THE POWERFUL MTOR INHIBITOR, NOT A WALK IN THE PARK!

Important Safety Information

AFINITOR is contraindicated in patients with hypersensitivity to everolimus, to other rapamycin derivatives, or to any of the excipients.

Noninfectious Pneumonitis:

• Noninfectious pneumonitis was reported in up to 19% of patients treated with AFINITOR. The incidence of Common Terminology Criteria (CTC) grade 3 and 4 noninfectious pneumonitis was up to 4.0% and up to 0.2%, respectively. Fatal outcomes have been observed
• If symptoms are moderate, patients should be managed with dose interruption until symptoms improve
• The use of corticosteroids may be indicated. For grade 4 cases, discontinue AFINITOR. Corticosteroids may be indicated until symptoms resolve
• For grade 3 cases, interrupt AFINITOR until resolution to grade ≤1
• AFINITOR may be reintroduced at a daily dose approximately 50% lower than the dose previously administered, depending on the individual clinical circumstances. If toxicity recurs at grade 3, consider discontinuation of AFINITOR
• The development of pneumonitis has been reported even at a reduced dose

Infections:

• AFINITOR has immunosuppressive properties and may predispose patients to bacterial, fungal, viral, or protozoal infections (including those with opportunistic pathogens). Localized and systemic infections, including pneumonia, mycobacterial infections, other bacterial infections, invasive fungal infections such as aspergillosis or candidiasis, and viral infections, including reactivation of hepatitis B virus, have occurred
• Some of these infections have been severe (eg, leading to respiratory or hepatic failure) or fatal
• Physicians and patients should be aware of the increased risk of infection with AFINITOR
• Treatment of preexisting invasive fungal infections should be completed prior to starting treatment
• Be vigilant for signs and symptoms of infection and institute appropriate treatment promptly; interruption or discontinuation of AFINITOR should be considered
• Discontinue AFINITOR if invasive systemic fungal infection is diagnosed and institute appropriate antifungal treatment

Oral Ulceration:

• Mouth ulcers, stomatitis, and oral mucositis have occurred in patients treated with AFINITOR at an incidence ranging from 44% to 86% across the clinical trial experience. Grade 3/4 stomatitis was reported in 4% to 9% of patients
• In such cases, topical treatments are recommended, but alcohol-, peroxide-, iodine-, or thyme-containing mouthwashes should be avoided
• Antifungal agents should not be used unless fungal infection has been diagnosed

Renal Failure:

• Cases of renal failure (including acute renal failure), some with a fatal outcome, have been observed in patients treated with AFINITOR

Geriatric Patients:

• In the randomized advanced hormone receptor-positive, HER2-negative breast cancer study, the incidence of deaths due to any cause within 28 days of the last AFINITOR dose was 6% in patients ≥65 years of age compared to 2% in patients <65 years of age
• Adverse reactions leading to permanent discontinuation occurred in 33% of patients ≥65 years of age compared with 17% in patients <65 years of age
• Careful monitoring and appropriate dose adjustments for adverse reactions are recommended

Laboratory Tests and Monitoring:

• Elevations of serum creatinine, proteinuria, glucose, lipids, and triglycerides, and reductions of hemoglobin, lymphocytes, neutrophils, and platelets, have been reported
• Renal function (including measurement of blood urea nitrogen, urinary protein, or serum creatinine), blood glucose, lipids, and hematologic parameters should be evaluated prior to treatment and periodically thereafter
• When possible, optimal glucose and lipid control should be achieved before starting a patient on AFINITOR

Drug-Drug Interactions:

• Avoid coadministration with strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole)
• Use caution and reduce the AFINITOR dose to 2.5 mg daily if coadministration with a moderate CYP3A4 and/or PgP inhibitor is required (eg, amprenavir, fosamprenavir, aprepitant, erythromycin, fluconazole, verapamil, diltiazem)
• Avoid coadministration with strong CYP3A4 inducers (eg, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital); however, if coadministration is required, increase the AFINITOR dose from 10 mg daily up to 20 mg daily, using 5-mg increments

Hepatic Impairment:

• Exposure of everolimus was increased in patients with hepatic impairment
• For patients with severe hepatic impairment (Child-Pugh class C), AFINITOR may be used at a reduced dose if the desired benefit outweighs the risk. For patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment, a dose reduction is recommended

Vaccinations:

• The use of live vaccines and close contact with those who have received live vaccines should be avoided during treatment with AFINITOR

Embryo-Fetal Toxicity:

• Fetal harm can occur if AFINITOR is administered to a pregnant woman. Women of childbearing potential should be advised to use a highly effective method of contraception while using AFINITOR and for up to 8 weeks after ending treatment

Adverse Reactions:

• The most common adverse reactions (incidence ≥30%) were stomatitis (67%), infections (50%), rash (39%), fatigue (36%), diarrhea (33%), and decreased appetite (30%)
• The most common grade 3/4 adverse reactions (incidence ≥2%) were stomatitis (8%), infections (5%), hyperglycemia (5%), fatigue (4%), dyspnea (4%), pneumonitis (4%), and diarrhea (2%)

Laboratory Abnormalities:

• The most common laboratory abnormalities (incidence ≥50%) were hypercholesterolemia (70%), hyperglycemia (69%), increased aspartate transaminase (AST) concentrations (69%), anemia (68%), leukopenia (58%), thrombocytopenia (54%), lymphopenia (54%), increased alanine transaminase (ALT) concentrations (51%), and hypertriglyceridemia (50%)
• The most common grade 3/4 laboratory abnormalities (incidence ≥3%) were lymphopenia (12%), hyperglycemia (9%), anemia (7%), decreased potassium (4%), increased AST (4%), increased ALT (4%), and thrombocytopenia (3%)

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch, or call 1-800-FDA-1088.

