KNOW MORE ABOUT SUTENT

Indication

SUTENT® (sunitinib malate) is indicated for the treatment of advanced renal cell carcinoma (RCC).

Important Safety Information

Hepatotoxicity has been observed in clinical trials and post-marketing experience. This hepatotoxicity may be severe, and deaths have been reported. Monitor liver function tests before initiation of treatment, during each cycle of treatment, and as clinically indicated. SUTENT should be interrupted for Grade 3 or 4 drug-related hepatic adverse events and discontinued if there is no resolution. Do not restart SUTENT if patients subsequently experience severe changes in liver function tests or have other signs and symptoms of liver failure.

Women of childbearing potential should be advised of the potential hazard to the fetus and to avoid becoming pregnant.

Given the potential for serious adverse reactions (ARs) in nursing infants, a decision should be made whether to discontinue nursing or SUTENT.

Cardiovascular events, including heart failure, myocardial disorders, and cardiomyopathy, some of which were fatal, have been reported. Monitor patients for signs and symptoms of congestive heart failure (CHF) and, in the presence of clinical manifestations, discontinuation is recommended. Patients who presented with cardiac events, pulmonary embolism, or cerebrovascular events within the previous 12 months were excluded from clinical studies.

SUTENT has been shown to prolong QT interval in a dose-dependent manner, which may lead to an increased risk for ventricular arrhythmias including torsades de pointes, which has been seen in <0.1% of patients. Monitoring with on-treatment electrocardiograms and electrolytes should be considered.

Hypertension may occur. Monitor blood pressure and treat as needed with standard antihypertensive therapy. In cases of severe hypertension, temporary suspension of SUTENT is recommended until hypertension is controlled.

There have been rare (<1%) nonfatal reports of subjects presenting with seizures and radiological evidence of reversible posterior leukoencephalopathy syndrome (RPLS).

Hemorrhagic events, including tumor-related hemorrhage such as pulmonary hemorrhage, have occurred. Some of these events were fatal. Perform serial complete blood counts (CBCs) and physical examinations.

Osteonecrosis of the jaw (ONJ) has been reported. Consider preventive dentistry prior to treatment with SUTENT. If possible, avoid invasive dental procedures, particularly in patients receiving bisphosphonates.

Cases of tumor lysis syndrome (TLS) have been reported primarily in patients with high tumor burden. Monitor these patients closely and treat as clinically indicated.

Thyroid dysfunction may occur. Monitor thyroid function in patients with signs and/or symptoms of hypothyroidism or hyperthyroidism and treat per standard medical practice.

Cases of impaired wound healing have been reported. Temporary interruption of therapy with SUTENT is recommended in patients undergoing major surgical procedures.

Adrenal hemorrhage was observed in animal studies. Monitor adrenal function in case of stress such as surgery, trauma, or severe infection.

CBCs with platelet count and serum chemistries including phosphate should be performed at the beginning of each treatment cycle for patients receiving treatment with SUTENT.

Dose adjustments are recommended when administered with CYP3A4 inhibitors or inducers.

The most common ARs occurring in ≥20% of patients receiving SUTENT for treatment-naïve metastatic RCC (all grades, vs IFNα) were diarrhea (66% vs 21%), fatigue (62% vs 56%), nausea (58% vs 41%), anorexia (48% vs 42%), altered taste (47% vs 15%), mucositis/stomatitis (47% vs 5%), pain in extremity/limb discomfort (40% vs 30%), vomiting (39% vs 17%), bleeding, all sites (37% vs 10%), hypertension (34% vs 4%), dyspepsia (34% vs 4%), arthralgia (30% vs 19%), abdominal pain (30% vs 12%), rash (29% vs 11%), hand-foot syndrome (29% vs 1%), back pain (28% vs 14%), cough (27% vs 14%), asthenia (26% vs 22%), dyspnea (26% vs 20%), skin discoloration/yellow skin (25% vs 0%), peripheral edema (24% vs 5%), headache (23% vs 19%), constipation (23% vs 14%), dry skin (23% vs 7%), fever (22% vs 37%), and hair color changes (20% vs <1%). The most common grade 3/4 ARs (occurring in ≥5% of patients with RCC receiving SUTENT vs IFNα) were fatigue (15% vs 15%), hypertension (13% vs <1%), asthenia (11% vs 6%), diarrhea (10% vs <1%), hand-foot syndrome (8% vs 0%), dyspnea (6% vs 4%), nausea (6% vs 2%), back pain (5% vs 2%), pain in extremity/limb discomfort (5% vs 2%), vomiting (5% vs 1%), and abdominal pain (5% vs 1%).

The most common grade 3/4 lab abnormalities (occurring in ≥5% of patients with RCC receiving SUTENT vs IFNα) included lymphocytes (18% vs 26%), lipase (18% vs 8%), neutrophils (17% vs 9%), uric acid (14% vs 8%), platelets (9% vs 1%), hemoglobin (8% vs 5%), sodium decreased (8% vs 4%), leukocytes (8% vs 2%), glucose increased (6% vs 6%), phosphorus (6% vs 6%), and amylase (6% vs 3%).

Please see full Prescribing Information, including Boxed Warning, for SUTENT® (sunitinib malate).

PFIZER!

TARGET THERAPY IS ON TARGET!

ONLINE FIRST: Phase II Mantle Cell Lymphoma Study Shows 100%...

Online First/Online Only Articles/items published ahead of print or only online.

