Showing posts with label crbcm breast cancer mortality paradox. Show all posts
Showing posts with label crbcm breast cancer mortality paradox. Show all posts

Tuesday, February 18, 2014

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.

Thursday, December 19, 2013


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".[6][17] wikipedia


Monday, December 16, 2013

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!!!

Thursday, November 14, 2013


"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!
Physician-Owned Hospital Agrees to Resolve its Civil and Criminal Liability for Benefiting from Illegal Kickbacks to Physicians
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.

Monday, November 4, 2013

Email not displaying correctly? View it in your browser.
State of Texas Seal
CPRIT’s Oversight Committee met November 1 for the first time since February beginning a new era for the agency – one with a higher level of transparency, improved processes and strengthened accountability to the taxpayers of Texas. As I reported to the Oversight Committee, in addition to provisions in SB 149 which modified CPRIT’s enabling legislation, the agency has taken action to implement all 41 of the State Auditor’s January 2013 recommendations.

We accomplished a number of important items at the meeting that will allow CPRIT’s work to move forward. We also began our commitment to transparency by holding the meeting at the State Capitol and streaming the meeting live over the web – a first for CPRIT. Within days, we’ll post a video of the proceedings to our website as well. Major actions of the Oversight Committee include:
  • Adopting new bylaws for how the Oversight Committee will operate as a governing body, including an updated code of conduct. These bylaws indicate the Oversight Committee commitment to operating with the highest level of integrity;
  • Posting revised administrative rules to the Texas Register for public comment. The rules expanded from 40 to over 120 pages, and implement many of the State Auditor’s recommendations as well as other process and accountability improvements;
  • Restarting our grantmaking process, including the approval of Scientific Review Council appointees. This action allows CPRIT to resume review of grants and enable healthcare and medical professionals to apply for new grants. We expect additional steps at the next Oversight Committee meeting scheduled for November 22, 2013. At that session, I anticipate discussion about research and prevention program priorities, and a number of other actions important to our continuing operations.
I want to express my gratitude to the members of the 83rd Legislature and their staffs, state leadership offices and CPRIT staff for getting us to November 1. The new Oversight Committee came to the meeting well-prepared and eager to resume the important responsibilities assigned to CPRIT by the citizens of Texas.

It’s nice to be back at work!


Wayne R. Roberts
Interim Executive Director
Cancer Prevention & Research Institute of Texas
P.O. Box 12097
Austin, Texas 78711

Thursday, October 31, 2013


Email not displaying correctly? View it in your browser.
State of Texas Seal
The CPRIT Oversight Committee meeting this Friday, November 1, 2013 will be broadcast live online. To access the livestream of the meeting, please click here.

Please note, to view the broadcast, you will need to have the basic RealPlayer installed, which can be downloaded for free from:

The meeting agenda and supporting materials are available on the CPRIT website.
CPRIT Oversight Committee Meeting
Texas State Capitol Extension

1400 N. Congress Avenue, Austin, Texas 78701

 Room: E1.012

November 1, 2013

9:00 A.M.


Nothing is simple but yet as determinant as an Adapter gene.
The cell continues to amaze scientists.
When a stimulant attaches to a receptor, the 2, stimulant and receptor, enter the cell in some cases, detaching from the membrane and enter the cell.  Most of the time there is a triggering of main pathways such as the RAS, but sometimes, at the site of attachment, the raw edges of the membrane are not healing and wage their own it is the focal Adhesion kinases that are going to war.  Now, that war is not necessarily random.  Depending on the nature of the stimulant and receptor involved, the FAK can turn to a Gerb2, Lyn or Flyn with a totally new orientation in the metabolism of the cell.  Sometimes the adapter is simply a b-cell linker or it is a T-cell linker and the cell will follow that path or attract these different cells.  It may use RUS1 to block the excited RAS that we spoke about or orient the cell to Rho in order to exacerbate metastasis.  
These linkers are a way to control differentiation, but when erratic, they could compromise the host!  Certain genes are destined to help many proteins such as a portion of an Antibody, imagine them wrongly linked to some other gene leading to unwarranted  multiplication! Things are set for hematologic malignancies!

