201242545.
Driving IL-17⁺ γδ T-cell migration in allergic reactions: a new
"inflammatory" role for the "homeostatic" chemokine CCL25.

Silva-Santos B.

Source
Instituto de Medicina Molecular, Faculdade de Medicina da Universidade
de Lisboa, Lisboa, Portugal. bssa...@fm.ul.pt

Abstract
Chemokines are traditionally classified as homeostatic or inflammatory
depending on whether they direct leukocyte migration in the absence or
presence of inflammatory stimuli. CC chemokine ligand (CCL)25, a
ligand for CC chemokine receptor (CCR)9, has mostly been characterized
as a homeostatic chemokine that determines the migration pathway of T-
cell progenitors within the thymus, and the recruitment of various
lymphocyte subsets to the intestinal mucosa. In this issue of the
European Journal of Immunology, Costa et al. [Eur. J. Immunol. 2012.
42: 1250-1260] describe a new inflammatory role for CCL25/CCR9 in
controlling the migration of a subset of γδ T cells committed to IL-17
production (γδ17 cells) in a model of allergic pleurisy.
Interestingly, the effect of CCL25 was selective for γδ17 cells, as it
did not extend to other γδ or αβ T-cell subsets, and resulted in a
specific increase of IL-17 (but not IL-4 or IFN-γ) levels in the
allergic pleura. In this commentary, I discuss these results in the
context of chemokine-mediated recruitment of γδ T cells to
inflammatory sites, and the as yet unclear and controversial role of
IL-17 in allergic reactions.

Comment on
CCL25 induces α₄β₇ integrin-dependent migration of IL-17⁺ γδ T
lymphocytes during an allergic reaction. [Eur J Immunol. 2012]
http://www.ncbi.nlm.nih.gov/pubmed/22539297

PMID: 22539284


But still a lack of input:

only 10 hits: chemokine 25 + ccr9 + ccl25- pubmed
http://www.ncbi.nlm.nih.gov/pubmed?term=chemokine%2025%20%20ccr9%20%20ccl25

yet ... getting smart like maxwell we do have

116 hits: ccr9 ccl25 -pubmed
http://www.ncbi.nlm.nih.gov/pubmed?term=ccr9%20ccl25


#2 of 116

http://www.ncbi.nlm.nih.gov/pubmed/22626536
Immunol Lett. 2012 Aug 30;146(1-2):64-9. Epub 2012 May 22.
CCR9(+) plasmacytoid dendritic cells in the small intestine suppress
development of intestinal inflammation in mice.

Mizuno S, Kanai T, Mikami Y, Sujino T, Ono Y, Hayashi A, Handa T,
Matsumoto A, Nakamoto N, Matsuoka K, Hisamatsu T, Takaishi H, Hibi T.

Source
Department of Gastroenterology and Hepatology, Keio University School
of Medicine, Tokyo 160-8582, Japan.

Abstract
Almost all mice lacking specific molecules associated with regulatory
T cells or barrier function develop intestinal inflammation in the
colon, but not in the small intestine (SI). Therefore, intestinal
homeostasis of the SI may be tightly controlled by other mechanisms.
To determine the role of CCR9(+) plasmacytoid dendritic cells (pDCs)
in intestinal homeostasis of the SI we transferred CD4(+)CD45RB(high)
T cells into ccr9(-/-)×rag-2(-/-) mice. We showed that CCL25, a
counterpart chemokine for CCR9, is constitutively expressed in the SI
but not the colon and spleen of rag-2(-/-) or ccr9(-/-)×rag-2(-/-)
mice before or after transfer of CD4(+)CD45RB(high) T cells. The
ccr9(-/-)×rag-2(-/-) mice did not develop spontaneous intestinal
inflammation in the SI and colon. Mice of both genotype where
CD4(+)CD45RB(high) T cells were transferred developed colitis.
However, the ccr9(-/-)×rag-2(-/-) mice also developed ileitis with
marked infiltration of Th1 cells. These results suggest that CCR9(+)
pDCs are possibly small, regulatory, antigen-presenting cells of the
intestine that suppress intestinal inflammation.

