The Combination of Etoposide and Histone Deacetylases applied to Cancers with high levels of c-MYC and c-FOS gene expression

The Combination of Etoposide and Histone Deacetylases applied to Cancers with high levels of c-MYC and c-FOS gene expression:

This research project investigates the possibility of combining Etoposide with Histone Deacetylases in the treatment of cancers that display a significant expression of te c-Myc and c-Fos gene.  The drugs proposed for this trial are Etoposide and Histone Deacetylases.

Etoposide was first synthesized in 1966 and is a drug widely used in chemotherapy since 1983 when it obtained  FDA approval. Etoposide forms a ternary complex with DNA and the topoisomerase II enzyme which participates in the unwinding of DNA, hence prevents the rwligation of the DNA strands, and by doing so causes DNA strands to break. This action then  leads to DNA synthesis errors and subsequently to cell death. Etoposide has, however, some reported side effects such as low blood pressure, hair loss, pain or burning at the injection site .

Histone deacetylation has been an effective treatment for various types of cancers. By the removal of acetyl groups from histones, histone deacetylases create a non-permissive chromatin conformation that prevents the transcription of genes that regulate the expression of proteins involved in tumor development such as c-FOS. In addition to histones, histone deacetylases deacetylate a variety of other proteins including transcription factors and other abundant cellular proteins involved  in the regulation of cell growth, differentiation and cell death. Histone Deacetylases are among the most promising therapeutic targets for cancer treatment, and they have inspired researchers to study and develop HDAC inhibitors worldwide.

The present research project consists in computerized and laboratory testing of the efficacy of combining these two treatments in cases of observed overexpression of both the c-MYC and c-FOS gene.  Although the two drugs already exist and are used in cancer therapy, the interaction of  the two drugs when used in combination needs to be examined. This can be achieved by using a mouse model bearing specified tumors to be done at the University of Texas at El Paso (UTEP). Preliminary testing should be conducted by implanting cancer cells in the skin of mice. The combined treatment should then be applied indiscriminately to mice presenting high expression of c-Myc and c-FOS, and to those with low expression of these genes. The response to the treatment will be monitored to evaluate the efficacy of the treatment in mice with high c-Myc and c-FOS expression as compared to the control group with low c-Myc and low c-FOS expression. In a later phase, testing would be conducted  in cancer patients presenting high expression of c-Myc and c-FOS, especially for patients treated for triple negative breast cancer, but also for ovarian cancer and other types of cancer with an overexpression of c-MYC.

The combination of Etoposide with Histone Deacetylases represents de facto a novelty in cancer treatment, especially in the case of triple negative breast cancer that is until today associated with a worse prognosis than other breast cancer types. It has a characteristic recurrence pattern with the peak risk of recurrence and the majority of deaths occurring in the first 3 and 5 years after the initial treatment, respectively.

TRYING OUR BEST TO TALK TO THESE GENES IN BREAST CANCERS: MED1,6 and 12

With the clinical finding that Bicalutamide, a non steroidal anti-androgen, has a role in some of the luminal forms of Breast cancers, genes affecting the Hormones have quickly become the focus of intensive research. So we venture to explores some of the genes having links to Hormone.  At CRBCM we are looking at DAX1 as it interacts with COPS2 and through the thyroid Hormone Receptor alpha gene will affect the MEDs which ultimately the Glucocorticoid Receptors and a slew of other critical receptors and genes (even the BRCA-1) is in the line of fire!
Now how important this observation is in triple negative breast cancer is still a matter of debates.  Proof of concept work is still needed but it is a clear start, join the discussion!

" MED1 has been shown to interact with Thyroid hormone receptor alpha,^[4] Androgen receptor,^[5] Cyclin-dependent kinase 8,^[6][7] Glucocorticoid receptor,^[8][9] BRCA1,^[10] Hepatocyte nuclear factor 4 alpha,^[11][12] Peroxisome proliferator-activated receptor gamma,^[13] PPARGC1A,^[14] P53,^[15][16] Estrogen receptor alpha,^[7][17] TGS1^[18] and Calcitriol receptor".<sup>[6][17] wikipedia


WHERE ELSE COULD THINGS BE HAPPENING BUT HERE!
THE INVOLVMENT IS THE CALCITRIOL RECEPTOR IS ANOTHER AREA OF INTEREST.  THIS MED1 SEEMS LIKE A GIFT THAT KEEP ON GIVING.   THE ANDROGEN RECEPTOR INVOLVEMENT IS A CRITICAL STEP SINCE IT BELONGS TO THE "WILD GENES"</sup>

Proof that target therapy has come in to change things in cancers!

