OTHER GENES IN BREAST CANCER/ and questions at CRBCM

1-RRM2
A ribonucleotide reductase transforming RNA to DNA, 
Zang et al "Overexpression of RRM2 significantly enhances the invasive and metastatic potential of tumor. Angiogenesis is critical to tumor malignancy; it plays an essential role in tumor growth and metastasis...the angiogenic potential of tumor is affected by RRM2."

Overexpression of RRM2 decreases thrombspondin-1 and increases VEGF production in human cancer cells in vitro and in vivo: implication of RRM2 in angiogenesis.

Boukovinas et al

" Overexpression of RRM1 and RRM2 has been associated with gemcitabine resistance. BRCA1 overexpression increases sensitivity to paclitaxel and docetaxel. "

 Duxbury MS, Whang EE (2007). "RRM2 induces NF-kappaB-dependent MMP-9 activation and enhances cellular invasiveness". Biochem. Biophys. Res. Commun. 354 (1): 190–6.

  Zhang:" Silencing of RRM1 and RRM2, which encode the large and small subunits of the human ribonucleotide reductase complex, respectively, markedly enhanced the cytotoxicity of the topoisomerase I inhibitor camptothecin (CPT). Silencing of RRM2 was also found to enhance DNA damage as measured by histone γ-H2AX. Further studies showed that CPT up-regulates both RRM1 and RRM2 mRNA and protein levels and induces the nuclear translocation of RRM2. The checkpoint kinase 1 (Chk1) was up-regulated and activated in response to CPT, and CHEK1 down-regulation by siRNA and small molecule inhibitors of Chk1 blocked RRM2 induction by CPT. CHEK1 siRNA also suppressed E2F1 up-regulation by CPT, and silencing of E2F1 suppressed the up-regulation of RRM2. Silencing of ATR or ATM and inhibition of ATM activity by KU-55933 blocked Chk1 activation and RRM2 up-regulation. This study links the known components of CPT-induced DNA damage response with proteins required for the synthesis of dNTPs and DNA repair. Specifically, we propose that upon DNA damage, Chk1 activation, mediated by ATM and ATR, up-regulates RRM2 expression through the E2F1 transcription factor. Up-regulation in RRM2 expression levels coupled with its nuclear recruitment suggests an active role for ribonucleotide reductase in the cellular response to CPT-mediated DNA damage that could potentially be exploited as a strategy for enhancing the efficacy of topoisomerase I inhibitors.Two water-soluble DNA topoisomerase 1 (Top1)² inhibitors, derived from camptothecin (CPT), are in clinical use; topotecan, for the treatment of ovarian and lung cancers, and irinotecan, for colorectal cancers."

Mutation of RRM2B, encoding p53-controlled ribonucleotide reductase (p53R2), causes severe mitochondrial DNA depletion

Alice Bourdon^1"The mtDNA depletion triggered by p53R2 alterations in both human and mouse implies that p53R2 has a crucial role in dNTP supply for mtDNA synthesis."
^{==============================================================
how does RRM2B mutation affect the MTOR inhibitors? 
is this the marker for use of Irinotecan
Is MMP9 informative (prognosis) in patient on CPT-11 
what is the frequency of RRM2 Mutations in Ovarian cancers?
WHEN IS THE LAST TIME YOU SED TOPOTECAN AND IRINOTECAN IN BREAST CANCER? DOES MUTATION IN RRM2 CONVINCE YOU TO TRY IT?}

GI CANCERS UPDATE

*Following CEA every 3 months and CT once every year was compared to CT every 6 months -no difference in progression free survival or OS,
*Maintenance Xeloda and Avastin in Metastatic Colorectal cancer?  read CAIRO3 by the Dutch!
*"An interesting negative study from Charles Loprinzi and his colleagues^[4] looked at the impact of infused magnesium and calcium on the prevention of the sensory neurotoxicity associated with oxaliplatin and found no benefit. This was a large, well-designed study that leaves that myth to rest, which may be of benefit in some way." DAVID KERR.
*Abraxane -gemzar a new standard in metastatic pancreatic cancer!

ACTIVITIES AT CRBCM

We promised to submit an RFA at NIH yesterday, little did we know how tricky the process is.   The process is so tricky you wonder if it is designed to discourage the novice. We failed in our attempt.  But we are a Coalition fighting for a just cause, we do not give-up.  We are going back right at it as sunrise comes tomorrow because we have to keep fighting until the resistances are brought down, until they hear our voice and/or until the enemy becomes irrelevant!
The process of filling up the the application is full of exasperating moments made for you to quit. We understood quickly that after filling up one answer, you have to give time to the computer to process the full file with the new information and save the document!  Literally, after each input you got to save the full file otherwise you lose it all every 2-3 minutes!  For the makers of the Internet, the government has ZERO for computer "practicality and easiness" of their program.  The RED TAPE is in full display.  You need numbers to make Albert Einstein think again!    You need EIN, DUNS,NUNS,SAMS AND CAGE,ERA commons, and the surprise wait for you when you want to submit, there and you will MPIN.  Why all these and why wait until the end at submission, just to frustrate the hell out of you: "you are not the AOR".  The all purpose is to frustrate applicants.  And get this, when we called them, they do not have either your DUNS which they gave you, and that you need to access the SAMS. And they try to help you but can't because you do not have the same "options on the screen".   Your screen offer you less options then theirs!  The government does not give you the options to register by your self for the MPIN. They select who they give it to!  So we could not file.  Tommorrow, we are back at it!  try it but take some Xanax first!
ONE THING THEY HAVE TO REALIZE, WE WILL NOT QUIT THE FIGHT!

DON'T RESIST, JUST GO TO ARTICLE! IT WILL SET YOU FREE AND MAKE YOU AWARE,

Medscape Medical News from the:

• American Medical Association (AMA) 2013 Annual Meeting

This coverage is not sanctioned by, nor a part of, the American Medical Association.

