INTERESTING OBSERVATIONS

?Is it true that Azacitine will work better in warm conditions.
?will Azacidine work better in DNMT1 mutated cells
?is DNMT1 critical to the Polycomb/trithorax complex function
De-methylating without disabling this polycomb function mitigates the impact of demethylation because of memory issues!  The cell seems to remember its status before de-methylation, you need to knock down DNMT1to potentiate the effect of 5-Azacitidine!  May be adding Retinoic Acid?

COMBINATION OF ATRA WITH 5-AZACITIDINE?

?

Methylation of the estrogen receptor gene is associated with aging and atherosclerosis in the cardiovascular system.

Post WS

KIM " This activity was augmented by histone deacetylase inhibition. These findings provide evidence of epigenetic dysregulation of estrogen receptor beta in atherosclerosis and vascular aging. We suggest that focal epigenetic changes in estrogen receptor beta contribute to the development of atherosclerosis and vascular aging." 
POST MENOPAUSAL WOMEN SEE A DROP OF ESTROGEN, A METHYLATION OR THE GENE MAKING THE ESTROGEN RECEPTOR IS A PROGRAMMED EVENT, WILL DYSREGULATION OF THE POLYCOMB CHANGE THAT? OR IS-IT MUTATION OF THE DNMT1 AGAIN ENOUGH?

MicroRNA-152 mediates DNMT1-regulated DNA methylation in the estrogen receptor α gene.

Wang Y ET AL

WHY LUPUS IS ACTIVE IN WOMEN AGE 15-44

IT HAS TO DO WITH THIS!

CESCHIN ET AL
"Multiple signaling pathways ultimately modulate the epigenetic information embedded in the chromatin of gene promoters by recruiting epigenetic enzymes. We found that, in estrogen-regulated gene programming, the acetyltransferase CREB-binding protein (CBP) is specifically and exclusively methylated by the coactivator-associated arginine methyltransferase (CARM1) in vivo. CARM1-dependent CBP methylation and p160 coactivators were required for estrogen-induced recruitment to chromatin targets. Notably, methylation increased the histone acetyltransferase (HAT) activity of CBP and stimulated its autoacetylation. Comparative genome-wide chromatin immunoprecipitation sequencing (ChIP-seq) studies revealed a variety of patterns by which p160, CBP, and methyl-CBP (meCBP) are recruited (or not) by estrogen to chromatin targets. Moreover, significant target gene-specific variation in the recruitment of (1) the p160 RAC3 protein, (2) the fraction of a given meCBP species within the total CBP, and (3) the relative recruitment of different meCBP species suggests the existence of a target gene-specific “fingerprint” for coregulator recruitment."

BELIEVE ME, ESTROGEN INCREASES GENE METHYLATION
PEGGY SUGGESTED OOPHORECTOMY AS MEANS TO CONTROL BAD LUPUS  IN WOMEN OF REPRODUCTIVE AGE WHO HAVE HAD THEIR CHILDREN !? WHAT DO YOU THINK?

INTERESTING ASSUMPTION!
The observation that Systemic Lupus Erythematosus occurs mostly in female patients to a rate of 8-9:1 over males, and mostly between the age 15 to 44 points to the female reproductive years.  These years are characterized by the reign of Estrogen and its potential suppression of class I Antigen (HLA Antigens) to protect the child from rejection.  We are suggesting that Estrogen would somehow increase epigenic events through Methylation most likely, affects type I Interferon, the destroyer in Lupus, and causes exacerbation of Lupus!
If methylation is that important, Azacytidine could be important in the treatment of Lupus particularly those patient with TET2 Mutation positive ???LET'S GO TO WORK
THE NEW KNOWLEDGE THAT AZACITIDINE HAS IMMUNE IMPLICATION FURTHER SUPPORTS THESE ASSUMPTIONS!

REASON FOR OUR COALITION: THE BREAST CANCER PARADOX
RACIAL DISPARITIES IN INCIDENCE AND MORTALITY OF BREAST CANCER.
=============================================================

Population based research have indeed  pointed out unique racial disparities into the prevalence and mortality of breast cancers in the United States. These disparities have been CONSISTENTLY occurring without being met effectively because of lack of political will by mostly white leaders, and a weak misrepresented minority populations (Hispanic and black population appear equally affected) which has not grasp the extent of this problem!  And the fact that it represents the LARGEST OPPORTUNITY  to curb mortality for this particular disease. (after Mammogram, hormone treatment, the BRCA discovery, are just some of the major interventions that curbed Mortality of Breast Cancer)

As stated above, these disparity have been consistently occurring years after years and grown into a sad phenomena well coined "The Breast Cancer Paradox".  People (researchers) have taken the time to coin it but relatively nothing is being done about it!  THE PARADOX IS FOUND IN THE FACT THAT THE INCIDENCE OF BREAST CANCER IN HISPANIC AND AFRICAN AMERICAN POPULATIONS IS LOW (YES LOW LOW LOW) AS IT COMPARES TO THE WHITE POPULATION.  BUT DID YOU KNOW THAT THE MORTALITY IN THE MINORITY POPULATION IS HIGHER (YES HIGH, HIGH, HIGH!).  BASICALLY MANY PEOPLE  (3000 (OUT OF 6000) AFRICAN AMERICAN WOMEN ALONE DIE A YEAR FROM BREAST CANCER FOR LACK OF INTERVENTION).