PMID: 22626536

http://en.wikipedia.org/wiki/CCL25
Chemokine (C-C motif) ligand 25 (CCL25) is a small cytokine belonging
to the CC chemokine family that is also known as TECK (Thymus-
Expressed Chemokine). CCL25 is believed to play a role in the
development of T-cells.[1] It is chemotactic for thymocytes,
macrophages, and dendritic cells. CCL25 elicits its effects by binding
the chemokine receptors CCR9.[2][3] Human CCL25 is produced as a
protein precursor containing 151 amino acids. The gene for CCL25
(scya25) is located on human chromosome 19.[4]
<snip>

But does VDR and D3 from uvb knock down or build up ... you know? LoL


3 or 4 hits how you look at it:
https://groups.google.com/groups/search?qt_s=1&q=ccl25+randall+psoriasis

So?

Is the thymus some unEXplored region?

But what beyond:
http://en.wikipedia.org/wiki/Thymocyte

[...] Additional mechanisms of peripheral tolerance active in the
periphery exist to silence these cells such as anergy, deletion, and
regulatory T cells. If these peripheral tolerance mechanisms also
fail, autoimmunity may arise.
<snip>

So it HAS AROSE... ?

About 225 times for : thymus - p ng
https://groups.google.com/group/alt.support.skin-diseases.psoriasis/search?q=thymus&start=0&

So?

Since: "CCR9, and its ligand chemokine CCL25"

we go to ccr9 - p ng- 15 hits
https://groups.google.com/groups/search?q=ccr9+randall+psoriasis&btnG=Search&sitesearch=

whoops that was all groups:
https://groups.google.com/group/alt.support.skin-diseases.psoriasis/search?q=ccr9&start=0&


and : 2 hits: thymus + ccr9 + ccl25 - p ng
https://groups.google.com/group/alt.support.skin-diseases.psoriasis/search?q=thymus+ccr9+ccl25&start=0&


And only 13 hits in ALL groups (same thing)
https://groups.google.com/groups/search?qt_s=1&q=thymus+ccr9+ccl25

And going to mainline google:

2,400 hits: thymus ccr9 ccl25 lps cd70- google search:
http://www.google.com/webhp?hl=en&tab=gw&q=thymus%20ccr9%20ccl25#hl=en&sclient=psy-ab&q=thymus+ccr9+ccl25+lps+cd70&oq=thymus+ccr9+ccl25+lps+cd70&gs_l=hp.3...7610.12119.1.12739.9.9.0.0.0.0.187.1220.0j9.9.0.les%3B..0.0...1c.1.HZtDFDA1dyk&pbx=1&bav=on.2,or.r_gc.r_pw.r_qf.&fp=dd4e74f5654acd20&biw=1680&bih=931

adding : psoriasis - 895 hits
http://www.google.com/webhp?hl=en&tab=gw&q=thymus%20ccr9%20ccl25#hl=en&sclient=psy-ab&q=thymus+ccr9+ccl25+lps+cd70+psoriasis&oq=thymus+ccr9+ccl25+lps+cd70+psoriasis&gs_l=serp.3...54907.56506.0.56853.10.10.0.0.0.0.244.1594.0j8j2.10.0.les%3B..0.0...1c.1.3kAYhi4QsMo&pbx=1&bav=on.2,or.r_gc.r_pw.r_qf.&fp=dd4e74f5654acd20&biw=1680&bih=931

#3 of 895

Shining a Light on Intestinal Traffic
www.downloads.hindawi.com/journals/cdi/2012/808157.pdf

or try this instead:

http://www.ncbi.nlm.nih.gov/pubmed/22162719
Clin Dev Immunol. 2012;2012:808157. doi: 10.1155/2012/808157. Epub
2011 Nov 22.
Shining a light on intestinal traffic.

Murphy CT, Nally K, Shanahan F, Melgar S.

Source
Alimentary Pharmabiotic Centre, University College Cork, National
University of Ireland.

Abstract
Inflammatory bowel disease (IBD), encompassing Crohn's disease and
ulcerative colitis, is associated with enhanced leukocyte infiltration
to the gut, which is directly linked to the clinical aspects of these
disorders. Thus, leukocyte trafficking is a major target for IBD
therapy. Past and emerging techniques to study leukocyte trafficking
both in vitro and in vivo have expanded our knowledge of the leukocyte
migration process and the role of inhibitors. Various strategies have
been employed to target chemokine- and integrin-ligand interactions
within the multistep adhesion cascade and the S1P/S1PR1 axis in
leukocyte migration. Though there is an abundance of preclinical data
demonstrating efficacy of leukocyte trafficking inhibitors, many have
yet to be confirmed in clinical studies. Vigilance for toxicity and
further research is required into this complex and emerging area of
IBD therapy.
PMID: 22162719
Free PMC Article
http://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22162719/


What?