Please see full Prescribing Information for AFINITOR.

Reference: 1. AFINITOR [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; August 2012.

KEEP UP WITH ME! FOR YOUR INFORMATION!

Recent cases and outbreaks of antibiotic resistant organisms, including methicillin resistant Staphylococcus aureus (MRSA), Clostridium difficile infection (CDI), extremely-drug resistant tuberculosis (XDR-TB), and carbapenemase-resistant Enterobacteriaceae (CRE), have shown that antibiotic resistance represents a serious threat to public health.  These organisms are associated with high mortality rates and have the potential to spread widely.  They also represent a significant burden to the health care system.  To address this major public health threat, the Indiana State Department of Health (ISDH), in collaboration with many partners, has convened the Indiana Antibiotic Resistance Advisory Committee. 

 

Health care providers and hospital administrators will receive a survey via Survey Monkey in the coming weeks to measure knowledge, attitudes, and beliefs regarding aspects of antibiotic resistance.  Responses to this survey will provide data to describe antibiotic resistance in Indiana and allow the committee to identify priorities.  We look forward to your active collaboration as we strive to mitigate antibiotic resistance in Indiana.  For additional information on management of multi-drug resistant organisms in healthcare settings, visit http://1.usa.gov/12sCPip.    

 

Please see attached letter.

 

 

William C. VanNess II, MD

State Health Commissioner

FDA Approvals > Medscape Medical News

FDA Approves First Companion Diagnostic for Lung Cancer

May 14, 2013

Editors' Recommendations

• Reflex Testing of Lung Cancer Tissue Needs to Be Improved
• 'Tragedy' Not to Use EGFR Inhibitors in EGRF+ NSCLC
• ASCO Recommends EGFR Testing for NSCLC, But for Which Patients?

Topic Alert

Receive an email from Medscape whenever new articles on this topic are available.

• Add Lung Cancer to My Topic Alert

Drug & Reference Information

• Non-Small Cell Lung Cancer
• Non-Small Cell Lung Cancer Staging
• Imaging in Non-Small Cell Lung Cancer

The US Food and Drug Administration today announced the approval of the cobas EGFR Mutation Test, a companion diagnostic for the cancer drug erlotinib (Tarceva). This is the first FDA-approved companion diagnostic that can detect epidermal growth factor receptor (EGFR) gene mutations, which are present in approximately 10% of non–small cell lung cancers (NSCLCs).
The approval of this test comes at the same time as an expanded indication for erlotinib. The FDA has also announced a labeling change for erlotinib, and the drug is now indicated for first-line use in patients with metastasized NSCLC that tests positive for EGRF mutations. Until now, the official indication was second- or third-line use in advanced NSCLC.
"The approval of the cobas EGFR Mutation Test will allow physicians to identify non–small cell lung cancer patients who are candidates for receiving Tarceva as first-line therapy," said Alberto Gutierrez, PhD, director of the Office of In Vitro Diagnostics and Radiological Health in the FDA's Center for Devices and Radiological Health, in a statement. "Companion diagnostics play an important role in determining which therapies are the safest and most effective for a particular patient."
The safety and effectiveness of the cobas EGFR Mutation Test was established with clinical data showing progression-free survival in NSCLC patients with specific types of EGFR mutations (exon 19 deletions or exon 21 L858R substitution mutations) for 10.4 months when they received erlotinib treatment, compared with 5.4 months for those who received standard therapy.
In the United States, erlotinib is currently the only drug available for use in EGFR-positive NSCLC, although elsewhere in the world, another similar drug is widely used: gefitinib (Iressa). A third drug in this class of EGFR tyrosine kinase inhibitors (TKIs), afatanib (Boehringer Ingelheim), is close to approval, with an FDA decision expected in July 2013. Afatanib will also have its own companion diagnostic test ( Therascreen EGFR PCR Kit, from Qiagen).
Using an EGFR TKI in the first-line treatment of EGFR-mutated NSCLC is recommended by several clinical guidelines, including the American Society of Clinical Oncology.

Information from Industry

Dose reduction is not always an option when trying to meet individual patient needs in relapsing MS

Read about dosing flexibility

Patient outcomes are significantly better when compared with chemotherapy, so much so that it "would be a tragedy not to use" an EGFR inhibitor in an EGFR-positive patients, according to one expert in the field, Edward Kim, MD, PhD, assistant professor of medicine and director of clinical operations at the University of Texas M.D. Anderson Cancer Center in Houston. To not know whether the tumor is mutation-positive is not acceptable anymore, he added.
However, testing for mutations is not yet routine, and there are difficulties with obtaining lung cancer samples of sufficient size and quality, as well as disagreement over which is the best method for obtaining such samples, as recently reported by Medscape Medical News. In addition, there are issues with the costs of such testing, as outlined in a comment from a surgeon is response to that article.
The cobas EGFR Mutation Test is manufactured by the Roche Molecular Systems. Erlotinib is co-marketed by California-based Genentech, a member of the Roche Group and OSI Pharmaceuticals.