Wednesday, April 24, 2013 ONLINE FIRST: Phase II Mantle Cell Lymphoma Study Shows 100% Response with Epigenetic Therapy BY ROBERT H. CARLSON WASHINGTON -- Hematologic malignancies set the precedent for conventional therapies of cancer many years ago in terms of combination chemotherapy, and they continue to do so with some exciting new trends in therapy. In one report here at the American Association for Cancer Research an epigenetic/immunotherapy regimen of cladribine, rituximab, and vorinostat produced a 100 percent response rate with 86 percent complete remissions in newly diagnosed mantle cell lymphoma.

======================================
YOU CANNOT BEAT 100%!
=====================================

JUST A TASTE OF THE DEBATE, GO TO ORIGINAL ARTICLE AND READ IT!

Medscape Medical News from the:

• 15th European Congress of Endocrinology (ECE)

This coverage is not sanctioned by, nor a part of, the European Society of Endocrinology.

Medscape Medical News > Conference News

To [Vitamin] D or Not to D? That Is the Question

Lisa Nainggolan

Apr 29, 2013

 

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Editors' Recommendations

• Vitamin D Supplements Reverse Deficiency in Pregnant Women
• Pregnancy Vitamin-D Levels Do Not Affect Bones of Kids
• Endocrine Society Issues Practice Guideline on Vitamin D

Drug & Reference Information

• Pediatric Hypercalciuria
• Vitamin Toxicity
• Triple Arthrodesis

COPENHAGEN, Denmark — Two leading experts in the field of vitamin D agreed to disagree yesterday here at the 2013 European Congress on Endocrinology during a lighthearted debate on the subject of whether or not everyone needs more vitamin D.
But their arguments were backed up by some serious science, and they both concurred that there are certain groups of people in whom it is necessary to ensure that vitamin-D levels are sufficient, such as pregnant women and those at risk for or with osteoporosis. And they also agreed on one way people can obtain more vitamin D: by going out in the sun for 30 minutes per day.
Where they differed, however, was that the vitamin-D proponent, Chantal Mathieu, MD, from Catholic University, Leuven, Belgium, said the list of people who need sufficient vitamin D "is so long that it really just makes more sense to give everyone small doses."
In the opposite corner, however, Mark Cooper, MD, from University Hospital, Birmingham, United Kingdom, argued that it is really only necessary to supplement specific, at-risk groups of people. "I am an investigator in randomized clinical trials of vitamin D, and I have nothing personally against [it], and I use it in my patients. But I tend to give it to people who actually need it, and that doesn't really include most of us," he observed.
And Dr. Cooper — who noted that there is a huge sector of the scientific community that is "evangelical" in its pro–vitamin-D stance — warned that physicians have been here before, with many other nutrients that subsequently, in large intervention trials, turned out to have a null effect or even be harmful. In fact, there is already evidence of risks with supplements of vitamin D from randomized clinical trials, with no evidence of benefit, he argued.
"Vitamin D — we all need more? Most of us don't, and more could actually do more harm than good."
What Does Vitamin D Do, and How Is "Deficiency" Defined?
Dr. Mathieu said the key role of vitamin D "is to promote resorption of calcium via the gut. One big lesson from all of the literature is that vitamin-D deficiency is not only bad because it's vitamin-D deficiency, but it also creates a bad calcemic status."
Vitamin-D deficiency is generally defined as a level of less than 20 ng/mL (<50 nm/L), and there are correlations in large observational studies "indicating that if you are vitamin-D deficient you get more cancer, especially colon cancer, you get more cardiovascular diseases, your immune system doesn't function properly, and overall you have a higher risk of dying," she stressed.
Going out in the sun is one option to boost vitamin D, she explained, noting that "even the dermatologists in Australia have reversed their zero-tolerance stance on the sun" in the past 2 years and conceded that 15 to 30 minutes per day in the sun "is allowed because it gives benefits." Nevertheless, the benefits must be balanced with the risks, she added, noting that "it's exactly the same wavelength of UV that you need to make vitamin D that also causes skin damage, aging, and skin cancers. So go back to nature and expose yourself to the sun, but do it with caution."
And she noted that UV rays in Northern Hemisphere winters are not strong enough to produce adequate levels of vitamin D, regardless of how long is spent in the sun. In addition, darker-skinned people, particularly those who do not expose themselves to the sun or who cover themselves, are particularly at risk. "We still see rickets in my country, in dark-skinned children who are exclusively breast-fed and whose mothers avoid the sun or are covered," she observed.
"You can also take it from foods," she explained, but added that the "only really rich food source" of vitamin D is cod-liver oil. "Salmon and mackerel from the ocean is a good source"; however, most of this fish is now bred in farms, and farm-bred fish do not have a lot of vitamin D.

 

If our skin cannot make enough vitamin D under the UV, just give vitamin D, give the hormone. Dr. Chantal Mathieu

 

"So what do we do? We are endocrinologists. If the thyroid fails, we give thyroid-hormone substitution. If our skin cannot make enough vitamin D under the UV, just give vitamin D, give the hormone itself."
But the key, she said, is to use smaller doses of vitamin D than have previously been recommended. The US Endocrine Society guidance, for example, advises supplementation with up to 2000 IU per day, but this is overzealous, she said. "A more reasonable dose is 600 to 800 IU per day," she noted, adding that she is an author on a new guidance, soon to be published in the Journal of Clinical Endocrinology and Metabolism, which will state that 2000 IU per day "is not warranted."

YOU TOO ARE INVITED!