1.Combining Ibrutinib with R-CHOP is not only feasible but yield 100% response in Diffuse Large cell Lymphoma.

For decades, CHOP had remained King of treatment of diffuse large cell lymphoma
Elaborate combinations of chemotherapy drugs failed to improve on CHOP, until the targeting of CD20 by Rituxan.  And now with the arrival of the almighty powerful Ibrutinib, response rates seem to be overwhelming although not all seems to be complete Responses, at least not yet since analysis of data is still ongoing!

The secret of triple negative breast cancer

Common sense tells us that events happening in your women when they acquire childbearing age contribute significantly to the happening of triple negative breast cancer.   The young woman has gone through infancy when events here are more related to the setting of class I HLA antigens first for self tolerance, then comes exposure to the outside world and the building of defense mechanisms.  Implying development of class II HLA Antigens which we know by now are very much linked in their variations to racial disparity.  Then the young woman enters puberty which brings in the reign of the Estrogen with its extensive methylation of genes dampening the Class I HLA to prepare the young lady's body to receive the foreign "body" of the potential infant.  We have touched in one of our precedent writings about the effects of Estrogen on the immune system.   We have extensively discussed the interaction of Interferon and TNF /TGFs on receptors of Estrogen (Activation followed by desensitization or lack thereof.  The female individual with autoimmune disease will be much more affected by the surge of cytokines above.  Then come the menses with their resulting Iron deficiency which prones the body to the danger of Reactive Oxidative species.  But as far as genes are a concern, the most important event is the development of the breasts.  It is the reign of the PROLACTINS.....
Indeed, it is Prolactins that will happen on this background of Estrogen/Cytokines effects.   Don't think of Prolactin as a hormone, it is a Cytokine!  Yes, it comes in to not only have a direct effect on the Janus Kinase 2 and induce the JAK-2-STAT pathways, but through its Dopamin Receptor, it will pound on the c-MET effect and exert numerous pounding on the PIK (effect include on its regulators (AGAP2) pathway....If you happen to have another genetic abnormality such as BRCA, or too much free Iron stimulating the HIF or any other failure....something wrong is bound to happen....such as ...triple negative breast cancer.....The point is, don't forget the Prolactin reign!!!

The Hedgehog, Ptch1, AND the Gli zinc-finger transcription factors

If there is an example where GENE INTERFERENCE could have a meaningful impact, it is in this pathway like a deluge of gene activations.  The impact could extend from Basal cell to bladder cancers to Gliomas!

"PTCH1 is a member of the patched gene family and is the receptor for sonic hedgehog, a secreted molecule implicated in the formation of embryonic structures and in tumorigenesis. This gene functions as a tumor suppressor. The PTCH1 gene product, is a transmembrane protein that suppresses the release of another protein called smoothened, and when sonic hedgheog binds PTCH1, smoothened is released and signals cell proliferation." wikipedia.

POLIZIO ET AL
 The vertebrate Hedgehog (Hh) pathway has essential functions during development and tissue homeostasis in normal physiology, and its dysregulation is a common theme in cancer. The Hh ligands (Sonic Hh, Indian Hh, and Desert Hh) bind to the receptors Patched1 and Patched2, resulting in inhibition of their repressive effect on Smoothened (Smo). Smo is a seven-transmembrane protein, which was only recently shown to function as a G protein–coupled receptor (GPCR) with specificity toward the heterotrimeric guanine nucleotide-binding protein G_i. In addition to activating G_i, Smo signals through its C-terminal tail to inhibit Suppressor of Fused, resulting in stabilization and activation of the Gli family of transcription factors, which execute a transcriptional response to so-called "canonical Hh signaling."

WHEN YOU TALK ABOUT ZINC-FINGER YOU KNOW YOU ARE TALKING ABOUT HISTONE MODULATION AND DIRECT DNA INTERACTION, ALL OCCURING MOSTLY THE EPIGENETIC ZONE MOSTLY!  THEREFORE THIS COULD EFFECT EVEN THE LEUKEMIAS!
THE CRBCM IS TAKING A CLOSER LOOK!