Preliminary impression:
- Attachment to Lyn- B cell differentiation (some) and if Gerb2 involved, T cell differentiation definitely if the stimulant is TGF alpha!
Flyn- well may be muscle dystrophy, of some form.
Attachment to TBS - mental retardation
Lck-depression such as seen with chronic autoimmune disease (locus Coereleus)

Watch your Adaptor genes carefully!  Otherwise things are going in a direction you may not wish!

Wednesday, October 30, 2013


Cancer Prevention and Research Institute of Texas via 
2:24 PM (16 hours ago)
to me
Email not displaying correctly? View it in your browser.
State of Texas Seal
CPRIT has been notified by Governor
Perry, Lt. Governor Dewhurst and
Speaker Straus that the moratorium
  on CPRIT’s grant award processes
has been lifted.

Over the last ten months CPRIT has
taken purposeful strides to strengthen
agency governance and restore trust
in its commitment to the fight against
 cancer in Texas. CPRIT appreciates
the confidence state leadership has
in the agency’s efforts – this action
marks a critical milestone for CPRIT.
We have been working hard in preparation
 for this moment and are ready to move
forward with deliberate purpose,
accountability and transparency to
 serve all Texans.

Staff will contact CPRIT grantees
affected by the moratorium to provide
additional information and next steps
 per this announcement. On November 1, 
2013, the CPRIT Oversight Committee
 will discuss restarting all of CPRIT’s review
processes including resuming review of
applications that have been submitted
and the release of new requests for

Monday, October 7, 2013


In this month of re-commitment to fighting Breast cancer, it is imperative to stop a while in a moment of reflection for those who have lost the fight, remind ourselves of who they were, what lives they touched as they made us who we are today in many ways.   I remember  my mother who was afflicted by this disease, a kind loving soul, who despite our number (family of 15) had managed to make all of us feel special.  I grew up truly believing that of all her kids, I was the one.  But talking to my other siblings, each one of us felt that special feeling! In 1974, 3 years before she was diagnosed and treated in Belgium, she added to my name a secret portion, "Muendela yenda" (the one who will walk alone) and here I am today, far from the country of origin, in  El Paso, Texas, the sole American Citizen of my family!  Preaching to a silent choir on this blog.  Breast cancer victims are our mothers, sisters, daughters and friends who have affected our lives in many ways. Survivors continue their paths and work touching our lives everyday, reminding us that our fight is needed and is just because there is a price to fight for.  Reminding us that until the cure happens, there is no stone that should remain unturned, no places we should not go, no politician we should not talk to, no genes,proteins, and other molecules that could make a difference we should not explore, poke and tease.  We could wander to other matters of our lives, but this month of October, we should renew our commitment to the fight for the cure of breast cancer.

Efforts made so far have made a meaningful difference, our eyes have opened to new dimensions of cancer research, and the belief in the cure has hardened because through advances in targeting therapy and genetic works, THE CURE IS MORE POSSIBLE, REACHABLE AND REAL!
All we need is cast off the doubt, stop infighting, keep the eyes open, and bring the cure to the shores of our daily reality! We have the means, we have the science, we are full of justified hope, let's keep on marching until the victory rings, making the CURE REAL, PALPABLE  AND ALIVE!

Monday, September 23, 2013

Major implication of the Gli-1

I.  The Gli-1 gene
affects the following other genes
---PDGFR in mesenchymal tissue
---SP1, USF1

II. PTCH1:  Act as a receptor to the Hedgehog ---the contact releases the SMO
Revant Info-Vismodegib
"The substance acts as a cyclopamine-competitive antagonist of the smoothened receptor (SMO) which is part of the hedgehog signaling pathway.[2] SMO inhibition causes the transcription factors GLI1 and GLI2 to remain inactive, which prevents the expression of tumor mediating genes within the hedgehog pathway.[4] This pathway is pathogenetically relevant in more than 90% of basal-cell carcinomas.[5]"wikipedia

link to chondrosarcoma is most puzzling
role in bladder cancer still to be explored, mostly I guess in the squamous type?
in Medulloblastoma?

