CRBCM IS INVITED AS A SPEAKER!

14th Annual Rio Grande Trauma Conference & Pediatric Update - December 5-6, 2013

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I.Role of Avastin-Anti-JAK2 and Anti-c-MET in Metastatic triple negative and possibly inflammatory Breast Cancer

PART I  (speculative thoughts)

1.It is increasingly recognized that the development of the triple negative breast cancer is  linked to abnormalities of gene expression at the Wnt (& NOTCH) pathways,  abnormal levels of Cytokines/growth factors and perturbances or predisposition to autoimmune diseases (AS SUGGESTED BY THE bASAL LIKE CELL MORPHOLOGY which comes from autoimmune component involvement)!
The various genetic pathways involved provide tremendous opportunities for target therapy interventions. Testing through clinical trials and laboratory studies appear to be the main ways to ascertain the effectiveness of proposed interventions.
Here we submit the Hypothesis that a known Anti-JAK-2 in combination with both an Anti-c-MET and an Anti-VEGF could slow down the metastatic progression of triple negative breast cancer and secondarily have a role in inflammatory breast cancers.

We are also going to identify through this study other opportunities of therapeutic interventions as we discuss the flow of causal events leading to the malignant transformation of Breast cells.

2.Potential Pathophysiology in these Breast Cancers.
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2.1 As women enter the reproductive age, with the advent of Menarche, starts a period of their lives with increased Estrogen production. It has been reported (K-S et al)  that" Estrogens have been shown to markedly modulate the immune system...mostly by regulating " namely IL-2 and Interferon-gamma.  The increase of these cytokines was driven through the modulation of their promoter activities.
It is worth mentioning here that IL-4 production was not increased by this Estrogen surge.
N. et al suggested that under Estrogen stimulation "the production of interferon-gamma was enhanced by E2 stimulation. And that E2 increases not only the number of cells expressing IFN-gamma but also the IFN-gamma  levels in each cells".  These authors did emphasize that the enhancement of interferon was through the Estrogen Receptor (ER) ie ER alpha, beta and mERs.

The positive regulatory feedback loop between Interferons and Estrogen Receptor-alpha was also the focus of work reported by R. et al.  Indeed "patients with Systemic Lupus Erythematosis, an Autoimmune disease, AFFECTING WOMEN OF CHILD BEARING AGE, were found to have an even more of an increase in Interferon-gamma which increases levels of Receptors for Estrogen.   This Estrogen Receptor response was driven through "activation of signal transducers and activation of Transcription 1 (STAT1) by Interferon".
(This provide the link to autoimmune diseases, It also means that all of the sudden you have a period of life with high Estrogen with too many receptors, you know they will be a "violent" desensitization of these receptors which in fact you will not find in Triple negative Breast Cancers which happen in women of "child bearing age").(And here comes the intervention of the STATS! with STAT5a the more specific one!)

2.2Overexpression of TNF is also induced by Estrogen
----------------------------------------------------------
Kod... et al:
"Certain autoimmune diseases are also associated with excess levels of Tumor Necrosis Factor-TNF alpha, and Anti-TNF drugs are known to be useful".  The elevation of TNF alpha is known to activate the NF-kB pathways. (HERE COMES CYTOKINES' EXPANSION).  And through the MAPK, the same activation will reach the JNK which leads to transcription of C-jun and ATF2, opening the door to cell proliferation.
Wikipedia suggests that TNF also can lead to"induction of death signaling and therefore could be pro-Apoptotic" but remember this is the thing taken care of by SMAD4-E3 which help escape proliferative control!  The path to Neoplastic proliferation is set!
Through the Ubiquitins comes also the involvement of the NOTCH!
(see for yourself NOTCH-MAML1-EP300..........ubiquitins 8---E3 (RNF 41)
and with the NOTCH comes  in the Wnt, loss of cellular boundaries and shape, and "consensus" to survive!

Continuing here!

Estrogen is known to "upregulate TNF production by increasing the number of TNF producing cells"

AND IN BREAST CANCER BIOLOGY, THE ELEVATION OF TNF SYNERGIZES THE ELEVATION OF INTERFERON gamma EFFECT ON  CTGF/CCN2   (SCH...et al!)

this is the same CCN that drive by chemotaxis bone metastatic invasion 9 and metastasis is driven! wonder why the bone marrow is an early relatively "irrelevant" metastasis ! (keep  you knives where they are, I see you ready to brandish them!).  Science is talking for now!

TO BE CONTINUED ....BY

2.3. TNF, INTERFERON-gamma, JAK-2, AND CCN2.
===========================================

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!
=======================================================
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

====================================
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.

Yes, don't forget the TELOMERES!

• October 2013
• > Vannier et al., 342 (6155): 239-242

Prev | Table of Contents | Next

 WATCH THIS ONE!

RTEL1 Is a Replisome-Associated Helicase That Promotes Telomere and Genome-Wide Replication

1. Jean-Baptiste Vannier¹,*,
2. Sumit Sandhu²,*,
3. Mark IR. Petalcorin¹,
4. Xiaoli Wu²,
5. Zinnatun Nabi²,
6. Hao Ding²,³,^†,
7. Simon J. Boulton¹,^†

+ Author Affiliations

1. ¹DNA Damage Response laboratory, London Research Institute, Cancer Research UK, Clare Hall, South Mimms EN6 3LD, UK.
2. ²Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Manitoba R3E 3J7, Canada.
3. ³Manitoba Institute of Child Health, Winnipeg, Manitoba, R3E 3P4, Canada.