"Gli regulation by the opposing activities of Fused and Suppressor of Fused

Maximilien Murone^{1,2ET AL!}

Hedgehog (Hh) proteins are secreted factors that control cell proliferation and cell-fate specification¹. Hh signalling is mediated in vertebrates by the Gli zinc-finger transcription factors (Gli1, Gli2 and Gli3) and in Drosophila by the Gli homologue Cubitus interruptus"

OTHER GENES IMPLICATED!

PTCH1 gene

WNT3A

IRF6

GLI

TGF-beta

TrkC: Neurotropin -Receptor

AND THE DANCE OF GENES CONTINUE!

NEW GENES ARE BEING INCLUDED IN THE CLINICAL THERAPY OF LUNG CANCERS!

ASIDE FROM THOSE INCORPORATED IN THE GUIDELINES OF ONCOLOGY PRACTICE
1.EGFR
2.ALK

Now we are hearing about the following
1.ROS-1
2.MEK-1
3.RET
4.BRAF
5.HER-2
6.PI3KCA
7.KRAS
8.PD-1,2
9.ERCC1
10.BRCA-1 mRNA
11 P53

What about the therapeutic roles of :
GSTM-1 and GSTT1,FAK, Wnt, Notch, p16,
HIF and VGEF and the CYP1A1,P ?

WE WELCOME AND ACKNOWLEDGE OUR NEW READERS FROM MALAYSIA

WE WELCOME AND ACKNOWLEDGE  YOU, OUR NEW READERS FROM MALAYSIA, AND THANK YOU FOR YOUR UPCOMING COMMENTS!
WE ARE PROUD TO ANNOUNCE THAT WE HAVE BEEN INVITED TO PRESENT AND DEFEND OUR POSTER RELATED TO TRAUMATIC BRAIN INJURY (TBI) : EARLY USE OF BUTEIN, A SIRTUIN ACTIVATOR IN TRAUMATIC BRAIN INJURY!
JOIN THE AUDIENCE AT THE UNIVERSITY MEDICAL CENTER IN EL PASO on DECEMBER 5TH, 2013. 10:00 AM.
FOR DIRECTIONS CALL 915-307-3354.

DARK ACTIVITIES ARE PLENTIFUL, DISCRIMINATING, CHEATING, YOU WILL CROSS THE LINE!

ANOTHER EXAMPLE!
"Cheating refers to an immoral way of achieving a goal. It is generally used for the breaking of rules to gain unfair advantage in a competitive situation." (DICTIONARY), THE CRBCM IS A VICTIM ALL THE TIME, LIVING WITH IT, UNTIL THE ENEMIES CEASE AND DESIST OR OTHERWISE BECOME IRRELEVANT!  THE FBI IS WATCHING!
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Physician-Owned Hospital Agrees to Resolve its Civil and Criminal Liability for Benefiting from Illegal Kickbacks to Physicians

FOR IMMEDIATE RELEASE (http://www.justice.gov/usao/txn/PressRelease/2013/SEP2013/sep12FPMC_sett.html)

September 12, 2013

DALLAS - Forest Park Medical Center, LLC (FPMC), a North Texas physician-owned hospital, paid over $258,000 to settle allegations that it violated the civil False Claims Act, announced U.S. Attorney Sarah R. Saldaña of the Northern District of Texas.  The United States contends that a FPMC representative paid illegal kickbacks to area physicians to obtain referrals for Tricare patients, a federally funded health care program, in violation of the federal law, between 2008 and 2012.  Based on the same allegations, FPMC entered into a Non-Prosecution Agreement with the United States and agreed to certain conditions, as well as a federally imposed monitor for not more than 24 months.  FPMC fully cooperated with the investigation, and by settling civilly and criminally, did not admit any wrong-doing or liability.

