May 6, 2013 Dear Dr. Kankonde, When I was approached by Medscape to become the new Editor-in-Chief, I was thrilled. Why? It certainly wasn't because I was looking for more to do, with multiple roles at Scripps Health, Scripps Clinic, and The Scripps Research Institute. The reason: Medscape is the largest electronic/digital network of physicians in the world. Millions of doctors and other healthcare professionals look to Medscape for the most useful, practical information to help their patients and their practice. This is the most exciting, momentous time in the history of medicine. For the first time, we can rapidly and affordably sequence a human genome. We have sensors that can remotely track virtually any physiologic metric, from vital signs to glucose to intraocular pressure. We can add a lab-on-a-chip to a smartphone to assay almost any routine chemistry and digitize pills to ensure adherence. Or use a smartphone to conduct all the components of the physical examination. This is superimposed and convergent with a remarkable digital infrastructure that includes ever-increasing bandwidth, pervasive connectivity, cloud- and supercomputing, enormous social networks, and those little mobile devices that we cannot put down. Medicine is thus poised for its biggest shakeup ever as it transforms to a more precise, individualized, and democratized model. My charge at Medscape is to help capture this excitement, the changes and opportunities, along with the challenges and the need for validation. Medscape will be expanding its breadth of coverage in areas that will be rebooting, which include not only diagnostics, imaging, and medical devices but also the operational aspects of office visits, hospitals, and medical informatics. We have an outstanding team of experts across all medical disciplines, and we'll provide you with timely and insightful commentary on the most important topics in medicine. We intend to take Medscape to the next level, one that embraces the need for change and zooms in on the ways to get there -- the ways to provide better, more efficient care for your patients. We are all connected, with only a few electrons that separate us. I welcome your ideas and feedback about Medscape, so please direct emails to etopol@medscape.net or follow me on Twitter at @EricTopol. Sincerely, Eric J. Topol, MD Editor-in-Chief of Medscape

PHENOMENA SUGGESTING EVOLUTION OF GENETIC AND METABOLIC PROCESSES!

*It is now suggested that as receptor fail, there is a secondary increase of its specific growth factors which lead to stimulation of other susceptible receptors including MUC gene.  What trigger the neoplastic transformation is fuzzy.  However we know that the quantity of stimulation, the persistence of the stimulation, the stress induced at the failing receptor, stress which induces the NF-kB, c-JUN and eventually c-Fos and c-MYC the gene global amplifier, methylation of genes and reversal of mesenchymal transformation at MEK most likely, with its impact on EGFR.   And through the RAS/MAPK,  which interacts with PTEN, by now repressed!   Neoplastic transformation is bound to happen.  Particularly on a background of genetic Heterogenity, something unpredictable is bound to happen!

*The closeness of VEGF and Hypoxic stress/ phenomena is now legendary!   Hypoxia is disturbing at cellular membrane but principally in the Mitochondria where the respiratory system of the cell is located.
It leads to formation of (Reactive oxygen species) superoxide and oxygen free radicals that need dampen by natural anti-oxidants which by the way include Uric Acid.  Because of lack of these anti-oxidant (Asian "obsession" with veggies, in a subset of Asians, we hypothesize that insufficient anti-Oxidant and certain genetic susceptibility factor, ultimately lead to a number of Mutations including EGFR Mutation.  Effects on other genes including the MUC2 gene will lead to respiratory system failure, in other words, occurrence of lung cancer (Adenocarcinoma) in these women. Sex/Steroid receptors in female patients may be involved in the susceptibility.  The story does not stop here however since the Mitochondria takes the full effect of MTOR, the preserver of survival,  As the process evolve, the MTOR will take the brunt of the changes and therefore will be increasingly important suggesting MTOR are more important after failure of Anti-VEGF!  It is not surprising that combination of the 2 agents failed.  VEGF effect seems to depend on MTOR preservation at some level but once the VEGF is incapacitated (resitant disease) MTOR inhibition is a logical step!

Reelin

From Wikipedia, the free encyclopedia

Jump to: navigation, search

Reelin
Crystallographic structure of the third reelin repeat domain.[1]
Available structures PDB Ortholog search: PDBe, RCSB [show]List of PDB id codes
Identifiers
Symbols	RELN; LIS2; PRO1598; RL
External IDs	OMIM: 600514 MGI: 103022 HomoloGene: 3699 GeneCards: RELN Gene
EC number	3.4.21.-
[show]Gene Ontology
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	5649	19699
Ensembl	ENSG00000189056	ENSMUSG00000042453
UniProt	P78509	Q60841
RefSeq (mRNA)	NM_005045	NM_011261
RefSeq (protein)	NP_005036	NP_035391
Location (UCSC)	Chr 7: 103.11 – 103.63 Mb	Chr 5: 21.88 – 22.34 Mb
PubMed search	[1]	[2]
This box: view talk edit