Medscape Medical News > Conference News

AMA Declares Obesity a Disease

Marcia Frellick

Jun 19, 2013

 

Editors' Recommendations

• Obesity, Hypertension Prevalent in Growing Number of Children
• US Children Consume Fewer Calories, Too Much Saturated Fat
• Obesity and Weight Management News & Perspectives

Topic Alert

CHICAGO — Physicians voted overwhelmingly to label obesity as a disease that requires a range of interventions to advance treatment and prevention.

THE CRUX IN AUTO-IMMUNE DISEASE, PLENTY OF CRITICAL TARGET PER WIKIPEDIA!

Signaling pathway of toll-like receptors. Dashed grey lines represent unknown associations

 

AND DON'T TELL ME YOU DON'T SEE THE POTENTIALS!

SMAD6-- MAP3K7---TRAF6 AND HERE YOU ARE DANCING WITH WITH NF-kB AND C-JUN...

QUESTION BEFORE CPRIT!

"However, some important context is missing even as legitimate questions are asked. We have heard a lot over the last 12 months about the three questionable grants which CPRIT awarded. But we haven’t heard much about the other 498 grants issued by the agency since it started operating in 2009. The headlines leave out the tremendous impact $835 million in CPRIT grant dollars have made in Texas on cancer prevention, research and product development during the past three years."The LIVESTRONG Foundation.

A FULL ASSESSMENT IS DUE,
HOW THESE ACHIEVEMENTS FIT WITHIN THE DREAM FOR CANCER CURE PLAN! IS JUST ANOTHER QUESTION.  

SADNESS HAS STRICKEN THE CRBCM WITH THE DEATH OF JIMMY

Actor James Gandolfini dead at age 51

CONDOLEANCES TO  FAMILY AND FRIENDS!

ASK YOURSELF, CAN YOU USE OF ANTI-TNF AND OR MACROLIDE IN COMBINATION OF ANTI-VIRAL ENOUGH TO CUT DOWN MORTALITY DURING A FLU EPIDEMIC?
AND WHILE YOU ARE ASKING YOURSELF THIS, I AM WRITING AN RFA FOR NCI.

The assumption here is that death from the flu is directly linked to TNF secretion and cyclins secretions under activation of the NF-kB, and these 2 drugs can tamper these 2 components/PATHWAYS.  check it out!

================================================================
ROLE OF BAFETINIB IN CMML AND MONOCYTIC LEUKEMIA
FOLLOWING THE LYN GENE DANCE!
SHOULD GLIMEPIRIDE BE CONTRE-INDICATED IN THESE DISEASES BECAUSE IT IS A LYN ACTIVATOR?
ACTIVATION OF LYN LEADS TO ACTIVATION OF INPP5D WHICH IS DEFINED AS FOLLOW: "Overall, the protein functions as a negative regulator of myeliod cell proliferation and survival. Alternate transcriptional splice variants, encoding different isoforms, have been characterized.[" AND THEREFORE A LEGITIMATE TARGET FOR THERAPY!

COMING THROUGH MEDSCAPE!
*35% of paroxysmal nocturnal hemoglobinuria (PNH) patients die within 5 years of diagnosis¹ Three experts discuss how the pathophysiology of PNH can manifest in life-threatening complications such as chronic kidney disease, pulmonary hypertension, and thrombosis.

*GO TOARTICLE

Association of metformin use with cancer incidence and mortality: A meta-analysis
Cancer Epidemiology, 04/16/2013  Review Article

Zhang P et al. – Metformin can reduce the incidence of overall cancer, liver cancer, pancreatic cancer, colorectal cancer and breast cancer as well as the mortality of overall cancer, liver cancer and breast cancer. No beneficial effect on prostate cancer incidence was found for meformin intake in the meta-analysis."

*GO TO ARTICLE!

FDA Investigates 2 Deaths Involving Olanzapine

Mark Crane

Jun 18, 2013

Editors' Recommendations

• Four Atypicals Lack Safety, Efficacy in the Elderly
• 
  

The US Food and Drug Administration (FDA) is investigating 2 unexplained deaths of patients who received an intramuscular injection of the antipsychotic drug olanzapine pamoate (Zyprexa Relprevv, Eli Lilly).

instruments

What is Smarter Screening?
High throughput screening (HTS), or the process by which libraries of small molecule compounds are individually assessed for binding, activating or inactivating biological activity in drug target molecules, has been part of the drug discovery process for more than two decades. Its primary purpose is to rapidly select which compounds possess the desired activity and thereby undergo further testing and optimization. Since its inception, HTS methods have undergone significant change: the early dependence on “home-brewed” assay chemistries and basic research instruments evolved into industrialized methods incorporating millions of compounds that could be screened against purified drug targets using sophisticated liquid handling, detection and robotics.
In this Application Guide, we describe key liquid handling and detection instrumentation for HTS methods and provide four HTS case studies. The case studies use commercially available compound libraries and assay chemistries suitable for nuclear receptor, GPCR, cellular kinase, as well as epigenetic drug targets.

This Application Guide covers:

• Androgen Receptor Agonist/Antagonist Studies using the Cell-based Human AR Reporter Assay System from INDIGO Biosciences
  
• GLP-1 Ligand Binding Analysis using a Cell-Based HTRF® Tag-lite® Assay
  
• Quantification of Endogenous Cellular Kinase Activity using a Cell-Based HTRF Phospho-STAT3 (Tyr705) Protein Kinase Assay
  
• Assessment of Histone Deacetylase 1 Inhibition using the Bioluminescent HDAC-Glo™ I/II Assay
  

Tag-lite and HTRF are registered trademarks of Cisbio Bioassays.
HDAC-Glo is a trademark of Promega Corporation. 