FPMC, located in Dallas, did not seek reimbursement from any federal sources such as Medicare and Medicaid, but only commercial payors and self-pay.  Federal and State law usually limits the amount of compensation paid to physicians and their ability to refer certain patients under federally-insured programs.  Because FPMC believed it did not accept federal funds, its representatives, to the benefit of FPMC’s behalf, offered and paid excessive remuneration and other things of value to actual and potential referring physicians or others, including amounts for “marketing” or “advertising.”  Payments also were made in the form of cash and giftcards/coupons for luxury items.  The United States alleges such payments were made to obtain federal health care program patients, such as TRICARE, a program for military retirees and their dependents.  The United States contends such payments were unlawful kickbacks for the referral of federal health care program patients in violation of the federal Anti-Kickback Statute between January 1, 2008, and October 31, 2012.  The United States initiated the investigation in response to numerous complaints.

In the Non-Prosecution Agreement, FPMC acknowledged the United States has sufficient evidence to seek an indictment for the offering and payment of illegal kickbacks in violation of federal law.  In return for the non-prosecution of the hospital, FPMC selected and retained an independent monitor to address any compliance issues and the United States’ concerns regarding the allegations of illegal conduct.  The monitor will be in place for not more than 24 months and will review and evaluate inpatient and outpatient claims submitted to all payors, not just federal programs. FPMC also agreed to cooperate with the United States’ ongoing investigation into certain individuals.  No persons were released under the civil and criminal agreements. The United States’ investigation remains ongoing.

U.S. Attorney Saldaña praised the efforts of the investigating agencies, including the Defense Criminal Investigative Services; FBI; Department of Labor, EBSA; Office of Inspector General of the Office of Personnel Management; and FDA-CI.

“This civil and criminal resolution spares the honest employees and investors of FPMC, while holding the hospital accountable for allowing an environment where its representatives paid illegal kickbacks for referrals,” said U.S. Attorney Saldaña.  “This outcome imposes well-deserved measures that we expect will ensure FPMC becomes fully compliant with federal and private health care program requirements.  Whether physician-owned, not-for-profit or for-profit, the Department of Justice expects, and requires, all providers to be trustworthy and abide by the law,” Saldaña continued. 

The case was handled by Assistant U.S. Attorneys Sean McKenna, Errin Martin and Lynette Wilson, and Special Assistant U.S. Attorney Glenn Harrison.

Activity at CRBCM

Today we have concluded a meeting with DR Zhang and (UTEP) and DR Bryan (Texas Tech) on future projects.  We have discussed our collaborative efforts on several  projects, and discussed to use "gene interference" techniques to affect several genes and see whether we can affect several pathways for the cure of cancer.
Several critical areas:
ie.  Could blocking PMS2 (MLH-1  or MLH1 protein ) increase the efficiency of 5-FU in Colon cancer?
ie. Could activation of ARF amplify MDM2 with increased proteosomal degration of P53 in certain Sarcoma?
ie. Could a genetically engineered AATCC Nucleotide set keep Telomeres busy to increase Apoptosis?
ie. Could genetic instability induced by inactivation of telomerase increase radiation sensitivity and response to certain chemotherapy agents?
ie. Examining the role of RPTPs in Alzheimer dementia
ie. Blocking the Farnesyl to delocalize RAS in lung cancers
ie. Blocking Phospholipase C in PIK3 driven cancers?

The meeting was concluded with a tour of the Laboratory.
Our work is cut out, CRBCM, is still working hard for the cure, no stone will stay unturned!

FROM C-AMP, as an Immune modulator, TO COMPLEX LYMPHOPROLIFERATIVE DISORDERS

It is well known that cyclins which include the TNF alpha will only have a full effect on inflammatory processes after depletion of c-AMP.  That is for the inflammatory process to reach full effect activations of FRA-1( FosB) and C-Fos that need to occur. The mere stimulation of c-JUN which results from stress at the Receptor is also accompanied by CRE (CRE-tkCAT) increase (through the CRE-binding proteins) which, in a feedback process activates c-AMP to dampen the c-JUN stimulation.  The amount of activity at c-AMP is therefore a clear modulator of  inflammatory processes!
Anti -COX2 which decreases transcription of related genes, will in fact stimulate the C-JUN.
It is important to stress that as c-JUN, JUNB and subsequently c-Fos increase in number, the AP-1 complex is more formed and activated:

"The activator protein 1 (AP-1) is a transcription factor which is a heterodimeric protein composed of proteins belonging to the c-Fos, c-Jun, ATF and JDP families. It regulates gene expression in response to a variety of stimuli, including cytokines, growth factors, stress, and bacterial and viral infections.^[1] AP-1 in turn controls a number of cellular processes including differentiation, proliferation, and apoptosis.^[2]
AP-1 upregulates transcription of genes containing the TPA DNA response element (TRE; 5'-TGAG/CTCA-3').^[1] AP-1 binds to this DNA sequence via a basic amino acid region, while the dimeric structure is formed by a leucine zipper.^[3]　" wikipedia. CBPA, overexpressed in some leukemas, is a leucine Zipper!

