THE CURE IS WITHIN REACH,
DON'T GET DISTRACTED, FOCUS ON WHAT IS AT STAKE
ONE CLEAR PATH, THE ROLE OF BIM GENE FOR THE CURE!
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Past use of chemotherapy and early interventions have shown us that cancer killing is possible by chemotherapy drug use, by radiation, by infection induced Cytokines, and by the immune system itself.   One of the major pathway to death, is the CELLULAR PROGRAMMED DEATH CALLED APOPTOSIS.
We have now sufficient compelling evidences that all the cancer cell needs to die is to be provided critical circumstances or message that given these conditions pathway to Apoptosis is the logical attitude to adopt!
Aside from chemotherapy and target therapies, severe sepsis delivers the same message to our white cells and other cells, with death of the individual as a result.

Cellular nature provides us with several opportunities to kill the cell, but our knowledge is at present not enough to talk to cell appropriately, and give instructions for Apoptosis.  So for now we try the rough ways!  We kind of brutalize the cell and see what comes out!  And we are still doing so because our knowledge of how the cell work remains rudimentary and fragmented at best.

With our fragmented knowledge, we know now that when we give Etoposide, one of the cell protection mechanism at Mitochondrial level is Bcl-2, and we call this molecule ANTI-APOPTOTIC MOLECULE because it protects the cell against programmed cell death.

But to be fair, nature also gives a chance to cell killing by providing a close Molecule to Bcl-2 called Bcl2L11, which has that BH-3 characteristic, and is PRO-APOPTOTIC, this is the BIM.  Increase this and you have a higher self destruction of cancer cells!  Now how to tell cancer cell, "increase your BIM please!" that where the challenge is!

We have preliminary knowledge, but it needs to be more focused, coordinated and understandable to the cell!
ie. while reviewing MITF gene, we clearly told you that MITF activates RUNX3 and RUNX3 activates BIM, that's the way to do this simply.  But don't kill the messenger, we know this but we really don't know how to every time and effectively achieve this today!

We know a all lot today but not enough ...
 
Here is what we know!
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ATLAS

*BIM is a pro-apoptotic member of the Bcl-2 family important in mediating apoptosis in response to various intrinsic stimuli. Studies using BIM knockout mice showed that it plays a large part in maintaining hematopoietic homeostasis. (THIS GIVE US INSIGHT THAT IN THE BLOOD CELL LINEAGE DISEASE, BIM IS OF A TREMENDOUS IMPORTANCE, AND ACTION AT BIM SHOULD HELP US CONTROL HEMATOLOGIC DISEASES)

*shown to mediate apoptosis in response to stimuli such as cytokine deprivation, deregulated calcium flux and microtubule perturbation. In vivo, BCL2L11/BIM is essential for hematopoietic homeostasis, thymocyte negative selection and as a barrier against autoimmunity. (WHEN STIMULATION OF NERVE CEASES UNDER DEPRIVATION OF NERVE GROWTH FACTOR, BIM GOES TO WORK TO KILL THE NERVE CELL)

*are either bound to DLC1 cytoplasmic dynein light chain and sequestered to the microtubule-associated dynein motor complex or associated with the pro-survival proteins on the mitochondria. A C-terminal hydrophobic domain present in all three major isoforms of BIM localizes the protein to intracytoplasmic membranes. (Making DLC1 a target, IF YOU REMOVE DLC1 FROM THE EQUATION, 2 THINGS MAY HAPPEN, ONE BIM IS FREE TO ACT OR WATCH OUT IT MAY BE MORE DESTROYED BY IBIQUITINATION POTENTIALLY OR "MISLOCATED" MISSING ITS POINT OF ACTION, THESE ARE FACTS WE STILL NEED TO CLEARLY ESTABLISH)

*Gaviraghi et al

  E2F, a characterized transcriptional regulator of BCL2L11 expression. (CHECK OUR BLOG, WE SPOKE ABOUT E2F EXTENSIVELY, HERE IT IS COMING BACK TO REEMPHASIZE ITS "PLAYER STATUS", THIS IS A BOOSTER TO BIM!)
  Expression of BCL2L11 is induced by a diverse range of apoptotic stimuli such as deprivation of growth factors/cytokines, ionizing radiation, and cytotoxic peptides [2,6,14,22].
  Interestingly, the analysis presented in this manuscript indicates that the highest expression levels of BCL2L11 transcripts were detected in pancreas, placenta and thyroid tissue, suggesting an important role for BCL2L11 in the normal physiology of these tissues. With respect to P1-derived transcripts, up to 70% of total BCL2L11 transcripts are contributed from the newly identified promoter in the testis, an organ where BCL2L11 activity was shown to contribute critically to spermatogenesis [25], suggestive for a prominent role for the putative BCL2L11 P1 in the expression of BCL2L11 in this tissue.  (IN WHICH CANCERS AGAIN THIS BIM CAN HAVE A ROLE?)

*atlas!

"BIM-deficient mice developed a fatal systemic lupus erythematosus (SLE)-like disease. Lymphocytes lacking BIM are refractory to a number of stimuli including cytokine deprivation, deregulated calcium ion flux. BIM is also important in turning off immune responses following acute viral infection. BIM cooperates with the death ligand Fas (which triggers the extrinsic pathway) to shut down immune responses following chronic viral infection and to prevent autoimmunity. Experiments using mice deficient for both BIM and pro-survival Bcl-2 demonstrated that Bcl-2 is an essential guardian of BIM. Indeed, removal of just one allele of BIM prevented polycystic kidney disease and restored normal growth of Bcl-2-deficient mice. Loss of both alleles restored a robust hematopoietic system and prevented graying."  (LET'S REEMPHASIZE THAT YOU INDEED HAVE READ THE ROLE OF BIM IN POLYCYSTIC KIDNEY DISEASE, DOES METHYLATING ONE ALLELE A THERAPEUTIC OPTION?)

REGULATION (atlas)

" BIM is regulated by transcriptional control which differs with cell types by transcription factors including FOXO-3a and c-JUN . BIM is also controlled via alternative splicing that produces many different isoforms. BIM is regulated as well by post-translational modifications such as phosphorylation by ERK1, ERK2 and JNK. Phosphorylation-dependant ubiquitylation is thought to regulates BIM's half life.
Interactions:
Unlike some BH3-only proteins, BIM is a promiscuous binder of pro-survival proteins and can bind BCL2, BCLX, BCLW , MCL1 and BCL2A1 with high affinity. There are also some reports that BIMS is able to bind BAX (multidomain pro-apoptotic effector of the pathway) and activate it directly, but whether this binding occurs physiologically is unclear.

BIM belongs to the Bcl-2 family of proteins and contains the BH3 domain which is homologous to the BH3 domains of:"  (EVERY TIME c-JUN IS MENTIONED, I THINK CYTOKINE PRODUCTION, AND CYTOKINES/GROWTH FACTOR DEPENDENT PROCESSES, BLOCKAGE AT RECEPTORS MAY HAVE SIGNIFICANT EFFECTS)

The pro-survival proteins: BCL2, BCLX, BCLW, MCL1, BCL2A1/BFL1, Bcl-B/BOO. The multidomain pro-apoptotic proteins: BAX, BAK, BOK. The other BH3-only proteins: PUMA, NOXA, BAD, HRK, BMF, BIK, BID.(NICE TARGETS SIMILAR TO BIM!)  (LET'S GO OUT THERE AND INCREASE THIS STUFF FOR THE CURE!)