 

Absolutely stunning this news that 5 years after treatment using Stereotatic Radiotherapy, 97% of patients with localized Prostate cancer did not have biochemical relapse!  That's some result.  Can surgery beat that?  By how much?  Was this a cohort with low Gleason score? will find out!
YES most >92% had Gleason 6 or 7.
IT PAYS TO DISCOVER THE TRUTH!
BUT STILL...STUNNING!

CONFLICT OF INTEREST

As a scientist, you tend to believe that your reason will protect against bias.  But reason itself is biased by information it gets from so called experts, culture and Media, to just mention a few sources.   But when an expert working for a drug company is "pitching" a few key messages to which you are sensitive, somewhere you wonder if the expert opinion is not coerced by someone else's suggestion.
Some of us who have seen the worst cases of Neuropathy induced by Taxanes, have become somewhat "sensitized" to the subject.  So to hear that a piano player or artist (who need needs fine hands for their craft) with Metastatic Prostate cancer has to choose between Docetaxel and Abiraterone.  To the sensitized oncologist, the choice is clear.  Abiraterone is the winner!  But was creating a fictitious case of the artist necessary?  Or is-it one of the techniques of brain manipulation?
During residency and fellowship, some directors of  programs banned lunches from drug companies and avoided drug companies contact with trainees.  These decisions are generally unpopular among the trainees who are precluded from free lunches, but are rid of drug companies' influence.  As a trainee, I myself had to question the necessity of such exclusive and drastic decision.  Ultimately, can we trust a trainee to make up his or her mind?  Drug companies on the other hand have their survival in mind and keep sharpening those messages that will influence your practice by any mean they can!

A gardener and writer, spare him the neuropathy! but of course! and the winner is Abiraterone!  But know this: soon or later, the Docetaxel conversation is bound to happen!  It is the power of the drug and the reliability in providing the cure!

How much confidence do you have by prescribing Abiraterone vs Docetaxel in a patient with metastatic prostate cancer, that you will have a response? and the winner is........  Oncologists, just come on and say it!  Let's say in a very symptomatic patient, which drug will you give first? That phase III will not occur in real life!

To mark this fact, researchers did not sleep! It has been reported, at the British Columbia Cancer Agency in Vancouver, they noted that the introduction of Taxotere in the treatment of Hormone Refractory Prostate Cancer has yielded an absolute 6.8% improvement of number of patients alive at 2 years.  That's a small town population alive because of the drug!  That's the power of a drug (when it hits or follows the law of nature!).  Make us believe more and more that the cure is within reach!   By the way, that 6.8% was also a 43 % relative improvement in men alive after 2 years! if you don't understand this statistic, well don't kill the messenger ! Just don't you look at ME as a Culprit!

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FOR PERIPHERAL T-CELL LYMPHOMA

FOR PERIPHERAL T-CELL LYMPHOMA

CHOP + ETOPOSIDE = CHOEP
CHOP + CAMPATH(30MG)
CHOP ALONE NO LONGER AN OPTION WITH 2Y SURVIVAL POOR!
ARE SOME OF THE OPTIONS DISCUSSED

Ramucirumab

From Wikipedia, the free encyclopedia

Jump to: navigation, search

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 breast cancer,^[2] metastatic gastric adenocarcinoma,^[3] non-small cell lung cancer,^[4] among other types of cancer.
This drug was developed by ImClone Systems Inc. It was isolated from a native phage display library from Dyax.


=====================================================
RAMUCIRUMAB  IS REPORTED TO HAVE DEMONSTRATED OVERALL SURVIVAL BENEFIT IN SECOND LINE METASTATIC ESOPHAGEAL CANCER 5.2 MONTHS VS 3.8.  iT WAS TESTED AGAINST PLACEBO REPORTEDLY!  BRAVE PEOPLE!  BUT THE RESULT IS NOTICEABLE !  HYPERTENSION, ANEMIA AND FATIGUE WERE THE MOST COMMON SIDE EFFECTS HAPPENING GENERALLY IN IN LESS THAN 10% OF PATIENTS.

============================================================

WE HAVE SO MANY MEDICINE FOR MYELOMA, IT IS TIME TO TREAT THOSE WE HAVE OBSERVED SO FAR.  AND HIGH RISK  SMOLDERING MYELOMA CAN'T ESCAPE.  AT THE EUROPEAN CONGRESS ON HEMATOLOGIC MALIGNANCIES, THE SALVO HAS BEEN SHOT, HIGH RISK MYELOMA HAS BEEN REPORTED TO PROGRESS TO FULL BLOWN MYELOMA  IN A MEDIAN TIME OF 2 YEARS OR LESS.  SO TREATMENT SEEMS AN ATTRACTIVE OPTION! WITH A MEDIAN SURVIVAL OF 94%  vS 85%  FOR THOSE OBSERVED AFTER A 47 MONTH FOLLOW-UP!  WE ARE WAY INTO TREATING PATIENTS WE USED TO OBSERVE! REV-DEX WAS THE TREATMENT USED!