In the JDP families is located JDP2, an inhibitor of AP-1.
Interaction of AP-1 through its ATF component will lead to activation of EP300, a gene we talked about, and which leads to cellular differentiation by its contact with the NOTCH, MAML1 and the Merlin, Again here the EP300 binds to the CREB to activate c-AMP, the immune modulator discussed.

"This gene encodes the adenovirus E1A-associated cellular p300 transcriptional co-activator protein.
The protein functions as histone acetyltransferase ^[4] that regulates transcription via chromatin remodeling, and is important in the processes of cell proliferation and differentiation. It mediates cAMP-gene regulation by binding specifically to phosphorylated CREB protein.
This gene has also been identified as a co-activator of HIF1A (hypoxia-inducible factor 1 alpha), and, thus, plays a role in the stimulation of hypoxia-induced genes such as VEGF.<sup>[5] wikipedia



Other virus affect JDP2, Cyclin D, and the Pim</sup>


"E1A binding protein p300 also known as EP300 or p300 is a protein that, in humans, is encoded by the EP300 gene.^[1] This protein regulates the activity of many genes in tissues throughout the body. It plays an essential role in regulating cell growth and division, prompting cells to mature and assume specialized functions (differentiate), and preventing the growth of cancerous tumors. The p300 protein appears to be critical for normal development before and after birth.
The p300 protein carries out its function by activating transcription. To be specific, p300 connects transcription factors, which are proteins that start the transcription process, with the complex of proteins that carry out transcription in the cell's nucleus. On the basis of this function, p300 is called a transcriptional coactivator. The p300 interaction with transcription factors is managed by one or more of p300 domains: the nuclear receptor interaction domain (RID), the CREB and MYB interaction domain (KIX), the cysteine/histidine regions (TAZ1/CH1 and TAZ2/CH3) and the interferon response binding domain (IBiD). The last four domains, KIX, TAZ1, TAZ2 and IBiD of p300, each bind tightly to a sequence spanning both transactivation domains 9aaTADs of transcription factor p53.^[2][3]
The EP300 gene is located on the long (q) arm of the human chromosome 22 at position 13.2.
EP300 is closely related to another gene, CREB binding protein, which is found on human chromosome 16." (wikipedia)

Please note the MYB involvement:
-as it will play a role in hair discoloration,
-is downstream from the PDGF and plays a role in giving longevity to Notch dependent processes
-regulated through the miR155 in CLL
-involve Flavonoids
-involve the Avian Myeloblastosis Virus.

Note also IBiD as it modulates response to Interferon!
Please refuse to see (and I see you resisting) that P53 is engaged by this!
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THIS IS HOW THE CELL GOES FROM A SIMPLE C-AMP TO COMPLEX ACTS OF SURVIVAL VERY RAPIDLY!

CLINICAL ASPECTS OF HIV INFECTION

The HIV challenge has many interesting aspects when it comes to pathophysiology and genetic based studies.  It goes without saying that the disease is bad and has caused many deplorable deaths.  But for scientists it has provided significant opportunity for advances as it has shed light on several aspects of this disease:
1. Viral infection: the takeover of the Human genome to the benefit of the life of the Virus
2. Sexually transmitted diseases and difficulties in controlling this line of infections, particularly in poor populations
3. Impact of hormone (Testosterone and corticoids which tend to worsen the disease such as in Kaposi Sarcoma)
4. Revealing weaknesses in the structure of our Immune systems for the decrease of CD4, to the development of lymphoproliferative disorders, to the development of opportunistic infections, to the increased risk of AIDS related lymphomas (ARL) in patients expressing Stromal cell derived Factor 1  ( and decrease risk in those having a deletion in Chemokine Receptor CCR5)
5. On the genetic front, Mutations, suppression and translocations of the c-MYC, P53, and Bcl6...
6. The disease causes the body to be swamped with Cytokines ( IL-1,6,10)
7. The disease has shown us the importance of duration of exposure as various diseases develop the longer you stay under the curb of low CD4 (less than 100) with certain diseases being seen only at certain CD4 counts.
8. New biomarkers are now defined CD30 (heightened risk of progression of ARL)
and new diagnosis  (CD138, VS38c for Plasmablastic lymphoma)
9. Early introduction of Etoposide in the treatment plan seems to be important with the resurgence of the EPOCH regimen rather than CHOP; Etoposide seems to control those Epigenetic events better!
10. Eminence of Macrophages in the inflammatory process as they drive the EGFR
and the use of Anti-VEGF in KS. An angiosarcoma...(where is Avastin?)

