CARNITINE
"In some of the studies, L-carnitine therapy was subsequently given for six months to a year, suggesting a possible role not only in acute management but also secondary prevention, according to the authors, led by Dr James J DiNicolantonio (Wegmans Pharmacy, Ithaca, NY)
The apparent survival gains from L-carnitine, which were only modestly significant, seemed to come from infarct-size limitation and cardiomyocyte membrane stabilization, with chronic improvements in cellular energy metabolism, according to their report published online today in the Mayo Clinic Proceedings."
THE ATTRACTION HERE IS ITS RELATION TO THE MTOR
THEY BOTH ACT ON GLUCOSE METABOLISM!

AVANDIA

"Rosiglitazone is a diabetes drug from the thiazolidinedione class; in September 2010, it was suspended by the European Medicines Agency (EMA) because it deemed that the product's cardiovascular risk outweighed its benefits.
At the same time, the FDA deemed there was "a signal of harm" but decided not to suspend the drug. Instead it requested readjudication of the Rosiglitazone Evaluated for Cardiovascular Outcomes and Regulation of Glycemia in Diabetes (RECORD) study at the individual patient-data level. The agency also required that rosiglitazone-containing medicines be subject to a risk evaluation and mitigation strategy (REMS) program to ensure the safe use of the medicine in patients with no other options. (MEDSCAPE)

was avandia going to be pulled from the market? that was the 12 millions question in the article...
don't kill the messenger!

YOU WHO GOT A LAB  (THE CRBCM CAN'T, CRBCM DOES NOT HAVE  POLITICAL BACK BONE, WE ARE MUZZLED, POLITICALLY STOPPED FOR DOING RESEARCH, SO WE GIVE YOU THE CUES)
GO GET THE CURE FOR US!

USE shRNA TO SILENCE PI3K IN MELANOMA
OR RESTORE PTEN FUNCTION!

Small hairpin RNA

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Lentiviral delivery of shRNA and the mechanism of RNA interference in mammalian cells.

A small hairpin RNA or short hairpin RNA (shRNA) is a sequence of RNA that makes a tight hairpin turn that can be used to silence target gene expression via RNA interference (RNAi). Expression of shRNA in cells is typically accomplished by delivery of plasmids or through viral or bacterial vectors. The promoter choice is essential to achieve robust shRNA expression. At first, polymerase III promoters such as U6 and H1 were used; however, these promoters lack spatial and temporal control.^[1] As such, there has been a shift to using polymerase II promoters to regulate expression of shRNA. shRNA is an advantageous mediator of RNAi in that it has a relatively low rate of degradation and turnover. However, shRNA is disadvantageous in that it requires use of an expression vector which can pose safety concerns.

IMPORTANT GENE INTERACTIONS II
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2.
*In order to control Triple Negative Breast cancer, you got to control the Wnt pathway!!!
Loss of PTEN desactivates BRAFeffect by abrogating BRAF induced oncogen driven Senescence
of cancer cells.
* ACTIVATION OF BRAF INDUCES BENIGN OR GOOD PROGNOSIS LESIONS, HOWEVER MELANOMA SUPPOSE ASSOCIATED ALTERATIONS IN THE PTEN AND THEREFORE THE PI3K SIGNALING PATHWAYS OPENING THE DOOR TO A ROLE FOR THE MTOR IN MELANOMA..

*NON INHIBITION OF THE MTOR LEAD TO SUPPRESSION OF THE p15INK 48 WHICH INCREASE TELOMERE STABILITY!

IF THIS IS TRUE, PROTECTION OR RESTORATION (activation) OF PTEN SHOULD PROTECT OR PREVENT MELANOMA!

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SUPPORTIVE EVIDENCES


2.1 

PTEN Loss Confers BRAF Inhibitor Resistance to Melanoma Cells through the Suppression of BIM Expression

Kim H.T. Paraiso1 et al.

"PI3K inhibitor enhanced BIM expression at both the mRNA and protein level and increased the level of apoptosis through a mechanism involving AKT3 and the activation of FOXO3a."

2.2  " Upon induction of BRaf(V600E) expression, mice developed benign melanocytic hyperplasias that failed to progress to melanoma over 15-20 months. By contrast, expression of BRaf(V600E) combined with Pten tumor suppressor gene silencing elicited development of melanoma with 100% penetrance, short latency and with metastases observed in lymph nodes and lungs. Melanoma was prevented by inhibitors of mTorc1 (rapamycin) or MEK1/2 (PD325901) but, upon cessation of drug administration, mice developed melanoma,"   Dankort et al.

3."β-catenin levels control tumor differentiation and regulate both MAPK/Erk and PI3K/Akt signaling. Highly metastatic tumors with β-catenin stabilization are very similar to a subset of human melanomas. Together these findings establish Wnt signaling as a metastasis regulator in melanoma"  Damsky et al.