*1. Hughes et al

  "Bim protein and that NF-Y is important for apoptosis following NGF withdrawal. Furthermore, I found that the transcriptional coactivators CBP/p300 are required for the activation of bim-LUC following NGF withdrawal and that CBP/p300 may interact with NF-Y to enhance bim transcription. In addition to this, the prosurvival MEK/ERK pathway has been found to inhibit bim expression independently of the PI3-K/Akt pathway. 3' RACE and experiments in sympathetic neurons with a new bim-LUC+3'UTR reporter construct revealed that this negative regulation is mediated through the bim 3' UTR. Mutational analysis and RNA stability experiments have been employed to further investigate this mechanism."
(block NGF all the way, and see what happens!)
*2. Gilley et al.
  We find that overexpression of FOXO transcription factors induces BIM expression and promotes death of sympathetic neurons in a BIM-dependent manner. In addition, we find that FKHRL1 (FOXO3a) directly activates the bim promoter via two conserved FOXO binding sites and that mutation of these sites abolishes bim promoter activation after NGF withdrawal. Finally, we show that FOXO activity contributes to the NGF deprivation–induced death of sympathetic neurons.
(WE HAVE SAID, BEHIND THE FOXO LAYS THE PUMA (gene))

Ong et al.

 Now the team at Duke-NUS Graduate Medical School in Singapore, working with the Genome Institute of Singapore (GIS), Singapore General Hospital and the National Cancer Centre Singapore, has discovered that there is a common variation in the BIM gene in people of East Asian descent that contributes to some patients' failure to benefit from these tyrosine kinase inhibitor drugs.
(RE-EMPHASIZING THE NEED TO HAVE THE RIGHT BIM!)

 IN sepsis Bim is upregulated   Weber et al

Available online

http://ccforum.com/content/12/5/R128

Page 5 of 10

(page number not for citation purposes)

ciitis (n = 2), faecal peritonitis (n = 8) and pneumonia (n = 6).

Nine of the ten critically ill non-septic patients were included in

their post-operative period afte

r trauma, abdominal or pharyn-

geal cancer, or aortic aneurysm rupture with a delayed recov-

ery. These patients received prophylactic antibiotic treatment

with no signs of infection in the perioperative phase. One

patient had abacterial pancreatiti

s and did not receive antibiot-

ics. Patients did not receive immunosuppressants or drotrec-

ogin alfa (activated) before or during their treatment. Eight

patients with severe sepsis

received 3 mg/kg hydrocortisone

before or at the time of sampling. No difference in white blood

cells counts was found comparing critically ill patients with

patients with sepsis. However, lymphocyte counts were

decreased in severe sepsis as compared with critically ill

patients and dropped below the local reference range of 1–4

G/l (Table 1).

Phosphatidylserine externalisation and caspase-3

activation

Phosphatidylserine externalisation marks cells for phagocyto-

sis as an early event of the apoptotic process. Cells were con-

sidered early apoptotic when phosphatidylserine was

externalised on cells with a still intact membrane, as indicated

by negative staining for 7-AAD. CD4

+

and CD8

+

T-cells and

CD19

+

B-cells exhibited significantl

y raised portions of phos-

phatidylserine-positive population

s in severe sepsis, but not in

critically ill patients (Figure 1a).

Caspase-3 is the central executioner caspase. Activation of

caspase-3 leads to de

gradation of multiple intracellular sub-

strates and to the typical morphological features of classical

apoptosis. In the current study,

activation of caspase-3 was

measured by an antibody specific to the active fragment of

cleaved caspase-3 (Figures 1b and 1c). In patients with

severe sepsis, the subpopulation

with active caspase-3 was

elevated in CD4+ T-cells and CD8+ T-cells compared with

critically ill patients or healthy

controls. Also, B-

cells from sep-

tic patients were found to cont

ain significantly more activated

caspase-3 than B-cells from critically ill patients or healthy

controls.

Bcl-2 expression

Since the Bcl-2 family of proteins is known to regulate the

mitochondrial integrity, we analysed the expression of Bcl-2

(Figure 2). The amount of Bcl-2 in CD4

+

T-cells of critically ill

non-septic patients did not differ significantly from healthy con-

trols. However, in patients with sepsis, Bcl-2 protein levels

dropped by about 25%. In CD8

+

T-cells, no significant change

between the three groups could be observed. The decrease in

mitochondrial Bcl-2 was most pronounced in B-cells, where

Bcl-2 dropped by 36% when compared with healthy controls.

mRNA expression of Bcl-2 family members

When investigating the mRNA expression of mobile pro-apop-

totic BH3-only proteins of the Bcl-2 family, massive induction

was observed in severe sepsis (Figure 3a). When compared

with healthy controls and critically ill patients, mRNA expres-

sion of Bim was upregulated.

This corresponds to a 310.5-fold

increase compared with critically ill patients and a 51.7-fold

rise compared with healthy controls. While Bid was decreased

in critically ill patients, it was markedly upregulated in severe

sepsis.

 WE THANK THE RESEARCHER FOR THEIR WORKS WHICH HAVE BROUGHT US CLOSER TO THE CURE, CRBCM RAISES ITS HAT TO YOUR HONOR!   THIS IS REAL SCIENCE DEVOID OF POLITICAL INTRIGUES, JUST PURE PROGRESS, THANK YOU FROM THE BOTTOM OF OUR HEARTS!

PLENTY OF TARGETS OFFERED HERE!

INTERNET BASED MEDICAL SURVEY INCREASINGLY A FALSE TRAP!
=======================================================

Criminals have gotten in the medical survey business.  So until you know where it is coming from it is not worth your time to take them.  They will get information from you, but at the end, there is "looping" where you come back to the same question until you get tired, and never complete the survey.   Or simply a message that you did not qualify to take the survey in the first place. and "thank you".
The surveyor by then has gotten questions answered and may be paid to do that.
You end up frustrated and a bit "violated".  So please keep your Blood pressure in check by just deleting these so called "offers".

VARIOUS NEWS.

*FROM ASCO, ABOUT PROSTATE CANCER/EXCERPT
"
Despite its challenges, PSA remains the best serum-based biomarker in prostate cancer. Variations of PSA such as free-to-total PSA ratio may be used to risk stratify patients. Assessment of urine PCA3 (Progensa PCA3 assay), or assessment of prostate biopsy tissue GSTP1 methylation (ConfirmMDx assay), are marketed to help avoid unnecessary repeat biopsies.
The Oncotype DX prostate biopsy-based genomic test recently became commercially available, and is marketed to identify the presence of an aggressive genotype to aid initial treatment decision making.
Notably, none of these novel tests has been prospectively evaluated to assess effect on clinically meaningful outcomes such as survival or quality of life.
In the United States, there is limited regulatory oversight of molecular diagnostic tests. The FDA regulates “companion” diagnostic assays that are used to predict patient responses to approved products (e.g., KRAS). But for non-companion tests, there is no requirement prior to marketing that benefits be demonstrated in survival or quality of life."

*METASTATIC MELANOMA TREATMENT
AGENTS

1. Ipilimumab - antagonist of CTLA-4
2.Nivolumab -  antagonist of PD-1
3. MK-3475-  antagonist of PD-1
4. Vemurafenib- (this is Zelboraf)  - positive BRAF Mutation
5. Dabrafenib - positive BRAF Mutation
6. Trametinib -  MEK is the target
7. Combination of Trametinib and Dabrafenib have been successfully combined for greater effect
8. Nexavar, Sutent, Gleevec, Sprycel, Tasigna  are used in c-KIT positive Mutation
9. Adoptive T cell therapy

Adapted from YUSHAK et al.