You name HIV, the syndrome does it.  The push for us is to go back to the genetic bases of this disease!

Genes in Breast CANCERS

1.Variants in the PALB2 gene are associated with an increased risk of developing breast cancer ^[5] and PALB2-deficient cells are sensitive to PARP inhibitors. ^[4]
PALB2 was recently identified as a susceptibility gene for familial pancreatic cancer by scientists at the Sol Goldman Pancreatic Cancer Research Center at Johns Hopkins. This has paved for the way for developing a new gene test for families where pancreatic cancer occurs in multiple family members.^[6] Tests for PALB2 have been developed by Ambry Genetics ^[7]and Myriad Genetics^[8] that are now available through a genetic counselor.
Biallelic mutations in PALB2 (also known as FANCN), similar to biallelic BRCA2 mutations, cause Fanconi anemia.<sup>[3]wikipedia


2 xia et al: described superbly the role of PALB2
"</sup> the identification of PALB2, a BRCA2 binding protein. PALB2 colocalizes with BRCA2 in nuclear foci, promotes its localization and stability in key nuclear structures (e.g., chromatin and nuclear matrix), and enables its recombinational repair and checkpoint functions. In addition, multiple, germline BRCA2 missense mutations identified in breast cancer patients but of heretofore unknown biological/clinical consequence appear to disrupt PALB2 binding and disable BRCA2 HR/DSBR function. Thus, PALB2 licenses key cellular biochemical properties of BRCA2 and ensures its tumor suppression function."

3. And has mentioned hematologic complication is not very far!

" Fanconi anemia is a rare, recessive, chromosomal instability disorder characterized by growth retardation, congenital malformations, progressive bone marrow failure, cancer predisposition and cellular hypersensitivity to DNA cross-linking agents¹. The syndrome is genetically heterogeneous with 12 complementation groups currently recognized, 11 of which have been attributed to distinct genes: FANCA (FA-A), FANCB (FA-B), FANCC (FA-C), BRCA2 (FA-D1), FANCD2 (FA-D2), FANCE (FA-E), FANCF (FA-F), FANCG (FA-G), BRIP1 (FA-J), FANCL (FA-L) and FANCM (FA-M)^{2, 3}." Sarah Reid et al....

4. And the devastation does not stop to Fanconi and Breast cancer!

ERKKO et al:

"These results indicate that PALB2 is a breast cancer susceptibility gene that, in a suitably mutant form, may also contribute to familial prostate cancer development." in a Finnish population

SIAN JONES ET AL

"the role of PALB2 as a susceptibility gene for pancreatic cancer. PALB2 mutations have been previously reported in patients with familial breast cancer, and the PALB2 protein is a binding partner for BRCA2. "

SOME AUTHORS ADD GALLBLADDER,MELANOMA AND GASTRIC CANCERS TO THIS SAD LITANY.
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6.RAD51

"In humans, RAD51 is a 339-amino acid protein that plays a major role in homologous recombination of DNA during double strand break repair. In this process, an ATP dependent DNA strand exchange takes place in which a template strand invades base-paired strands of homologous DNA molecules. RAD51 is involved in the search for homology and strand pairing stages of the process.
Unlike other proteins involved in DNA metabolism, the RecA/Rad51 family forms a helical nucleoprotein filament on DNA.^[2]
This protein can interact with the ssDNA-binding protein RPA, BRCA2, PALB2^[3] and RAD52."WIKIPEDIA

RAD 51 KEEPS BAD ASSOCIATIONS, BROADENING THE DANGER!