1. ↵†Corresponding author. E-mail: dingh@cc.umanitoba.ca (H.D.); simon.boulton@cancer.org.uk (S.J.B.)

1. ↵* These authors contributed equally to this work.

• Abstract
• Editor's Summary

Regulator of telomere length 1 (RTEL1) is an essential DNA helicase that disassembles telomere loops (T loops) and suppresses telomere fragility to maintain the integrity of chromosome ends. We established that RTEL1 also associates with the replisome through binding to proliferating cell nuclear antigen (PCNA). Mouse cells disrupted for the RTEL1-PCNA interaction (PIP mutant) exhibited accelerated senescence, replication fork instability, reduced replication fork extension rates, and increased origin usage. Although T-loop disassembly at telomeres was unaffected in the mutant cells, telomere replication was compromised, leading to fragile sites at telomeres. RTEL1-PIP mutant mice were viable, but loss of the RTEL1-PCNA interaction accelerated the onset of tumorigenesis in p53-deficient mice. We propose that RTEL1 plays a critical role in both telomere and genome-wide replication, which is crucial for genetic stability and tumor avoidance.
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PLEASE GO TO THE FULL ARTICLE,
GOOD JOB FOR THESE SCIENTISTS!

Until we can talk to the CBX, the piccolo, and the IKAROS, Brain tumors and certain Leukemia will remain elusive!

It is striking what similarities exist between brain tissue function and white blood cell function at the molecular level.  When it comes to Neoplasia, Medulloblastoma is linked to hematologic neoplasm!
And any therapeutic intervention against blood cell proliferative disorders may have Neurologic side effects, and it is important that Phase 1 studies be conducted in centers that can handle seizures and accurately evaluate mental status changes (Leucodystrophic Encephalopathy)!  The similarities are not only found at the membrane where the frizzled and the Lck, and Merlin (Neurofibromatosis) are located, but deep inside the cells at the Nuclear/Chromatin level where the Ikoros and CBX5 are plenty at play!
It is evident that the CBXs and the Ikoros are epigenetic and this is where Leukemia and most malignant Brain tumors come to hide their source and powers.  And guess who is following them, the triple negative breast cancers!  It is actually amazing that this last disease may be more likely Cytokine driven given its selective appearance in certain groups of our population (HLADRs implicated).
The CRBCM continues its unfettered progress, not distracted by belligerent political forces, but tracking down this disease from the Wnt, Notch, Wisp3, non expressed Hormone Receptors, to the STAT5, SMADs, and now to the SUV39H1-CBX, Ikoros, Piccolo,Tousled, a Ku70, and to chromatin modulation.
Progress is slow but deliberate.  It is surprising that even deep here, through the FADD-MBD4, the Caspases can help achieve Apoptosis...there is hope for the cure!

Controversial but reportable (marginal benefit)-Ramucirumab

ONLINE FIRST: FDA Grants Priority Review of Ramucirumab for Gastric Cancer, Phase III REGARD Findings Now Online in Lancet; Concerns, Though, from a Lead Recruiter to the Trial(from Oncology Times)
what we know about the drug
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Ramucirumab

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Ramucirumab ^?

Monoclonal antibody
Type	Whole antibody
Source	Human
Target	VEGFR2 (KDR)
Clinical data
Pregnancy cat.	?
Legal status	Investigational
Identifiers
CAS number	947687-13-0
ATC code	None
UNII	D99YVK4L0X
Chemical data
Formula	C6374H9864N1692O1996S46
Mol. mass	143.6 kDa
(what is this?)  (verify)

Ramucirumab (IMC-1121B)^[1] is a fully human monoclonal antibody (IgG1) being developed for the treatment of solid tumors. It is directed against the vascular endothelial growth factor receptor 2 (VEGFR2). By binding to VEGFR2 it works as a receptor antagonist blocking the binding of vascular endothelial growth factor (VEGF) to VEGFR2. VEGFR2 is known to mediate the majority of the downstream effects of VEGF in angiogenesis.
Ramucirumab is being tested in several phase III clinical trials for the treatment of metastatic gastric adenocarcinoma,^[2] non-small cell lung cancer,^[3] among other types of cancer. On September 26, 2013 Eli Lilly announced that its Phase III study for ramucirumab failed to hit its primary endpoint on progression-free survival among women with metastatic breast cancer.^[4][5]
This drug was developed by ImClone Systems Inc. It was isolated from a native phage display library from Dyax. " wikipedia

Real clinical questions

1. Identifying best chemotherapy drugs in patients with Mutation in the NOTCH pathway?
Taxotere?
association with Her-2 overexpression and use of Herceptin
NF-kB blocker
or AKT blocker.
Histone de-acetylator

2. Understanding the patterns of Metastasis between epithelial (squamous) (more local recurrence)  Vs AdenoCA (more distant recurrence in Esophageal cancer? Genes at play.
Does mesenchymalization dictate or drive long distance metastasis?

3. Mitomycin in NFKB amplification/Mutations