Reelin is a large secreted extracellular matrix glycoprotein that helps regulate processes of neuronal migration and positioning in the developing brain by controlling cell–cell interactions. Besides this important role in early development, reelin continues to work in the adult brain. It modulates synaptic plasticity by enhancing the induction and maintenance of long-term potentiation.^[2][3] It also stimulates dendrite^[4] and dendritic spine^[5] development and regulates the continuing migration of neuroblasts generated in adult neurogenesis sites like subventricular and subgranular zones. It is found not only in the brain, but also in the spinal cord, blood, and other body organs and tissues.
Reelin has been suggested to be implicated in pathogenesis of several brain diseases. The expression of the protein has been found to be significantly lower in schizophrenia and psychotic bipolar disorder, but the cause of this observation remains uncertain as studies show that psychotropic medication itself affects reelin expression. Moreover, the epigenetic hypothesis aimed at explaining the changed levels^[6] has received some contradictory evidence.^[7][8] Total lack of reelin causes a form of lissencephaly. Reelin may also play a role in Alzheimer's disease, temporal lobe epilepsy and autism.
Reelin's name comes from the abnormal reeling gait of reeler mice,^[9] which were later found to have a deficiency of this brain protein and were homozygous for mutation of the RELN gene. The primary phenotype associated with loss of reelin function is a failure of neuronal positioning throughout the developing central nervous system (CNS). The mice heterozygous for the reelin gene, while having little neuroanatomical defects, display the endophenotypic traits linked to psychotic disorders.<sup>[10]WIKIPEDIA


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NEXT INTEREST AT CRBCM</sup>

Crizotinib (trade name Xalkori,^[1] Pfizer), is an anti-cancer drug acting as an ALK (anaplastic lymphoma kinase) and ROS1 (c-ros oncogene 1) inhibitor, approved for treatment of some non-small cell lung carcinoma (NSCLC) in the US and some other countries, and undergoing clinical trials testing its safety and efficacy in anaplastic large cell lymphoma, neuroblastoma, and other advanced solid tumors in both adults and children.<sup>[2]WIKIPEDIA

CONCEPTUALLY, THROUGH ITS PTPN6 ACTIVITY, THIS DRUG SHOULD HAVE SIGNIFICANT JAK-2 ACTIVITY AND SHOULD THEREFORE HAVE A ROLE IN MYELOPROLIFERATIVE DISORDERS THAT HAVE JAK-2 POSITIVITY, AND IN FACT THROUGH THE SAME, IT HAS EFFECT ON THE ERYTHROPOIETIN RECEPTOR!</sup>

VARIOUS NEWS

*FOR patients on chronic Doxil,  watch for
-Renal failure
-squamous cell cancer of the tongue and oral cavity as a secondary malignancy
-and of course the hand foot syndrome

prolonged exposure to Anti-topoisomerase II (doxo,epirubicin)
leads to APL,AML and MDS.In children, various pediatric malignancies have been reported.   

*Adding Pertuzumab to Trastuzumab plus Taxotere did not add to cardiac toxicity in Cleopatra!

*ixabepilone may induce radiation recall and decreased wound healing.

*10-20% of patients treated develop grade 3 Hypertension side effect, and development of Hypertension is not predictive of response to therapy!
*In cancer of the Salivary duct, the Her-2 status may be important since use of Herceptin can impact survival!

*Up to 95% of patients treated with Vemurafenib (used in BRAF positive Melanoma) will develop a dermatologic side effect to be treated supportively.  Dose interruptions or modification occurs in less than 10% of cases only!

*Breast implant can be associated with the development of a CD30 Anaplastic ALK negative large cell lymphoma  (ALCL).