SPLENIC LYMPHOMA

A recent Greek study described Rituxan treatment as a valid alternative to Splenic Lymphoma.
In that study (Kalpadakis et al) Rituxan was given at standard dose for 6 weeks, some of the patient went on to a maintenance Rituxan program "it clearly improves the duration of remission".  Rituxan was offered as an alternative treatment particularly in the elderly in whom  Splenectomy could be a "major surgical procedure with significant comorbidities".
"The 5 year overall and progression free survival for Rituxan-treated patients versus Splenectomized patients" were 92% Vs 77% (p=0.9)
and 73% Vs 58% (p=0.6)

Well , it's just good to know it is an option, I don't know about the results as reported
? is it worth considering Maintenance post Splenectomy
? does Removal of spleen affect response to Rituxan (that controversy was there a while ago!)


 ======================================================IN OTHER NEWS!
Xarelto taking over Enoxaprim and Coumadin since Approval by the FDA for DVT and PE!

"
“Xarelto is the first oral anti-clotting drug approved to treat and reduce the recurrence of blood clots since the approval of warfarin nearly 60 years ago,” said Richard Pazdur, M.D., director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research in a press release.
Xarelto’s safety and effectiveness were evaluated in three clinical studies totaling 9,478 patients with DVT or PE. Patients were randomly assigned to receive either Xarelto, enoxaparin and warfarin, or placebo. The studies measured recurrent DVT, PE or death after randomization.
Results showed Xarelto worked as well as enoxaparin with warfarin for treating DVT and PE. About 2% of people treated with Xarelto vs. 1.8% – 3% of those treated with warfarin / enoxaparin had a recurrent DVT or PE. A third study showed prolonged Xarelto treatment reduced the risk of recurrent DVT and PE. About 1.3% of people treated with Xarelto compared with 7% percent of patients receiving placebo experienced a recurrent DVT or PE.
Unlike warfarin, Xarelto does not require initial “overlap” or “bridging” with heparin / enoxaparin, and also does not require blood level monitoring, simplifying treatment. These benefits come at a price: Xarelto costs $3,000 a year, as compared to about $200 for warfarin."  PulmCCM

one caution possible interaction with Amiodarone causing increase bleeding! (FURTHER INVESTIGATE THIS)

WANT MORE ON XARELTO

Help intercept thrombotic risk with a single-agent treatment approach

• The first and only oral anticoagulant without the need for routine international normalized ratio (INR) monitoring^1-3 approved by the FDA for:
  
  • Treating DVT and PE.
    
  • Reducing the risk of recurrence of DVT and PE.
    
• Results confirmed in the largest DVT and PE phase 3 clinical trial program ever conducted (N=9477)
  

DVT = deep vein thrombosis; LMWH = low-molecular-weight heparin;
PE = pulmonary embolism.

XARELTO^® is also approved for the following indications:

Reducing Stroke Risk in Patients With Nonvalvular Atrial Fibrillation

DVT Prophylaxis After Knee or Hip Replacement Surgery

Important Safety Information

WARNING: (A) DISCONTINUING XARELTO^® IN PATIENTS WITH NONVALVULAR ATRIAL FIBRILLATION INCREASES RISK OF STROKE, (B) SPINAL/EPIDURAL HEMATOMA

A. DISCONTINUING XARELTO^® IN PATIENTS WITH NONVALVULAR ATRIAL FIBRILLATION

Discontinuing XARELTO^® places patients at an increased risk of thrombotic events. An increased rate of stroke was observed following XARELTO^® discontinuation in clinical trials in atrial fibrillation patients. If anticoagulation with XARELTO^® must be discontinued for a reason other than pathological bleeding, consider administering another anticoagulant.

B. SPINAL/EPIDURAL HEMATOMA

Epidural or spinal hematomas have occurred in patients treated with XARELTO^® who are receiving neuraxial anesthesia or undergoing spinal puncture. These hematomas may result in long-term or permanent paralysis. Consider these risks when scheduling patients for spinal procedures. Factors that can increase the risk of developing epidural or spinal hematomas in these patients include:

• Use of indwelling epidural catheters
• Concomitant use of other drugs that affect hemostasis, such as non-steroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, other anticoagulants, see Drug Interactions
• A history of traumatic or repeated epidural or spinal punctures
• A history of spinal deformity or spinal surgery

Monitor patients frequently for signs and symptoms of neurological impairment. If neurological compromise is noted, urgent treatment is necessary.

Consider the benefits and risks before neuraxial intervention in patients anticoagulated or to be anticoagulated for thromboprophylaxis.

CONTRAINDICATIONS

• Active pathological bleeding
• Severe hypersensitivity reaction to XARELTO^® (eg, anaphylactic reactions)

WARNINGS AND PRECAUTIONS

• Increased Risk of Stroke After Discontinuation in Nonvalvular Atrial Fibrillation: Discontinuing XARELTO^® in the absence of adequate alternative anticoagulation increases the risk of thrombotic events. An increased rate of stroke was observed during the transition from XARELTO^® to warfarin in clinical trials in atrial fibrillation patients. If XARELTO^® must be discontinued for a reason other than pathological bleeding, consider administering another anticoagulant.
• Risk of Bleeding: XARELTO^® increases the risk of bleeding and can cause serious or fatal bleeding. In deciding whether to prescribe XARELTO^® to patients at increased risk of bleeding, the risk of thrombotic events should be weighed against the risk of bleeding. Promptly evaluate any signs or symptoms of blood loss and consider the need for blood replacement. Discontinue XARELTO^® in patients with active pathological hemorrhage. The terminal elimination half-life of rivaroxaban is 5 to 9 hours in healthy subjects aged 20 to 45 years.
  • A specific antidote for rivaroxaban is not available. Because of high plasma protein binding, rivaroxaban is not expected to be dialyzable. Protamine sulfate and vitamin K are not expected to affect the anticoagulant activity of rivaroxaban. There is no experience with antifibrinolytic agents (tranexamic acid, aminocaproic acid) in individuals receiving rivaroxaban. There is neither scientific rationale for benefit nor experience with systemic hemostatics (desmopressin and aprotinin) in individuals receiving rivaroxaban. Use of procoagulant reversal agents such as prothrombin complex concentrate (PCC), activated prothrombin complex concentrate (APCC), or recombinant factor VIIa (rFVIIa) may be considered, but has not been evaluated in clinical trials.
  • Concomitant use of other drugs affecting hemostasis increases the risk of bleeding. These include aspirin, P2Y₁₂ platelet inhibitors, other antithrombotic agents, fibrinolytic therapy, and NSAIDs.
  • Concomitant use of drugs that are combined P-gp and CYP3A4 inhibitors (eg, ketoconazole and ritonavir) increases rivaroxaban exposure and may increase bleeding risk.
• Spinal/Epidural Anesthesia or Puncture: When neuraxial anesthesia (spinal/epidural anesthesia) or spinal puncture is employed, patients treated with anticoagulant agents for prevention of thromboembolic complications are at risk of developing an epidural or spinal hematoma, which can result in long-term or permanent paralysis.
  An epidural catheter should not be removed earlier than 18 hours after the last administration of XARELTO^®. The next XARELTO^® dose is not to be administered earlier than 6 hours after the removal of the catheter. If traumatic puncture occurs, the administration of XARELTO^® is to be delayed 24 hours.
• Use in Patients With Renal Impairment:
  • Nonvalvular Atrial Fibrillation: Avoid the use of XARELTO^® in patients with creatinine clearance (CrCl) <15 mL/min since drug exposure is increased. Periodically assess renal function as clinically indicated (ie, more frequently in situations in which renal function may decline) and adjust therapy accordingly. Discontinue XARELTO^® in patients who develop acute renal failure while on XARELTO^®.
  • Treatment of DVT, PE, and Reduction in the Risk of Recurrence of DVT and of PE: Avoid the use of XARELTO^® in patients with CrCl <30 mL/min due to an expected increase in rivaroxaban exposure and pharmacodynamic effects in this patient population.
  • Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery: Avoid the use of XARELTO^® in patients with CrCl <30 mL/min due to an expected increase in rivaroxaban exposure and pharmacodynamic effects in this patient population. Observe closely and promptly evaluate any signs or symptoms of blood loss in patients with CrCl 30 to 50 mL/min. Patients who develop acute renal failure while on XARELTO^® should discontinue the treatment.
• Use in Patients With Hepatic Impairment: No clinical data are available for patients with severe hepatic impairment. Avoid use of XARELTO^® in patients with moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment or with any hepatic disease associated with coagulopathy, since drug exposure and bleeding risk may be increased.
• Use With P-gp and Strong CYP3A4 Inhibitors or Inducers: Avoid concomitant use of XARELTO^® with combined P-gp and strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, lopinavir/ritonavir, ritonavir, indinavir/ritonavir, and conivaptan). Avoid concomitant use of XARELTO^® with drugs that are P-gp and strong CYP3A4 inducers (eg, carbamazepine, phenytoin, rifampin, St. John’s wort).
• Risk of Pregnancy-Related Hemorrhage: In pregnant women, XARELTO^® should be used only if the potential benefit justifies the potential risk to the mother and fetus. XARELTO^® dosing in pregnancy has not been studied. The anticoagulant effect of XARELTO^® cannot be monitored with standard laboratory testing and is not readily reversed. Promptly evaluate any signs or symptoms suggesting blood loss (eg, a drop in hemoglobin and/or hematocrit, hypotension, or fetal distress).