Exclusive Interview - Broad Institute's Brian Haas on RNA-Seq

Inbox

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Izzy Scott-Moncrieff	Apr 26 (4 days ago)
to me

  Dear MUTOMBO,

I’m getting in touch to share some hot off the press, exclusive RNA Sequencing content with you.  I recently picked the impressive brains of Brian Haas (Manager of Genome Annotation, Outreach, Bioinformatics and Analysis at the Broad Institute) to learn more about the exciting prospects for RNA-Seq technology. You can download the full interview here. With RNA-Seq 2013 just around the corner, (well, Boston, 18 - 20 June) and with Brian on the agenda and hosting an interactive workshop I thought you may like a sneak peek into what he will be sharing.   Brian is currently the lead developer of Trinity software at the Broad Institute - a novel method for the efficient and robust de novo reconstruction of transcriptomes from RNA-seq data.  I learned that despite some really exciting developments since the emergence of RNA-Seq technology, big challenges still remain. One of the biggest of which is identifying what tools to use, how to use them, and what the requirements are in terms of bioinformatics skills, hardware and compute resources. He is making it the mission of his group at the Broad to find the answers to the bioinformatics challenges that seem to be restricting the genomics field. You can download the interview for free here and read more about the really exciting research his team is focussing on.  Brian is one of the expert speakers at RNA-Seq 2013, co-leading a workshop with Cole Trapnell and giving a presentation on the program with the likes of Mark Gerstein (Yale), Thomas Wu (Genentech) and Edward Oakeley (Novartis). You can have a look at the full speaker line up and program on the website or if you download the brochure.  We are closing early registration on Friday 10th May, so make sure you register before then to get best rates. Also workshops places are limited and filling up fast. To secure your place at the meeting for RNA-Seq pioneers visit www.rna-seqsummit.com/register   Please don’t hesitate to get in touch with any questions about the meeting. It would be great to hear from you. Best regards,  Izzy Izzy Scott-Moncrieff Hanson Wade www.rna-seqsummit.com

Dr. Susan M. Nedza Case Study A 52 year old gentleman was diagnosed with stage IV pancreatic cancer with liver and lung metastases. His initial therapy included FOLFIRINOX, a 5-FU based combination with irinotecan, leucovorin and oxaliplatin. Imaging studies showed disease progression after 3 months of treatment. The oncologist is now requesting bevacizumab (Avastin), and plans to add it to the current regimen. Background Pancreatic cancer is a highly lethal malignancy, with a 5 year overall survival rate of 5%. In the setting of metastatic disease, this cancer is uniformly fatal, with a median survival of approximately 6 months. Treatment has been used primarily as a palliative measure, for clinical benefit and symptom improvement. Gemcitabine combinations Gemcitabine has been the backbone of pancreatic cancer treatment since 1996, and multiple combinations have been studied since that time. Unfortunately, very few treatments have led to a significant improvement in overall survival. A recent exception has been the use of gemcitabine in combination with nab-paclitaxel (Abraxane® ). The MPACT trial, which compared this combination with single agent gemcitabine, showed an increase in overall survival with combination therapy (8.5 months vs. 6.7 months). FOLFIRINOX A randomized, phase III trial (PRODIGE) published in 2011 evaluated the combination (FOLFIRINOX) versus single agent gemcitabine in patients with metastatic pancreatic cancer and good performance status. Combination therapy demonstrated significant improvement in progression-free survival and median overall survival, but with significantly greater toxicity than gemcitabine alone. This regimen has been added to the National Comprehensive Cancer Network (NCCN) guidelines as a category 1 recommendation for first-line treatment of metastatic pancreatic cancer in patients with good functional status. Bevacizumab (Avastin®) The introduction of bevacizumab (Avastin®) has been groundbreaking in cancer treatment, demonstrating efficacy in colorectal cancer and lung cancer, among others. Side effects are considered to be generally mild, with high blood pressure and mild nosebleeds among the most common. Though rare, Avastin® has also been linked to gastrointestinal perforation, thrombosis, and fatal hemorrhage. With respect to pancreatic cancer, however, randomized phase III studies of gemcitabine in combination with Avastin® have failed to demonstrate improvements in overall survival, progression-free survival, or overall response rates. Furthermore, there was a significant increase in hypertension and proteinuria, though no toxic deaths were reported.

Discussion In our case, the patient has received a 5-FU-based regimen with disease progression. To date, there have been no published studies demonstrating the efficacy or safety of adding Avastin® to this regimen. Because of its efficacy in other tumor types and some activity demonstrated in Phase I/II trials, this drug is often requested off-label. Current consensus opinion would recommend either gemcitabine/gemcitabine combination or a 5FU-based regimen for first-line treatment. Upon progression, NCCN recommends a change to a regimen with a different backbone. In the case presented, changing to a gemcitabine-based regimen would be the recommended approach. Current evidence does not support the use of bevacizumab (Avastin®) for pancreatic cancer. In cases such as this, a pathways program can guide the ordering physician in selecting an evidence-supported approach and discourage continuation of a failing regimen. We believe that providing physicians with advanced cancer treatment decision support will translate into improved, cost-effective care. Learn more about AIM’s Integrated Oncology Solution here.

This email was sent by: AIM Specialty Health
8600 W. Bryn Mawr Ave. Ste. 800 Chicago, IL, 60631, USA
     

TRIPLE NEGATIVE BREAST CANCER TREATMENT

The reading about mechanisms of resistance of to Taxol calls for a new strategy for treatment of triple negative breast cancer; while it is true that PARP inhibitor should still be considered in BRCA positive cancers, adding AURORA inhibitors seems to offer logically the best opportunity to increase the activity of proposed first line drugs.