HER-2 REVIEW/ FROM MEDSCAPE Mechanisms and Actions of HER2-Targeting Agents in Breast Cancer Dear Dr. Mutombo Kankonde, Below are some key learning points to help reinforce the educational impact of this activity. Recommended Activities Clinical Application of HER2-Directed Therapies in Breast Cancer Oncology Exchange: Emerging Agents in HER2-positive Breast Cancer Case Challenges: First-Line Treatment for Newly Diagnosed HER2-Positive Metastatic Breast Cancer Emerging HER2-Targeted Options for Advanced Breast Cancer Targeting HER2: Developmental Milestones More than 20 years have passed since the discovery that patients with breast cancer who overexpressed the HER2 protein or had amplification of this gene had a poor prognosis, and since the clinical development of the anti-HER2 monoclonal antibody trastuzumab, which has revolutionized the treatment of this disease, began. In 2005, data from 2 large randomized trials (NSABP B-31 and  NCCTG N9831) that evaluated a conventional adjuvant cytotoxic regimen, plus or  minus trastuzumab,  were reported. The success with trastuzumab led to further research and development  of pertuzumab,  a novel monoclonal antibody that was recently approved for first-line  treatment of  metastatic breast cancer in conjunction with trastuzumab and  docetaxel based on  the results of the CLEOPATRA trial. Trastuzumab and Pertuzumab: Mechanisms of Action Trastuzumab inhibits ligand-independent HER2 signaling, activates  antibody-dependent  cellular cytotoxicity, and prevents HER2 extracellular domain shedding. Pertuzumab inhibits ligand-dependent HER2 dimerization and signaling,  while also  activating antibody-dependent cellular cytotoxicity. Ado-Trastuzumab-Emtansine (T-DM1): Antibody-Drug Conjugate T-DM1 consists of the trastuzumab antibody as a backbone, a linker,  and a  cytotoxic, a maytansinoid compound that is 20 to 100 times more  potent than  the commonly used vinca alkaloids. Upon binding to HER2, T-DM1 is internalized by the cancer cell,  disrupting  the linker and releasing the cytotoxic agent, which eventually kills  the cancer cell. Encouraging results seen in phase 1 and 2 trials led to the pivotal  EMILIA  phase 3 trial that compared T-DM1 with the combination of  lapatinib plus  capecitabine. T-DM1 was recently approved by the US Food  and Drug  Administration (FDA) for treatment of patients with HER2-positive  metastatic  breast cancer who have received prior treatment with trastuzumab  and taxane  chemotherapy. Phase 3 EMILIA Trial One of the most important outcomes of this study is the duration  of response  to T-DM1, which is double that seen with capecitabine and lapatinib. Substantial improvement was seen in progression-free survival for  all patients  receiving T-DM1, regardless of their geographic location, amount  of prior  therapy received, presence of visceral disease, or estrogen  receptor/progesterone  receptor status. Patients in the T-DM1 arm had a median overall survival exceeding  30 months.  Median overall survival for those in the capecitabine/lapatinib arm  was 25 months,  which compared favorably with the 16 months seen in the original trial of  capecitabine/lapatinib. With regard to nonhematologic toxicities and most other adverse  events, results  strongly favored T-DM1. Investigational T-DM1/Pertuzumab Combination Preliminary data from a phase 1b/2 study showed that subjects  tolerated full doses  of both of these antibodies. Despite the fact that patients had had multiple prior lines of therapy  (up to 14 prior  regimens), more than one-third achieved disease regression or a  durable response  with the dual antibody combination. These data led to a first-line phase 3 trial (BO22589/TDM4788g,  MARIANNE)  in which patients with metastatic breast cancer are randomly assigned  to receive  either a control arm of trastuzumab plus a taxane (either docetaxel or  paclitaxel  at the investigator's choice); the dual antibodies T-DM1 plus pertuzumab;  or only  the targeted therapy, T-DM1. The trial results should be reported next  year and  are expected to help clarify how best to use these antibodies. Other HER2-Targeting Agents Lapatinib is an FDA-approved, orally available dual tyrosine kinase  inhibitor  of HER2 and epidermal growth factor receptor. A study of the  combination  of lapatinib and trastuzumab in patients with metastatic breast cancer  yielded  promising data, and the FDA-approved regimen of lapatinib plus  capecitabine  is an all-oral option for patients who have had disease  progression on  trastuzumab. For patients with estrogen receptor-positive and  HER2+ breast  cancer, a combination of letrozole and lapatinib is another all-oral,  non-cytotoxic  option. Neratinib is an investigational oral, multi-targeted, irreversible  tyrosine kinase  inhibitor. As the clinical development of neratinib moves forward,  several  strategies are being proposed to limit the diarrhea and gastrointestinal  toxicities  associated with this potentially promising agent. Afatinib, another investigational tyrosine kinase inhibitor, is being  studied in a  randomized phase 3 trial that is currently recruiting participants  (ClinicalTrials.gov  Identifier: NCT01125566). Future Developments A number of new treatment combinations and strategies currently  in clinical trials  are expected to result in continued improvements in the treatment  of patients  with HER2-positive breast cancer. Building on the results seen in the metastatic setting, these drugs  may move into  the adjuvant and neoadjuvant settings. Kind regards, Howard A. Burris III, MD Chief Medical Officer Executive Director, Drug Development Program Sarah Cannon Research Institute Nashville, Tennessee Emir Hadzic, PhD Scientific Director Medscape, LLC

Supported by an independent educational grant from Genentech.

JAMA Updates

*JAMA
"In the United States, there was a substantial decrease in mortality rates over time among children and adolescents initiating ESKD treatment with dialysis between 1990 and 2010. Further research is needed to determine the specific factors responsible for this decrease."
*Antiplatelet agents reduce myocardial infarction but increase major bleeding. Risks may outweigh benefits among people with low annual risks of cardiovascular events, including those with early stages of CKD who do not have clinically-evident occlusive cardiovascular disease. (PALMER ET AL)
*Although antioxidant therapy does not reduce the risk of cardiovascular and all-cause death or major cardiovascular events in people with CKD, it is possible that some benefit may be present, particularly in those on dialysis. However, the small size and generally suboptimal quality of the included studies highlighted the need for sufficiently powered studies to confirm this possibility. Current evidence suggests that antioxidant therapy in predialysis CKD patients may prevent progression to ESKD; this finding was however based on a very small number of events. Further studies with longer follow-up are needed for confirmation. Appropriately powered studies are needed to reliably assess the effects of antioxidant therapy in people with CKD.    JUN ET AL

*Pigeon heart mitochondria produce H(2)O(2) at a maximal rate of about 20nmol/min per mg of protein. BOVERIS ET AL

* Food restriction (FR) is a well-recognized method of extending mean and maximum longevity of rodents, but the mode of its action remains to be uncovered. This article reviews the effect of FR on the physical-chemical properties and lipid peroxidizability of cellular membranes. FR prevents the age-dependent increase in microviscosity and peroxidizability of cellular membranes. It has been suggested that a decrease in the body temperature occurring in undernourished animals may play a fundamental role in the process. Indeed, the lowering of average body temperature occurring in FR animals may induce a modification in membrane lipid composition, stimulating the cells to counteract the rigidifying effect of lower temperature. Thus, membranes are maintained in a proper functional state by a mechanism similar to that found in poikilotherm animals.   AGE ET AL

*All cellular membranes are especially vulnerable to oxidation due to their high concentration of polyunsaturated fatty acids. These processes combine to produce changes in the biophysical properties of membranes that can have profound effects on the activity of membrane-bound proteins. This review deals with aspects for lipid peroxidation of biological membranes in general, but with some emphasis on changes of polyunsaturated fatty acids, which arise most prominently in membranes and have been studied extensively in our laboratory. The article provides current information on the effect of melatonin on biological membranes, changes in fluidity, fatty acid composition and lipid-protein modifications during the lipid peroxidation process of photoreceptor membranes and modulation of gene expression by the hormone and its preventive effects on adriamycin-induced lipid peroxidation

The ability of melatonin to counteract lipid peroxidation in biological membranes.