Focus on Peroxisome

Peroxisomes IPA: [pɛɜˈɹɒksɪˌsoʊmz][1] (also called microbodies) are organelles found in virtually all eukaryotic cells.[2] They are involved in the catabolism of very long chain fatty acids, branched chain fatty acids, D-amino acids, polyamines, and biosynthesis of plasmalogens, i.e. ether phospholipids critical for the normal function of mammalian brains and lungs.[3] They also contain approximately 10% of the total activity of two enzymes in the pentose phosphate pathway, which is important for energy metabolism.[3] It is vigorously debated if peroxisomes are involved in isoprenoid and cholesterol synthesis in animals.[3] Other known peroxisomal functions include the glyoxylate cycle in germinating seeds ("glyoxysomes"), photorespiration in leaves,[4] glycolysis in trypanosomes ("glycosomes"), and methanol and/or amine oxidation and assimilation in some yeasts.(Wikipedia)
 with our discussion on the PEX26 and Sufu, we are working on opportunities of interventions through the peroxisome!

Sunday, September 22, 2013

"Bigger is better"

New York — Memorial Sloan-Kettering Cancer Center has launched a transformative initiative to improve the quality of cancer care and the lives of cancer patients. Hartford HealthCare, a multi-hospital health care system in Connecticut, was selected as a pioneering member of the newly formed Memorial Sloan-Kettering Cancer Alliance.

The MSK Cancer Alliance is designed to enable an ongoing, living, breathing dynamic partnership between the comprehensive cancer center and community oncology providers, in order to bring the newest knowledge into the community setting.

The critical need for such an Alliance can be found in a report recently issued by the Institute of Medicine (IOM) that described the challenge of delivering high-quality cancer care as a national “crisis” and noted advances in treatment may be unavailable to patients who lack access to sophisticated genetic tests or clinical trials.
“Currently, the vast majority of cancer care in the United States is delivered by community oncologists, but cancer advances can take years to be adopted in a community setting,” said José Baselga, MD, Physician-in-Chief of Memorial Sloan-Kettering, who notes that ongoing, interactive real-time relationships are needed to effectively close this gap. “We want to rapidly accelerate the pace of integrating the latest advances of cancer care into a community setting. This unprecedented approach will demonstrate real value to both organizations and most importantly will improve the lives of cancer patients,” he added.
Researchers are taking over main Oncology publications by publishing non readily useable information while support for conferences is dwindling.  It is amazing how many Oncologists do not read Blood or JCO because the immediate relevancy of information/articles are perceived as relevant to day to day practice.  Among oncologists, FDA approval and whether a randomized phase III trial has demonstrated benefits, seems to be the overwhelming standard for adoption of new therapeutics.  Of course the input from trusted authors and opinions from their local referral center also drives the practice.
Larger Institutions could serve a purpose of streamlining referrals if carefully orchestrated, however something may be lost in quality of care (may be because staff there lose a bit of compassion) and money and administrative weight increase dramatically to impair the quick delivery of care they mean to better!
The weight of overheads, the number of meetings, size of committees and political infighting, tends to slow the process by the nature of the beast!  These larger institutions attract more research money for a relatively poor output.  The CPRIT experience proves this case.  Over half of the money given to date went to large institutions in Texas, we are still waiting for the return on investment, and communities overall have still to see lingering effects.
At the CRBCM we like the idea of smaller, more versatile organizations with more effect and efficiency. We believe that science does not belong to any particular institution,  and that we can not lead from behind and that we absolutely need to create new paths.  This is driving how we perceive new scientific progress results,  and most of all how readers will note that our interpretation of facts may be at odds, but that is deliberate and ready to open new approaches! And at least open the debate!  If we have not progressed as fast as wished, it is because of political elephants in the room!