" RAD51 has been shown to interact with BRE,^[12] RAD54B,^[13] Ataxia telangiectasia mutated,^[14] BRCC3,^[12] BARD1,^[12] BRCA2,^{[12][15][16][17][18][19][20][21][6][22][23][24][25]} UBE2I,^[26][27] Abl gene,^[14] BRCA1,^{[12][24][28][29]} ATRX,^[13][30] RAD52,^[14] DMC1,^[31] P53^[12][32][33] and Bloom syndrome protein.<sup>[34]"WIKIPEDIA

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ON TOP OF ALL THIS 
YOU STILL HAVE 
- CDH1
- p53 MUTATIONS
- PTEN

OUR WORK IS CUT OUT TO TRAVEL THIS MAZE!</sup>

SOME LITTLE GENES WITH A BIG IDEA: SHP GENE

IF YOU KNOW HOW IMPORTANT ESTROGEN RECEPTORS ARE IN BREAST CANCERS,
IF YOU KNOW HOW IMPORTANT ANDROGEN RECEPTORS ARE IN PROSTATE CANCER
IF YOU REALIZE HOW IMPORTANT THE THYROID FUNCTION IS DRIVING THE RATE OF METABOLISM
IF YOU REALIZE THE DIFFICULTY THAT POSES HEPATOMA IN TERMS OF TREATMENT,
IF YOU KNOW THAT SARCOMA IS TOUGH TO TREAT,

THEN YOU SHOULD DIG DEEPER IN UNDERSTANDING THAT ALL THESE RECEPTORS HAVE ONLY ONE INHIBITOR, THE "SMALL HETERODIMER PARTNER"  GENE!

WHAT IS IT AND HOW AND WHEN SHOULD IT COME IN?

Small heterodimer partner has been shown to interact with:

• Androgen receptor,^[4]
• Estrogen receptor alpha,^[5]
• Hepatocyte nuclear factor 4 alpha,^[6]
• Liver receptor homolog-1,^[7][8]
• Liver X receptor alpha,^[7]
• Peroxisome proliferator-activated receptor gamma,^[9]
• Retinoic acid receptor alpha,^[10][11] and
• Retinoid X receptor alpha.^[6][7]

I refuse to comment on the PPARgamma for now, did you know that this is the staff that interacts with Rb1?  watch it as it is coming to a Diabetic control and evaluation near you!

At CRBCM we are working hard!

A WILD GENE! THE EP 300

Every time we talk about a "wild gene", we get a reaction from our readers.  This is a good sign.  Basically, what we call wild gene is one full of interactions.  We talked about adapter genes which basically direct in one or the other direction of global Metabolism, but we also make sure that readers understand that these adapters can allow a gene to acquire proliferative potential by hooking it to another gene that routinely drives proliferation (such as the gene that pushes Antibody formation).  By all definitions, EP300 is a wild gene.

Another power to this gene is the fact that it leads to Malformation when it is missing:
"Rubinstein-Taybi syndrome.", THROUGH THE MAML1 GENE, THIS GENE IS IN COMPLICITY WITH THE NOTCH1.  And you know how we hold dearly the Notch as an important gene/pathway...

EP300 is involved in all major cancers including Acute Leukemia.  You remember that Acute AML cells have not fully completed differentiation.  EP300 is the master of differentiation and of course will be mutated or altered in bad AML.  So, in a way, it is prognostic!

" Somatic mutations in the EP300 gene have been found in a small number of solid tumors, including cancers of the colon and rectum, stomach, breast, and pancreas. Studies suggest that EP300 mutations may also play a role in the development of some prostate cancers, and could help predict whether these tumors will increase in size or spread to other parts of the body. In cancer cells, EP300 mutations prevent the gene from producing any functional protein. Without p300, cells cannot effectively restrain growth and division, which can allow cancerous tumors to form."

HOW MANY GENES INTERACT WITH EP300? YOU BE THE JUDGE!