Catalá A.

Reactive oxygen species (ROS)

This is scary stuff that makes you think free radical build up is the cause of strokes, coronary artery disease and dementia!  with uric acid one of our best defense, it makes you wonder if too much use of diuretics inducing low uric acid is contributing to these events.  Makes you want to take coQ10 and vitamin C quickly!  and reenforce the notion that one apple a day will keep the doctor away!

COULD ROS EXPLAIN LUNG CANCER OCCURRENCE IN ASIAN WOMEN WHO DEVELOP ADENOCARCINOMA? AND IF SO coQ, VITAMIN C COULD PREVENT THESE CANCERS?

Asian women nonsmokers with NSCLC have a high rate of EGFR + mutations and they have a better prognosis also. Could ROS be the underlying deficiency?

Zhang et al!

"Once thought of as toxic by-products of cellular metabolism, reactive oxygen species (ROS) have been implicated in a large variety of cell-signaling processes. Several enzymatic systems contribute to ROS production in vascular endothelial cells, including NA(D)PH oxidase, xanthine oxidase, uncoupled endothelial nitric oxide synthase, and the mitochondrial electron transport chain. The respiratory chain is the major source of ROS in most mammalian cells, but the role of mitochondria-derived ROS in vascular cell signaling has received little attention. A new paradigm has evolved in recent years postulating that, in addition to producing ATP, mitochondria also play a key role in cell signaling and regulate a variety of cellular functions. This review focuses on the emerging role of mitochondrial ROS as signaling molecules in vascular endothelial cells. Specifically, we discuss some recent findings that indicate that mitochondrial ROS regulate vascular endothelial function, focusing on major sites of ROS production in endothelial mitochondria, factors modulating mitochondrial ROS production, the physiological and clinical implications of endothelial mitochondrial ROS, and methodological considerations in the study of mitochondrial contribution to vascular ROS generation."
 WIKIPEDIA!
" Normally, cells defend themselves against ROS damage with enzymes such as alpha-1-microglobulin, superoxide dismutases, catalases, lactoperoxidases, glutathione peroxidases and peroxiredoxins. Small molecule antioxidants such as ascorbic acid (vitamin C), tocopherol (vitamin E), uric acid, and glutathione also play important roles as cellular antioxidants. In a similar manner, polyphenol antioxidants assist in preventing ROS damage by scavenging free radicals. In contrast, the antioxidant ability of the extracellular space is less - e.g., the most important plasma antioxidant in humans is uric acid."

WHAT IS THE AFFECTED WOMEN'S LEVEL OF URIC ACID?
ARE THESE WOMEN TAKING A URICOSURIC?

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

UNDER HYPOXIC CONDITIONS, LACK OF ATP AND DECREASED coQ, A DANGER START GROWING IN THE MITOCHONDRIA, SUPEROXIDE ARE BUILDING UP AND UNLESS CONDITIONS CHANGE OR UNLESS THE ABOVE ENZYMES INTERVENE TO DILUTE THE SITUATION, THE OXIDE FREE RADICAL WILL SPILL OVER THE CYTOSOL  (CYTOCHROME B WILL ALSO BE INVOLVED) WHERE THEY WILL OXYDIZE VARIOUS MOLECULES AND INDUCE INFLAMMATORY AND POTENTIALLY NEOPLASTIC PROCESSES!

" In general, harmful effects of reactive oxygen species on the cell are most often:^[4]

1. damage of DNA
2. oxidations of polyunsaturated fatty acids in lipids (lipid peroxidation)
3. oxidations of amino acids in proteins
4. oxidatively inactivate specific enzymes by oxidation of co-factors"

Metabolic adaptation in tumours balances the cells' need for energy with equally important need for macromolecular building blocks and tighter control of redox balance. As a result, production of NADPH is greatly enhanced, which functions as a cofactor to provide reducing power in many enzymatic reactions for macromolecular biosynthesis and at the same time rescuing the cells from excessive ROS produced during rapid proliferation. Cells counterbalance the detrimental effects of ROS by producing antioxidant molecules, such as reduced glutathione (GSH) and thioredoxin (TRX), which rely on the reducing power of NADPH to maintain their activities.^[19]
Most risk factors associated with cancer interact with cells through the generation of ROS. ROS then activate various transcription factors such as nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), activator protein-1 (AP-1), hypoxia-inducible factor-1α and signal transducer and activtor of transcription 3 (STAT3), leading to expression of proteins that control inflammation; cellular transformation; tumor cell survival; tumor cell proliferation; and invasion, agiogenesis as well as metastasis. And ROS also control the expression of various tumor supressor genes such as p53, retinoblastoma gene (Rb), and phosphatase and tensin homolog (PTEN).<sup>[20]"

HOW THESE DRAMATIC EVENTS IMPACT THE MUC GENES FAMILY AND EGFR HAS NOT BEEN DESCRIBED FULLY AND COULD EXPLAIN HOW IN THE LUNG, AN ADENOCARCINOMA COULD RESULT.  THE GOOD RESPONSE TO ANTI EGFR POINT TO A SINGLE CAUSAL EVENT THAT IS REVERSED OR ATTENUATED BY INITIATION OF TARCEVA AND RELATED MOLECULES.  BEING MITOCHONDRIAL, IT MAY BE A CLUE TO MTOR INHIBITOR ACTIVITY AFTER FAILURE OF EGFR (SECOND LINE AS DISCUSSED PREVIOULSY)</sup>

*THE FDA AND MORE SPECIFICALLY ODAC SAYS NO TO TIVOZANIB IN METASTATIC RENAL CELL CANCER.   TIVOZANIB, a second generation anti-VEGF kinase was being tested against Nexavar.  The panel was not convinced enough to let it win approval.  17 studies were globally reviewed to arrive to this conclusion which will not let the drug moving forward!