Friday, September 20, 2013

The Crux of Tumorgenesis

The secret of cancer proliferation and persistence lays in phenomena at the membrane, where the NOTCH, Wnt and Hedgehog are located.  These functions of the membrane start and drive the cancer with help from the ABCG2, MRp1, Pgp gene;  it gives it resistance to powerful medications (Adriamycin, CPT11), with SuFu/PEX it reaches a gene capable of inducing malformation, with FOXM1, proliferation is guaranteed, through GLI1, Cyclin D2 is reached. Differentiation is reached though the MEK and failure of control is assured by dysregulation at the FAK.  The Cancer's mind set is driven by the FOXM1 for sure.  Other genes involve the NANOG, the PTCH1, The SOX and the OCT, CDH1, Shh,Twist, Plakoglobulin...

Profiling through at the CRBCM!

At the CRBCM something is coming through:

1. Deterioration at membrane receptor by lack of stimulation or "false or abnormal stimulation" could not only alter the nature of the "glycan" covering the protein portion of the receptor, but also induce stress like molecules.(HSP)
2. As a result of receptor failure new cytokines and TGFs are secreted which unfortunately fail at the initial receptor, but induce other receptors, amplifying standard pathways like RAS or PIK
3. Certains TGFs have an intrinsic power to maintain life of cells no matter what and induce metastasis.
4. Certain genes have an auto-phosphorylation or self-limiting mechanism that can easily go wrong  (RAS, FAK) driving to neoplastic process
5. FAK plays a larger role in aggressive prostate cancer than it has been recognized!
6. FAK has a closer relation to Androgen than recognized
7. NOTCH has closer relation with MEK and "stem cell potential" than recognized.
8. FAK disturbance prominence in cancer explains its sensitivity to Taxanes!  That is on top of Microtubule disturbances induced by the drug!
9. Metalloproteases are the ultimate Biomarkers of membrane events !
10.  Epigenetic methylation and its patterns are one of the largest mystery still to be elucidated!

Friday, August 23, 2013


Dear Mutombo,
Thank you for attending Genetics and Genomics BioConference Live!

We have great news! The event was so successful that it will now be available on-demand until January 2, 2014.

Feel free to log in to attend the webcasts, visit exhibitor booths, and exchange messages with experts and sponsors.
Earn CME, CE, and CEU Credits.  Learn more by clicking here.

Thank you for your participation! We look forward to seeing you at the next event!
- the BioConference Live team

Need technical support?
Phone: +1-714-463-4673
See our
Frequently Asked Questions 

Thursday, August 22, 2013

Example of neoplastic phenomena at work.

One example  of constant  stimulation is an estrogenic supply which leads to type I endometrial cancers. It appears that constantly giving Estrogens unopposed by progestins  leads to the stimulation of many genes including Grb2, a" wild gene" that provokes amplification of critical genes that are controlling the epithelium of the Uterus (Catenins and Muc1) leading to the disturbance of cell polarity and adhesions, events that are preceding hypertrophic transformation.  MUC 1 amplification will shield the cell from immune detection.  How much Sp1, EP 300, and RELA play to further broaden NF-kB amplification in this process remains to be further defined.
RELA is another "wild gene" very much in control of epigenetic phenomena induced by amplification of the NF-kB.
"RELA has been shown to interact with:

A few questions in triple negative breast cancer

1.Could amplification of PIAS modulate enough the STAT to impact progression of triple negative Breast cancer?
2.Could modifiers of Sumoylation impact the prognosis of triple negative breast cancer?
3.Status of the Zimp10 in triple negative breast cancer?
4. Amplifying ART-27 to stop cellular proliferation?
5.blocking RCHY1 could restore P53 function in patient with non Mutated P53?
6.can anti-cortactin and supervillin block metastatic propensity of triple negative breast cancers?
watch brain mets?

Wednesday, August 21, 2013

Science without Borders!

Readers from 10 different countries visited the CRBCM blog today!
Thank you, friends and like-minded research fellows around the World,
including the USA, France, China, the United Kingdom, India, Malaysia,
the Netherlands, the Philippines and Serbia.
Your feedback matters to us, thank you, again!