NO DEED GOES UNPUNISHED, THE STORY OF SECONDARY CANCER, WE JUST HAVE TO BRACE FOR IT!

As we are being increasingly successful at treating cancers, we are being faced with the decision of how long to keep a patient on treatment and maintenance therapy is increasingly pushed. In some surveys, 70 to 80% of oncologists are treating patients "until disease progression" and that could be a year or even several years".  The truth is that on a cellular level this is a prolongation of stress and sooner or later something is "gonna break".  It is of interest that at the cellular level, that treatment of Hematologic malignancy leads to solid tumors.  It goes to show that heterogeneity of genetic material or variation of genes within the same family is exposed to the same stress as imposed by treatments and yields a various effect on a different lineage of cells. Meaning that the suppression of A molecule could affect A2 of the same family, but with a different outcome.

It is clear that prolonged suppression of non intended genes, is the reason for secondary tumors.  In some cases, new altered genes are caused by the fragility or susceptibility of the host genome!  The point is though, now that we have a secondary cancer with the specific cause, do we look to treat the same as the de-novo cancers?  Do we go to the NCCN standard of care, or do we need to aim at the target mutation caused by our previous treatment?  Empirically, we suggest that a target therapy would be more efficient, secondary tumors call for a different approach since we have more specific information as to the cause.  But a new clinical trial needs to be designed to answer this question!

Secondary tumors happen:
1. When new receptors are completely, irreversibly compromised by our treatment
2. When an related or unrelated gene is is either over-expressed or suppressed (i.e suppression of PTEN) by the treatment.
3. When a bypass activation of collateral gene exists and involves a major pathway (i.e Wnt or Notch pathway by-standing there in the neighborhood!)
4. Some combinations of drugs seem to be prone to causing these secondary tumors (alkylating agents and immunomodulators in myeloma treatment!)

SECONDARY TUMOR IS WAY DIFFERENT FOR DE-NOVO TUMOR!  LET'S FACE IT AND BRACE FOR IT! 

NOW THAT IT IS HERE, WE WILL USE IT WHENEVER ABRAXANE IS INVOLVED
ABOUT SPARC LEVEL

Desai et al:
"There were 11 responders (CR/PR) and 5 nonresponders (SD/PD) among the 16 nab-paclitaxel-treated patients (12/16 SPARC-positive, 75%). Response to nab-paclitaxel was higher for SPARC-positive patients (10/12, 83%) than SPARC-negative patients (1/4, 25%). The SPARC-negative patients exhibited significantly lower response than the overall response rate among all 60 patients (1/4, 25% vs 45/60, 75%). Although preliminary, data are supportive of the hypothesis that SPARC overexpression may correlate with response to nab-paclitaxel."  This was about Head & Neck cancer, now they are pushing this SPARC level even in Pancreatic cancer without a clinical trial!

Esposito et al

Pancreatic ductal adenocarcinoma (PDAC) and other pancreatic neoplasms exhibited increased SPARCL1 mRNA levels compared to those of the normal pancreas. SPARCL1 mRNA levels were low to absent in microdissected and cultured pancreatic cancer cells, and promoter demethylation increased SPARCL1 levels only slightly in three of eight cell lines. SPARCL1 was observed in small capillaries in areas of inflammation/tumor growth and in some islet cells. In PDAC, 15.4% of vessels were SPARCL1-positive. In contrast, the percentage of SPARCL1-positive vessels was higher in chronic pancreatitis and benign and borderline pancreatic tumors. Recombinant SPARCL1 inhibited pancreatic cancer cell invasion and exerted moderate growth-inhibitory effects. In conclusion, SPARCL1 expression in pancreatic tissues is highly correlated with level of vascularity. Its anti-invasive effects and reduced expression in metastasis indicate tumor-suppressor function."

people are actually testing this sparc1 before giving chemotherapy!

WHY THE NOTCH IS SO IMPORTANT: IT'S WHAT IT DOES AND THE COMPANY IT KEEPS

Like other stimulant-receptor, the notch is stimulated by an external stimulator (delta) which is sensed by O-glycose derivative before the signal is processed by the protein part of the receptor, here that processing end up by clivage of the internal portion of the protein receptor which is internalized and moved directly the nucleus stimulate mostly genes of proliferation such as c-MYC

But it is not the portion internalized only that is important, the portion left at the membrane is vibrating with effects, electronic polarization, release of TNF and Metalloprotease 2, activation of endocytosis in neighboring   , cells and in the cell itself, offering itself to death,
but most interesting NOTCH at the membrane is sending to other cell a consensus and reminder message "this is what we all should be doing" if it "cease" and "desist" or "we keep on going", and that message is cease...you are dead.

if resuscitation is started and the notch says its ok, you are alive again!

The TNF is in charge when infection is the aggressor,  so don't go out there upsetting your notch, remember the electric current in your brain and heart is notch driven, don't you go out there to upset it!  for some people just the sight of blood is enough to pass out!

NOTCH is the "consensus" gene about what a group of cells should be doing "or cellular fate gene". if the notch is not ready and you are in coma, vegetative life is allowed!
Notch controls immunization by the memory of exposure, it controls resistance to drug by giving the consensus "we ought to resist" and provide the machinery to back up the decision.  well wake-up to the fact that certain cancer cells are just darn resistant, and wherever they are, they get the message! 