Psoriasis gets ONE mention :


[...] 4.3. Alicaforsen- (ISIS2302-) and LFA-1-Targeting Drugs
Alicaforsen, a human ICAM-1 antisense oligonucleotide, inhibits ICAM-1
production preventing T-cell adhesion, extravasation, and subsequent
migration to inflamed areas [127]. Blocking ICAM-1 ameliorated colitis
in a number of preclinical models [63, 64, 67]. In clinical studies,
this approach has had variable success and in general has yielded
disappointing results in the treatment of CD [128–130]. However, there
have been promising results with an enema formulation of Alicaforsen
in the treatment of UC [65] and refractory pouchitis [131].
Efalizumab, a humanized monoclonal IgG1 antibody treatment for plaque
psoriasis, is FDA approved and also acts by blocking the LFA-1/ICAM-1
interaction. By doing this it inhibits T-cell migration to the
inflamed dermal and epidermal tissues. However, similar to
Natalizumab, serious adverse effects, such as the Epstein-Barr virus-
associated B-cell lymphoma development, were reported following
treatment [132].

<snip>
http://www.ncbi.nlm.nih.gov/pubmed/17668531

And looking at author:

42 hits - Melgar S[Author] -pubmed
http://www.ncbi.nlm.nih.gov/pubmed?term=Melgar%20S%5BAuthor%5D

And another melgar i like is the most recent:

http://www.ncbi.nlm.nih.gov/pubmed/22961803
Am J Physiol Gastrointest Liver Physiol. 2012 Sep 6.
Mechanism of protection of transepithelial barrier function by
Lactobacillus salivarius: strain-dependence and attenuation by
bacteriocin production.

Miyauchi E, O'Callaghan J, Butto LF, Hurley G, Melgar S, Tanabe S,
Shanahan F, Nally K, O'Toole PW.

Source
1Hiroshima University.

Abstract
Enhanced barrier function is one mechanism whereby commensals and
probiotic bacteria limit translocation of foreign antigens or
pathogens in the gut. However, barrier protection is not exhibited by
all probiotic or commensals and the strain-specific molecules involved
remain to be clarified. We evaluated the effects of 33 individual
Lactobacillus salivarius strains on the hydrogen peroxide (H(2)O(2))-
induced barrier impairment in human epithelial Caco-2 cells. These
strains showed markedly different effects on H(2)O(2)-induced
reduction in transepithelial resistance (TER). The effective strains
such as UCC118 and CCUG38008 attenuated H(2)O(2)-induced disassembly
and relocalization of tight junction proteins, but the ineffective
strain AH43324 did not. Strains UCC118 and CCUG38008 induced
phosphorylation of extracellular signal-regulated kinase (ERK) in
Caco-2 cells, and the ERK inhibitor U0126 attenuated the barrier-
protecting effect of these strains. In contrast, the AH43324 strain
induced phosphorylation of Akt and p38, which was associated with an
absence of a protective effect. Global transcriptome analysis of
UCC118 and AH43324 revealed that some genes in a bacteriocin gene
cluster were up-regulated in AH43324 under TER assay conditions. A
bacteriocin-negative UCC118 mutant displayed significantly greater
suppressive effect on H(2)O(2)-induced reduction in TER compared to
wild type UCC118. The wild type strain augmented H(2)O(2)-induced
phosphorylation of Akt and p38, while a bacteriocin-negative UCC118
mutant did not. These observations indicate that L. salivarius strains
are widely divergent in their capacity for barrier protection and this
is underpinned by differences in the activation of intracellular
signaling pathways. Furthermore, bacteriocin production appears to
have an attenuating influence on lactobacillus-mediated barrier
protection.

PMID: 22961803


And special kudos to the O'Toole PW lab:

http://www.ncbi.nlm.nih.gov/pubmed/22895081
Gut Microbes. 2012 Nov 1;3(6).
The microbiota link to Irritable Bowel Syndrome: An emerging story.

Jeffery IB, Quigley EM, Ohman L, Simrén M, O'Toole PW.