 

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 GO TO ARTICLE OF INTEREST

6 months versus 12 months of adjuvant trastuzumab for patients with HER2-positive early breast cancer (PHARE): a randomised phase 3 trial
The Lancet Oncology, 06/12/2013  Clinical Article

Pivot X et al. – After 3·5 years follow-up, we failed to show that 6 months of treatment with trastuzumab was non-inferior to 12 months of trastuzumab. Despite the higher rates of cardiac events, 12 months of adjuvant trastuzmab should remain the standard of care.
GO TO ARTICLES OF INTEREST
===================================================
AFTER FAILURE OF AVASTIN, THE TUMOR IS READY FOR MTOR INHIBITOR

Phase ii study of everolimus in patients with metastatic colorectal adenocarcinoma previously treated with bevacizumab-, fluoropyrimidine-, oxaliplatin-, and irinotecan-based regimens
Clinical Cancer Research, 06/11/2013  Clinical Article

Ng K et al. – Everolimus 70 mg/week or 10 mg/day was well tolerated but did not confer meaningful efficacy in heavily pretreated mCRC patients.

GO TO ARTICLE
=====================================================
USEFUL TIPR FOR PRACTITIONER!

Lactate dehydrogenase B: a metabolic marker of response to neoadjuvant chemotherapy in breast cancer
Clinical Cancer Research, 06/13/2013

Dennison JB et al. – Expression of LDHB predicted response to neoadjuvant chemotherapy within clinical subtypes independently of standard prognostic markers and PAM50 subtyping. These observations support prospective clinical evaluation of LDHB as a predictive marker of response for patients with breast cancer receiving neoadjuvant chemotherapy.

GO TO ARTICLE!
======================================= I AM GOING :HMMMMM, SOME RESEARCHER ARE STILL WORKING AT THIS NOW?

One year of adjuvant tamoxifen compared with chemotherapy and tamoxifen in postmenopausal patients with stage II breast cancer
European Journal of Cancer, 06/13/2013  Clinical Article

Ejlertsen B et al. – CMF added to 1year of tamoxifen reduces the risk of a DFS event. The benefit from CMF was not significantly different in Luminal A and B subtypes.

GO TO ARTICLE!

CPRIT AND THE CURE OF CANCER

As it is preparing to relaunch its funding of cancer research and prevention, it is imperative that its leaders realize that external influences have realized its opulence and weaknesses, and are ready to seduce and suck it of all its juices once more with pretentious programs that may fit universities'objectives but not CPRIT's.
The previous experience is summarized like this, almost 1 billion went to 72 institutions instead of 200 (or more) and nothing tangible really to show for! Obsession with funding universities without creating real competition had created a sens of entitlement and real production  of innovation is still lacking! Many institutions had pulled old projects from their past and submitted them for funding visiting old paths to known outcome!  Sold findings and patents were refunded and relocated to Texas without shame, wasting resources.  The idea that we promised to fund this and that has now stolen the power to reexamined projects as to their true validity.  CPRIT needs to regroup, recapture its soul, and focus on the cure.
The difference between development and lack of it is man made, Africa is where it is not because of lack of potentials but because of lack of understanding by humans shackled by traditional practices and mis-guided understanding of currents systems.  The rise of China and some prominent countries is a demonstration that vision and focus can lead to success of different shape.  What is lacking here is an understanding of what cure should look like which will allow to pick and choose projects of relevant importance that will show advances toward a cure as it looks to CPRIT.  Lack of this type of focus, will not only lead to waste and open to  political games, distractions and false tendencies!  It is imperative that CPRIT recaptures its soul, knows that as a source of funding, it is the independent decider of how the game should be played, and where to lead this boat.  It should be mindful that all Texas is funding this, and its actions should touch the life of Texans as a whole not just few cities.  Its meeting should show a spirit of freedom when it comes  to deciding where to place money.  Same beneficiaries at each meeting leads to waste of resources and fails to show respect to the whole Texans while reducing the pool of solicited imagination.  Cancer cure may not come from the standard suspects!  Small incremental progress may!
There are Cities like El Paso that has been ignored all together despite the existence of brave researchers here.  72 beneficiaries of 1 billions dollars is a club! Not a true competition!  The Number of participants matter because the more they are, the more they can attract other federal funding to Texas!   CPRIT wants to be richer by finding new target therapies, but creating various viable institutions that could potentially apply for other grants is an ignored potential for true revenues today (not tomorrow or by chance!).  It takes vision to see this!
The bringing in of an oncologist on board will allow to not only define a cure better, but put CPRIT at the edge of progress and get a feedback from Doctors as to where the interest is today in Oncology practice!  Not all bright researcher idea is well received by practitioners who are the first to handle side effects in patients!
We have seen the expressed will to comply with recommendations from the legislature, what is left to be seen is if there is indeed a soul, vision and courage  to CPRIT and its leaders!

CPRIT/ GONE FOR THE SECOND ROUND! WISH THEY WILL DO THE RIGHT THING NOW! BUT ONLY HISTORY WILL TELL!

Governor Perry has signed into law Senate Bill 149, the reform bill revising CPRIT’s enabling legislation. We appreciate the leadership and vision of the Legislature and Governor Perry to pass this important measure. The legislation strengthens CPRIT and allows the agency to fulfill its vital mission to fight cancer in Texas with transparency and accountability. The CPRIT staff has already begun to implement the reforms contained in SB 149, and once authorized to do so by state leadership, will restart our grant-making processes.
  =======================================================

INSTITUTIONS, LIKE PEOPLE ARE JUDGED BY WHAT THEY DO, NOT BY WHAT THEY PROMISE.  CAUSE THOSE WHO RUINED IT FIRST TIME ARE STILL STANDING, AND READY TO TAKE IT AGAIN FIR THE 2 BILLIONS REMAINING...LIKE THE SENATORS WHO WANT FINE CONTROL, THEY HAVE SHARPEN THEIR TACTICS AND DEVISE BETTER WAYS TO MAKE IT LEGIT!  PHONE CALLS HAVE BEEN MADE TO READY INSIDERS, FOR A NEW BALL DANCE ONCE MORE.  ALL WE HAVE TO PRAY FOR, THAT ONE LEADER WILL RISE TO GIVE THE REST OF US A CHANCE ! CPRIT IS STILL A PROMISE WITH FULL POTENTIAL TO BE REALIZED! WILL IT?

WHEN IT WORKS, GIVE IT FOR 3 YEARS!