Indeed, triple negative breast cancer assumes that the receptors to conventional stimulants of the breast cancer cell are not functional or responsive.  Therefore, increasing the role of a direct attack of either the nuclear material or the microfilament/microtubule.  Taxol - Cisplatin combination achieves that!  Adding Avastin and other receptor stimulators could be a riskier proposition if you assume a questionable sensitivity of receptor in general.  Your best bet is an action on the Histones and further DNA destruction.  The cell division is your focus here and this is re-emphasized by the importance of CDKs as described by MD Anderson researchers.  As a matter of fact, the AURORA inhibitors by binding to Adenine and to the Histone appear to offer a potential and logical choice to recruit in first line to boost response rates!  So, pending proof of concept, we support the idea of adding Aurora inhibitors to a Taxane-Cisplatin core combination. Some of the Aurora Kinase also target CDKs and JAK2.  These will be my choice for new trials!

After the cancer has seen chemotherapy, endothelial cells have been altered, hypoxia has been triggered by closure of some of the blood vessel closure, the MTOR has been stimulated, we believe adding the MTOR makes more sense.  This has been also suggested after failure of Avastin,  These concepts have been publicized, It is time to move to clinical trial! (FOR THOSE WHO CAN, WE HAVE OUR HANDS TIED BY HUMAN HISTORY!)

AAPS Sues over Maintenance of Certification

SOMEBODY HAD TO SPEAK UP AS THIS CERTIFICATION PROCESS HAS BECOME ALMOST UN-DO-ABLE with intricacies and often undisclosed PASS MARK LEVELS... !
Who in his healthy mind would want to pay dearly and take a very tough exam for which nobody knows what the requirements are to pass (number or % of questions answered correctly) .As a rule now, the exams take place, then all the individual physician's results of the session get corrected and average is computed, to which they then apply a mysterious and never publicized pass mark and then send out the "Pass" and "Fail" letters. We suspect that the computer program is set to always "Fail" at least 33 % of the candidates to assure repeat cash flow thanks to failed candidates having to re-register for an upcoming session. The hospital's requirement of board certification puts undue pressure on specialist and experts of long and good standing and thus deprives the population of valuable medical knowledge and best treatment options.
----------------------
Blog | April 28, 2013 | Healthcare Careers, Performance, Training

By Martin Merritt

The Association of American Physicians & Surgeons (AAPS) filed suit April 23, 2013, against the American Board of Medical Specialties (ABMS) over their maintenance of certification program. The suit, filed in a New Jersey federal court, alleges that the ABMS is restraining trade and causing a reduction in patient access due to burdensome recertification processes.

Jane Orient, MD, the AAPS' executive director, graciously agreed to discuss the issues with me.
Martin Merritt: I understand maintenance of certification (MOC) is one of the hottest topics in the field of medicine today?
Jane Orient: Yes. Many physicians are outraged, not only by the cost an expense which must be incurred to maintain certification, but also by the fear that MOC  is being advanced as a requirement for hospital privileges, and perhaps even maintenance of licensure (MOL).
MM: The public might think the ABMS is a government entity?
Jane Orient, MD JO: The ABMS is a not-for-profit corporation. According to the lawsuit filed by AAPS, the ABMS seems to exist to enrich its own executives, with little appreciable evidence that the MOC program has an effect on the quality of care.
MM: How does the ABMS MOC program actually work?
JO: I can mostly speak about what the lawsuit contains. ABMS and 24 separate corporations, which make up the 24 recognized board-certified specialties have agreed to impose on physicians a recertification program called the ABMS Maintenance of Certification. At one time, a physician could voluntarily choose to become board certified, and upon completion of the process, he or she was board certified for life. Now, the ABMS has decided to force board certified physicians to purchase its products every 10 years. If a physician cannot afford the time or the expense of recertification, he or she may be designated as "not meeting" the requirements of the ABMS, which tends to imply that a physician is less than qualified to care for patients.
MM: What is the AAPS seeking in the suit?
JO: AAPS’ lawsuit, seeks declaratory and injunctive relief to enjoin ABMS’s continuing violations of antitrust law and misrepresentations about the medical skills of physicians who decline to purchase and spend time on its program. AAPS also seeks a refund of fees paid by its members to ABMS and its 24 other corporations as a result of ABMS’ conduct.
Again, the lawsuit itself is the best source for information about the relief requested, but in a nutshell, what we are worried about is the fact that perfectly capable physicians are being black-balled, or locked out of the ability to treat patients, because they do not have the time, or inclination to purchase a product from a private corporation, which has nothing to do with the physician’s ability to treat patients.
MM. You cite an example in the lawsuit, I believe.
JO: In a case cited in this lawsuit, a first-rate physician in New Jersey was excluded from the medical staff at a hospital in his state simply because he had not paid for and spent time on recertification with one of these private corporations. He runs a charity clinic that has logged more than 30,000 visits, but now none of those patients can see him at the local hospital because of the money-making scheme of recertification.
MM: I would like to thank Dr. Orient for speaking with us. You can follow this lawsuit and other issues of concern at the AAPS website.

THE PROOF IS IN!