This fact has been described time and time again, it has been coined "Breast cancer Paradox", it has been looked at and ponder on, BUT NO EMERGENCY HAS BEEN DECLARED IN OUR TRILLION DOLLAR ECONOMY, NO PRIORITY HAS BEEN DECLARED, NO-ONE REALLY CARE ENOUGH TO RAISE THE ISSUE THE WAY IT SHOULD BE !

YET! The dichotomy has been observed years after years, and suscitated some comments some interest as a social curiosity can, or a scientific oberservation would.  But nothing comprehensive has been declared.  Our attempt to involve CPRIT has fallen in political quagmire and died with the CPRIT debacle.  The COALITION  will bring back the fore front!  It is a shame for this great nation to fail to recognize what is really happening with unchanged deaths in its minority population!

OF EVEN GREATER INTEREST IS THE OBSERVATION THAT:
-------------------------------------------------------------------------
This Unique and deadly Breast cancer has unique charasteristics that strengthen the notion that it is genetic based.  Indeed the Breast cancers involving minorities, are mostly triple negative therefore cannot benefit meaningfully from 2 major therapeutic interventions:  Hormonal treatment and Herceptin and related drugs that seems the focus of our new drug developments.  Research seems to look the other way all together folks!  
Furthermore and to re-enforce the monolytic and genetic basis of the Breast cancer observed in blacks and Hispanics, up to 70% in some areas of these triple negative cases, have the unique Basal cell like morphology WELL DESCRIBED AGAIN. THE UNIQUENESS OF THIS PATHOLOGY SHOULD IN NORMAL CIRCUMSTANCES BEG AND CALL FOR IMMEDIATE INVESTIGATIONS WITH THE MEANS WE HAVE TODAY.   BUT SILENCE IS WHAT WE HAVE TODAY!

WE HAD HOPED THAT THE DISCOVERY OF THE HUMAN GENOME WILL BRING CLEAR ANSWERS.  BUT YES THEY DECODED THE GENOME OF THE TRIPLE NEGATIVE BREAST CANCER.  BUT ALL WE GOT IS THAT IT LOOKS LIKE OVARIAN CANCERS.  THAT IS DRUGS USED IN THAT DISEASE (TAXANE, PLATINUM) CAN BE USED IN THIS TRIPLE NEGATIVE BREAST CANCER, THIS WAS ALREADY IN PRACTICE, NO ADVANCEMENT THERE. SO WHERE DO WE GO FROM HERE. FOLKS ARE STILL DYING!

CRBCM HAS BEEN PUSHING FOR A COMPREHENSIVE - PRIORITY BASED PROGRAM BUT OUR EFFORTS ARE DYING IN DEATH EARS, NO POLITICIAN IS FULLY EMBRACING THE CAUSE!   CRBCM EARLY CONCERNS WERE SURVIVAL OF THE ORGANIZATION, NOW THAT GREATER EAST CANCER CENTER, THE PARENT ORGANIZATION, IS OF FIRM GROUNDS, AND WE ARE NOT GOING ANYWHERE, WE ARE LAUNCHING A SECOND WIND OF CONSCIENCE-RAISING-ACTIVITIES TO ADDRESS THIS DISPARITY IN CANCER RESEARCH.

CRBCM IS DEDICATED TO OPEN THE DOOR TO THIS EMERGENCY!  AND YOU CAN HELP!

MUTATIONS AT THE TET2 GENE, LET'S STOP THE NOISE!
==============================================

WE HAVE EXPLAINED THAT DURING CELL DEVELOPMENT, AND DEPENDING ON LOCATION AND FUNCTION, SOME GENES WILL BE SILENCED.  AND ONE OF THE WAY THE GENE ARE SILENCED IS THROUGH A CERTAIN LEVEL OF METHYLATION. ONE OF THE REGULATOR THAT CHECK LEVEL OF METHYLATION IN HEMATOPOIETIC LINEAGE IS TET2.
IT APPEARS THAT MUTATION OF TET2 HAPPENS AS A RESULT  OF NEOPLASTIC TRANSFORMATION THAT TRIGGERS DEMETHYLATION (DE-SILENCING) OF GENES OF PROLIFERATION,PUSHING  UNCONTROLLED GROWTH.