Developed under the direction and sponsorship of Novartis Pharmaceuticals Corporation. 3 years of adjuvant therapy with GLEEVEC reduced the risk of recurrence by 54% vs 1 year of therapy in KIT+ GIST patients (median follow-up of 42 months)1 Orchestrate continued success by extending adjuvant treatment in KIT+ GIST1 View Indication and Important Safety Information The results from the Scandinavian Sarcoma Group (SSG) XVIII/AIO Phase 3 trial showed a significant improvement in recurrence-free survival (RFS) when adjuvant treatment with GLEEVEC® (imatinib mesylate) was extended to 3 years vs 1 year of therapy (median follow-up of 42 months). In addition to improving RFS, trial results demonstrated an overall survival (OS) benefit, with mortality reduced by half in the 3-year arm vs the 1-year arm (12 vs 25 deaths, respectively; median follow-up of 48 months). These findings have prompted updates to the FDA-approved Prescribing Information for GLEEVEC and the NCCN guidelines supporting 3 years of adjuvant treatment for appropriate resected patients with KIT+ GIST.1,2 Please consider this information when making clinical decisions and recommendations for your KIT+ GIST patients. Important Safety Information Serious adverse reactions may occur, including edema, cytopenias, severe congestive heart failure, left ventricular dysfunction, hepatotoxicity, hemorrhage, GI disorders, hypereosinophilic toxicity, dermatologic toxicities, hypothyroidism, toxicities from long-term use, fetal harm, and tumor lysis syndrome. Caution should be recommended when driving a car or operating machinery.1 Download latest Prescribing Information In the SSG trial, risk of tumor recurrence was reduced by half with 3 years vs 1 year of adjuvant GLEEVEC therapy (median 42-month follow-up)1 Recurrence events were 68% higher in the 1-year arm vs the 3-year arm (84 vs 50 events) aSSG XVIII/AIO study was a multicenter, open-label, Phase 3 trial conducted to determine the clinical benefits of 3 years (n=198) vs 1 year (n=199) of adjuvant therapy with GLEEVEC 400 mg/day. Inclusion criteria were tumor diameter >5 cm and mitotic count >5/50 high-power fields (HPFs), or tumor diameter >10 cm and any mitotic count, or tumor of any size with mitotic count >10/50 HPFs, or tumor rupture. The primary end point was RFS defined as the time from date of randomization to the date of recurrence or death from any cause. OS was a secondary end point. Median time of follow-up was 42 and 48 months, respectively.1 GIST=gastrointestinal stromal tumor; NCCN=National Comprehensive Cancer Network; RFS=recurrence-free survival; OS=overall survival. In the SSG trial, no new adverse reactions were reported with longer duration of therapy (3-year arm vs 1-year arm)1 •  As in previous trials, the most frequently reported adverse reactions in this clinical trial were diarrhea, fatigue, nausea, edema, decreased hemoglobin, rash, vomiting, and abdominal pain —  14% of patients in the 3-year arm vs 8% of patients in the 1-year arm discontinued treatment due to adverse events (AEs) —  The incidence of serious AEs (Grade ≥3) was 33% in the 3-year arm vs 20% in the 1-year arm Indications and Important Safety Information GLEEVEC® (imatinib mesylate) tablets are indicated for: •  Patients with KIT (CD117)-positive unresectable and/or metastatic malignant gastrointestinal stromal tumors (GIST) •  Adjuvant treatment of adult patients following complete gross resection of KIT (CD117)-positive GIST Important Safety Information •  GLEEVEC is often associated with edema and, occasionally, serious fluid retention. Severe fluid retention was reported in 9% to 13.1% of patients taking GLEEVEC for GIST. Patients should be weighed and monitored regularly for signs and symptoms of fluid retention, which can be serious or life threatening, and be advised to report any rapid, unexpected weight gain. The probability of edema tended to be increased among older patients (>65 years) or those taking higher doses of GLEEVEC. Severe edema was observed in 182 patients (11.1%). If severe fluid retention occurs, manage with diuretic therapy and withhold GLEEVEC until the event has resolved, and then resume, depending on the initial severity of the event •  Cytopenias have been reported. Complete blood counts should be performed weekly for the first month, biweekly for the second month, and periodically thereafter as clinically indicated (eg, every 2 to 3 months). Dose reduction, treatment interruption, or in rare cases discontinuation of treatment may be required for severe neutropenia or thrombocytopenia (see full Prescribing Information for dose adjustment recommendations) •  Severe congestive heart failure and left ventricular dysfunction have been reported. Most of the patients with reported cardiac events have had other comorbidities and risk factors, including advanced age and previous medical history of cardiac disease. Patients with cardiac disease or risk factors for cardiac disease or history of renal failure should be monitored carefully, and any patient with signs or symptoms consistent with cardiac or renal failure should be evaluated and treated •  Hepatotoxicity, occasionally severe, may occur. Cases of fatal liver failure and severe liver injury requiring liver transplants have been reported with both short-term and long-term use of GLEEVEC. Assess liver function before initiation of treatment and monthly thereafter, or as clinically indicated. A 25% decrease in the recommended dose should be used for patients with severe hepatic impairment. If severe hepatotoxicity occurs, GLEEVEC should be withheld until the event has resolved and then resumed, depending on the initial severity of the event •  When GLEEVEC is combined with chemotherapy, liver toxicity in the form of transaminase elevation and hyperbilirubinemia has been observed. Additionally, there have been reports of acute liver failure. Monitoring of hepatic function is recommended •  In the Phase 3 unresectable or metastatic GIST studies, 13% of patients reported hemorrhage (NCI Grades 3/4) at any site. In the Phase 2 unresectable or metastatic GIST study, 5% of patients were reported to have severe gastrointestinal (GI) bleeds and/or intratumoral bleeds. GI tumor sites may have been the source of GI bleeds; therefore, GI symptoms should be monitored at the start of therapy •  In patients with hypereosinophilic syndrome with occult infiltration of HES cells within the myocardium, cardiogenic shock and left ventricular dysfunction have been associated with HES cell degranulation upon initiation of GLEEVEC. The condition was reported to be reversible with the administration of systemic steroids, circulatory support measures, and temporarily withholding GLEEVEC •  Bullous dermatologic reactions (eg, erythema multiforme and Stevens-Johnson syndrome) have also been reported. In some cases, the reaction recurred upon rechallenge. Several postmarketing reports describe patients able to tolerate the reintroduction of GLEEVEC at a lower dose, with or without concomitant corticosteroids or antihistamines following resolution or improvement of the bullous reaction •  Clinical cases of hypothyroidism have been reported in thyroidectomy patients undergoing levothyroxine replacement during treatment with GLEEVEC. TSH levels should be closely monitored in such patients •  Consider potential toxicities—specifically liver, kidney, and cardiac toxicity—and immunosuppression from long-term use •  Fetal harm can occur when administered to a pregnant woman. Therefore, women of reproductive potential should be advised not to become pregnant while taking GLEEVEC tablets and to avoid breastfeeding while taking GLEEVEC because of the potential for serious adverse reactions in nursing infants. Sexually active female patients taking GLEEVEC should use highly effective contraception. If the patient does become pregnant while taking GLEEVEC, the patient should be advised of the potential hazard to the fetus •  Growth retardation has been reported in children and preadolescents receiving GLEEVEC. The long-term effects of prolonged treatment with GLEEVEC on growth in children are unknown; therefore, monitoring of growth in children taking GLEEVEC is