• "β- catenin loss in Pten/Braf melanomas improves survival and inhibits metastasis
• β-catenin stabilization in Pten/Braf melanomas enhances metastasis
• Highly differentiated melanomas can be very metastatic in vivo
• β-catenin status in melanoma regulates PI3K/Akt and MAPK/Erk signaling"

2.4  " It has been reported that oncogenic activations of intracellular signaling pathways downstream of EGFR, including the RAS-RAF-MAPK and PI3K-PTEN-AKT signaling pathways, are important mechanisms for generating resistance to anti-EGFR MoAbs. In the RAS-RAF-MAPK pathway, active mutations of KRAS or BRAF are not uncommon"  Zhou et al
"The loss of PTEN expression, which was reported to occur in 19.0%–42.0% of Western and 30.0%–64.0% of Chinese CRC tumors, induces an increase in PIP-3 concentration and PIK3CA pathway activation"

2.5 "Beta-catenin Controls Metastasis in Braf-activated Pten-inactivated Melanomas" "beta-catenin levels control tumor differentiation and regulate both MAPK/Erk and PI3K/Akt signaling."

 

see the article.

2.6.

Abrogation of BRAF^V600E-induced senescence by PI3K pathway activation contributes to melanomagenesis PTEN depletion abrogates BRAF^V600E-induced senescence in human fibroblasts and melanocytes."

Liesbeth C.W. ET AL."

"  The PI3K pathway was often activated through either decreased PTEN or increased AKT3 expression in melanomas relative to their adjacent nevi. Pharmacologic PI3K inhibition in melanoma cells suppressed proliferation and induced the senescence-associated tumor suppressor p15^INK4B. This treatment also eliminated subpopulations resistant to targeted BRAF^V600E inhibition."

2.7

ICAM-1 Has a Critical Role in the Regulation of Metastatic Melanoma Tumor Susceptibility to CTL Lysis by Interfering with PI3K/AKT Pathway

1. Ahmed Hamaï1,
2. Franck Meslin1 ET AL.

  "More importantly, we found that the level of ICAM-1 expression by melanoma cells correlated with decreased PTEN activity. ICAM-1 knockdown in T1 cells resulted in increased phosphorylation of PTEN and the subsequent activation of AKT. We have additionally shown that inhibition of the phosphatidylinositol (3,4,5)-triphosphate kinase (PI3K)/AKT pathway by the specific inhibitor wortmannin induced a significant potentiation of susceptibility of G1 and ICAM-1 small interfering RNA–treated T1 cells to CTL-induced lysis. The present study shows that a shift in ICAM-1 expression, which was associated with an activation of the PI3K/AKT pathway, can be used by metastatic melanoma cells to escape CTL-mediated killing."

(PLEASE NOTE MART-1 AND ITS ROLE OR INTERACTION WITH PTEN!)

IMPORTANT GENE INTERACTIONS TO KEEP IN MIND!

1.  Mutation to NF1 may desensitize tumor to BRAF inhibitors:

NF1--RAS--BRAF--MEK-ERK-MAPK
Desensitization to BRAF is expected in tumor with NF1 Mutant.
Resistance to Vemurafenib (Zelboraf) should be checked for Mutation to NF1 and RAS.
Recently prostate cancer has been associated with mutation in the PKC family which interacts with RAS suggesting RAS amplification or suppression may result.  This could alter sensitivity to Cabozantinib,
"Cabozantinib (XL184) is an orally bioavailable tyrosine kinase inhibitor with activity against MET and vascular endothelial growth factor receptor 2." Smith et al.

REMEMBER NOW THERE ARE AT LEAST 4 MEDICATIONS DOWN THIS PATHWAYS
ANTI-EGFR/VEGF, ZELBORAF, CABOZANTINIB, MTOR INHIBITORS 
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 SUPPORTIVE EVIDENCES


1.1 "The BRAF kinase is a serine-threonine kinase that mediates signal transduction through the MEK-ERK pathway. An activating mutation of the BRAF kinase gene, located on exon 15, was recently found to result in a valine-to-glutamic acid substitution at amino acid 600 (BRAF^V600E mutation) that is an oncogene in human cancer and the most common mutation in PTC [8]. In recent years, the BRAF^V600E mutation has shown a high specificity for PTC, and its prevalence is highly variable, ranging from 30% to more than 80%, depending on the study. In the present study, the BRAF^V600E mutation was identified by multiplex real-time PCR. This method is as sensitive as dual-priming oligonucleotide-based multiplex PCR (Seegene) for detecting BRAF^V600E mutations.

The NF1 gene located on chromosome 17q11.2 encodes neurofibromin. The Ras-GAP is a potentially functional domain of neurofibromin [9]. The Ras-GAP-related domain (Ras-GRD) accelerates the conversion of active Ras-GTP to inactive Ras-GDP in various cell types and acts as a negative regulator of the p21ras signaling pathway [10]. Ras GTPases interact with multiple pathways, including the RAF-MEK-ERK mitogen-activated protein kinase pathway. Mutations in the NF1 gene result in abnormal cell growth and in the formation of benign and malignant tumors [3]. Because BRAF^V600E mutation and NF1 gene mutation are both involved in the MEK-ERK pathway, Koksal et al.[3] suggested that the development of PTC (papillary Thyroid cancer) in patients with NF1 may be associated with the ras gene but that further evidence is necessary to confirm this association."   FROM

Neurofibromatosis type 1 associated with papillary thyroid carcinoma incidentally detected by thyroid ultrasonography: a case report

Bu K Kim<sup>1et al!
------------------------------------------------------------------------------------------------------------------------------------------------

1.2</sup>  

Suppression of oncogenic Ras by mutant neurofibromatosis type1 genes with single aminoacid substitutions

NAKAfuku et al.