THAT WHAT'S MUTATION OF TET2 MEANS (READ CAREFULLY DR GRANT COMMENTS)
ONCE THE DEMETHYLATION HAS OCCURRED LOGICALLY THE PRESENCE OF TET2 MUTATIONS SHOULD BE MINIMAL.  ITS PRESENCE MEANS NEW GENES ARE BEING DEMETHYLATED AND MAY EITHER PORTEND TO PERSISTENCE OF PROLIFERATIVE GENES AND THEREFORE ATTEST TO THE NEED OF FURTHER DE- METHYLATING AGENTS.  HYPOMETHYLATING AGENTS SEEMS TO AFFECT METHYLATON OR DISORGANIZE METHYLATION OF PROLIFERATIVE GENES.

LOGICALLY AT THE END OF THE PLANNED CYCLES OF AZACITIDINE OR DECITABINE, TET2 GENE MUTATION PERSISTENCE SHOULD MILITATE AGAINST STOPPING TREATMENT.

HYPOTHETICALLY, TET2 MUTATION MARKS THE FACTS THAT METHYLATION AND THE PROLIFERATIVE PROCESS HAVE BEGUN OR CONTINUE (THE MYELOPROLIFERATIVE PROCESS HAS STARTED), ITS PERSISTENCE     POINT TO NEW METHYLATION OCCURING AND THAT THERAPY WITH THESE AGENTS IS NEEDED STILL.

IN AML OF THE ELDERLY, IT WILL REENFORCE THE NEED FOR THE DECITABINE OPTION OR THAT DECITABINE OR AZACITIDINE SHOULD BE ADDED TO THE REGIMEN IN MAINTENANCE SETTING.

LET'S GO OUT THERE AND VERIFY THIS ASSUMPTION IN PRACTICE

OR CONTINUE THE FOLLOWING NOISE!
=========================================================================

 SMITH ET AL
The encoded protein is involved in myelopoiesis, and defects in this gene have been associated with several myeloproliferative disorders. (GENE RESOURCES)
TET2(mut) were identified in 7.6% of younger adult patients with AML and did not impact the response to therapy and survival. Mutations were mutually exclusive with IDH(mut), which supported recent data on a common mechanism of action that might obscure the impact of TET2(mut) if compared against all other patients with AML.(GAITZIK ET AL)
Tet2 deficiency led to decreased genomic levels of 5hmC and augmented the size of the hematopoietic stem/progenitor cell pool in a cell-autonomous manner.
There was no difference in the frequency of genome-wide aberrations, TET2 expression, or the JAK2V617F 46/1 haplotype between TET2-mutated and nonmutated patients. There was no significant prognostic association between TET2 mutations and World Health Organization subtypes, International Prognostic Scoring System score, cytogenetic status, or transformation to acute myeloid leukemia.

Italian researchers recently determined that mutations in the TET2 gene do not negatively influence the response of patients with myelodysplastic syndromes to treatment with Vidaza. However, they also found that certain modifications to the BCL2L10 gene negatively impacted outcomes following Vidaza treatment.
“TET2 mutations [...] were associated with higher response rates to [Vidaza]. This might help to identify patients at higher probability of response to [Vidaza] and avoid unnecessary burden to unresponsive patients,” said the study’s lead author, Dr. Maria Teresa Voso of the Università Cattolica del Sacro Cuore in Rome, Italy.(LANGHOLTZ)


 Our data indicate that Tet2 has a critical role in regulating the expansion and function of HSCs, presumably by controlling 5hmC levels at genes important for the self-renewal, proliferation, and differentiation of HSCs.(RAO)
  Indeed, while according to the authors TET2 mutations might be involved in the negative regulation of monocyte lineage determination, neither TET2 nor ASXL1 mutations are possibly sufficient in determining the disease establishment. A further interesting observation reported in this paper is that among 14 CMML patients who were tested after progression to acute leukemia (i.e. marrow blasts >20%), only 2 had a TET2 mutation, raising the question as to whether TET2 mutation, when present at diagnosis, might be lost upon leukemic transformation.(ONIDA)

Dr. Grant indicated no relevant conflicts of interest. 
Aberrant methylation of DNA, particularly hypermethylation of tumor suppressor genes, occurs frequently in many cancers, including hematopoietic malignancies. This has prompted the development of agents capable of reversing hypermethylation, such as DNA methyltransferase inhibitors. These agents have yielded encouraging results both alone and in combination with other epigenetic agents (e.g., histone deacetlyase inhibitors) in patients with myelodysplastic syndrome (MDS) and some acute leukemias. However, the endogenous factors regulating the hypermethylated state have not been fully elucidated.