recommended •  Cases of tumor lysis syndrome (TLS), including fatal cases, have been reported. The patients at risk for TLS are those with tumors having a high proliferative rate or high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken. Correction of clinically significant dehydration and treatment of high uric acid levels are recommended prior to initiation of GLEEVEC •  Motor vehicle accidents involving patients receiving GLEEVEC have been reported. Patients should be advised that they may experience undesirable effects such as dizziness, blurred vision, or somnolence during treatment with GLEEVEC. Caution should be recommended when driving a car or operating machinery •  In the Phase 2 unresectable or metastatic GIST trial (400 mg/day; 600 mg/day), severe (NCI Grades 3/4) lab abnormalities—including anemia (3%; 9%) and neutropenia (10%; 11%)—were reported among patients receiving GLEEVEC. In Phase 3 unresectable or metastatic GIST trials (400 mg/day; 800 mg/day), the most frequently reported adverse reactions included abdominal pain (14%; 12%), edema (9%; 13%), fatigue (12%; 12%), nausea (9%; 8%), vomiting (9%; 8%), diarrhea (8%; 9%), rash (8%; 9%), myalgia (6%; 4%), anemia (5%; 6%), and anorexia (7%; 5%). The percentages listed represent NCI Grades 3 and above •  In the adjuvant GIST study comparing 12 months of GLEEVEC vs placebo treatment (GLEEVEC; placebo), severe (NCI Grades 3 and above) lab abnormalities included increase in liver enzymes (ALT) (3%; 0%), (AST) (2%; 0%), decreased neutrophil count (3%; 1%), and decrease in hemoglobin (1%; 0%); severe (NCI Grades 3 and above reported at rates >1%) adverse reactions included abdominal pain (3%; 1%), diarrhea (3%; 1%), rash (3%; 0%), fatigue (2%; 1%), nausea (2%; 1%), vomiting (2%; 1%), decreased white blood cell count (1%; 0%), and periorbital edema (1%; 0%). The frequencies of these reported lab abnormalities and severe adverse reactions were similar in a study comparing 12 vs 36 months of GLEEVEC treatment (12 mo; 36 mo), except for liver enzyme AST (2%; 3%), decreased neutrophil count (5%; 5%), decreased white blood cell count (2%; 3%), pain (1%; 3%), infection (2%; 3%), and blurred vision (1%; 1%), which were higher among patients receiving 36 months of adjuvant treatment with GLEEVEC* •  There have also been reports, including fatalities, of cardiac tamponade, cerebral edema, acute respiratory failure, and GI perforation •  GLEEVEC is metabolized by the CYP3A4 isoenzyme and is an inhibitor of CYP3A4, CYP2D6, and CYP2C9. Significant reductions in imatinib concentrations may occur when GLEEVEC is administered concomitantly with agents that are strong CYP3A4 inducers such as rifampin, St. John's wort, and enzyme-inducing antiepileptic drugs, eg, phenytoin. The concomitant use of strong CYP3A4 inducers should be avoided. If patients must be administered a strong CYP3A4 inducer, the dosage of GLEEVEC should be increased by at least 50%, and clinical response should be carefully monitored. Caution is recommended when GLEEVEC is administered with CYP3A4 inhibitors such as ketoconazole, with CYP2D6 substrates that have a narrow therapeutic window, or with CYP3A4 substrates that have a narrow therapeutic window. Other examples of commonly used drugs that may significantly interact with GLEEVEC include acetaminophen, warfarin, erythromycin, and metoprolol. Grapefruit juice should also be avoided in patients taking GLEEVEC. (Please see full Prescribing Information for other potential drug interactions) •  Patients with moderate renal impairment (CrCL=20-39 mL/min) should receive a 50% decrease in the recommended starting dose; future doses can be increased as tolerated. Doses greater than 600 mg are not recommended in patients with mild renal impairment (CrCL=40-59 mL/min). For patients with moderate renal impairment, doses greater than 400 mg are not recommended. GLEEVEC should be used with caution in patients with severe renal impairment Common Side Effects of GLEEVEC Tablets •  Almost all patients who received GLEEVEC in the Phase 3 unresectable or metastatic GIST studies experienced adverse reactions at some time. Overall, the incidence of all grades of adverse reactions and the incidence of severe (CTC Grades 3 and above) adverse reactions were similar between the 2 treatment arms, except for edema and rash/related terms, which were reported more frequently in the 800-mg group. The most frequently reported adverse reactions (400 mg/day; 800 mg/day) (all grades) were edema (77%; 86%), fatigue (69%; 75%), nausea (58%; 65%), abdominal pain (57%; 55%), diarrhea (56%; 58%), rash and related terms (56%; 70%), vomiting (37%; 41%), myalgia (32%; 30%), anemia (32%; 35%), anorexia (31%; 36%), and arthralgia (14%; 12%). Therapy with GLEEVEC was discontinued for adverse reactions in 5% of patients studied* •  In the adjuvant treatment of GIST studies, almost all GLEEVEC- and placebo-treated patients experienced adverse reactions at some time. The most frequently reported adverse reactions were similar to those reported in other clinical studies in other patient populations. In Study 1, comparing 12 months of GLEEVEC treatment vs placebo (all grades), these included (GLEEVEC; placebo) diarrhea (59%; 29%), fatigue (57%; 41%), nausea (53%; 28%), periorbital edema (47%; 15%), decreased hemoglobin (47%; 27%), peripheral edema (27%; 15%), rash (26%; 13%), vomiting (26%; 14%), abdominal pain (21%; 22%), anorexia (17%; 9%), muscle spasms (16%; 3%), white blood cell count decreased (15%; 4%), arthralgia (15%; 15%), and myalgia (12%; 12%).* The frequencies of these reported adverse reactions were similar in Study 2, comparing 12 vs 36 months of GLEEVEC treatment (12 mo; 36 mo), except for decreased hemoglobin (72%; 80%), periorbital edema (59%; 74%), muscle spasms (31%; 49%), decreased white blood cell count (35%; 47%), pain (26%; 46%), peripheral edema (33%; 41%), rash (29%; 39%), arthralgia (9%; 17%), and myalgia (9%; 15%), which were higher among patients receiving 36 months of adjuvant treatment with GLEEVEC. Adverse reactions listed represent the most frequently reported for Study 1 with the addition of adverse reactions with higher rates in Study 2* •  In the adjuvant GIST study comparing GLEEVEC vs placebo, drug was discontinued for adverse events in 17% of GLEEVEC- and 3% of placebo-treated patients. Edema, GI disturbances (nausea, vomiting, abdominal distension, and diarrhea), fatigue, low hemoglobin, and rash were the most frequently reported adverse reactions at the time of discontinuation. In the adjuvant study comparing 12 vs 36 months of GLEEVEC treatment, drug was discontinued for adverse events in 8% of patients treated for 12 months and 14% of patients treated for 36 months* •  Supportive care may help reduce the severity of some mild to moderate adverse reactions. However, in some cases, either a dose reduction or interruption of treatment with GLEEVEC may be necessary •  Doses of 400 mg or 600 mg should be administered once daily, whereas a dose of 800 mg should be administered at 400 mg twice a day. For daily dosing of 800 mg and above, dosing should be accomplished using the 400-mg tablet to reduce exposure to iron •  GLEEVEC tablets should be taken with food and a large glass of water to minimize GI irritation •  Patients should be instructed to take GLEEVEC exactly as prescribed and not to change their dose or stop taking GLEEVEC unless they are told to do so by their doctor. If patients miss a dose, they should be advised to take their dose as soon as possible unless it is almost time for their next dose, in which case the missed dose should not be taken. A double dose should not be taken to make up for any missed dose *For more detailed study information, please see full Prescribing Information. References 1.  GLEEVEC® [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2013. 2.  The NCCN Soft Tissue Sarcoma Clinical Practice Guidelines in Oncology (Version 3.2012) ©2012 National Comprehensive Cancer Network, Inc. http://www.nccn.org. Accessed May 24, 2012. To view the most recent and complete version of the guidelines, go online to www.nccn.org. Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936-1080 © 2013 Novartis 4/13 GLI-1062742