Docetaxel-cisplatin might be superior to docetaxel-capecitabine in the first-line treatment of metastatic triple-negative breast cancer
ANOTHER CONFIRMATION THAT TRIPLE NEGATIVE  BREAST CANCER IS ANOTHER BEAST ALL TOGETHER.  AS WE HAVE SHOWN, HERE THE RECEPTORS ARE COMPLETELY DESENSITIZED, YOU HAVE TO GO TO MEDICATION DEALING WITH THE FIRST AND SECOND LAWS TO ATTACK THE CELL.  YOU HAVE TO GO "NUCLEAR" BY BREAKING DNA AND INTERFERING WITH MACROTUBULES.
WHAT IS UNCLEAR YET IS HOW THE DISEASE FINALLY ESCAPE.  CISPLATIN RESISTANCE MAY BE THROUGH INCREASING REPAIR OF DNA.

"These data demonstrated that overexpression of c-erbB-2/neu can lead to intrinsic Taxol resistance independent from mdr-1 mechanisms. Funding"  YU ET AL

THIS WAY RATHER!

"AURORA-A amplification overrides the mitotic spindle assembly checkpoint, inducing resistance to Taxol"

• Shubha Anand, 
•  They suggest that AURORA-A amplification will predict poor responsiveness to Taxol and other agents that target the spindle checkpoint. If so, inhibitors of Aurora-A activity may be a valuable adjunct to these agents in the treatment of cancers that overexpress AURORA-A.

"Defective microtubule-kinetochore attachment and spindle formation

Why should elevated Aurora-A activity result in cell cycle abnormalities and chromosomal instability? The yeast ortholog of mammalian Aurora kinases, IPL1p, has been implicated in the mechanisms that regulate the attachment of chromosomes to the mitotic spindle during the metaphase-anaphase transition during mitosis. Several data suggest that IPL1p may work at a proximal position in these mechanisms to regulate steps in the capture of microtubules by kinetochores Biggins et al. 1999 and Li et al. 2002, and after capture, to stabilize correctly attached kinetochores by sensing the tension exerted via bipolar microtubule attachment (Biggins and Murray, 2001). These functions are apparently dependent upon the kinase activity of IPL1p (Biggins et al., 1999).

ALSO:

.".. Aurora-A overexpression in mammalian cells dysregulates these processes," Function of Aurora kinase A in Taxol-resistant breast cancer and its correlation with P-gp
Authors: Yan Li,"

-----------------------------------------OTHER CONTINUE TO BELIEVE:

" Resistance to chemotherapeutic drugs generally, and to Taxol in particular, takes many forms. The best understood mechanism of resistance to Taxol involves the multidrug-resistance phenotype, mediated by the P-glycoprotein efflux pump"

" drug-resistant cancer cell lines and human tumor tissues have been shown to harbor tubulin gene mutations, alterations in total tubulin content, altered microtubule polymer levels, altered expression of tubulin isotypes, and altered microtubule-associated protein expression (13–20). All of these modifications in tubulin could, directly or indirectly, influence microtubule dynamics. Because suppression of microtubule dynamic instability is the event most sensitive to the lowest concentrations of Taxol, we have hypothesized that drug-sensitive and -resistant cells might display altered dynamic instability profiles that could ultimately be responsible for the resistance."

Resistance to Taxol in lung cancer cells associated with increased microtubule dynamics

A. Gonçalves*

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

LAI ET AL BELIEVE

" Taxol (paclitaxel) resistance represents a major challenge in breast cancer treatment. The TAZ (transcriptional co-activator with PDZ-binding motif) oncogene is a major component of the novel Hippo-LATS signaling pathway and a transcriptional coactivator that interacts with and activates multiple transcription factors to regulate various biological processes. Here, we report that elevated levels of TAZ found in human breast cancer cells are responsible for their resistance to Taxol."

" higher level of TAZ in mammary cells may be responsible for their resistance to Taxol."

 AND SAY ALL THIS COULD BE PREDICTED!

Prediction of paclitaxel sensitivity by CDK1 and CDK2 activity in human breast cancer cells

Satoshi Nakayama¹

^{THESE AUTHORS CONTEND:}

"We found that changes in CDK1 specific activity after paclitaxel treatment predicted the paclitaxel sensitivity of breast cancer cells and xenograft tumors. Baseline CDK2 specific activity was higher in tumors that were sensitive to paclitaxel than in tumors that were resistant to paclitaxel."

FURTHERMORE

" We found that an increase in CDK1 specific activity after paclitaxel treatment correlates with sensitivity of the xenografts to paclitaxel, and a lack of change in CDK1 specific activity correlates with a lack of sensitivity of the xenografts to paclitaxel. These findings indicate that analysis of CDK1 activity could be a powerful approach for predicting paclitaxel sensitivity."

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

MOST INTRIGUING THOUGH :

"MICRORNA-125B CONFERS THE RESISTANCE

OF BREAST CANCER CELLS TO

PACLITAXEL THROUGH SUPRESSION OF PRO-APOPTOTIC BCL-2 ANTAGONIST

KILLER 1 ( BAK 1) EXPRESSION"

MING ZHOU ET AL

THIS APPEAR TO BE THE STUFF TO BELIEVE IN BECAUSE IT GOES ALONG WITH HYPOXIA

WE KNOW THAT ENDOTHELIAL DISTURBANCE BY CHEMOTHERAPY INDUCES HYPOXIA OR HYPOXIC CONDITION STRESSING THE CELL, AND INDIRECTLY INDUCING THE MTOR FOR SURVIVAL.   THIS IS MY FAVORITE CHOICE AND CREATE AN OPPORTUNITY FOR MTOR INHIBITION AFTER FAILURE OF CHEMOTHERAPY!