The protein encoded by this gene is a methylcytosine dioxygenase that catalyzes the conversion of methylcytosine to 5-

5-hydroxymethylcytosine. The encoded protein is involved in myelopoiesis, and defects in this gene have been associated with several myeloproliferative disorders TET2 protein is involved in regulating the process of transcription, which is the first step in protein production. Although this protein is found throughout the body, it may play a particularly important role in the production of blood cells from hematopoietic stem cells. These stem cells are located within the bone marrow and have the potential to develop into red blood cells, white blood cells, and platelets. The TET2 protein appears to act as a tumor suppressor, which is a protein that prevents cells from growing and dividing in an uncontrolled way.

TET2 gene alterations are more frequent in chronic myelomonocytic leukemia than in other subgroups of hematopoietic diseases studied so far and could negatively affect the patients’ outcome. The striking association between TET2 gene alterations and monocytosis, already observed in patients with systemic mastocytosis, could indicate a negative role of TET2 in the control of monocytic lineage determination.KOSMIDER ET AL.

PROGRESS IN CANCER CURE FIGHT!

Progress in the search for cancer cure is slowed not only by the true challenge posed by this disease, but also and mainly by politicians at various levels.  Some politicians speculate with funding levels, some are discontent with distribution of funding, some don't like who is asking for funding.   These political concerns have a heavy burden on the search for a cure of which difficulties they compound.

In El Paso,TX, universities which have the the expertise and public funded facilities resist to help us in the completion of funded projects of public health importance.  Now we have to fight a political fight rather than progressing in our search for the cure.  WHAT PEOPLE FORGET IS THAT WE ARE A "COALITION" WHICH BY DEFINITION MEAN GROUP DESTINED TO FIGHT FOR A CAUSE.  AND WE ARE READY!

NEW RANDOM NEWS

*5 POWERFUL DRUG RECOGNIZED BY THE FDA, CHECK THEM OUT
  1--DARATUMUMAB FOR MYELOMA
  2--PALBOCICLIB FOR BREAST CANCER
  3--LDK 378 FOR LUNG CANCER
  4--LAMBROLIZUMAB FOR MELANOMA
  5--IBRUTINIB FOR A SLEW OF HEMATOLOGIC MALIGNANCY CLL,MANTLE CELL LYMPHOMA AND WALDENSTROM MACROGLOBULINEMIA

*HAPPY ANNIVERSARY TO 85 YEAR OLD DR JAMES D.WATSON, NOBEL LAUREATE FOR HIS DISCOVERY AND CHARACTERIZATION OF THE DOUBLE HELIX DNA 60 YEARS AGO!
HE IS STILL LIVING IN NEW YORK!  SALUTE!

*HYPEREOSINOPHILIC SYNDROME TREATED WITH CAMPATH, AN ANTI-CD52
EOSINOPHIL REPORTEDLY DO EXPRESS CD52
10 OUT OF 12 PATIENT HAD SYMPTOMS RELIEVED, AND RESPONSE TO THERAPY. PROOF IS IN THE PUDDING (SEE THE FULL ARTICLE BY PAOLO STRATI ET AL!

INSUFFICIENCY OF IMMUNOTHERAPY IN MUCINOUS CANCERS.

Interesting this case in point by Baretta et al. published in Clinical Breast Cancer:

"RESISTANCE TO TRASTUZUMAB IN HER-2 POSITIVE MUCINOUS INVASIVE DUCTAL BREAST CARCINOMA"
BRAVO! For addressing this topic.  Yes indeed, while it is obvious that if a tumor is Her-2 positive it would more likely respond to Herceptin, their 2 cases demonstrate the power of Mucin into shielding these receptors from their Agonist Herceptin.   They specify that to be consider Mucinous, the tumor should have a greater than 50% Mucinous component (you figure it out or just wait for the pathologist to call it).  the other component is "ductal" of course.  And as a matter of proportion, a "Mixed" type could be defined!
And yes the authors believed that "Mucin acted as a barrier against Trastuzumab".  They went on to comment that "Mucins has a central role in maintaining homeostasis and protecting the luminal surfaces of epithelium-lined ducts in the human body."  They went on to conclude that appreciating the peculiarity of Mucin presence should allow a early change in therapy!  And Bravo again to the team!