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GENES IN LUPUS

TREX1" the major 3'->5' DNA exonuclease in human cells. The protein is a non-processive exonuclease that may serve a proofreading function for a human DNA polymerase. It is also a component of the SET complex, and acts to rapidly degrade 3' ends of nicked DNA during granzyme A-mediated cell death. Mutations in this gene result in Aicardi-Goutieres syndrome, chilblain lupus, RVCL (Retinal Vasculopathy with Cerebral Leukodystrophy), and Cree encephalitis. Multiple transcript variants encoding different isoforms have been found for this gene.<sup>[4]wikipedia"

This explanation have 3 fundamental points that underlie auto-immune disease  
deficiency is 
1. genetic based
2. Involve degradation and disposing of debris
3. Heterogeneity is a strong variable
but it also points to 2 additional facts pattern of Methylation which by now we know to be strongly influenced Estrogen will mark significant difference in expression of this disease in the 2 sexes!</sup>

-------"
BANK1
It is involved in B-cell receptor induced Ca2+ mobilization from intracellular stores and promotes Lyn-mediated phosphorylation of IP3 receptors 1 and 2.. Lyn has emerged as a key enzyme involved in the regulation of cell activation. In these cells, a small amount of LYN is associated with cell surface receptor proteins, including the B cell antigen receptor (BCR),^[5][6] CD40,^[7] or CD19.^[8]..
Lyn has been described to have an inhibitory role in myeloid lineage proliferation.^[9] Following engagement of the B cell receptors, Lyn undergoes rapid phosphorylation and activation. LYN activation triggers a cascade of signaling events mediated by Lyn phosphorylation of tyrosine residues within the immunoreceptor tyrosine-based activation motifs (ITAM) of the receptor proteins, and subsequent recruitment and activation of other kinases including Syk, phosholipase Cγ2 (PLCγ2) and phosphatidyl inositol-3 kinase.^[8][10] These kinases provide activation signals, which play critical roles in proliferation, Ca²⁺ mobilization and cell differentiation. Lyn plays an essential role in the transmission of inhibitory signals through phosphorylation of tyrosine residues within the immunoreceptor tyrosine-based inhibitory motifs (ITIM) in regulatory proteins such as CD22, PIR-B and FCγRIIb1. Their ITIM phosphorylation subsequently leads to recruitment and activation of phosphatases such as SHIP-1 and SHP-1,^{[11][12][13][14][15]} which further downmodulate signaling pathways, attenuate cell activation and can mediate tolerance. In B cells, Lyn sets the threshold of cell signaling and maintains the balance between activation and inhibition. Lyn thus functions as a rheostat that modulates signaling rather than as a binary on-off switch.^[16][17][18]
Lyn has also been implicated to have a role in the insulin signaling pathway. Activated Lyn phosphorylates insulin receptor substrate 1 (IRS1). This phosphorylation of IRS1 leads to an increase in translocation of Glut-4 to the cell membrane and increased glucose utilization.^[19] In turn, activation of the insulin receptor has been shown to increase autophosphorylation of Lyn suggesting a possible feedback loop.^[20] The insulin secretagogue, glimepiride (Amaryl®) activates Lyn in adipocytes via the disruption of lipid rafts.^[21] This indirect Lyn activation may modulate the extrapancreatic glycemic control activity of glimepiride.^{[21][22]wikipedia} "