DRUG INTERACTIONS

• Drugs That Inhibit CYP3A4 Enzymes and Drug Transport Systems: Avoid concomitant administration of XARELTO^® with combined P-gp and strong CYP3A4 inhibitors.
• Drugs That Induce CYP3A4 Enzymes and Drug Transport Systems: Results from drug interaction studies and population pharmacokinetic (PK) analyses from clinical studies — coadministration of XARELTO^® with a combined P-gp and strong CYP3A4 inducer (eg, rifampin, phenytoin) decreased rivaroxaban exposure by 27%-50%. Similar decreases in pharmacodynamic effects were also observed. These decreases in exposure to rivaroxaban may decrease efficacy. Avoid concomitant use of XARELTO^® with drugs that are combined P-gp and strong CYP3A4 inducers (eg, carbamazepine, phenytoin, rifampin, St. John’s wort).
• Anticoagulants and NSAIDs/Aspirin: Single doses of enoxaparin and XARELTO^® given concomitantly resulted in an additive effect on anti-factor Xa activity. Single doses of warfarin and XARELTO^® resulted in an additive effect on factor Xa inhibition and PT. Concomitant aspirin use has been identified as an independent risk factor for major bleeding in efficacy trials. NSAIDs are known to increase bleeding, and bleeding risk may be increased when NSAIDs are used concomitantly with XARELTO^®. Avoid concurrent use of XARELTO^® with other anticoagulants due to increased bleeding risk unless benefit outweighs risk. Promptly evaluate any signs or symptoms of blood loss if patients are treated concomitantly with aspirin, other platelet aggregation inhibitors, or NSAIDs.
• Drug-Disease Interactions With Drugs That Inhibit CYP3A4 Enzymes and Drug Transport Systems: Patients with renal impairment receiving full dose XARELTO^® in combination with drugs classified as combined P-gp and weak or moderate CYP3A4 inhibitors (eg, amiodarone, diltiazem, verapamil, quinidine, ranolazine, dronedarone, felodipine, erythromycin, and azithromycin) may have increases in exposure compared with patients with normal renal function and no inhibitor use, since both pathways of rivaroxaban elimination are affected. XARELTO^® should be used in patients with CrCl 15 to 50 mL/min who are receiving concomitant combined P-gp and weak or moderate CYP3A4 inhibitors only if the potential benefit justifies the potential risk.

USE IN SPECIFIC POPULATIONS

• Pregnancy Category C: There are no adequate or well-controlled studies of XARELTO^® in pregnant women, and dosing for pregnant women has not been established. Use XARELTO^® with caution in pregnant patients because of the potential for pregnancy-related hemorrhage and/or emergent delivery with an anticoagulant that is not readily reversible. The anticoagulant effect of XARELTO^® cannot be reliably monitored with standard laboratory testing. Animal reproduction studies showed no increased risk of structural malformations, but increased post implantation pregnancy loss occurred in rabbits. XARELTO^® should be used during pregnancy only if the potential benefit justifies the potential risk to mother and fetus.
• Labor and Delivery: Safety and effectiveness of XARELTO^® during labor and delivery have not been studied in clinical trials. However, in animal studies maternal bleeding and maternal and fetal death occurred at the rivaroxaban dose of 40 mg/kg (about 6 times maximum exposure of the unbound drug at the human dose of 20 mg/day).
• Nursing Mothers: It is not known if rivaroxaban is excreted in human milk. Rivaroxaban and/or its metabolites were excreted into the milk of rats. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from rivaroxaban, a decision should be made whether to discontinue nursing or discontinue XARELTO^®, taking into account the importance of the drug to the mother.
• Pediatric Use: Safety and effectiveness in pediatric patients have not been established.
• Geriatric Use: In the EINSTEIN DVT, PE, and Extension clinical studies, approximately 37% were 65 years and over and about 16% were >75 years. In clinical trials the efficacy of XARELTO^® in the elderly (65 years or older) was similar to that seen in patients younger than 65 years. Both thrombotic and bleeding event rates were higher in these older patients, but the risk-benefit profile was favorable in all age groups.
• Females of Reproductive Potential: Females of reproductive potential requiring anticoagulation should discuss pregnancy planning with their physician.
• Renal Impairment: In a pharmacokinetic study, comparing healthy subjects with normal creatinine clearance, rivaroxaban exposure increased by approximately 44% to 64% in subjects with renal impairment. Increases in pharmacodynamic effects were also observed. In the EINSTEIN trials, patients with CrCl values <30 mL/min at screening were excluded from the studies. Avoid the use of XARELTO^® in patients with CrCl <30 mL/min.
• Hepatic Impairment: In a pharmacokinetic study, comparing healthy subjects with normal liver function, AUC increases of 127% were observed in subjects with moderate hepatic impairment (Child-Pugh B). The safety and PK of XARELTO^® in patients with hepatic impairment (Child-Pugh C) have not been evaluated. Avoid the use of XARELTO^® in patients with moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment or with any hepatic disease associated with coagulopathy.

OVERDOSAGE

• Overdose of XARELTO^® may lead to hemorrhage. Discontinue XARELTO^® and initiate appropriate therapy if bleeding complications associated with overdosage occur. A specific antidote for rivaroxaban is not available. Rivaroxaban systemic exposure is not further increased at single doses >50 mg due to limited absorption. The use of activated charcoal to reduce absorption in case of XARELTO^® overdose may be considered. Due to the high plasma protein binding, rivaroxaban is not expected to be dialyzable.