Several other aspect of immunothereapy were discussed by RUDY, a fellow in Oncology,
She suggested in a comprehensive review that infiltration of the lymphocyte in the tumor was a good prognosis (our pathologists need to report this to us) and the bad role of TWIST gene,
"  Twist was a tumor-associated antigen recognized by tumor-specific CD8⁺ T cells; thus, this study provided a rationale for further exploration of immunotherapy using the pTw9 epitope. Additional animal studies must be done before human studies to determine the value of targeting Twist in the adjuvant setting may begin. Investigators hope to find out whether targeting Twist may prevent gross metastasis of breast cancer in patients with Twist-positive micrometastatic disease."  RUDY ET AL

TAKE A NOTE OF THIS UPCOMING MEETING IN BOSTON, LA BELLE VILLE!

Dear MUTOMBO,

A couple of weeks ago I released the final agenda for NGS for Cancer Drug Development. Since this meeting is all about bringing you the latest results from the most recent clinical trials, I thought I’d highlight today some of the exclusive data not available at any other drug development meeting… Christopher Maher from Washington University delves deep into his group’s work on the discovery of druggable gene fusions in solid tumors, and prioritizing clinically meaningful therapeutics targets George Mulligan, Director of Translational Medicine at Millennium walks through the treatment of myeloma and mantle cell lymphoma with Velcade, and how his group are using NGS in the clinic for accurate patient subgroup selection Joel Parker from the University of North Carolina releases exclusive data from his recent research applying mRNA–sequencing analysis in breast cancer to explore isoform switching and mutation expression Brian Dougherty, Translational Genomics Lead, Oncology at AstraZeneca talks in detail about how his team are applying NGS to develop biomarkers and optimize patient stratification efforts   The agenda is packed full of cutting edge data from leading oncology experts using NGS as an integral technology in their research efforts Download the brochure for more details on the data packed sessions. This is the number one opportunity to discover how pharma are using the latest cutting-edge NGS technologies in oncology, but more importantly how you can learn from them and best apply NGS in your cancer drug discovery and development efforts. So that’s it in a nutshell. If you want to keep up to speed with leading pharma and get the most out of your sequencing projects, be sure to make time to attend NGS for Cancer Drug Development in Boston in September. You can secure your place at www.ngs-cancer.com/register Thank you, and see you in Boston. Kind regards, Izzy Izzy Scott-Moncrieff Hanson Wade

ACTIVITY AT CRBCM
(AS OF 6/62013)

WE THANK VISITORS OF OUR BLOG, WE HAVE CROSSED THE 20,000 REVIEWS, POINTING TO THE INTENSITY AND ORIGINALITY OF OUR WORK, THE CRBCM FOOT PRINT IS RAPIDLY INCREASING.  THANK YOU FOR VISITING!

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 AGE RELATED EXPRESSION OF DEFICIENT GENE

Although one may have deficient gene,death from its consequences varies based on how critical lack of expression is to the body. Lack of function in a critical tissue leads rapidly to death. Expression of a deficient gene depends on whether it it dominant or recessive, and whether one is homo or heterozygotic as related to the gene in question.  many diseases of genetic basis express themselves at a letter stage in life.  Polycystic Kidney disease for example gives its full blown syndrome only after 30 years of age, and starts worsening  to finally take the life of the bearesr in  their 5th ot sixth decade of life. Althto though one cannot say for sure what intervened with age for the syndrome to fully express, we know that immune and hormonal developments contribute significantly to this unfortunate unfolding.
We know that in infectious processes we encounter as we age, there is disturbances of Interferons levels, and if one has an autoimmune disease, these interferon levelsare somewhat permanent or constant.  Interferon activate T cell and boost Immunity but also secondarily immune system surveillance of cancer occurrence. This interferon seems linked to Class I histocompatibilty HLA-A,B,C.

In Women however, as they age and enter reproductive age, there is need to suppress class I HLAin order to "tolerate" a child/fetus.  It is assumed that a vague of hormone driven gene methylation seems to be the mechanism.  Gene methylation will silence many genes and could potentially silence normal genes that where conterbalancing the gene defect.  Defectuous genes will this way get there chance to finally express themselves and cause progression of syndromes thay can cause.  Androgenic development in males achieves the same deterioration.  Giving Azacytidine had reversed these methylation by the way although clinical trials are still ongoing on whetehr it can meaningfully change the course of these gene based diseases.That is before irreversible tissue damage sets in.