TNFSF4, a member of the dangerous Tumor Necrosis Factor family,  TNF is bad because its devastating effect escape mitigation by steroids and Interferon gamma at certain thresholds!
direct involvement with Death receptors are to be feared!

BLK
TNFAIP3
C2
C1QA
STAT4
PTPN22
LYN
IRAK1
ITGAM
IRFS
C4A,B
CRP
DRB1 1501
 DRB1 0301
FCGR2A, 3A

Evolution of the Role of the Oncologist!

The evolution of the role of the Oncologist has remarkably evolved from the one who had to manage chemotherapy, hormone therapy and immunotherapy to the one who detect and advise carriers of genetic predisposition to cancer when it comes to heritable neoplasms, determination of needed and actionable driver mutations, selecting appropriate referrals for genetic counseling, advising as to recommended Maintenance therapy for survivors and helping them survive with sequellae of various therapies in the management of cancers!
In Prostate Cancer, hormone therapy has been so successful and is relatively benign, that Urologist have encroached and taken over this role that used to be mainly performed by Oncologists.  With the advent of target therapy which now comes in pill form, there will be an increasing shrinkage of the roll of the Oncologist as more physician continue to familiarize themselves with these pills.  To survive, the oncologist needs to further master cell biology to keep a noticeable edge.  And doing so He will find himself encroaching in other specialties of which Immunology/Rheumatology will be more likely the area given the fact that it too is a cell biology based science, and chemotherapy drug have been used here mostly at low doses!
 

INTERESTING ASPECTS OF GERM CELL TUMORS

*In the retroperitoneum, involvement is always associated with Testicular involvement (even non palpable)
whereas Mediastinal involvement could be primary.
*no matter the stage, the objective of the treatment is cure.
*Cryptorchidism needs to be corrected before Puberty to monitor the testicle and reduce the risk of Neoplastic transformation.
*men with HIV, are more likely to have a Seminoma
*klinefelter syndrome is associated with Mediastinal involvement
*In situ presence marks a 50%risk of cancer development within 5 years
*with a Seminoma in 1 Testicule, there is a 2 % concurrent chances of presence in the other testicle!
*Deletion of short arm of  Xsome 12 is present in 80%, the rest have some form of hyperpliody involving 12p.

Genes involved

1.KRAS, " normal tissue signaling, and the mutation of a KRAS gene is an essential step in the development of many cancers.^[3] Like other members of the Ras family, the KRAS protein is a GTPase and is an early player in many signal transduction pathways. KRAS is usually tethered to cell membranes because of the presence of an isoprenyl group on its C-terminus." wikipedia
It is interesting to know that with KRAS activation follow the activation of RALGDS which through the Arrestins wake up the DVL (devil) preparing the cell to early proliferation and metastasis through the Wnt.

2.SOX5
a member of a Core Binding protein /Homebox that direct toward male differentiation, blockage here by Mutation returns some of the totipotentiality to the cell by blocking differentiation (which include Male Brain transformation).
It is believed or speculated that Older Man will have methylation issue at this gene leading to autistic children since this gene is definitely involved with Brain formation/Autistic transformation!

3.CCND2:  BELONGS TO THE CYCLINS!
" This protein has been shown to interact with and be involved in the phosphorylation of tumor suppressor protein Rb. Knockout studies of the homologous gene in mouse suggest the essential roles of this gene in ovarian granulosa and germ cell proliferation. High level expression of this gene was observed in ovarian and testicular tumors.^[2]WIKIPEDIA


 4.JAW1
re-enforcing the notion that membrane perturbances are critical in Testicular cancer
as this gene allow the eluding from Class I molecule detection and disturb anti-proliferative and pro-apoptotic function!

" JAW-1 affects
Calcium release from the endoplasmic reticulum controls a number of cellular processes, including proliferation and contraction of smooth muscle and other cells and contributes to the antiproliferative and proapoptotic effects of nitric oxide and cGMP. (from LocusLink and OMIM)".   WHAT IS IN COMMON TO THESE 4 GENES TO SHOW THAT THEY POTENT GENES, DEFICIENCY OF THESE GENES LEADS TO MALFORMATION (FACIAL OR OTHERWISE!)

ASCO NEWS!
Anti-PD1, a misnomer, yes I believe!
isn't it longer true that if you block programmed cell death, you worsen a cancer?
well don't believe what make sense, "Antibody mediated blockade of the programmed cell death protein-1 and its ligand PD-L1 resulted in a potent and durable tumor regression and prolonged stabilization of disease in patients with solid tumors"...Nivolumad in combination with Ipilumumab yielded a 40% response rate in advanced Melanoma, this is impressive!  "The Synergie between Anti-PD-1 and an Anti-CTLA-4 has been confirmed".

*pomalidomide has been approved for Multiple Myeloma after failure of 2 regimens which contained Velcade and Revlimid. Officially approval was not based on increased survival! 

*Now enroling Trial "A Phase 3 trial for Newly diagnosed EGFRvIII-positive Glioblastoma :Rindopepimut and Temodar Vs Blinded KLH control and Temodar" NCT01480479

TRANSGENDER?