More from the "NOTCH"

DESPITE THE FACT THAT THE NOTCH PATHWAY IS CRITICAL IN THE NORMAL FUNCTION OF THE PANCREAS, A FEW TREATMENTS AIMING AT PARALYZING THE NOTCH DID NOT WORK EITHER BECAUSE THEY DID NOT EFFECTIVELY DISABLE IT, OR BECAUSE THEY COULD ONLY OPEN UP THE DOOR TO SUSCEPTIBILITY OR REFRACTORINESS TO DRUGS THAT SUBSEQUENTLY WERE NOT GIVEN.
NOW WE KNOW WHY ANTI-VEGF BY THEMSELVES DO NOT WORK (TUMOR OVER EXPRESSION OF VEGFR2 ?DECOY). 

WE SHOULD REMEMBER THAT MAIN THE PATHWAYS THERE ARE NOT HEDGEHOG, NOTCH OR ANGIOGENESIS, BUT CLEARLY RECEPTOR FAILURE AND SUBSEQUENT UPSET OF THE NF-kB...(IN PANCREATIC CANCERS) . THE NOTCH, HOWEVER, INTERVENES IN THE PAIN THIS CANCER GIVES!

PHENOMENA AT THE "NOTCH"

THE NOTCH PROVIDES MANY OPPORTUNITIES FOR CURE OR INTERVENTIONS FOR THE CURE IN THOSE CANCERS:

1. WE KNOW THE Numb INHIBITS IT
2. IT IS REGULATED BY DELTEX
3. IT REGULATES BMP10, NRG1, Ephrin-B2
(CHECK OUT Rex-1)

INFLUENCED BY DII4

LIGAND DELTA STIMULATE IT

DLL1, DLL3, JAG-1,2

INDUCE PROLIFERATION BY ACTING ON c-MYC, p21, HES FAMILY

REDUCES AVASTIN EFFECT BY OVER-EXPRESSION OF VEGFR2

INTERACT WITH HEY GENE AND   Cbf-1

PRESENILINS 1,2

THE BEAUTY IS THAT BEING A RECEPTOR, IT'S GLYCOSYLATION IS CRUCIAL TO ITS FUNCTION, DESTROY POFUT-1 AND SOMETHING WILL HAPPEN  OR IMPAIR O-GLYCOSYLATION AND THE RECEPTOR FUNCTION IS KAPUTT!

FIBROBLAST GROWTH FACTOR 10,

WE ARE LOOKING AT ALL THIS AT CRBCM,
BUT KNOW THIS: YOU ARE DANCING WITH DEATH WHILE AT THE "NOTCH"

THE SECRET OF LIFE IS LOCKED IN THE NOTCH PATHWAY

1. DO YOU KNOW WHY YOU DIE AFTER A LARGE STROKE? IT IS BECAUSE OF THE NOTCH PATHWAY.  (The notch commend the electrical impulse that can tell the brain to quit all together, it can send the message that this is too much ABORT!)

2. DO YOU KNOW WHY YOU DIE AFTER A HEART ATTACK? IT IS BECAUSE OF THE NOTCH PATHWAY   (send message ABORT to cardiac electricity)
3. DO YOU KNOW WHY YOU HAVE A GOOD MEMORY? IT IS BECAUSE OF THE NOTCH PATHWAY.   (Notch allow memory to form on thing it is able to transmit to other cell)
4. DO YOU KNOW WHY YOU GET DEMENTIA (ALZHEIMER OR NOT) ? BECAUSE OF THE NOTCH PATHWAY (memory of old things already made "accepted" (consensus) are the last to disappear )
5. DO YOU SEE SOMEONE (EVEN  A PRESIDENT) PASS OUT AND WONDER WHY?  BECAUSE OF THE NOTCH PATHWAY (Notch "abort" message was triggered may be through vaso-vagal nerve!)
6. DO YOU KNOW WHY AN INFECTION CAN KILL YOU, AND WHY? BECAUSE OF THE NOTCH (proximity of the notch with TNF which in excess kills you even in the best hospitals in the world, there no defense against massive liberation of TNF)
7. SOMEONE WALKING AND SMILING DROPS DEAD, THE NOTCH DID IT!  ALL OTHER ORGANS CAN BE GOOD, IN FACT WE TAKE THEM FOR TRANSPLANT, BUT THE NOTCH DID IT  (ABORT! message was sent)
8. CAR ACCIDENT DEATH, THE NOTCH....JUST FINISH THE PHRASE FOR ME (Abort!)
9. MACROPHAGE DESTROY OTHER CELLS BY EATING THEM, THE NOTCH TELL THEM TO DO SO    (Notch is involved with endophage, and vacuole formation)
10. WHY IMMUNIZATION WORKS, THE NOTCH DID IT (memory of the biologic agent-aggressor is kept because of ....)
WHY WE AGREE ON BASIC THINGS , THE NOTCH DID THAT (we remember what make sense to all)
WHY WE STAND AND BELIEVE IN FUNDAMENTAL HUMAN RIGHTS, SOMEWHERE IN US WE REMEMBER WHAT IS RIGHT, WELL THE NOTCH DID THAT!