CRK GENE
It is a co-factor to many Kinases, and sometime act as a regulator
CRK (gene) has been shown to interact with:

• BCAR1,^{[7][8][9][10][11][12][13][14][15]}
• Cbl gene,^[16][17]
• Dock180,^{[18][9][10][19][20]}
• EPS15,^[21]
• Epidermal growth factor receptor,^[22][23]
• Grb2,^{[24][18][25] (A WILD WILD GENE)}
  The focal adhesion kinase (FAK), a protein-tyrosine kinase (PTK), associates with integrin receptors and is activated by cell binding to extracellular matrix proteins, such as fibronectin (FN). FAK autophosphorylation at Tyr-397 promotes Src homology 2 (SH2) domain binding of Src family PTKs, and c-Src phosphorylation of FAK at Tyr-925 creates an SH2 binding site for the Grb2 SH2-SH3 adaptor protein. FN-stimulated Grb2 binding to FAK may facilitate intracellular signaling to targets such as ERK2-mitogen-activated protein kinase. We examined FN-stimulated signaling to ERK2 and found that ERK2 activation was reduced 10-fold in Src- fibroblasts, compared to that of Src- fibroblasts stably reexpressing wild-type c-Src. FN-stimulated FAK phosphotyrosine (P.Tyr) and Grb2 binding to FAK were reduced, whereas the tyrosine phosphorylation of another signaling protein, p130cas, was not detected in the Src- cells.
• IRS4,^[26][27]
• MAP4K1,^[28][29][30]
• MAPK8,^[31]
• NEDD9,^[32][33]
• PDGFRA,^[34][35]
• PDGFRB,^[34]
• PTK2,^[9][12]
• Paxillin^[12][36]
• RAPGEF1,^[37]
• RICS,^[38][39]
• SH3KBP1,^[40] and
• SOS1.^{[25]wikipedia}
•  Crk together with CrkL participates in the Reelin signaling cascade downstream of DAB1.^[2][3]
• ^{We could get your attention that REELIN defect leads to brain MALFORMATION, POINTING TO CRK AND DAB1 AS IMPORTANT TARGET GENES IN SARCOMA!}
•  
  Reelin is a large secreted extracellular matrix glycoprotein that helps regulate processes of neuronal migration and positioning in the developing brain by controlling cell–cell interactions. Besides this important role in early development, reelin continues to work in the adult brain. It modulates synaptic plasticity by enhancing the induction and maintenance of long-term potentiation.^[2][3] It also stimulates dendrite^[4] and dendritic spine^[5] development and regulates the continuing migration of neuroblasts generated in adult neurogenesis sites like subventricular and subgranular zones. It is found not only in the brain, but also in the spinal cord, blood, and other body organs and tissues.
  Reelin has been suggested to be implicated in pathogenesis of several brain diseases. The expression of the protein has been found to be significantly lower in schizophrenia and psychotic bipolar disorder, but the cause of this observation remains uncertain as studies show that psychotropic medication itself affects reelin expression. Moreover, the epigenetic hypothesis aimed at explaining the changed levels^[6] has received some contradictory evidence.^[7][8] Total lack of reelin causes a form of lissencephaly. Reelin may also play a role in Alzheimer's disease, temporal lobe epilepsy and autism.(WIKIPEDIA)
  
   Reelin takes part in the developmental change of NMDA receptor configuration, increasing mobility of NR2B-containing receptors and thus decreasing the time they spend at the synapse.^{[53][dead link][54][55]} It has been hypothesized that this may be a part of the mechanism behind the "NR2B-NR2A switch" that is observed in the brain during its postnatal development.^[56] Ongoing reelin secretion by GABAergic hippocampal neurons is necessary to keep NR2B-containing NMDA receptors at a low level.^[52]
   The Disabled-1 (Dab1) gene encodes a key regulator of Reelin signaling. Reelin is a large glycoprotein secreted by neurons of the developing brain, particularly Cajal-Retzius cells. DAB1 functions downstream of Reln in a signaling pathway that controls cell positioning in the developing brain and during adult neurogenesis

IMPORTANT TARGET OF IMMUNOTHERAPY
MUNITIAE AT THE CELLULAR MEMBRANE

TO FIGURE OUT THE FOLLOWING EXCERPTS ONE SHOULD REMEMBER THE PHENOMENA OCCURRING DURING INJURY TO THE BLOOD VESSEL. WHEN A BLOOD VESSEL IS OPEN DURING AN INJURY, IT IS THE SUDDEN EXPOSURE OF BLOOD CELL WITH OUTSIDE TISSUE/PROTEIN (COLLAGEN) THAT TRIGGERS COAGULATION, PLATELET ACTIVATION.