CNN PRESENTED LAST NIGHT: FROM CHRIST TO CHRISTIN, THE STORY OF A MAN WHO HAS GONE TROUGH A "NAVY SEAL" TO A TRANSGENDER WOMAN CURRENTLY ESTROGEN TREATMENT, AND WANTING TO LIVE AS "JUST ANOTHER WOMAN AROUND THE CORNER". THE STORY WAS FASCINATING, AND SOMEWHAT DIFFICULT FOR THE REPORTER WHO COULD NOT LOOK AT "CHRISTINE" IN THE EYE AS MUCH AS CHRISTINE DID!
THIS STORY DID BRING TO MIND ALSO A WEIRD QUESTION THAT POPPED UP ONE DAY BEFORE A CONFERENCE: A TRANSGENDER WOMAN HARD AT WORK ON ESTROGEN TREATMENT, SHOW-UP WITH AN ADVANCED PROSTATE CANCER, QUESTION WAS HOW TO TREAT?
BUT LET GO BACK TO THE GENETIC BASIS OF "TRANS-SEXUALITY" 
THIS FIELD IS CONTROVERSIAL, WITH PSYCHOLOGISTS FIGHTING TO CONSIDER THIS A STRICTLY BEHAVIORAL WHEN GENETICISTS MAINTAIN IT IS STRICTLY A GENETIC DISTURBANCE.
MY FAVORITE THINKING IS THAT IT IS A FAILURE OF METHYLATION OF CRITICAL HORMONAL GENES, BUT OTHER MAINTAIN IT IS AN ABERRATION OF A GENES WHICH IS CHARACTERIZED BY AN ATTACHMENT OF A PROLONGED REPEAT OF MOLECULES.
THERE IS NO FUMES OR SMOKE (IF YOU WANT A LIGHTER OPTION) WITHOUT A FIRE I WANT TO MAINTAIN, SO I LEAN FOR A GENETIC BASIS TO THIS ARGUMENT.
WIKIPEDIA:
"

Genetics

The androgen receptor (AR), also known as NR3C4, is activated by the binding of testosterone or dihydrotestosterone, where it plays a critical role in the forming of primary and secondary male sex characteristics. Hare et al. found that male-to-female transsexuals were found to have longer repeat lengths on the gene, which reduced its effectiveness at binding testosterone.^[18]
A variant genotype for a gene called CYP17, which acts on the sex hormones pregnenolone and progesterone, has been found to be linked to female-to-male transsexualism but not MTF transsexualism. Most notably, the FTM subjects not only had the variant genotype more frequently, but had an allele distribution equivalent to male controls, unlike the female controls. The paper concluded that the loss of a female-specific CYP17 T -34C allele distribution pattern is associated with FtM transsexualism.^[19]"
  Currently, there are numerous scientific explanations of the cause of transsexualism, linking the cause to genetics, brain structure, brain function and prenatal androgen exposure; in addition, other theories have proposed linking the cause to psychological and behavioral reasons. These theories are not necessarily mutually exclusive."

STC1 gene, role in Alzheimer disease?

wikipedia, Stanniocalcin-1 is a " glycoprotein that is expressed in a wide variety of tissues and may have autocrine or paracrine functions. Human Stanniocalcin-1 is a putative molecular biomarker of leukemic microenvironment and the only molecular function known up to date is a SUMO E3 ligase activity in the SUMOylation cycle. STC1 interacts with lots of proteins in the cytoplasm, mithocondria, endoplasmatic reticulum and and dot-like fashion in the nucleus. The N-terminal region of STC1 is the function region which is responsible to establish the interaction with its partners, including SUMO1.[3"
Researchers" found a dramatically upregulated expression of STC during induced neural differentiation in a human neural crest-derived cell line", Paju.(Zhang et al)
"Overexpression of human stanniocalcin 1 in mice produces high serum phosphate levels, dwarfism, and increased metabolic rate. This gene has altered expression in hepatocellular, ovarian, and breast cancers.<sup>[2]wikipedia".

Tamura "</sup>
"The relative expression levels of the STC1 gene were higher in the cancer tissue than in the normal adjacent mucosa and high expression of STC1 correlated with poor postoperative survival.

CONCLUSION:

High expression of the STC1 gene might be a useful predictor of poor postoperative outcome in patients with colorectal cancer."

GUO: " Here, we found that STC1 is down-regulated in Clinical tissues of cervical cancer compared to the adjacent normal cervical tissues (15 cases). Subsequently, the expression of STC1 was knocked down by RNA interference in cervical cancer CaSki cells and the low expression promoted cell growth, migration and invasion."

ASIDE FROM IT BEING A CLEAR TARGET FOR INTERVENTION IN CANCER, THIS GENE SEEMS  TO AFFECT AN IMPORTANT COMPONENT OF MICROFIBRILLARY TANGLES THAT CHARACTERIZE ALZHEIMER DEMENCIA, WHICH IS SHIFT IN CALCIUM PHOSPHATE RATIOS.  IT BEGS A QUESTION : WHAT IS THE ROLE OF STC1 IN ALZHEIMER DISEASE?

GET A LITTLE DIRTY MAY BE GOOD FOR YOU!

I know coming from a health professional it is somewhat surprising or even shocking, but take a moment and read about this statement!

ALLERGIES ARE ON THE RISE!

"The increase in allergic diseases noted in the last 2 decades is thought to result from better hygiene conditions, decreases in infant and childhood infections,and an increasingly sedentary and indoor lifestyles." (Wasserman)
yes the less you have been exposed to antigen the more likely you could become allergic.  You have not challenged your innate immune system enough.  The author suggest that this fact somehow "alters the protective maturation of the acquired immune system".  Now this statement is heavy in implications!  It implies that the development of class II Major Histocompatibility (MHC) is some what influenced in their development by class I Antigen? or am I over-reaching?
Innate immune system is Tolerance of self Antigens?  Acquired Immunity is the stuff mostly class II antigens deal with!
Challenging this statement, will need to read more about this!  At CRBCM, we like this form of challenge! keeps one with sharp mind!
This is germaine to genetics because its throws you next into methylation of genes involved in immunity!
Indeed the "Hygiene Hypothesis" suggested switch off of T2H was not fully completed in favor of T1H...Methylation could have been the silencing mechanism!? check this out!