Source
Department of Microbiology; University College Cork; Cork, Ireland.

Abstract
Irritable Bowel Syndrome (IBS) is a clinically heterogeneous disorder
which is likely to involve a number of causative factors. The
contribution of altered intestinal microbiota composition or function
to this disorder is controversial, and is the subject of much current
research. Until recently, the technical limitations of the
methodologies available have not permitted an adequate survey of low-
abundance microbial species. Recent technological developments have
enabled the analysis of the global population of the microbiome using
high through-put, culture independent, 16S rRNA amplicon
pyrosequencing. Using these new methodologies, we are able to gain
important biological insights into the link between functional bowel
disorders and the microbiome. This addendum contextualizes and
summarizes the results of these studies, and defines the future
challenges and opportunities in the field.

PMID: 22895081



====================Going back to CANCER....


http://www.sciencedaily.com/releases/2012/09/120910122109.htm
Cancer-Causing Gene Alone Doesn’t Trigger Pancreatic Cancer, Research
Finds

ScienceDaily (Sep. 10, 2012) — More than a cancer-causing gene is
needed to trigger pancreatic cancer, a study led by Mayo Clinic has
found. A second factor creates a "perfect storm" that allows tumors to
form, the researchers say. The study, published in the Sept. 10 issue
of Cancer Cell, overturns the current belief that a mutation in the
KRAS oncogene is enough to initiate pancreatic cancer and unrestrained
cell growth.

The findings uncover critical clues on how pancreatic cancer develops
and why few patients benefit from current therapies. The findings also
provide ideas about how to improve treatment and prevention of
pancreatic cancer.

The research team, led by Howard C. Crawford, Ph.D., a cancer
biologist at Mayo Clinic's campus in Florida, and Jens Siveke, M.D.,
at Technical University in Munich, Germany, found that for pancreatic
cancer to form, mutated KRAS must recruit a second player: the
epidermal growth factor receptor, or EGFR.A third genetic participant
known as Trp53 makes pancreatic tumors very difficult to treat, the
study showed.

The scientists also found that EGFR was required in pancreatic cancer
initiated by pancreatic inflammation known as pancreatitis.

"We believe the perfect storm needed to trigger pancreatic cancer
include KRAS mutations and inflammation in the organ, which then work
synergistically to turn on EGFR," says Dr. Crawford.

"The bottom line is, without EGFR, tumors don't form -- and that was
never known before this study," he says. "We also think that
inflammation in the pancreas has a big impact on turning on EGFR."

The researchers discovered that when they blocked EGFR activity, the
mice studied were protected against developing chronic pancreatitis
and pancreatic cancer.

They further found that in mice that had lost expression of the TP53
tumor suppressor -- a situation that mirrors up to 60 percent of human
pancreatic cancer cases -- tumors escape the dependency on EGFR for
initiation and continued growth of pancreatic cancer, Dr. Crawford
says.

Pancreatic cancer is a highly lethal disease; no drug has been able to
target the mutant KRAS protein. The study suggests some patients, such
as those with chronic pancreatitis, may be good candidates for
treatment with EGFR inhibitors to fight or prevent pancreatic cancer,
Dr. Crawford says.

"The clinical implications of this study are exciting. It suggests
that pancreatic cancer patients with normal p53 activity, as well as
patients with chronic pancreatitis, may be good candidates for
treatment with EGFR inhibitors," Dr. Crawford says.

The EGFR inhibitor erlotinib is part of the standard therapy for
pancreatic cancer patients, but has minimal effects in the patient
population as a whole, he adds. "But that may be because many of the
patients likely had a mutation in the TRP53 tumor suppressor, so
erlotinib would not help them, since EGFR was no longer necessary for
tumor growth.

"Perhaps erlotinib or other EGFR inhibitors would work much better in
patients who do not have a TRP53 mutation," he says. "We also believe
this kind of drug could prevent pancreatic cancer formation in
patients with chronic pancreatitis, which is a significant risk factor
for development of pancreatic tumors."

"These findings give us some greatly needed clues about how pancreatic
cancer develops and progresses," Dr. Crawford says. "The more we
understand about these early tumors, the more we will be able to work
on diagnosis and therapy."