WHY AN ORGAN STOP AND ANOTHER START, THE NOTCH PLAYS HERE  (Notch is at the transition of proliferation and differentiation  this is where Numb comes in!)

WHY CERTAIN TYPES OF CANCER ARE REFRACTORY TO CANCER KILLING DRUGS NO MATTER WHAT, THE NOTCH DOES THAT TOO.  IT'S AS IF THEY "REMEMBER" TO BE REFRACTORY

WHY CERTAIN TISSUES HAVE A FUNCTION AND NOT ANOTHER, THE NOTCH DID IT

WHY HORMONES ARE SECRETED BY SOME ORGAN NO MATTER WHERE THEY ARE, THE NOTCH (keep remember what they are about!)

WHY AVASTIN STOPS WORKING AND ALL THE CANCERS KNOW HOW TO RESIST (BY VEGFR2)

LADIES AND GENTLEMEN, THIS IS NOTCH PATHWAY IS THE SECRET OF LIFE!

PLAY WITH THE NOTCH, YOU WILL STOP BREATHING, AND YOUR HEART WILL STOP, YOUR EYES WILL STOP SEEING, AND YOU CAN'T READ ME......

VEGETATIVE LIFE IS DUE TO THE NOTCH!
why basket ball player drops dead, drug overdose- it's all in the notch!

Resuscitation and resurrection, the NOTCH again!

BY DETERMINING CELLULAR FATE, IT IS THE CONDUCTOR OF THE ORCHESTRA .

News Alerts > Medscape Medical News

FDA Warns Against Products From The Compounding Shop

Megan Brooks

DisclosuresMay 08, 2013

 

Editors' Recommendations

• Another Compounding Company Recalls All Sterile Product
• FDA Announces Recall of ApotheCure and NuVision Products
• Green Valley Drugs Announces Nationwide Recall

Healthcare providers should not administer any products produced by The Compounding Shop of St. Petersburg, Florida, the US Food and Drug Administration (FDA) advised today.
During a recent inspection of the facility, FDA inspectors observed "poor sterile production practices that raise concerns about a lack of sterility assurance of The Compounding Shop's sterile drug products. Therefore, these products should not be administered to patients," according to the agency.
"If an injectable drug product that is intended to be sterile is contaminated, it could result in a life-threatening infection in patients," Janet Woodcock, MD, director of the FDA's Center for Drug Evaluation and Research, said in a statement.
"We do not have reports of patient infections. However, due to concerns about a lack of sterility assurance at the facility and out of an abundance of caution, we have advised the firm to remove its sterile products from the market to protect patients," she added.
The Compounding Shop has informed the FDA that it is recalling sterile products and is in the process of notifying customers, the agency said.
The FDA advises healthcare providers and hospital staff to immediately check their medical supplies, quarantine any sterile products from The Compounding Shop, not administer them to patients, and await further instructions from the company regarding the recalled products.
Patients who have received any product produced by The Compounding Shop and have concerns are being advised to contact their healthcare provider.

Information from Industry

Do your patients with relapsing MS need support to start and stay on therapy?

MS LifeLines^® has trained reimbursement experts, nurses, an award-winning call center, and much more.

Learn more

The problems and product recall involving The Compounding Shop in St. Petersburg, Florida, comes on the heels of recalls last month at other compounding pharmacies because of similar problems and concerns about sterility of products after FDA inspections.
As reported by Medscape Medical News, those companies include ApothéCure Inc and NuVision, Green Valley Drugs, and Balanced Solutions Compounding Pharmacy.
Healthcare professionals and patients are encouraged to report adverse events potentially related to the use of these or other products to MedWatch, the FDA's safety information and adverse event reporting program, by telephone at 1-800-FDA-1088; by fax at 1-800-FDA-0178; online at https://www.accessdata.fda.gov/scripts/medwatch/medwatch-online.htm; with postage-paid FDA form 3500, available at http://www.fda.gov/MedWatch/getforms.htm; or by mail to MedWatch, 5600 Fishers Lane, Rockville, Maryland 20852-9787.

MTOR Inhibitor ....

THE NOTION THAT MTOR INHIBITOR SHOULD FOLLOW VEGF INHIBITOR FAILURE HAS BEEN ADOPTED BY THE MSKCC PHASE 3 STUDY OF Anti-PD1 ANTIBODY (BMS) vs EVEROLIMUS "FOLLOWING VEGF-TARGETED THERAPY FOR RENAL CANCER.

In this study, patients with Renal cell cancer who have progressed after 1 or 2 anti-VEGF systemic treatments are randomized to Anti-PD1 Antibody or Everolimus.

The primary endpoint is survival whereas secondary endpoints include progression free survival, safety of drugs and quality of life!

Please access the trial through clinicaltrials.gov

----------------------------------------------------------------------------------------------
TREATMENT RECOMMENDATION FOR CLEAR CELL RENAL CELL CANCER

SETTING                          PATIENT                    LEVEL 1                            HIGHER LEVEL
---------------------------------------------------------------------------------------------------
                                       Good or                        Sunitinib
                                   Intermediate risk           Bevaczumab +INF-alpha         high dose IL2
1st line                                                              Pazopanib                               Sorafenib
                                   ---------------------------------------------------------------------------

                                    Poor risk                      Temsirolimus                    
                                                                         (Sunitinib)
==================================================================
                                                                        Sorafenib                                  Sunitinib
                                   Prior Cytokine               Pazopanib                               Bevacizumab
2nd and 3rd line          ----------------------------------------------------------------------------

                                   Prior VEGF-TKI           Everolimus or Axitinib              Sorafenib
                                   Prior MTOR Inhib.        Axitinib

=================================================================

from Molina et al....