ADVERSE REACTIONS IN CLINICAL STUDIES

• Hemorrhage: The most common adverse reactions with XARELTO^® were bleeding complications.
• Nonvalvular Atrial Fibrillation: In the ROCKET AF trial, the most frequent adverse reactions associated with permanent drug discontinuation were bleeding events, with incidence rates of 4.3% for XARELTO^® versus 3.1% for warfarin. The incidence of discontinuations for non-bleeding adverse events was similar in both treatment groups.
• Treatment of DVT, PE, and to Reduce the Risk of Recurrence of DVT and of PE: In the pooled analysis of the EINSTEIN DVT and PE clinical studies, the most frequent adverse reactions leading to permanent drug discontinuation were bleeding events, with XARELTO^® versus enoxaparin/vitamin K antagonist (VKA) incidence rates of 1.7% versus 1.5%, respectively. The mean duration of treatment was 208 days for XARELTO^® - treated patients and 204 days for enoxaparin/VKA-treated patients. In the EINSTEIN Extension clinical study, the most frequent adverse reactions associated with permanent drug discontinuation were bleeding events, with incidence rates of 1.8% for XARELTO^® versus 0.2% for placebo treatment groups. The mean duration of treatment was 190 days for both XARELTO^® and placebo treatment groups.
• Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery: In the RECORD clinical trials, the overall incidence rate of adverse reactions leading to permanent treatment discontinuation was 3.7% with XARELTO^®.
• Other Clinical Trial Experience: In an investigational study of acute medically ill patients being treated with XARELTO^® 10-mg tablets, cases of pulmonary hemorrhage and pulmonary hemorrhage with bronchiectasis were observed.

RANDOM NEWS FROM ONCOLOGY RELATED LITERATURE

*A JAPANESE GOVERNMENT FUNDED STUDY, proposed 4 new Bio-markers for pancreatic cancer,
1-Xylitol
2-1,5-anhydro-D-glucitol
3- Histidine
4-Inositol
These are Metabolites implicated in the function of the pancreas and excerbated mechanisms during tumorigenesis

CEA and CA19-9 were also mentioned in the report.

*A STUDY WAS STOPPED FOR BAD OUTCOME!
ADDING CETUXIMAB TO UNSELECTED PATIENTS WITH EARLY STAGE ESOPHAGEAL CANCER RECEIVING CONCURRENT CISPLATIN-XELODA AND RADIATION ADDED TOO MUCH SIDE EFFECTS, AND WORSEN SURVIVAL!

*IN GASTRIC CANCER, RESPONSE BY PET HAS PROGNOSIS MEANING!
PATIENTS WHO SHOWED RESPONSE HAD REPORTEDLY 29.7 MONTHS Vs 14.1 MONTHS FOR NON RESPONDERS
QUESTION IS THIS PET TESTING SENSITIVITY BEING PROVEN, OR IS IT TUMOR RESPONSIVENESS BEING TESTED!  THAT IS CHEMOSENSITIVE TUMORS HAVE BETTER PROGNOSIS!  WELL THE REPORTED WOULD RATHER SAY IT THE PET THAT HAS PREDICTIVE VALUE. YOU DECIDE!

*SUPPORTIVE CARE
ESCITALOPRAM, FOR HEAD AND NECK CANCER PATIENT DEPRESSION
AND DULOXETINE, FOR PERIPHERAL NEUROPATHY!

(THANKS TO THE "ONCOLOGY REPORT"! READ IT!)

HARD TO BELIEVE NEWS FOR NPR OR IS IT!

GMO Wheat Found In Oregon Field. How Did It Get There?

An Oregon farmer discovered the genetically engineered wheat growing in his field about a month ago. Nobody knows how it got there, how widely it has spread, or whether it has been in fields harvested for food. GMO wheat is not approved for sale in the U.S.

THE MAIN QUESTIONS HOW THIS IS LINKED TO CANCER !  IS THIS A TRUE THREAT? WE SHALL EXPLORE THE QUESTION...

ASSOCIATED GENES TO THE TWIST GENES

 The following is a list of conditions commonly confused/misdiagnosed for SCS, some of their symptoms, and which mutated gene each contains:

Disease/Condition	Symptoms	Mutated Gene
SCS	Widely-spaced eyes, Low-set hairline, Drooping eyes, Interdigital webbing, Deformed ears, Crossed eyes, and downward sloping palpebral fissures	TWIST1
Robinow-Sorauf Syndrome	Widely-spaced eyes, Deviated septum, Flat skull posterior, Deformed ears, Crossed eyes, Protruding jaw, and Duplication of distal phalanx	TWIST1
Muenke Syndrome	Widely-spaced eyes, Enlarged head, Hearing loss, Flat cheeks, and Low-set ears	FGFR3
Crouzon Syndrome	Widely-spaced eyes, Short-broad head, Hearing loss, Bulging eyes, Beaked nose, Low-set ears, Strabismus, Protruding chin, and Short humerus and femur	FGFR2 & FGFR3
Pfeiffer Syndrome	Widely-spaced eyes, Underdeveloped jaw, Beaked nose, Hearing loss, and bulging eyes	FGFR1 & FGFR2
Apert Syndrome	Widely-spaced eyes, Prominent forehead, Flat skull posterior, Bulging eyes, Low-set ears, Flat or concave face, Short thumb, and Webbed fingers	FGFR2
Isolated Unilateral Coronal Synostosis	Only malformation is the premature fusion of sutures; If left untreated, can lead to facial asymmetry resembling SCS	FGFR (any)
Baller-Gerold Syndrome (BGS)	Short broad head, Bulging eyes, Flat forehead, Poikiloderma, Radial deformity with reduced number of digits, underdeveloped or missing thumb and radius, and Growth retardation	RECQL4

WIKIPIDIA!

Saethre–Chotzen syndrome? TWIST GENE

http://www.youtube.com/watch?v=0fjZi9aSHsM

 As we reviewed Epigenetic phenomena, one outstanding gene is the TWIST1,2 genes

This gene is important because abnormality at this location cause short stature.  Like Thalidomid causing limbs we continue to insist that genes causing short stature are definitely important genes when mutated in cancers.  This gene can be mutated in Thyroid cancer comfering an Anaplastic feature to the cancer according to researchers.  It has been found also in Breast cancer (?triple negaltive).

The picture on the video describes a 28 year old with a nine months body shape, and Doctors in Brazil supposedly called it a case of Cretinism based on Hypothyroidism.  Hypothyroidism only would not fully explain all that is seen here.  And coincidentally, TWIST2 abnormality is described in Anaplastic Cancers of the Thyroid!

TWIT1,2 have epigenetic action since they (or their product) bind double stranded DNA, blocking expressing of genes in the targeted area.  They have a role in the differentiation and mesodermal /endodermal transformation.   The interesting fact is that short stature individual have appropriate length of blood vessel and function in appropriate, adapted to their size.  Adaptations at the Wnt and Notch appear critical for this individual syndrome to exist.  Certainly craniosynostosis and syndactyly   attest to their involvement as membrane "termination or delineation" seems involved.

It would have been a great opportunity if we had access to these Doctors to discuss this case.  It is obvious that these are great opportunities that nature give us for insight as long as all measures are taken to protect human dignity and rights.

The role of immunomodulator (ie the Thalidomide experience) brings to mind an opportunity of intervention in the Anaplastic Cancer of the Thyroid if TWIST2 is involved.  I am sure that Histone Deacetylase and Hypomethylating agents will need further exploratory trials in conditions where TWIST amplification is found!

One should mention now that it appears increasingly that when the Wnt and Notch are involved, epigenetic controls or  intervention would be the strongest to try as a target intervention.