MTOR EQUAL SURVIVAL

Expression of the anti-apoptotic gene survivin correlates with taxol resistance in human ovarian cancer

• N. Zaffaroni,
• M. Pennati,

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

IF YOU WONDER ABOUT TAXOTERE  :   NO CROSS RESISTANCE!

No cross-resistance of taxotere and taxol to conventional chemotherapeutic agents against gastric cancers as detected by MTT assay.

Maeda S, Saikawa Y,

" both intrinsic and acquired TXT-related drug resistance in these PAC cell lines is mainly mediated by P-gp, but had no relationship to MRP and LRP expressions"  lIU ET AL!

----------------------------------------------------------------------------

IN PROSTATE CANCER THIS IS NOT GOOD NEWS HOWEVER GIVEN THE CURRENT PATTERNS OF TREATMENT IN THIS DISEASE

"Abiraterone before Taxotere/Docetaxel chemotherapy may cause resistance to Taxotere/Docetaxel

Started By JimJimJimJim , Jul 13 2012 10:54 AM"  

REPORTEDLY BECAUSE OF COMPETITIVE ACTION OR SIMILARITY OF ACTION ON SAME RECEPTORS.

NEW STUDY from cancer network!

"• Median OS with Avastin plus PC was 12.3 months vs 10.3 months with PC alone (HR=0.80 [95% CI, 0.68–0.94], P=0.013)1 • Patients receiving Avastin plus PC vs PC alone were 16% more likely to be alive at 1 year (51% vs 44%) and 53% more likely to be alive at 2 years (23% vs 15%)2 • Avastin plus PC demonstrated a median progression-free survival of 6.2 months (vs 4.5 months with PC alone, HR=0.66 [95% CI, 0.57-0.77], P<0.001) in Study E4599, based on investigator assessment (not independently verified)1,2 • Avastin plus PC had a response rate of 35% vs 15% with PC alone (P<0.001), based on investigator assessment (not independently verified)2

As shown in Study E4599, Avastin plus PC demonstrated an acceptable safety profile

Most common grade 3–5 adverse events in first-line metastatic non-squamous NSCLC patients (≥2% higher incidence in the Avastin arm)1"

1.BAZIA
Binker et al!
"Acclimation of cellular metabolism to high salt concentrations involved re-modelling of amino acid and protein biosynthesis and increased expression of molecular chaperones (dehydrins, osmotin). Leaves suffered initially from dehydration which resulted in changes in transcript levels of mitochondrial and photosynthetic genes indicating adjustment of energy metabolism."
AtTIL
AtSIS "
This is the stuff of events at the membrane again!

 2. Inflammatory genes!

14	GALINDO_ACT_UP (Inflammatory and apoptosis signaling)	IL1B, CXCL2, ILI8RAP, ILIRN, PTGS2, PDGFB, LILRB4, DUSP1, NFKB1A, IER3, FOSL1, CSF3, ICAM1, CCL3, RREB1, TNFSF9, BCL3, UBC, TNFAIP2, CCL4	2.04	0.008
15	CMV_UV-CMV_COMMON_HCMV_6HRS_UP (IFN and inflammatory signaling)	RSAD2, MX1, OASL, NR4A2, IFIT3, ILI1, ZC3HAV1, RIPK1, PMAIP1, POLG2, ATF3, CREM, GCH1, C12ORF22, PSCD1, NR4A3, BTRC, SLC745, NR4A1

3. SMARCA5.
4. Harvesting Meis1 for the cure
" Meis1 to determine whether doing so produced an effect on the generation of new heart cells in mice."
 U.S. National Library of Medicine - The World's Largest Medical Library
(to be continued)

Does malignant transformation established once permanently PTEN is depressed, or is it when c-MYC is amplified? or is it when receptors are permanently desensitized? is glycosylation of receptor protein or lack of,  the permanent trigger  of neoplastic transformation? will discuss further these topics!
Activation of P53 and mutation of mutation of Rb1.
EGFR amplification could be secondary to blockage at its receptors
PDGFRA amplification also
HOX gene
or mutation at the Meis1 and equivalent genes
No matter what cancers, these events may happen.
We will delve on these paths.

THE QUESTION HAS BEEN RAISED: BIOTIN?

GIVEN THE IMPACT OF BIOTIN USE BY PATIENTS ON LEUCIN AND METHIONINE METABOLISMS, CAN BIOTIN USE COMPROMISE THE EFFECTIVENESS OF MTOR INHIBITORS? 
WE ARE GOING TO EXPLORE FURTHER THIS IMPORTANT QUESTION GIVEN THE GROWING IMPORTANCE OF MTOR INHIBITOR IN OUR ARMAMENTARIUM AGAINST CANCER AND THE WIDESPREAD USE OF BIOTIN IN OUR POPULATION!  (OR MULTIVITAMIN). WE ALSO KNOW THAT MOST OF US PRODUCE ENOUGH BIOTIN IN OUR COLON FOR DAILY NEED, BUT IS IT OF IMPORTANCE TO TRY TO SEE LEVELS OF BIOTIN IN PATIENTS WITH RESISTANT DISEASES?  IS DECREASING BIOTIN FROM THE BOWEL TO BE PURSUED IN PATIENTS ON MTOR INHIBITORS?  WILL SEARCH FURTHER THIS QUESTION!

YOU WANT TO TRY SOMETHING NEW AGAINST SARCOMA AND LEUKEMIA
GO AFTER THESE GENES!