"Interactions"

EP300 has been shown to interact with Mothers against decapentaplegic homolog 7,^[6] MAF,^[7] TSG101,^[8] Peroxisome proliferator-activated receptor alpha,^[9][10] NPAS2,^[11] PAX6,^[12] DDX5,^[13] MYBL2,^[14] Mothers against decapentaplegic homolog 1,^[15][16] Mothers against decapentaplegic homolog 2,^[17][18] Lymphoid enhancer-binding factor 1,^[19] SNIP1,^[20] TRERF1,^[21] STAT3,^[16] EID1,^[22][23] RAR-related orphan receptor alpha,^[24] ELK1,^[25] HIF1A,^[26][27] ING5,^[28] Peroxisome proliferator-activated receptor gamma,^[29][30] SS18,^[31] TCF3,^[32] Zif268,^[33] Estrogen receptor alpha,^[29][34][35] GPS2,^[36] MyoD,^[24][37] YY1,^[38][39] ING4,^[28] PROX1,^[7] CITED1,^[40] HNF1A,^[41] MEF2C,^[37] MEF2D,^[42][43] MAML1,^[44][45] Twist transcription factor,^[46] PTMA,^[47] IRF2,^[48] DTX1,^[49] Flap structure-specific endonuclease 1,^[50] Myocyte-specific enhancer factor 2A,^[51] CDX2,^[12] BRCA1,^[34][52] HNRPU,^[53] STAT6,^[54] CITED2,^{[55][56][57][58]} RELA,^[59][60] TGS1,^[61] CEBPB,^[62] Mdm2,^[63] NCOA6,^[64] NFATC2,^[65] Thyroid hormone receptor alpha,^[51] BCL3,^[66] TFAP2A,^[56] PCNA,^[67] P53^{[68][63][69][70][71]} and TAL1.^{[72]wikipedia"}

TANTALIZING PRESENTATION OF NEW TECHNOLOGIES!

Presentations from GSK, Broad Institute, Indiana University on RNA-Seq

Izzy Scott-Moncrieff	6:05 AM (6 hours ago)
to me

  Dear Mutombo,

Sick of my emails? Bear with me. Because this week I have something very exciting for you.  Not one, or even two, but THREE PRESENTATIONS from the inaugural RNA-Seq 2013 meeting  that took place in Boston earlier this year. Have a read through the summaries below. Which gets your number 1 vote? We’re running  a poll on our Linkedin page (search Linkedin groups for RNA-Seq Forum) to establish which,  of groups from GSK, Broad Institute or Indiana University School of Medicine are engrossed  in the most exciting work at the moment.  Numéro un (1). Ganesh Sathe, DNA Sequencing Manager, GSK. “Applications of RNA-Seq within Research & Development at GSK” Ganesh spoke about using RNA-Seq for cancer target identification using very small amount of starting material. How GSK are going about sequencing blood samples for biomarker identification. Which new technologies are they using for cell line validation? Download the presentation here for free Numero due (2). Brian Haas, Senior Computational Biologist, Broad Institute “Trinity de novo RNA-Seq Assembly for Analysis of Model and Non-Model Organisms” Brain gave a fascinating comparison of Trinity software when used with model and non-model organisms. An overview of how, in the absence of a reference genome , this software coupled with companion utilities enables de novo transcript reconstruction. And subsequently how this yields insights into gene content and transcriptional regulation.  Free download of the presentation here Nummer drei (3). Yunlong Liu, Assistant Professor, Medical and Molecular Genetics,  Indiana University  “Statistical Modelling in Non-Coding RNA Mediated Regulatory Networks” Yunlong presents a bioinformatics strategy to construct the microRNA mediated regulatory network using genome-wide binding patterns of transcription factors. As well as this, brand new findings on long noncoding RNA in determining alcohol dependence in rat brains, using RNA-seq derived transcriptome mapping data.  You know the drill by now. Click here to download the presentation And if you thought that was all, not at all! These three presentations are brought you in  the run up to RNA-Seq Europe (3-5 December, Basel), where we’ll be bringing you even more top rate presentations on everything RNA-Seq. Make sure you check out the brochure. Remember, visit the Linkedin group to cast your vote on which is your number 1  presentation. As per, drop me a reply if you want more info on how to register. You can also send  me your vote directly. Maybe your company will hit the top spot next year… Bye for now! Izzy  Genomics Programme Director Hanson Wade P.S If you like the free presentations then check out the RNA-Seq website. You can peruse  the other exciting bits of RNA-Seq themed content there.