 Evidence of Notch involvement

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

 Twist transcription factor has been shown to interact with EP300,^[15] TCF3^[16] and PCAF.^[15]

TCF3

From Wikipedia, the free encyclopedia

Jump to: navigation, search

Transcription factor 3

"Transcription factor 3 (E2A immunoglobulin enhancer-binding factors E12/E47), also known as TCF3, is a protein that in humans is encoded by the TCF3 gene.^[1][2][3] TCF3 has been shown to directly enhance Hes1 (a well-known target of Notch signaling) expression.^[4]"

 " PCAF has separate acetyltransferase and E3 ubiquitin ligase domains as well as a bromodomain for interaction with other proteins. PCAF also possesses sites for its own acetylation and ubiquitination.^{[1]"wikipidia}


This gene encodes the adenovirus E1A-associated cellular p300 transcriptional co-activator protein.
The protein functions as histone acetyltransferase ^[4] that regulates transcription via chromatin remodeling, and is important in the processes of cell proliferation and differentiation. It mediates cAMP-gene regulation by binding specifically to phosphorylated CREB protein.
This gene has also been identified as a co-activator of HIF1A (hypoxia-inducible factor 1 alpha), and, thus, plays a role in the stimulation of hypoxia-induced genes such as VEGF.<sup>[5]wikipedia

=====================================================================
WITH THESE TWIST CONNECTIONS, QUESTIONS ARE RAISED

1. IS ANAPLASTIC CANCER OF THE THYROID ASSOCIATED WITH AN ADENOVIRUS?
2. DEFINITELY VEGF CONNECTION OPEN THE DOOR TO ROLE OF AVASTIN IN ANAPLASTIC CANCER
3.SHOULD COMBINATION OF THALIDOMID -AVASTIN BE TRIED IN THIS DISEASE
4.A CAN OF WORM IS OPENED!</sup>

 

FDA Approvals > Medscape Medical News

Dabrafenib and Trametinib Approved for Metastatic Melanoma

Zosia Chustecka

DisclosuresMay 29, 2013

Two new drugs have been approved by the US Food and Drug Administration (FDA) for use in certain patients with metastatic or unresectable melanoma, along with a diagnostic test to identify patients who are suitable for treatment.
The new products, dabrafenib (Tafinalar) and trametinib (Mekinist), were both developed by GlaxoSmithKline. Both are orally available tablets, but they have slightly different mechanisms of action.
Dabrafenib acts as a BRAF inhibitor and is approved for use in patients with melanoma whose tumors express the BRAF V600E gene mutation. It is seen as being a next-generation product but is in the same class as the first BRAF inhibitor to reach the market, vemurafenib (Zelboraf, Genentech).
Trametinib has a related but slightly different mechanism and acts as a mitogen-activated, extracellular signal-regulated kinase inhibitor (MEK inhibitor). It is the first drug in this class to be approved and is indicated for use in patients with whose tumors express the BRAF V600E or V600K gene mutations.
Approximately half of melanomas arising in the skin have a BRAF gene mutation, the FDA notes in its approval notice. Alongside the new drugs, the agency also approved a genetic test, the THxID BRAF test, a companion diagnostic developed in collaboration with bioMérieux that will help determine wither a patient's melanoma cells have the V600E or V600K mutation in the BRAF gene.
Melanoma is the leading cause of death from skin disease, the FDA adds. The National Cancer Institute estimates 76,690 Americans will be diagnosed with melanoma and 9480 will die from the disease in 2013.
Clinical Trial Data
Dabrafenib was approved on the basis of data from the BREAK 3 study, conducted in 250 patients with previously untreated BRAF V600 mutation–positive metastatic melanoma. It showed that in such patients, dabrafenib significantly improved the median progression-free survival compared with chemotherapy with dacarbazine (5.1 vs 2.7 months; P < .0001). These results were published in July 2012 issue of the Lancet (2012;380:358-365).
The FDA notes that the most serious adverse effects reported in patients receiving dabrafenib included an increased risk for cutaneous squamous cell carcinoma, fevers that may be complicated by hypotension, severe rigors, dehydration, kidney failure, and increased blood sugar levels requiring changes in diabetes medication or the need to start medicines to control diabetes.
The most common adverse effects reported in patients receiving dabrafenib included hyperkeratosis, headache, fever, joint pain, noncancerous skin tumors, hair loss, and hand–foot syndrome.
The pivotal study for trametinib, the METRIC study, was a little different in that it was conducted in 322 patients who had already tried a prior regimen of chemotherapy. In this study, compared with chemotherapy, trametinib significantly improved progression-free survival as well as overall survival. The results were published in the New England Journal of Medicine.
The FDA notes that the most serious adverse effects reported in patients receiving trametinib included heart failure, lung inflammation, skin infections, and loss of vision. Common adverse effects included rash, diarrhea, tissue swelling (peripheral edema), and skin breakouts that resemble acne.
The agency also noted that women of childbearing years should be advised that dabrafenib and trametinib carry the potential to cause fetal harm. Men and women should also be advised that both drugs also carry the potential to cause infertility.
Being Investigated in Combination
Dabrafenib and trametinib have been approved for use as monotherapy, and not as a combination treatment, the FDA has emphasized. However, there is a lot of interest from clinicians in using both drugs together, and indeed the manufacturer is conducting a clinical trial with the combination.
Preliminary results from a clinical trial with the combination suggest that use of the 2 drugs together resulted in less toxicity, and specifically in fewer secondary skin cancers, than has been seen with vemurafenib used alone.
GlaxoSmithKline is now conducting a phase 3 study (known as COMBI-AD) of the combination of dabrafenib and trametinib in patients with BRAF V600 melanoma that has been completely removed by surgery. Such patients are at high risk for relapse, and the combination of drugs is being tested to see whether it can delay or prevent the recurrence of melanoma, the company noted.
Problem: Responses Are Short-lived
The new dabrafenib appears to be similar to the already-marketed vemurafenib, but there are important differences between the 2 BRAF inhibitors in their toxicity profiles, noted Kim Margolin, MD, from the Seattle Cancer Care Alliance in Washington, commenting in a recent Medscape videoblog.

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Skin toxicities, particularly the emergence of low-grade squamous cancers and keratoacanthomas, which occurred in a substantial number of patients taking vemurafenib, appear to be quite unusual with dabrafenib, Dr. Margolin noted. However, a systemic "pyrexia reaction," which is almost never seen with vemurafenib, has been seen in a substantial percentage of patients taking dabrafenib. "We don't know yet about the off-target mechanisms of these differences and how much may be due to the vehicle or the formulation for each of these oral agents," she added.
However, the biggest problem with the BRAF inhibitors in the treatment of melanoma has been the lack of durable response: These drugs "tend to work for an average of 5 to 6 months," Dr. Margolin noted. What to do when patients fail on these drugs remains a challenge, she added.
Ultimately, combination therapy with a BRAF inhibitor (such as vemurafenib or dabrafenib) plus a MEK inhibitor (such as trametinib) is "likely to be most valuable for improved and lasting results," according to Dr. Margolin, commenting on dabrafenib last year.