*from Medscape
"New guidelines on prostate cancer screening, issued today by the American Urological Association (AUA), are supportive of routine use of the prostate-specific antigen (PSA) test in healthy men, but only for a specified age group, and only after discussion between a man and his physician.
Specifically, the new guidelines state that men 55 to 69 years of age who are at average risk and asymptomatic can consider PSA screening. They should speak to the their physician about the benefits and harms of testing to determine the best course of action." go to full article.

Case study

A 65 year old man came to our clinic with weakness
he was found with mild pancytopenia
the marrow was hypercellular and the cytogenic findings on the bone Marrow suggested del 5q
RAEB-1 was the comment of the pathologist based on blast count
and the rate of Erythrpoietin was below 500.

standard recommendation per the Atlas of Genetics

Treatment ofthis condition in the elderly patient is largely supportive, including blood transfusion in patients with symptomatic anemia. Anemic patients with low serum erythropoietin (EPO) levels may benefit of the administration of rHu-EPO. Low dose cytarabine can be used to reduce the burden of blasts. Myeloablative regimens including anthracyclines and cytarabine in conventional or high doses can be used in high-risk patients under 60 years. Allogeneic bone marrow transplantation may offer a chance of cure in young patients.
Evolution	This is an oligoblastic leukemia, carrying a 20-40% probability of evolving into leukemia. In a study approximately 25% of the patient developed acute myeloid leukemia (AML) within 18 months. The probability of RAEB to transform into AML is lower in the RAEB-1 group (approximately 50% of the patients develop acute leukemia within 6 years) than in the RAEB-2 group (approximately 50% at 18 months with overt leukemia).
Prognosis	Median survival of RAEB falls in the 1-2 year range. The best outcome is usually observed in RAEB-1. Chromosomal abnormalities have independent prognostic significance and are to be included in risk assessment at diagnosis. Favourable cytogenetic features are normal karyotype, 5q- or 20q- isolated; unfavourable features are complex karyotype (i.e. 3 or more clonal anomalies) and abnormalities of chromosome 7q; other abnormalities identify patients in the intermediate cytogenetic-risk group.

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

BASED ON ONLY ONE FINDING
5q deletion
most oncologists will propose REVLIMID to this patient
that is the power of Genetic findings!

and indeed if a complex Cytogenetic finding was present and no 5q minus, Azacytidine would have been the choice in the UNITED STATES....
==========so what is 5q minus?

AZACYTIDINE
generally given at 75mg/m2 SC 7 days per months
achieves 7% complete response and 16% partial remission with most response reached after 3 to 4 months of therapy.  It also decreases the AML transformation and improves survival (11 Vs 18 months)

CLINICAL RESEARCH QUESTIONS:

1. COULD ANTIBODY TO MBD3 (AND OR  MTA2) BLOCK OR SLOW METASTASIS?
2.IS ANTI-NuRD A POWERFUL INHIBITOR OF HISTONE DEACETYLASE?  AND WHAT COULD BE ITS ROLE IN LEUKEMIAS!

LET'S GO TO WORK, PEOPLE!

CRBCM, AN INTERNATIONAL AWARD WINNER !  WE ARE STEADILY ADVANCING!

DISRUPTION AT BRCA IS TRULY BAD FOR OUR PATIENTS!

Before we start this discussion, let's remind ourselves what we know about the BRCAs by taking the example of BRCA-1
"
BRCA1 is expressed in the cells of breast and other tissue, where it helps repair damaged DNA, or destroy cells if DNA cannot be repaired. If BRCA1 itself is damaged, damaged DNA is not repaired properly and this increases risks for cancers (see BRCA mutation).^[7][8]
The protein encoded by the BRCA1 gene combines with other tumor suppressors, DNA damage sensors, and signal transducers to form a large multi-subunit protein complex known as the BRCA1-associated genome surveillance complex (BASC).^[9] The BRCA1 protein associates with RNA polymerase II, and through the C-terminal domain, also interacts with histone deacetylase complexes. Thus, this protein plays a role in transcription, DNA repair of double-stranded breaks^[8] ubiquitination, transcriptional regulation as well as other functions.<sup>[10]"wikipedia

This statement is a global description of many bad thing this BRCA does to people who have it. 

And until this is re-emphasized, one may not know the full extent of the danger lurking in BRCA positive patients! 
BRCA is not just a mere a DNA repair gene.  And cells have all kind of gene repair genes,  BRCA is also primarily a tumor suppression gene, in its wilde type it is attached to COBRA1, a true COBRA with its eyes on several bad genes that encode proteins which the cell wanted to keep in check.  These molecules are known as NEGATIVE ELONGATIONS PROTEINS.  And there is a number of them, and each once uncontrolled due to mutation of the BRCA gene will go to induce unduly other deleterious consequences...
Let's take the COBRA-1 itself, once unable to tie itself to the mutated BRCA, it will unnecessarily stimulate the Estrogen receptor alpha, and will reach at this area even the stress pathway c-JUN, and c-fos  triggering manufacturing of unnecssary cyclins and growth factors, or the stuff that worsen cancers!