Wednesday, May 1, 2013


1.NBS gene:
Nijmegen breakage syndrome
From Wikipedia, the free encyclopedia
Jump to: navigation, search
Nijmegen breakage syndrome
Classification and external resources
OMIM 251260
DiseasesDB 32395
eMedicine derm/725
MeSH D049932
Nijmegen breakage syndrome (NBS), also known as Berlin breakage syndrome and Seemanova syndrome, is a rare autosomal recessive[1] congenital disorder causing chromosomal instability, probably as a result of a defect in the Double Holliday junction DNA repair mechanism.
NBS1 codes for a protein that has two major functions: (1) to stop the cell cycle in the S phase, when there are errors in the cell DNA (2) to interact with FANCD2 that can activate the BRCA1/BRCA2 pathway of DNA repair. This explains clearly that mutations in the NBS1 gene lead to higher levels of cancer (see Fanconi anemia, Cockayne syndrome...)
The name derives from the Dutch city Nijmegen where the condition was first described.[2]
Most people with NBS have West Slavic origins. The largest number of them live in Poland.
Mrs Seemanova MD after whom the name of the syndrome was given, currently works at Motol Hospital, Prague, Czech Republic, as a Professor of medical genetics.===============================================

2. BLM gene
Bloom syndrome protein is a protein that in humans is encoded by the BLM gene and is not expressed in Bloom syndrome.[1]
The Bloom syndrome gene product is related to the RecQ subset of DExH box-containing DNA helicases and has both DNA-stimulated ATPase and ATP-dependent DNA helicase activities. Mutations causing Bloom syndrome delete or alter helicase motifs and may disable the 3' → 5' helicase activity. The normal protein may act to suppress inappropriate homologous recombination.[2]


Bloom syndrome protein has been shown to interact with CHEK1,[3] Replication protein A1,[4][5][6] Werner syndrome ATP-dependent helicase,[7] RAD51L3,[8] Ataxia telangiectasia mutated,[9][10] RAD51,[11] XRCC2,[8] Flap structure-specific endonuclease 1,[12] H2AFX,[3] TP53BP1,[3] FANCM,[13] P53,[3][14][15][16] TOP3A,[4][17][18][19] MLH1[9][18][20][21] and CHAF1A.[22]



From Wikipedia, the free encyclopedia
Jump to: navigation, search

Structure of E. coli helicase RuvA
DNA helicase
EC number
IntEnz IntEnz view
ExPASy NiceZyme view
MetaCyc metabolic pathway
PRIAM profile
PDB structures RCSB PDB PDBe PDBsum
RNA helicase
EC number
IntEnz IntEnz view
ExPASy NiceZyme view
MetaCyc metabolic pathway
PRIAM profile
PDB structures RCSB PDB PDBe PDBsum
Helicases are a class of enzymes vital to all living organisms. Their main function is to unpackage an organism's genes. They are motor proteins that move directionally along a nucleic acid phosphodiester backbone, separating two annealed nucleic acid strands (i.e., DNA, RNA, or RNA-DNA hybrid) using energy derived from ATP hydrolysis. There are many helicases resulting from the great variety of processes in which strand separation must be catalyzed. Approximately 1% of eukaryotic genes code for helicases.[1] In humans, 95 non-redundant helicases are coded for in the genome, 64 RNA helicases and 31 DNA helicases.[2] Many cellular processes, such as DNA replication, transcription, translation, recombination, DNA repair, and ribosome biogenesis involve the separation of nucleic acid strands that necessitates the use of helicases.
 KEEFE ET AL" Bloom syndrome occurs most frequently in the Ashkenazi Jewish population with patients almost exclusively homozygous for a frameshift mutation resulting from a 6 bp deletion/7 bp insertion at nucleotide 2,281 (BLMAsh). This mutation causes premature termination of the encoded gene product producing a truncated protein of 739 amino acids while the full length protein contains 1417 amino acids.
The mutated gene in Bloom syndrome, BLM, was localized to chromosome 15q26.1 and encodes a member of the RecQ family of DNA helicases. This family also contains several other genes that are associated with disease phenotypes including the Werner Syndrome protein (WRN) and the defective protein in Rothmund-Thomson syndrome (RecQL4). Both of these diseases also feature an increased incidence of cancer. BLM, along with the rest of the members of this family, exhibits 3'-5' helicase activity and plays a role in DNA repair and recombination. BLM functions during replication stress and is required for the recruitment of several other important repair proteins including NBS1, BRCA1, Rad51 and MLH1. In addition, the BLM helicase is involved in recombinational repair events as evidenced by its ability to promote branch migrations of Holliday junctions at stalled replication forks. BLM may also play a role in apoptosis since it directly interacts with p53 and helps regulate its transcriptional activity."