Nul n'est prophete chez soi!

No one is prophet at Home! (The French know best!)
In these United States, politics will block us from obtaining a grant, we understood that! Our cause, however, is just, and we will pursue it by all means found anywhere in the world!  Cancer is a common cause for the fight, let those who are distracted by local conditions they live in go by the wayside while we stick to the mission to cure cancer!
We cannot thank MDHonors enough for providing much needed funding for our research!

ONCE AGAIN FAILURE OF RECEPTORS PROVE TO BE THE REASON CANCER DEVELOPS.
WHILE IN TRIPLE NEGATIVE HEPARAN SULFATE ALTERATION OR LACK OF, SEEMS TO BE THE CULPRIT THAT WILL LEAD TO SECONDARY OVER-EXPRESSION OF TUMOR GROWTH FACTORS FOR BREAST CANCER, IN OVARIAN CANCER IT IS THE BETAGLYCAN WHICH APPEARS TO BE DEFICIENT AND TRIGGER A SECONDARY INCREASE OF ACTIVIN.  THE PROOF IS IN THE PUDDING,
IF YOU FIGHT ACTIVIN, YOU GO NOWHERE BUT IF YOU FIGHT BETAGLYCAN BY RESTORING ITS FUNCTION, THE RECEPTOR WORKS RELATIVELY AND YOU KIND OF STOP THE METASTASIS AND SPREAD OF THE DISEASE
NOBODY HAS SHOWN THIS YET BUT YOU WILL FIND A DROP OF ACTIVIN (HOW DIFFERENT IT IS FROM SURVIVIN? HELL DON'T LET ME CONFUSE YOU BY JUMPING FROM CAMELS TO RABBITS!)

THE GLYCAN ARE MORE IMPORTANT THAN YOU THINK
IT IS AN INTERESTING SPECULATION THAT HISTONE DEACETYLASE INHIBITOR WORK BECAUSE IN RESTORING THE GLYCAN OR IS IT CAUSATIVE OF THE ABNORMALITY.
ONE THING THAT IS WORRISOME IS THAT A SINGLE FRAME SHIFT AT THE m-ARNA COULD TRIGGER THESE EPIGENETIC EVENTS.

ALL IN ALL THIS AT THE RECEPTOR IS READ AS A CRISIS OR STRESS THE AKT IS OVEREXPRESSED AND CAUSE PTEN DEPRESSION, OR GSK DEPRESSION, AND AFFECT THE Wnt THROUGH CROSS TALK AND OVARIAN CANCER IS WELL ON ITS WAY EXACERBATED AT THIS POINT BY SECONDARY INCREASE OF TGF CALLED ACTIVIN!

yes CRBCMO25 WAS THE APPROVAL NUMBER OF THE STUDY ON LUNG CANCER EARLY DETECTION !  APPROVAL DATE WAS MARCH 1, 2013.
PLEASE TAKE NOTE OF IT!

GENETIC DISTURBANCES IN OVARIAN CANCERS! ANOTHER CASE OF RECEPTOR FAILURE

In many triple negative Breast Cancers, we have submitted that a failure of the receptor for either HER-2 or ER are the origin. Defective Heparan surface may be one example leading to Receptor ineffective performance.  There is a secondary over production of Tumor Growth factor which impact other Receptors which are naturally susceptible leading to hyperplasia and eventually to a neoplastic process.

In ovarian cancer, the findings that the DAB2 gene is suppressed appears to be central to the pathophysiology of this cancer.
==================================================================

DAB2

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Dab, mitogen-responsive phosphoprotein, homolog 2 (Drosophila)
PDB rendering based on 1m7e.
Available structures PDB Ortholog search: PDBe, RCSB [show]List of PDB id codes
Identifiers
Symbols	DAB2; DOC-2; DOC2
External IDs	OMIM: 601236 MGI: 109175 HomoloGene: 1026 GeneCards: DAB2 Gene
[show]Gene Ontology
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	1601	13132
Ensembl	ENSG00000153071	ENSMUSG00000022150
UniProt	P98082	P98078
RefSeq (mRNA)	NM_001244871	NM_001008702
RefSeq (protein)	NP_001231800	NP_001008702
Location (UCSC)	Chr 5: 39.37 – 39.46 Mb	Chr 15: 6.3 – 6.44 Mb
PubMed search	[1]	[2]
This box: view talk edit

Disabled homolog 2 is a protein that in humans is encoded by the DAB2 gene.^[1][2]
DAB2 mRNA is expressed in normal ovarian epithelial cells but is down-regulated or absent from ovarian carcinoma cell lines. The 770-amino acid predicted protein has an overall 83% identity with the mouse p96 protein, a putative mitogen-responsive phosphoprotein;=============================================================

IF YOU FOLLOW THE MONEY FOR A WHILE YOU WILL COME TO THE NATURAL CONCLUSION.  OVARIAN CANCERS HAPPEN IN MOTHERS! AND GUESS WHO DAB2 GENE WILL PICK ON, OF COURSE A GENE CALLED "MOTHER".