NOW IMAGINE A MOLECULE OF ESTROGEN ARRIVING AT CELL SURFACE AND BINDING TO ITS RECEPTOR, 2 THINGS HAPPEN, ONE IS THAT THE LINKAGE CAUSES AN INTERNAL SIGNAL TRANSDUCTION GOING THROUGH A PATHWAY
BUT SOMETIME THE ALL RECEPTOR DETACHES WITH ITS STIMULANT AND IS INTERNALIZED.  AT POINT OF DETACHEMENT, THERE IS CONTACT OF FIBRONECTIN  (EXTRACELLULAR) WITH CYTOSOL CONTENT FOCAL ADHESION KINASES (fak) AND THE REST FOLLOWS (5 BULLETS) 

1.the binding of a neuropeptide to its cognate GPCR triggers the activation of multiple signal transduction pathways that act in a synergistic and combinatorial fashion to relay the mitogenic signal to the nucleus and promote cell proliferation. A rapid increase in the synthesis of lipid-derived second messengers with subsequent activation of protein phosphorylation cascades is an important early response to neuropeptides. An emerging theme in signal transduction is that these agonists also induce rapid and coordinate tyrosine phosphorylation of cellular proteins including the nonreceptor tyrosine kinase p125^fak and the adaptor proteins p130^cas and paxillin. This tyrosine phosphorylation pathway depends on the integrity of the actin cytoskeleton and requires functional Rho.(ROZENGHURT)

THAT IS AFTER A GROWTH FACTOR HAS LINKED TO ITS RECEPTOR, COUPLING WITH A G-PROTEIN WILL TRIGGER AN EXPLOSION ON PHOSPHORYLATION IN ALL DIRECTION, ON THESE PHOSPHORYLATION HITS A KINASE OF AN IMPORTANT PATHWAY AND THE PATHWAY ENTER INTO ACTION.

2.This effect required the autophosphorylation site of FAK, which is a binding site for Src family kinases. Integrin-mediated phosphorylation of Cas was not, however, compromised in fibroblasts lacking FAK.
FAK seems not to be necessary for phosphorylation of Cas, but when autophosphorylated, FAK may recruit Src family kinases to phosphorylate Cas. Cas was found to form complexes with Src homology 2 (SH2) domain-containing signaling molecules, such as the SH2/SH3 adapter protein Crk, following integrin-induced tyrosine phosphorylation. Guanine nucleotide exchange factors C3G and Sos were found in the Cas-Crk complex upon integrin ligand binding. These observations suggest that Cas serves as a docking protein and may transduce signals to downstream signaling pathways following integrin-mediated cell adhesion.(VUORI ET AL)

3. The focal adhesion kinase (FAK), a protein-tyrosine kinase (PTK), associates with integrin receptors and is activated by cell binding to extracellular matrix proteins, such as fibronectin (FN). FAK autophosphorylation at Tyr-397 promotes Src homology 2 (SH2) domain binding of Src family PTKs, and c-Src phosphorylation of FAK at Tyr-925 creates an SH2 binding site for the Grb2 SH2-SH3 adaptor protein. FN-stimulated Grb2 binding to FAK may facilitate intracellular signaling to targets such as ERK2-mitogen-activated protein kinase. We examined FN-stimulated signaling to ERK2 and found that ERK2 activation was reduced 10-fold in Src- fibroblasts, compared to that of Src- fibroblasts stably reexpressing wild-type c-Src. FN-stimulated FAK phosphotyrosine (P.Tyr) and Grb2 binding to FAK were reduced, whereas the tyrosine phosphorylation of another signaling protein, p130cas, was not detected in the Src- cells.(SCHLAEPFER ET AL)
Src-family binding and phosphorylation of FAK at Tyr-925 creates a Grb2 SH2-domain binding site and provides a link to the activation of the Ras signal transduction pathway. In Src-transformed cells, this pathway may be constitutively activated as a result of FAK Tyr-925 phosphorylation in the absence of integrin stimulation.

4. Pyk2 overexpression enhanced FN-stimulated activation
5.RAFTK/Pyk2 is expressed mainly in the central nervous system and in cells derived from hematopoietic lineages, while FAK is widely expressed in various tissues and links transmembrane integrin receptors to intracellular pathways. This review describes the role of RAFTK/Pyk2 in various signalling cascades and details the differential signalling by FAK and RAFTK/Pyk2. of co-transfected ERK2.(AVRAHAM)
===============================================================

SO 2 MAIN ROUTES
THE ERK2

AND THE GRB2

DO REMEMBER GRB2 IS THE WILD WILD WEST OF GENES!

Function and expression

Grb2 is widely expressed and is essential for multiple cellular functions. Inhibition of Grb2 function impairs developmental processes in various organisms and blocks transformation and proliferation of various cell types, and so it is not surprising that a targeted gene disruption of Grb2 in mouse is lethal at an early embryonic stage. Grb2 is best known for its ability to link the epidermal growth factor receptor tyrosine kinase to the activation of Ras and its downstream kinases, ERK1,2. Grb2 is composed of an SH2 domain flanked on each side by an SH3 domain. Grb2 has two closely related proteins with similar domain organizations, Gads and Grap. Gads and Grap are expressed specifically in hematopoietic cells and function in the coordination of tyrosine kinase mediated signal transduction.