But we can choose to look at ARAF, another elongation proteins which, by being part of the RAF, will amplify the MAPK kinase pathway, this effect is seen even into the Mitochondria (waking the MTOR up )

if you pick the RDBP elongation factor, it will do what negative elongation factor generally do which is to amplify RNA polymerase and ready it to induce DNA polymerase for cell proliferation by DNA multiplicaton

the TH1L, will impact the DSIF and exacerbate RDBP actions!

You see that a good wild BRCA suppresses all these activities by elongation proteins, while repairing DNA mistakes.

I SHOULD EMPHASIZE THAT THE MOST IMPORTANT TARGET IN THIS TRACK IS THE RNA POLYMERASE THAT EVERY SINGLE NEGATIVE ELONGATION MOLECULE WANTS SO BADLY TO AMPLIFY!  IT HAS DOMINION OVER DNA POLYMERASE IN THIS CASE!</sup>

DID YOU KNOW?

"FDA Grants Breakthrough Therapy Designation For PD-1 Targeted Antibody Lambrolizumab

Staff Writer
Published Online: Thursday, April 25, 2013

An investigational antibody designed to target the programmed death-1 (PD-1) pathway in patients with advanced melanoma received a Breakthrough Therapy designation from the FDA. Lambrolizumab demonstrated benefit from a small single-arm study.

Lambrolizumab, developed by Merck and formerly known as MK-3475, is a humanized monoclonal IgG4 antibody that acts against PD-1. In the results of a phase I trial that were presented at the American Society of Clinical Oncology (ASCO) annual meeting in 2012, the antibody was studied in nine patients with a variety of tumor types, including two patients with melanoma. The drug was well-tolerated and generated antitumor activity in three different doses.

Interim results from a phase IB study reported in November revealed data from 85 of 132 patients enrolled in the single-arm study. Merck reported that 43 patients (51%) showed an objective anti-tumor response and 8 patients (9%) showed a complete response at or after an assessment performed at 12 weeks. Further, 11 of 27 patients (41%) who had been previously treated with ipilimumab monotherapy for late-stage melanoma showed an objective antitumor response.

In general, MK-3475 was well-tolerated, with the most common adverse events including fatigue, rash, diarrhea, nausea, cough, joint pain, fever, and itching. Seven grade 3/4 events were reported as potentially immune-related."

go TO FULL ARTICLE
DON'T SLEEP AT THE WHEEL,
THE WORLD IS MOVING A BIT FASTER!

SAN ANTONIO, Texas — Omalizumab (Xolair, Roche, Genentech, Novartis) appears to be safe and effective in the treatment of chronic idiopathic urticaria that is refractory to antihistamines, according to new phase 3 clinical trial results.(from Medscape)

Safety Of Triclosan, Antibacterial Soap Ingredient, Being Reviewed By FDA 

It's a chemical that's been in U.S. households for more than 40 years, from the body wash in your bathroom shower to the knives on your kitchen counter to the bedding in your baby's bassinet... The agency's review comes amid growing pressure from lawmakers, consumer advocates and others who are concerned about the safety of Triclosan. Recent studies of Triclosan in animals have led scientists to worry that it could increase the risk of infertility, early puberty and other hormone-related problems in humans.   By MATTHEW PERRONE

The MEANING OF THE MDHonors AWARD for CRBCM.

MEANING OF THE MDHonors AWARD for CRBCM.

The CRBCM would like to thank MDHonors for the Research award given to our Coalition and young clinic (Greater East cancer Center of El Paso Texas).  This award will allow to build our institution's primary steps into the research power house we intend to become.  It will formalize in practical terms (working on a tangible research project) some of our collaboration attempts with the University Medical Center in El Paso, and the UTEP (University of Texas in El Paso).  With this award, the CRBCM will continue to march toward the cure day by day, and with confidence and focused vision.   And with this steady progression, victory is certain.  MDHonors revived our hope in the belief that we still have a chance to succeed if we try hard enough!
The cure is within reach, we got to keep on believing that it is reachable, and not get discouraged by politicians and malicious institutions which are distracting our progress toward the cure! 
We can not thank MDHonors enough ; for now let's go to work as we face international scrutiny and the true challenge of a cure for cancers!

And God Bless CRBCM
La lucha continua !

Dr Kankonde.

CPRIT ASIDE
OUR COALITION WINS AN INTERNATIONAL RESEARCH AWARD
WE ARE ON THE GO!
WHEN POLITICS AND DISCRIMINATION STOPS, WE ARE TRUE CONTENDERS!

Selma Guessous (WorldOne.com) <selma.guessous@worldone.com>	10:51 AM (5 hours ago)
to me

Dear Dr. Kankonde,

We have the pleasure to inform you that you are the winner of the MDH Research Award funding this month for your project: Lung Cancer Biomarker Detection.

You win 10,000USD! Congratulations!

We would like to share this good news to all our MDHonors members, and communicate more about your project on MDHonors. Could you please reply to the interview document attached in this email, and send us a picture of you and one of your team?

In order to receive your prize, could you let us know your bank details ?

Please let me know if you have any question

Thanks in advance and again congratulations !

Best regards,

Selma Guessous

Panel Development Executive

+44 (0)20 3462 1118 ex 1707 | London
selma@mdhonors.com

===================================================
AND

INTERESTING CLINICAL VISIT AND QUESTION
IS IT TRUE THAT MUIR TORE AND MAY BE ALSO LYNCH SYNDROMES CAN BE EXACERBATED BY EMBREL USE?
WE NEED TO FURTHER INVESTIGATE THIS
CAN A PATIENT WITH RECURRENT SEBACEOUS CANCER OF THE SKIN RECEIVE EMBREL FOR TREATMENT?