Mothers against decapentaplegic homolog 3

From Wikipedia, the free encyclopedia

.
Mothers against decapentaplegic homolog 3 also known as SMAD family member 3 or SMAD3 is a protein that in humans is encoded by the SMAD3 gene.^[1][2] SMAD3 is a member of the SMAD family of proteins.
The human SMAD3 gene is located on chromosome 15. It is one of several human homologues of a gene that was originally discovered in the fruit fly Drosophila melanogaster.


Activin and inhibin are two closely related protein complexes that have almost directly opposite biological effects. Activin enhances FSH biosynthesis and secretion, and participates in the regulation of the menstrual cycle. Many other functions have been found to be exerted by activin, including roles in cell proliferation, differentiation, apoptosis,^[1] metabolism, homeostasis, immune response, wound repair,^[2] and endocrine function. Conversely inhibin downregulates FSH synthesis and inhibits FSH secretion.^[3]
Activin is a dimer composed of two identical or very similar beta subunits. Inhibin is also a dimer wherein the first component is a beta subunit similar or identical to the beta subunit in activin. However, in contrast to activin, the second component of the inhibin dimer is a more distantly-related alpha subunit.^[4][5] Activin, inhibin and a number of other structurally related proteins such as anti-Müllerian hormone, bone morphogenetic protein, and growth differentiation factor belong to the TGF-β protein superfamily.<sup>[6]

 ==============================================================================
SO CLEARLY DEPRESSION AT DAB2 WILL INDUCE DE-SENSITIZATION AT THE TGF-BETA RECEPTOR LEADING TO CHANGES OR MODULATION THAT FAVOR ACTIVIN'S ACTIVITY AND PROLIFERATION

BUT DEPRESSION OF DAB2 DOES NOT STOP THERE, THROUGH ITS GIPC1 CONNECTION IT WILL AFFECT VERY BAD ACTORS INCLUDING MYO6 (WHICH DISTURBS ORGANELLE MOVEMENT AND VACUOLE CONTROL TRAFFIC IN THE CELL) AND LPR1,2 A DISFIGURING GENE ASSOCIATED WITH A BAD SYNDROME AND THE "DEVIL" DVL3.  AND REMEMBER A GENE THAT INDUCES MORPHOLOGIC DISTURBANCE SUCH AS THE LRP2 IS DANGEROUS TO DANCE WITH!   ALWAYS REMEMBER THALIDOMIDE WITH ITS SHORT LIMB SYNDROME!
==================================================================================</sup>
 Mutations in the LRP2 gene are associated with Donnai-Barrow syndrome.^[6]


This disorder is characterized by unusual facial features, including prominent, wide-set eyes with outer corners that point downward; a short bulbous nose with a flat nasal bridge; ears that are rotated backward; and a widow's peak hairline.
Individuals with Donnai-Barrow syndrome have severe hearing loss caused by abnormalities of the inner ear (sensorineural hearing loss). In addition, they often experience vision problems, including extreme nearsightedness (high myopia), detachment or deterioration of the light-sensitive tissue in the back of the eye (the retina), and progressive vision loss. Some have a gap or split in the colored part of the eye (iris coloboma).^[2][3]
In almost all people with Donnai-Barrow syndrome, the tissue connecting the left and right halves of the brain (corpus callosum) is underdeveloped or absent. Affected individuals may also have other structural abnormalities of the brain. They generally have mild to moderate intellectual disability and developmental delay.
People with Donnai-Barrow syndrome may also have a hole in the muscle that separates the abdomen from the chest cavity (the diaphragm), which is called a diaphragmatic hernia. This potentially serious birth defect allows the stomach and intestines to move into the chest and possibly crowd the developing heart and lungs. An opening in the wall of the abdomen (an omphalocele) that allows the abdominal organs to protrude through the navel may also occur in affected individuals. Occasionally people with Donnai-Barrow syndrome have abnormalities of the intestine, heart, or other organs and scoliosis.^[2][3]

MYO6

From Wikipedia, the free encyclopedia

.
Myosin VI, also known as MYO6, is a protein. It has been found in humans, mice, fruit flies (Drosophila melanogaster), and nematodes (Caenorhabditis elegans).
Myosin VI is a molecular motor involved in intracellular vesicle and organelle transport. It is one of the so-called unconventional myosins.[supplied by OMIM]^[1]

Interactions

MYO6 has been shown to interact with GIPC1^[2][3] and DAB2.<sup>[4][5]
=============================================================================

CAN THIS ENTIRE MACHINERY BE SHUT DOWN BY AN ANTI-CD81
I BET YOU! 

THE CENTRAL GENE TO GO AFTER IS GIPC1 FROM MY VOTE, THERE IS THE CROSS-ROAD!  BUT IT INVOLVES THE ADRENAL RECEPTORS AND BETA RECEPTOR OF THE HEART SO CARDIAC MONITOR WOULD BE ADVISED DURING PHASE 1 STUDIES!</sup>

If LPR2 is amplified, will that predict activity of Avastin and other immunomodulation?  we know that when morphology is involved, these agents are active!