Domains

The SH2 domain of Grb2 binds to phosphorylated tyrosine-containing peptides on receptors or scaffold proteins with a preference for pY-X-N-X, where X is generally a hydrophobic residue such as valine (see [3]).
The N-terminal SH3 domain binds to proline-rich peptides and can bind to the Ras-guanine exchange factor SOS.
The C-terminal SH3 domain binds to peptides conforming to a P-X-I/L/V/-D/N-R-X-X-K-P motif that allows it to specifically bind to proteins such as Gab-1.^[4]

Interactions

Grb2 has been shown to interact with Arachidonate 5-lipoxygenase,^[5][6] Lymphocyte cytosolic protein 2,^{[7][8][9][10][11]} GAB2,^[12][13][14] B-cell linker,^{[15][16][17][18]} Abl gene,^[19][20] CD28,^[21][22] FRS2,^{[23][24][25][26]} Mitogen-activated protein kinase 9,^[27][28] CD22,^[29][30] NEU3,^[31] ETV6,^[12] MAP2,^[32][33] Dock180,^[34][35] PIK3R1,^[36][37] SH2B1,^[38][39] CRK,^[40][41][42] GAB1,^[7][43][44] MST1R,^[45][46] DNM1,^[47][48] Huntingtin,^[49] Src,^[50][51] Beta-2 adrenergic receptor,^[52] VAV2,^[53][54] ADAM15,^[55] RAPGEF1,^[56][57] VAV1,^{[58][59][60][61]} HER2/neu,^[54][62][63] Epidermal growth factor receptor,^{[2][43][53][62][64][65][66][67][68][69]} PDGFRB,^[69][70][71] PTK2,^{[72][73][74][75][76]} Erythropoietin receptor,^[77][78] Linker of activated T cells,^[79][80][81] Dystroglycan,^[82] SH3KBP1,^[83][84] Granulocyte colony-stimulating factor receptor,^[85] DCTN1,^[86] CDKN1B,^[87] Colony stimulating factor 1 receptor,^[88] EPH receptor A2,^[89] KHDRBS1,^[43][90][91] RET proto-oncogene,^[92][93] PLCG1,^[94][95][96] TrkA,^[97][98] PRKAR1A,^[66] Janus kinase 2,^[99][100] MUC1,^[101] CD117,^{[78][102][103]} Fas ligand,^[104][105] Janus kinase 1,^[100][106] VAV3,^[53][107] BCAR1,^[73][108] PTPN1,^[109][110] INPP5D,^[111] ITK,^[112][113] SHC1,^{[51][53][114][115][116][117][118][119][120][121][122][123][124][125][126][127][128][129][130][131][132]} PTPN12,^[133] C-Met,^[134][135] PTPN11,^{[71][85][127][136][137][138][139][140][141]} Glycoprotein 130,^[61] PTPN6,^{[51][136][142]} Syk,^[51][136] MAP4K1,^{[143][144][145][146]} Wiskott-Aldrich syndrome protein,^[147][148] NCKIPSD,^[149][150] PTPRA,^{[151][152][153]} BCR gene,^{[12][115][154][155][156][157]} CBLB,^{[158][159][160]} Cbl gene,^{[9][24][51][90][124][158][161][162][163][164][165][166][167]} SOS1,^{[8][24][42][43][48][51][53][60][68][90][95][101][115][122][124][131][168][169][170][171][172]} IRS1,^{[100][114][173]} TNK2,^[116][174] MED28,^[175] MAP3K1^[176] and HNRNPC.^[177]

IN OTHER NEWS

*USE OF GM-CSF BOOSTS IPILIMUMAB ACTIVITY! GO FIGURE THAT...
*NO SURPRISE HERE, CLASSIII BETA-TUBULIN PREDICT GOOD RESPONSE TO TAXANE IN ER NEGATIVE BREAST CANCER 
*MAKES PERFECT SENSE TO TINKLE WITH ANDROGEN RECEPTOR IN APOCRINE SUBTYPE OF CANCERS
*ONE GOOD NEGATIVE STUDY! OR IS IT? SEND COMMENTs!

Bevacizumab and erlotinib in previously untreated inoperable and metastatic hepatocellular carcinoma
American Journal of Clinical Oncology, 05/29/2013  Clinical Article

Govindarajan R et al. – The 28% progression-free survival rate at 27 weeks was not significantly higher than the recent historical control rate of 20% observed on the placebo arm of the Sorafenib Hepatocellular Carcinoma Assessment Randomized Protocol trial (P=0.28). The combination of bevacizumab and erlotinib does not appear to have sufficient efficacy in patients with unresectable and metastatic HCC not amenable to local therapy.