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Latest in Hematology-Oncology

VARIOUS ONCOLOGY NEWS (FROM Oncology time)

*AT ASCO, WE EXPECT NEWS ABOUT AVASTIN ACTIVITY IN GLIOBLASTOMA
*REGORAFENIB, APPROVED BY THE FDA FOR REFRACTORY GIST
IS SAID NOW TO HAVE ACTIVITY REGARDLESS OF THE FORMS OF RESISTANCEFOR GIST.  THIS DRUG BEHAVE LIKE IT DOES NOT MATTER WHAT REFRACTORINESS YOU GOT: "JUST BRING IT ON"

*CAR T CELL, CD19 CHIMERIC ANTIGEN  RECEPTOR (car) ACTIVATE T-CELL ENOUGH TO CAUSE COMPLETE REMISSION IN PEDIATRIC ACUTE LYMPHOBLASTIC LEUKEMIA (ALL) EVEN IN RELAPSE SETTING.
* A COMBINATION OF RITUXIMAB, VORINOSTAT, AND CLADRIBINE PRODUCED A 100% RESPONSE RATE IN MANTLE CELL LYMPHOMA

*OVARIAN CANCER IS BEING TARGETED BY OUR NEW APPROACH USING "CONJUGATE" DRUGS.  DMUC5754A IS THE NEW EFFECTIVE IMMUNOLOGIC TARGETING OPTION IN THIS DISEASE, CHCK IT OUT!

*REFRACTORY MYELOMA? CALL DARATUMUMAB!  THE FDA GRANTED "BREAKTHROUGH" STATUS TO THIS DRUG REPORTEDLY!

TALKING EPIGENETIC EVENTS: THE TET2 STORY

One of the gene that has marked its presence in the epigenetic region of the cell where gene Methylation belong, is TET2.
TET2, also known as TET (ten-eleven-translocation)2, belong to a family of genes that actually participate in methylation of genes.  Methylation of gene can block the expression of that gene, therefore TET2 is generally perceived as a Tumor suppressor gene.  TET2 seems to focus its attention somewhat exclusively on those genes that are involved in pluripotency particularly of the stem cell located in the Bone marrow.  The role of TET2 here to silence genes in order to influence somatic expression of genes in order to force stem cell differentiation in a specific lineage output.  That is if the body is Anemic with deficiency in red cells, the message is received at cell membrane, and possibly through the Wnt sent somehow to the TET2.  TET2 methylates gene blocking differentiation to platelets and white blood cells, forcing the stem cell to only express genes of red cell formation.

The Wnt assumption comes from the fact that TET2 is controlled by IDAX
again Ko et al:

"Here we show that IDAX (also known as CXXC4), a reported inhibitor of Wnt signalling⁷ that has been implicated in malignant renal cell carcinoma⁸ and colonic villous adenoma⁹, regulates TET2 protein expression. IDAX was originally encoded within an ancestral TET2 gene that underwent a chromosomal gene inversion during evolution, thus separating the TET2 CXXC domain from the catalytic domain. The IDAX CXXC domain binds DNA sequences containing unmethylated CpG dinucleotides, localizes to promoters and CpG islands in genomic DNA and interacts directly with the catalytic domain of TET2 "

The Wnt also will send a consensus message to other stem cell through the NOTCH so that the message is clear to what stem cells should be doing!

The IDAX has now been a target for therapy in order to further regulate TET2 in those MDS and leukemias in which Mutation at TET2 seems to contribute to malignant proliferation.   All in all, TET2 seems to belong to the molecules that gives stem cells potential of creating new combination of proteins!

OF NOTE TOO MUCH OF IDAX RECRUIT CASPASES AND LEADS TO CELL DEATH.

KO et al: " Unexpectedly, IDAX expression results in caspase activation"  SO BE CAREFUL HANDLING THESE STUFF !

CPRIT/Update from Interim Executive Director - 05/28/2013

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Cancer Prevention and Research Institute of Texas via mail175.atl21.rsgsv.net	11:01 AM (1 hour ago)
to me

Email not displaying correctly? View it in your browser. With the end of the 83rd Texas Legislature’s Regular Session, I want to provide an update on CPRIT’s progress and expectations going forward. Senate Bill 149, the reform bill revising CPRIT’s enabling legislation, has been sent to Gov. Rick Perry for his signature. This bill, which will become law immediately upon the governor’s signature, strengthens CPRIT operations and governance. Significant provisions include:   Heightened conflict-of-interest standards for CPRIT staff, Oversight Committee members, and reviewers; Process improvements for developing and approving grants, and; More consistent and effective monitoring of grantees’ performance. CPRIT thanks the Legislature, particularly Sen. Jane Nelson and Rep. Jim Keffer, for strengthening CPRIT to fulfill its vital mission. We are currently developing rules and procedures necessary to implement SB 149 and will update you as these measures are adopted. CPRIT is committed to achieving the high standards called for in SB 149 and in the January 2013 State Auditor’s report on agency operations. We will move carefully and deliberately in implementing these changes. Full funding for CPRIT grant programs was included in the 2014-15 biennial appropriations act. Provided Gov. Perry signs SB 149, we hope to release new requests for applications in fall 2013. We are unable to provide any additional information at this time concerning the August and December awards affected by the December 18th moratorium.  As soon as information is available, we will notify you. Thank you for your participation in and support of CPRIT’s vital mission to combat the scourge of cancer. We look forward to partnering with you as we renew our efforts to meet the purpose for which CPRIT was established. Regards, Wayne R. Roberts Interim Executive Director http://www.cprit.state.tx.us Unsubscribe from this list | Forward to a friend| Update your profile Our mailing address is: Cancer Prevention and Research Institute of Texas 211 E 7th Street Ste 300 Austin, Texas 78701 Add us to your address book Copyright (C) 2013 Cancer Prevention and Research Institute of Texas All rights reserved.

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HYPOMETHYLATION, NEW AREA OF RESEARCH

With the laws of nature described here, we continue to maintain that therapeutic interventions follow the various stages or layers of the cell.  That is there are drugs acting at membrane level, cytosolic level, mitochondria, nuclear etc...And combination therapy to be significant, should combine at least 2 different classes following these layers of cell division suggested.
In the Epigenic region, a prominent activity is methylation of genes.  This is achieved for promoting or  silencing certain genes.  The effect is certain when the genes involved are promoters or globally regulators of some function of significant.   In Leukemia, we have argued that the mains events are nuclear and epigenic (with a secondary lymphokine effect) putting center Hypomethylation as a therapeutic intervention. Indeed, other than induction chemotherapy using drugs inducing Nuclear havoc (Cytarabine and Daunorubicin), Decitabine and related Hypomethylating drugs have been the significant main intervention, particularly in the adult population because of perceived poor tolerance of standard induction approaches.

With the advance of target therapy, Hypomethylation has entered the microscopy of researcher.  It is now combined to standard induction in clinical trial.  Decitabine treatment has now been 10 days with better results, and much more is being done to further dissect how this group of drug works.  In fact, the knowledge that these medications are at risk of Deamination, has prompted studies of Anti-deaminasation (Plerixafor-an anti-CXCR4).   The challenge remains though!  which gene is actually being methylated and when. Methylation gene is a quick evolving history in a living cell and can quickly change however under effect of Core-binding like molecules, neoplastic processes, and or drug treatments!  Scientists are hard at work.

THE RETURN OF GEMTUZUMAB.

Here is a drug that was the FDA dis-approved believing it has closed the coffin on it.  But straight from the cemetery, an uproar is coming to rattle the FDA door once again!  The point is while the door closed on Gemtuzumab here in the USA, the European have continued using the drug at least at clinical trial basis.  Evidence suggesting that when added to Cytarabine, Gentuzumab could double or triple 2 year survival and increase by 10 months overall survival, is hard to conceal or reject.  This has forced Americans to reconsider, new clinical trial has been re-completed here, and soon the FDA has to convene for these new indications!