3.ATM gene
Ataxia telangiectasia mutated
From Wikipedia, the free encyclopedia
Jump to: navigation, search
Ataxia telangiectasia mutated
External IDs OMIM607585 MGI107202 HomoloGene30952 ChEMBL: 3797 GeneCards: ATM Gene
EC number
Species Human Mouse
Entrez 472 11920
Ensembl ENSG00000149311 ENSMUSG00000034218
UniProt Q13315 Q62388
RefSeq (mRNA) NM_000051 NM_007499
RefSeq (protein) NP_000042 NP_031525
Location (UCSC) Chr 11:
108.09 – 108.24 Mb
Chr 9:
53.44 – 53.54 Mb

PubMed search [1] [2]
Ataxia telangiectasia mutated (ATM) is a serine/threonine protein kinase that is recruited and activated by DNA double-strand breaks. It phosphorylates several key proteins that initiate activation of the DNA damage checkpoint, leading to cell cycle arrest, DNA repair or apoptosis. Several of these targets, including p53, CHK2 and H2AX are tumor suppressors.
The protein is named for the disorder Ataxia telangiectasia caused by mutations of ATM.[1]

GOLDGAR ET AL suggested:

"The risk estimates from this study suggest that women carrying the pathogenic variant, ATM c.7271T > G, or truncating mutations demonstrate a significantly increased risk of breast cancer with a penetrance that appears similar to that conferred by germline mutations in BRCA2."


4. MRE 11 gene


From Wikipedia, the free encyclopedia
Jump to: navigation, search
MRE11 meiotic recombination 11 homolog A (S. cerevisiae)
Available structures
PDB Ortholog search: PDBe, RCSB
Symbols MRE11A; ATLD; HNGS1; MRE11; MRE11B
External IDs OMIM600814 MGI1100512 HomoloGene4083 GeneCards: MRE11A Gene
RNA expression pattern
PBB GE MRE11A 205395 s at tn.png
More reference expression data
Species Human Mouse
Entrez 4361 17535
Ensembl ENSG00000020922 ENSMUSG00000031928
UniProt P49959 Q61216
RefSeq (mRNA) NM_005590 NM_018736
RefSeq (protein) NP_005581 NP_061206
Location (UCSC) Chr 11:
94.15 – 94.23 Mb
Chr 9:
14.78 – 14.84 Mb

PubMed search [1] [2]
Double-strand break repair protein MRE11A is a protein that in humans is encoded by the MRE11A gene.[1]
This gene encodes a nuclear protein involved in homologous recombination, telomere length maintenance, and DNA double-strand break repair. By itself, the protein has 3' to 5' exonuclease activity and endonuclease activity. The protein forms a complex with the RAD50 homolog; this complex is required for nonhomologous joining of DNA ends and possesses increased single-stranded DNA endonuclease and 3' to 5' exonuclease activities. In conjunction with a DNA ligase, this protein promotes the joining of noncomplementary ends in vitro using short homologies near the ends of the DNA fragments. This gene has a pseudogene on chromosome 3. Alternative splicing of this gene results in two transcript variants encoding different isoforms.[2]


MRE11A has been shown to interact with Ku70,[3] Ataxia telangiectasia mutated,[4][5] MDC1,[6] Rad50,[3][5][7][8][9] Nibrin,[5][9][10][11][12] TERF2[13] and BRCA1.[5][7][14][15]