The study was funded by the National Cancer Institute.
<snip>

Journal Reference:
Christine M. Ardito, Barbara M. Grüner, Kenneth K. Takeuchi, Clara
Lubeseder-Martellato, Nicole Teichmann, Pawel K. Mazur, Kathleen E.
DelGiorno, Eileen S. Carpenter, Christopher J. Halbrook, Jason C.
Hall, Debjani Pal, Thomas Briel, Alexander Herner, Marija Trajkovic-
Arsic, Bence Sipos, Geou-Yarh Liou, Peter Storz, Nicole R. Murray,
David W. Threadgill, Maria Sibilia, M. Kay Washington, Carole L.
Wilson, Roland M. Schmid, Elaine W. Raines, Howard C. Crawford, Jens
T. Siveke. EGF Receptor Is Required for KRAS-Induced Pancreatic
Tumorigenesis. Cancer Cell, 2012; 22 (3): 304 DOI: 10.1016/j.ccr.
2012.07.024


http://www.cell.com/cancer-cell/retrieve/pii/S1535610812003376

Summary

Initiation of pancreatic ductal adenocarcinoma (PDA) is definitively
linked to activating mutations in the KRAS oncogene. However, PDA
mouse models show that mutant Kras expression early in development
gives rise to a normal pancreas, with tumors forming only after a long
latency or pancreatitis induction. Here, we show that oncogenic KRAS
upregulates endogenous EGFR expression and activation, the latter
being dependent on the EGFR ligand sheddase, ADAM17. Genetic ablation
or pharmacological inhibition of EGFR or ADAM17 effectively eliminates
KRAS-driven tumorigenesis in vivo. Without EGFR activity, active RAS
levels are not sufficient to induce robust MEK/ERK activity, a
requirement for epithelial transformation.
<snip> < no pmid yet>

Check it here:
http://www.ncbi.nlm.nih.gov/pubmed?term=EGF%20Receptor%20KRAS-Induced%20ardito


http://en.wikipedia.org/wiki/KRAS
GTPase KRas also known as V-Ki-ras2 Kirsten rat sarcoma viral oncogene
homolog and KRAS, is a protein that in humans is encoded by the KRAS
gene.[1][2]
The protein product of the normal KRAS gene performs an essential
function in normal tissue signaling, and the mutation of a KRAS gene
is an essential step in the development of many cancers.[3]

Like other members of the Ras family, the KRAS protein is a GTPase and
is an early player in many signal transduction pathways. KRAS is
usually tethered to cell membranes because of the presence of an
isoprenyl group on its C-terminus.

[...] Function
KRAS acts as a molecular on/off switch. Once it is turned on it
recruits and activates proteins necessary for the propagation of
growth factor and other receptors' signal, such as c-Raf and PI 3-
kinase. KRAS binds to GTP in the active state and possesses an
intrinsic enzymatic activity which cleaves the terminal phosphate of
the nucleotide converting it to GDP. Upon conversion of GTP to GDP,
KRAS is turned off. The rate of conversion is usually slow but can be
sped up dramatically by an accessory protein of the GTPase activating
protein (GAP) class, for example RasGAP. In turn KRAS can bind to
proteins of the Guanine Nucleotide Exchange Factor (GEF) class, for
example SOS1, which forces the release of bound nucleotide.
Subsequently, KRAS binds GTP present in the cytosol and the GEF is
released from ras-GTP.

[...] Somatic KRAS mutations are found at high rates in Leukemias,
colon cancer,[6] pancreatic cancer[7] and lung cancer.[8]
<snip>


So if kras goes south and cancer goes north, what happened to BRCA1
and 2 skip to my LOU?


LOOKs like breast and not pancan or colon cancer:

http://www.cancer.gov/cancertopics/factsheet/Risk/BRCA

[...]BRCA1 and BRCA2 are human genes that belong to a class of genes
known as tumor suppressors. Mutation of these genes has been linked to
hereditary breast and ovarian cancer.
A woman's risk of developing breast and/or ovarian cancer is greatly
increased if she inherits a deleterious (harmful) BRCA1 or BRCA2
mutation. Men with these mutations also have an increased risk of
breast cancer. Both men and women who have harmful BRCA1 or BRCA2
mutations may be at increased risk of other cancers.
<snip>

ONLY ten hits: kras + brca -pubmed
http://www.ncbi.nlm.nih.gov/pubmed?term=kras%20brca



randall... more fun then a monkey... or a ton of them or just one
being a joker! which one? got me?