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1.3 "Once there, RAF proteins are activated and phosphorylated by different protein kinases.^24-28 Active RAF phosphorylates MEK that, in turn, phosphorylates and activates extracellular signal–regulated kinases 1 and 2 (ERK1/ 2).²⁹ Several studies have supported the importance of this effector pathway by showing the ability of Raf and MEK to transform rodent fibroblasts³⁰ as well as the ability of RAF inhibitors to revert aspects of the RAS-driven transformed phenotype, such as growth in soft agar.³¹

The second best-characterized RAS effector family is phosphoinositide 3-kinases (PI3Ks), which play important roles as mediators of RAS-mediated cell survival and proliferation.^32,33 When active, PI3K converts phosphatidylinositol (4,5)-bisphosphate (PIP₂) into phosphatidylinositol (3,4,5)-trisphosphate (PIP₃). PIP₃, in turn, binds the pleckstrin homology (PH) domain of Akt/PKB, stimulating its kinase activity, resulting in the phosphorylation of a host of other proteins that affect cell growth, cell cycle entry, and cell survival. PI3K can also activate Rac, and this activation is involved in cytoskeleton reorganization.³⁴ The functional importance of the RAS-PI3K pathway will be more extensively discussed in the next sections.

Another well-characterized RAS effector pathway involves Ral-GEF proteins. RalGEF members (RalGDS, RGL, RGL2, and RGL3) link RAS proteins to activation of the RalA and RalB small GTPases.³⁵ The biological function of these proteins is not yet fully understood, although there is evidence that they play an important role of this pathway in RAS-mediated transformation and tumorigenesis in vivo.^36,37 Expression of RalGDS cooperates with constitutively activated RAF to induce focus formation, suggesting a cooperation of RalGEF in RAS-mediated transformation in vitro.³⁸

Apart from the above-mentioned effectors, in recent years, an increasing number of molecules that specifically interact with RAS have been described, including Tiam1, p120GAP, NF1, MEKK1, Rin1, AF-6, PKC-ζ, Nore1, Canoe, and others. These proteins bind to RAS exclusively when it is in an activated state³⁹; however, the physiological role of some of these effectors has not yet been found. It has also been described that abnormal RAS signaling causes deregulation of the Rho GTPases family, including Rac1 and RhoA, but no direct association has been found yet."  (Castellano and downward)

1.4. "neurofibromatosis type I (NF1). While an association of NF1 with malignant gliomas has long been known in both adult and pediatric patients,^[32,33] this mutation was not previously known to be associated with sporadic GBM. By contrast, NF1-associated ras activation has been a hallmark of pediatric low-grade gliomas, particularly for optic pathway gliomas.^[33] These tumors lack many of the characteristic abnormalities observed in other astrocytic tumors and may help explain their excellent long-term prognosis.^[34] The rarity of low-grade glioma-development in adults with NF1 suggests a developmental period of sensitivity to this mutation in prenatal or early childhood.^[35]

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Non-NF1-associated low-grade gliomas in pediatric patients are classically associated with a truncated duplication of BRAF,^[36–40] with some variability in the breakpoint and partner rearrangement.^[41] Various researchers have shown that in these low-grade tumors, the fusion of BRAF with KIAA1549 leads to oncogene-induced senescence and improved clinical outcome."  Gilheeney et al

1.5."The most visible features of NF-1 are the neoplastic manifestations caused by the loss of Ras-GTPase-activating protein (Ras-GAP) activity mediated through the GAP-related domain (GRD) of neurofibromin (NF1), the protein encoded by NF1. However, the syndrome is also characterized by cognitive dysfunction and a number of developmental abnormalities."

 1.6"

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Novel Tumor Suppressor Identified for Prostate Cancer
Researchers have identified the enzyme PKCζ, which acts as a tumor suppressor in prostate cancer and is part of a pathway that partly controls cell growth and metastasis…Azvolinski et al.

AT CRBCM WE ARE PROUD!

The Internal Revenue Services (IRS) after a careful review of activities at the CRBCM has bestowed upon CRBCM the status of "charity organization".   This is a milestone for CRBCM because it represents for us the successful completion of a long awaited process of careful scrutiny by United states'government.  CRBCM is a legitimate institution at its dawn.  Tomorrow is bright!  Our plans are still green and ready to unfold to help the people of El Paso and beyond.  We are strongly committed to move forward carefully but with determination...To help, please call 915-307-3354.
or send a donation to CRBCM
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                                  El Paso Tx 79938

And Help Cancer Research.
And remember the truth is not the privilege of a few,  it belongs to all of us, and anyone looking in the right place can uncover it for the benefit of all of us!  Be a part of the movement for the cure!

Finally: The IRS acknowledges the CRBCM's status of Public Charity under section 501 (c) (3) !