The MUIR-TORRE results from alteration in function of mis-match repair genes particularly the MLH1 and the MSH2.  It belongs to the Lynch family of Syndromes affecting mostly the GI track but also many other organs including the brain!
Downstream from the MLH1 are  ATR, BRCA-1, CHEK-2,EXO1, MAX,MSH3, MSH6,P53 genes
AND DOWNSTREAM MLH2  are EXONUCLEASES, PMS2,MSH4,MYC, BLOOM SYNDROME PROTEIN, MBD4 (REMEMBER MBD4 IS UPSTREAM FROM FADD)

One the other side is EMBREL an anti-TNF
where is the intersection ?

RESPONSE TO HYPOXIA
ANGPTL4, ADM
SLC16A3
HER-2 IN BREAST CANCER

FOR AVASTIN RESPONSE.
=============================================================
You need an intact system in place to obtain Avastin action.
1.   Intact ANGPTL4

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Angiopoietin-like 4
Identifiers
Symbols	ANGPTL4; ANGPTL2; ARP4; FIAF; HFARP; NL2; PGAR; pp1158
External IDs	OMIM: 605910 MGI: 1888999 HomoloGene: 10755 GeneCards: ANGPTL4 Gene
[show]Gene Ontology
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	51129	57875
Ensembl	ENSG00000167772	ENSMUSG00000002289
UniProt	Q9BY76	Q9Z1P8
RefSeq (mRNA)	NM_001039667	NM_020581
RefSeq (protein)	NP_001034756	NP_065606
Location (UCSC)	Chr 19: 8.43 – 8.44 Mb	Chr 17: 33.77 – 33.78 Mb
PubMed search	[1]	[2]
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Angiopoietin-related protein 4 is a protein that in humans is encoded by the ANGPTL4 gene.^[1][2][3] Alternatively spliced transcript variants encoding different isoforms have been described. This gene was previously referred to as ANGPTL2, HFARP, PGAR, or FIAF but has been renamed ANGPTL4.

This gene is induced under hypoxic (low oxygen) conditions in various cell types and is the target of Peroxisome proliferator-activated receptors. The encoded protein is a serum hormone directly involved in regulating lipid metabolism and also acts as an apoptosis survival factor for vascular endothelial cells.

Clinical significance

The encoded protein may play a role in several cancers and it also has been shown to prevent the metastatic process by inhibiting vascular activity as well as tumor cell motility and invasiveness. ANGPTL4 contributed to tumor growth and protected cells from anoikis, a form of programmed cell death induced when contact-dependent cells detach from the surrounding tissue matrix. ANGPTL4 secreted from tumors can bind to integrins, activating downstream signaling and leading to the production of superoxide to promote tumorigenesis.^[5] ANGPTL4 disrupts endothelial cell junctions by directly interacting with integrin, VE-cadherin and claudin-5 in a sequential manner to facilitates metastasis. ANGPTL4 functions as a matricellular protein^[6] to facilitates skin wound healing. ANGPTL4-deficient mice exhibit delayed wound reepithelialization with impaired keratinocyte migration. ANGPTL4 inhibits lipoprotein lipase, LPL, by breaking the dimer molecule. ANGPTL4 has been unambiguously established as a potent inhibitor of blood plasma Triglyceride (TG) clearance, causing elevation of plasma TG levels. As a consequence, ANGPTL4 knockout mice have reduced serum triglyceride levels, whereas the opposite is true for mice over-expressing ANGPTL4. The reduction in LPL activity in adipose tissue during fasting is likely caused by increased local production of ANGPTL4. In other tissues such as heart, production of ANGPTL4 is stimulated by fatty acids and may serve to protect cells against excess fat uptake.^[7]"

 IF YOU LIKE YOUR PATIENT WITH CANCER, INHIBIT THIS MOLECULE WITH MIGHTY FORCE AND DO THIS PERSISTENTLY. WONDER WHY AVASTIN SHOULD NOT BE STOPPED UNTIL CLEAR EVIDENCE OF FAILURE IS DISPLAYED?  READ THIS AGAIN!   THIS IS A POWERFUL TARGET AND GIVES YOU THE SECRET TO AVASTIN POWERS IN METASTATIC DISEASES!

Decreased expression of this protein has been associated with type 2 diabetes. AND COULD CONTRIBUTE TO WHY LESS CANCERS ARE OBSERVED IN DIABETIC, AND WHY TRIGLYCERIDES GO WILD IN DIABETICS.

GRAY ET AL ADDED:
"Glucocorticoid receptor blockade prevented fasting-induced tissue Angptl4 expression and WAT TG hydrolysis in mice, and TG hydrolysis induced by fasts of 6 or 24 h was greatly reduced in mice lacking Angptl4 (Angptl4(-/-)). Glucocorticoid treatment mimicked the lipolytic effects of fasting, although with slower kinetics, and this too required Angptl4. Thus, fasting-induced WAT TG hydrolysis requires glucocorticoid action and Angptl4."   LOW DOSE PREDNISONE USED IN PROSTATE CANCER PROTOCOLS MAY BE VALUABLE BECAUSE OF THIS!
IT IS ALSO THE KEY TO WHY AVASTIN IS GOOD IN KEEPING PEOPLE FROM MALIGNANT ASCITES.   KNOCK OFF MICE DIE WITH ASCITES ! 
?IS THIS THE SINGLE MOLECULE EXPLAINING FLUID RETENTION OF STEROIDS,  IT MUST CONTRIBUTE I BELIEVE!  CERTAINLY, LIPODYSTROPHY IS EXPLAINED TOO!