"MRE11, RAD50, and XRS2 have been identified in yeast as components of the HR and NHEJ pathways (4) . A physical complex with these proteins has been identified. In vertebrates, MRE11 and RAD50 form a complex with NBS1, whose mutation causes NBS (5 , 6) . The clinical features of NBS overlap with those of AT. They are characterized by chromosome instability, increased hypersensitivity to ionizing radiation, immunodeficiency, and predisposition to cancer. AT is caused by mutations in the ATM gene, which encodes a protein kinase homologous with phosphatidylinositol-3 kinase (7) . ATM is a key regulator of the cellular response to DSBs. NBS1 is phosphorylated in an ATM-dependent manner after ionizing radiation, suggesting a link between ATM and NBS1 in a common signaling pathway (8) . MRE11 phosphorylation upon DNA damage is dependent on NBS1 (9) . Therefore, it is highly likely that MRE11 participates in the same pathway in response to DNA damage. Consistent with this functional interaction, hypomorphic mutations in the MRE11 gene cause ataxia-telangiectasia-like disorder, the phenotypes of which are indistinguishable from those of AT (10) ."

 ATM mutations play a causal role in AT and have been demonstrated in lymphoid malignancies

5.  RAD51
From Wikipedia, the free encyclopedia
Jump to: navigation, search
RAD51 homolog (S. cerevisiae)

A filament of Rad51 based on PDB 1SZP.[1]
Available structures
PDB Ortholog search: PDBe, RCSB
Symbols RAD51; BRCC5; HRAD51; HsRad51; HsT16930; MRMV2; RAD51A; RECA
External IDs OMIM179617 MGI97890 HomoloGene2155 GeneCards: RAD51 Gene
RNA expression pattern
PBB GE RAD51 205024 s at tn.png
PBB GE RAD51 205023 at tn.png
More reference expression data
Species Human Mouse
Entrez 5888 19361
Ensembl ENSG00000051180 ENSMUSG00000027323
UniProt Q06609 Q08297
RefSeq (mRNA) NM_001164269 NM_011234
RefSeq (protein) NP_001157741 NP_035364
Location (UCSC) Chr 15:
40.99 – 41.02 Mb
Chr 2:
119.11 – 119.15 Mb

PubMed search [1] [2]
"RAD51 is an eukaryote gene. The protein encoded by this gene is a member of the RAD51 protein family which assist in repair of DNA double strand breaks. RAD51 family members are homologous to the bacterial RecA and yeast Rad51. The protein is highly conserved in most eukaryotes, from yeast to humans.
BRCA genes

This protein can interact with the ssDNA-binding protein RPA, BRCA2, PALB2[3] and RAD52.
The structural basis for Rad51 filament formation and its functional mechanism still remain poorly understood. However, recent studies using fluorescent labeled Rad51[4] has indicated that Rad51 fragments elongate via multiple nucleation events followed by growth, with the total fragment terminating when it reaches about 2 μm in length. Disassociation of Rad51 from dsDNA, however, is slow and incomplete, suggesting that there is a separate mechanism that accomplishes this."

"The RAD51 gene family, genetic instability and cancer.


Medical Research Council, Radiation and Genome Stability Unit, Harwell, Oxfordshire OX11 0RD, UK.


Inefficient repair or mis-repair of DNA damage can cause genetic instability, and defects in some DNA repair genes are associated with rare human cancer-prone disorders. In the last few years, homologous recombination has been found to be a key pathway in human cells for the repair of severe DNA damage such as double-strand breaks. The RAD51 family of genes, including RAD51 and the five RAD51-like genes (XRCC2, XRCC3, RAD51L1, RAD51L2, RAD51L3) are known to have crucial non-redundant roles in this pathway."---------------------------------------------------------------------

THE BRCA ITSELF TO WORK NEED A BUNCH OF VARIOUS COFACTORS CALLED  FANCB-Related Fanconi Anemia, FANCC-Related Fanconi Anemia, FANCD2-Related Fanconi Anemia, FANCE-Related Fanconi Anemia, FANCF-Related Fanconi Anemia, FANCG-Related Fanconi Anemia, FANCI-Related Fanconi Anemia, FANCL-Related Fanconi Anemia, FANCM-Related Fanconi Anemia, PALB2-Related Fanconi Anemia, RAD51C-Related Fanconi Anemia, SLX4-Related Fanconi Anemia (ALTER ET AL!)


HPV Vaccine: 2 Doses as Good as 3 Doses in Young Women

Troy Brown.  go to article!