SATB1

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SATB homeobox 1
PDB rendering based on 1yse.
Available structures PDB Ortholog search: PDBe, RCSB [show]List of PDB id codes
Identifiers
Symbol	SATB1
External IDs	OMIM: 602075 MGI: 105084 HomoloGene: 2232 GeneCards: SATB1 Gene
[show]Gene Ontology
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	6304	20230
Ensembl	ENSG00000182568	ENSMUSG00000023927
UniProt	Q01826	Q60611
RefSeq (mRNA)	NM_001131010	NM_001163630
RefSeq (protein)	NP_001124482	NP_001157102
Location (UCSC)	Chr 3: 18.39 – 18.49 Mb	Chr 17: 51.74 – 51.83 Mb
PubMed search	[1]	[2]

SATB1 (special AT-rich sequence-binding protein-1) is a protein which in humans is encoded by the SATB1 gene.^[1]

Function

SATB1, the global chromatin organizer and transcription factor, has emerged as a key factor integrating higher-order chromatin architecture with gene regulation.^[2] Recent studies have unraveled the role of SATB1 in organization of chromatin 'loopscape' and its dynamic nature in response to physiological stimuli.^[3] At genome-wide level, SATB1 seems to play a role in organization of the transcriptionally poised chromatin. SATB1 organizes the MHC class-I locus into distinct chromatin loops by tethering MARs to nuclear matrix at fixed distances. Silencing of SATB1 mimics the effects of IFN-γ treatment on chromatin loop architecture of the MHC class I locus and altered expression of genes within the locus. SATB1 has also been shown to induce breast cancer tumor growth and metastasis through the altered expression of large numbers of genes.

Interactions

SATB1 has been shown to interact with HDAC1,^[4] SMARCA5,^[4] MTA2,^[4] CHD4,^[4] CUTL1,^[5] POLR2J^[6] and BAZ1A.^[4]

2. HDAS1
3.SMARCA5
4.MTA2
5.CHD4
6.CUTL1
7.POLR2J
8.BAZIA

MASTERING OF SOME GENES CONTROLLING RECEPTOR FUNCTIONS!

1.SLIT 2    Slit homolog 2 protein is a protein that in humans is encoded by the SLIT2 gene
                SLIT2 has been shown to interact with Glypican 1
 Cell surface heparan sulfate proteoglycans are composed of a membrane-associated protein core substituted with a variable number of heparan sulfate chains. Members of the glypican-related integral membrane proteoglycan family (GRIPS) contain a core protein anchored to the cytoplasmic membrane via a glycosyl phosphatidylinositol linkage. These proteins may play a role in the control of cell division and growth regulation.<sup>[2]  WIKIPEDIA

IF YOU RECALL OUR DISCUSSION  ABOUT RECEPTOR FAILURE, TUMOR GROWTH FACTOR FAILED TO STIMULATE OUR RECEPTOR BECAUSE OF LACK OF DERENGEMENT OF GLYCOSYLATION AND HEPARAN WAS THE FAILURE.  THIS PUT SLIT 2 AT THE RECEPTOR PARTICULARLY IN THE CENTRAL NERVOUS SYSTEM!</sup>
                              
2.MIG6:   The cytoplasmic protein MIG6 (mitogen-induced gene 6; also known as ERRFI1) interacts with and inhibits the kinase domains of EGFR and ERBB2 (refs 3–5). Crystal structures of complexes between the EGFR kinase domain and a fragment of MIG6 show that a 25-residue epitope (segment 1) from MIG6 binds to the distal surface of the C lobe of the kinase domain. Biochemical and cell-based analyses confirm that this interaction contributes to EGFR inhibition by blocking the formation of the activating dimer interface.(ZANG ET AL!)
 MIG-6 Negative regulator of EGFR signaling in skin morphogenesis. Acts as a negative regulator for several EGFR family members, including ERBB2, ERBB3 and ERBB4. Inhibits EGFR catalytic activity by interfering with its dimerization. Inhibits autophosphorylation of EGFR, ERBB2 and ERBB4. Important for normal keratinocyte proliferation and differentiation. Plays a role in modulating the response to steroid hormones in the uterus. Required for normal response to progesterone in the uterus and for fertility. Mediates epithelial estrogen responses in the uterus by regulating ESR1 levels and activation. Important for regulation of endometrium cell proliferation. Important for normal prenatal and perinatal lung development. Interacts with ERBB2. Interacts with EGFR. Levels are very low in quiescent cells. Up-regulated by mitogens. Belongs to the MIG6 family. Note: This description may include information from UniProtKB.

3.  SATB1  HERE BECAUSE OF THE CONNECTION WITH NUCLEAR MATERIAL.  interferon gamma act through here!

4.  SMAD6
Another powerful decoy
" Smad6 specifically competes with Smad4 for binding to receptor-activated Smad1, yielding an apparently inactive Smad1-Smad6 complex. Therefore, Smad6 selectively antagonizes BMP-activated Smad1 by acting as a Smad4 decoy."  Hata et al
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LTB4, because of its interactions with

Peroxisome proliferator-activated receptor gamma has been shown to interact with:

• EDF1^[8][9][10]
• EP300^[11][12]
• HDAC3^[13][11]
• MED1^[12]
• NCOA3^[12]
• NCOA4^[14]
• NCOA2^[12]
• NR0B2^[15]
• PPARGC1A^[16][17]
• RB1.^[11]