2.ADM GENE

IF YOU SEARCH WHY AVASTIN TREATMENT IS COMPLICATED BY HYPERTENSION, WELL IT BLOCK VASODILATORS SUCH AS THE  ADM GENE.

WIKIPEDIA

" 

Receptors of Adrenomedullin

Main article: Adrenomedullin receptor

At present AM is believed to function through combinations of the calcitonin receptor like receptor (CALCRL) and receptor activity-modifying proteins (RAMP2) complexes, as well as CGRP receptors. It is worth noting that unlike the classical one ligand-one receptor notion of receptor signalling, the interaction of both Calcitonin receptor-like (CALCRL) and RAMP ( Receptor activity-modifying protein) at the membrane, is required for AM to mediate its action. The outcome of AM stimulation of its receptor is the cellular production of both cyclic AMP (cAMP) and nitric oxide production. Some may find the production of these inside the cell to be at odds, since often they have opposing effects, but as yet, the timing of these effects remains to be studied.^{[citation needed]}

The physiological functions of Adrenomedullin

AM was initially identified as a vasodilator, some have cited this as the most potent endogenous vasodilatory peptide found in the body (Cockcroft et al., 1997). Differences in opinion regarding the ability of AM to relax vascular tone arises from the differences in the model system used (Hamid and Baxter, 2005). Other effects of AM include increasing the tolerance of cells to oxidative stress and hypoxic injury and angiogenesis. AM is seen as a positive influence in diseases such as hypertension, myocardial infarction, chronic obstructive pulmonary disease and other cardiovascular diseases, whereas it can be seen as a negative factor in potentiating the potential of cancerous cells to extend their blood supply and cause cell proliferation."

THIS KNOWLEDGE CAN HELP PICK THE BEST TREATMENT FOR COMPLICATION BY HYPERTENSION DURING AVASTIN USE!   INCIDENTALLY, IT UNVAIL THE RAMP2 AS A SECONDARY TARGET.  REMEMBER PERTURBING TRANSFER OF RECEPTOR IS A VALID THERAPEUTIC INTERVENTION CALLED "MISLOCALIZATION ".

" The protein encoded by this gene is a member of the RAMP family of single-transmembrane-domain proteins, called receptor (calcitonin) activity modifying proteins (RAMPs). RAMPs are type I transmembrane proteins with an extracellular N-terminus and a cytoplasmic C-terminus. RAMPs are required to transport calcitonin-receptor-like receptor (CRLR) to the plasma membrane. CRLR, a receptor with seven transmembrane domains, can function as either a calcitonin gene-related peptide (CGRP) receptor or an adrenomedullin receptor, depending on which members of the RAMP family are expressed. In the presence of this (RAMP2) protein, CRLR functions as an adrenomedullin receptor. The RAMP2 protein is involved in core glycosylation and transportation of adrenomedullin receptor to the cell surface.<sup>[1] WIKIPEDIA"

3.ANOTHER MISLOCALIZATION TARGET?  THIS ONE IN THE MEMBRANE!</sup>
 Entrez Gene summary for SLC16A3:

Lactic acid and pyruvate transport across plasma membranes is catalyzed by members of the proton-linked monocarboxylate transporter (MCT) family, which has been designated solute carrier family-16. Each MCT appears to have slightly different substrate and inhibitor specificities and transport kinetics, which are related to the metabolic requirements of the tissues in which it is found. The MCTs, which include MCT1 (SLC16A1; MIM 600682) and MCT2 (SLC16A7; MIM 603654), are characterized by 12 predicted transmembrane domains (Price et al., 1998 (PubMed 9425115)).(supplied by OMIM, Mar 2008)

 

A novel virus genome discovered in an extreme environment suggests recombination between unrelated groups of RNA and DNA viruses

Geoffrey S Diemer and Kenneth M Stedman^*

<sup>GO to the article ! 

This story truly deserve the reward given to those scientists
it is the story introducing the 9th law of nature
which is the law of adaptation to unusual conditions by adjusting genetic potential, by the power of recombination, and using cellular heterogeneity, and by activating NF-kB.
cells have an incredible versatility potential if given the time and if the programmed death is not triggered by an overwhelming stimulant... to adapt and develop new function ready to deal with change in the environment.  These changes could be dramatic! ie we lost our tail for god sake!
The reversal of mesenchymal transformation is another of change to adaptation and is the underlying reason of deviation of epithelialization driving the Barrett transformation in the lower 3rd of the Esophagus.  These changes are benign until receptor become desensitized to an overwhelming and relentless stimulation leading to the HSP (heat stroke protein ) gets as well as the provoked!  Prevention of progression to cancer should dampen growth factors and decrease HSP actions!
We have recently hypothesized that the MEK action  as well as the Wnt were membrane located and followed the Reticulum Endothelium tract to reach the nucleus.   With the involvement of the Hedgehog, Basaloid morphology resulted in triple negative breast cancer!  (Again if it is strong enough to induce a morphologic change, it is strong enough to cause an abnormality so significant as a neoplastic process.-even Fanconi abnormality associated with morphology changes (microcephaly) will lead to a Myelodysplastic  Syndrome.  (and we contend that these type of syndrome will respond to Revlimid and Thalidomide type of drugs).  We promise to discuss the gene involved in the 9th law soon but this text tells you already where we are going to fish them!</sup>