Clinical relevance

PPAR-gamma has been implicated in the pathology of numerous diseases including obesity, diabetes, atherosclerosis, and cancer. PPAR-gamma agonists have been used in the treatment of hyperlipidaemia and hyperglycemia.^[18] PPAR-gamma decreases the inflammatory response of many cardiovascular cells, particularly endothelial cells.^[19] PPAR-gamma activates the PON1 gene, increasing synthesis and release of paraoxonase 1 from the liver, reducing atherosclerosis.^[20]
Many insulin sensitizing drugs (namely, the thiazolidinediones) used in the treatment of diabetes target PPARG as a means to lower serum glucose without increasing pancreatic insulin secretion.
A fusion protein of PPAR-γ1 and the thyroid transcription factor PAX8 is present in approximately one-third of follicular thyroid carcinomas, to be specific those cancers with a chromosomal translocation of t(2;3)(q13;p25), which permits juxtaposition of portions of both genes.^{[21] [22]}
Recently pioglitazone, a PPAR-γ agonist has been shown to be effective in reducing inflammation in Parkinson's Disease models. Levels of MMPs and microglia (and therefore TNF-α and other cytokine levels) were found to be reduced. Thus it has been shown to be neuroprotective in MPTP mouse models.

BMP2

The protein encoded by this gene belongs to the transforming growth factor-beta (TGFB) superfamily. The encoded protein acts as a disulfide-linked homodimer and induces bone and cartilage formation. [provided by RefSeq, Jul 2008]

DERLINS, A STRONG MECHANISM OF NEOPLASTIC TRANSFORMATION IN BREAST CANCER BECAUSE IT LEADS TO FAILURE OF RECEPTORS!

We have seen that the cellular membrane is one of the most important part to the cell not only because it gives a limit to the cell, but also because of its content and attachment.  The cell provide a boundary to the cell content, it has flippase and floppase/scramblases to maintain certain molecules in or outside its boundaries at a certain gradient, it is full of integrins of all kind of function, it contains the "nervous system" of the cell,  through its reticulum endothelium, it connects rapidos with the Nucleus, and contains all kind of receptors to various stimulant.

We have also explained how receptors' (part of cellular membrane) failure lead to neoplastic transformation by over-stimulation related co-receptors susceptible to same growth factor!   What we did not elaborate on was how a receptor can fail!   AND HERE COME THE DERLINS and the IRHOMS!
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WIKIPEDIA
Derlin-1 also known as degradation in endoplasmic reticulum protein 1 is a protein that in humans is encoded by the DERL1 gene.^[1][2][3] It is a member of the rhomboid-like clan of polytopic membrane proteins.

Function

Derlin-1 is part of a complex (that includes VIMP, SEL1, HRD1, and HERP) that mediates endoplasmic-reticulum-associated degradation (ERAD) that detects misfolded proteins in the endoplasmic reticulum and targets them for destruction.^[4]

Clinical significance

Derlin 1 (DERL1) is up-regulated in metastatic canine mammary tumors as part of the unfolded protein response.

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IT is our understanding that growth factors, some of which are integrins, some are anchored to the membrane from which they need to spring into motion and complete their function.  There is of course an enzyme that lyse the anchor.  Enzymatic proteins in charge of freeing the growth factors, the cyclins and second messengers to the receptors belong to the clan of the Rhomboid-like proteins.  The Derlins are part of a complexe as stated.  To better understand the derlins let's go back to the cytosol where Ubiquitination attaches ubiquitin to a molecule tagging it to proteasome degradation, the derlins tag membrane proteins for degration by the ERAD complex in the Endoplasmic Reticulum.  The derlin seems to impose a certain folding to the protein (growth hormone) a certain folding incompatible with their use, and therefore destine them to destruction.
It has been shown that upregulation of derlins completely rob the receptors from having  appropriate stimulation by its corresponding growth factors.  Decoy receptor will also take a portion of the growth receptor.  Just remember they do not have the intracellular portion of the receptor so the second messenger will never be stimulated.
====================================================
The Irhoms are decoy Rhomboid like protein.  They are like the enzyme but missing the catalytic teeth to cut the anchor but can attach to the integrins and change it enough to destine it to destruction by the ERAD.

" ZETTL ET AL.
iRhoms are a conserved subfamily of proteins related to rhomboid intramembrane serine proteases that lack key catalytic residues....iRhoms prevent the cleavage of potential rhomboid substrates by promoting their destabilization by endoplasmic reticulum (ER)-associated degradation;"

RHBDF1

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Rhomboid 5 homolog 1 (Drosophila)
Identifiers
Symbols	RHBDF1; C16orf8; Dist1; EGFR-RS; gene-89; gene-90; hDist1
External IDs	OMIM: 614403 MGI: 104328 HomoloGene: 32085 GeneCards: RHBDF1 Gene
[show]Gene Ontology
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	64285	13650
Ensembl	ENSG00000007384	ENSMUSG00000020282
UniProt	Q96CC6	Q6PIX5
RefSeq (mRNA)	NM_022450	NM_010117
RefSeq (protein)	NP_071895	NP_034247
Location (UCSC)	Chr 16: 0.11 – 0.13 Mb	Chr 11: 32.21 – 32.22 Mb
PubMed search	[1]	[2]
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Inactive rhomboid protein 1 (iRhom1) also known as rhomboid 5 homolog 1 or rhomboid family member 1 (RHBDF1) is a protein that in humans is encoded by the RHBDF1 gene.^[1][2][3] The alternative name iRhom1 has been proposed, in order to clarify that it is a catalytically inactive member of the rhomboid family of intramembrane serine proteases.