GENES VERSUS CHROMOSOME ABNORMALITY

AS WE MOVE FORWARD, ABNORMALITY IN GENES WILL BE MORE IMPORTANT AS FAR AS CLINICAL RELEVANCE IS CONCERNED.  ONCE UPON A TIME CHROMOSOME ABNORMALITY WAS RELEVANT BUT WITH THE NOW RISING INTEREST IN TARGET THERAPY, THE GENE IS THE FOCUS OF ATTENTION.
IT IS TRUE KNOWING THAT ABNORMALITY OF THIS AND THAT CHROMOSOME WAS RARELY RELEVANT FROM THERAPEUTIC STAND POINT UNTIL YOU DISSECT THE GENES INVOLVED.  DEL OF 5q IN MYELODYSPLASIA WAS THE MOST CITED EXAMPLE OF HOW REVLIMID HELPED THE CHROMOSOMAL DETECTION EXAMPLE, BUT THE FACT IS, IT IS STILL UNCLEAR WHAT GENES IN THIS SCENARIO ARE AT PLAY.  AND  THE NEED TO DO BETTER AT TARGETING CALL FOR GENE IDENTIFICATION RATHER THAN GLOBAL CYTOGENETIC STUDIES!

LOOKING AT THIS CLOSER, EUROPEAN INVESTIGATORS ARE NOW THE TRUE MECHANISM OF ACTION OF SOME WELL ESTABLISH MEDICATIONS.  AZACITIDINE FOR EXAMPLE IS NOW INCREASING RECOGNIZED AS A IMMUNE-MODULATOR BECAUSE OF ITS EFFECT ON T-CELL.  IT IS ACTUALLY TRUE THAT IF YOU FOLLOW THE NF-kB, C-JUN AND FOS (INVOLVEMENT OF GROWTH FACTORS), YOU QUICKY WILL ARRIVE IN THE EPIGENIC REGION WHERE HYPOMETHYLATION, SPLICING, m-ARN TRANSFERASE AND OTHER RELEVANT ACTIVITY CO-MINGLE AND CO-ACTIVATE AT RAPID PACE MAKING DISSECTION AND ATTRIBUTION OF ROLE DICEY OR TRICKY.

ON OTHER FRONT, STILL LOOKING INTO MECHANISM OF ACTION OF KNOWN DRUG, THE THALIDOMID STORY GOT A NEW DEVELOPMENT WITH THE ANNOUNCEMENT THAT FDF8 WAS THE TERATOGENIC BASIS OF THALIDOMID ACTIVITY!  IF BY TERATOGENESIS, WE MEAN MORPHOLOGIC ABNORMALITY, THIS WILL BE A SIGNIFICANT DEVELOPMENT.  HOW IS FDF8 RELATED TO ANGIOGENESIS?  IS FDF8 RELEVENT ONLY TO THALIDOMID OR SHOULD ALTERATION HERE BE BROADLY APPLIED TO CHECK ALL DRUGS FOR TERATOGENIC POTENTIAL? HOW IS FDF8 RELATED TO MESENGIAL TRANSFORMATION...MUCH IS TO BE LEARNED YET!  SUFFICE IS TO SAY THAT A GENE INVOLVING SIGNIFICANT MORPHOLOGIC CHANGES IS DEFINITELY AN IMPORTANT GENE!

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Acute Myeloid Leukemia and Myelodysplastic Syndromes in Older Patients

May 28, 2013

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BONE MARROW TRANSPLANTERS ARE NOW COMING UP WITH A FLEXIBLE ARGUMENT.  THEY HAVE COME TO THE REALIZATION THAT THE CUT OFF POINT OF 65 YEARS OF AGE IS NOT WORKING OUT TOO GOOD FOR THEM!  MYELODYSPLASIA AND LEUKEMIAS ARE DISEASES OF AN EVER GROWING POPULATION.  AND THE ELDERLY ARE THE BULK OF THE PATIENTS.  AND 65 YEARS OF AGE IS NOT ENOUGH IN THE DEFINITION OF ELDERLY.

THE NEW WORD NOW IS "COMORBIDITY INDEX" AND INCLUDE
1. PERFORMANCE STATUS
2. ALBUMIN LEVEL
3. CREATININE LEVEL
4. AGE
5. PLATELET COUNT
6. BLAST COUNT
7. PRIMARY versus SECONDARY AML

YES MDS/AML ARE ON THE INCREASE
AND THERE MORE AND MORE ADULTS OVER 65 YEAR OF AGE UNDERGOING SOME FORM OF TRANSPLANT!

WHILE IT IS TRUE THAT UNIVERSITIES ARE BY DEFINITION LEADERS IN SCIENCE
IT IS ALSO TRUE THAT SCIENCE PROVIDE ENOUGH OPPORTUNITIES FOR RESEARCH TO PROVIDE ONE  WHO IS WILLING A CHANCE TO CREATE ORIGINAL.  TESTING AND EVALUATION OF RESULTS IS THE ONLY CONCRETE ADVANCES THAT PROVIDE THE FRAME WORK OF FUTURE WORK, GIVE US A CHANCE OR CLEAR THE WAY, AND LET FREEDOM OF THINKING REIGN WITHOUT HINDRANCE!

IT IS GOOD TO HAVE CONSENSUS ON WHAT IS IMPORTANT AND TRUE, BUT IN RESEARCH, LET IMAGINATION REIGN BECAUSE WHAT IS TRUE TODAY MAY NOT BE TOMORROW, AND UNTIL IMAGINATION IS FREED, NO NEW LEADS WILL BE CREATED, AND WHAT IS TRUE TODAY BUT FALSE TOMORROW WILL NOT BE CORRECTED.  WHEN IT COMES TO RESEARCH, FOLLOWING OUR LEADERS IS NOT THE ONLY WAY TO THE TRUTH OR THE CURE!  ONE HAS TO CONTINUOUSLY QUESTION THE PREMISES.  IT IS WHY THE SUPREME COURT EXISTS DESPITE THE DICTATES OF A CONSTITUTION WHICH HAS WITHSTAND THE TIME.

TO WIN, YOU CAN FOLLOW FOR A WHILE, BUT AT A CERTAIN TIME IN THE PATH, YOU HAVE GOT TO DEMARCATE, TAKE A DIFFERENT TANGENT AND BREAK FREE, AND THIS DESPITE THE UPROAR. AND WHILE YOU ARE FOLLOWING, KNOW THE OPPONENT WELL AND WHAT HE IS UP TO!

BUT REMEMBER, YOU CAN NOT WIN BY STRICTLY FOLLOWING!

•  RETINOBLASTOMA
•  
•  "One function of pRb is to prevent excessive cell growth by inhibiting cell cycle progression until a cell is ready to divide. It is also a recruiter of several chromatin remodeling enzymes such as methylases and acetylases. pRb belongs to the pocket protein family, whose members have a pocket for the functional binding of other proteins.^[2][3] Should an oncogenic protein, such as those produced by cells infected by high-risk types of human papillomaviruses, bind and inactivate pRb, this can lead to cancer."
  
  REPORTEDLY THIS EFFECT OF Rb GENE GO THROUGH CDKs
  
  "
   Cyclin-dependent kinases (CDKs) play essential roles in cell proliferation and gene expression. Although distinct sets of CDKs work in cell division and transcription by RNA polymerase II (Pol II), they share a CDK-activating kinase (CAK), which is itself a CDK-Cdk7-in metazoans."FISHER ET AL
  
  "
  
  
• cholera toxin - increase cAMP levelsIn a cAMP-dependent pathway, the activated G_s alpha subunit binds to and activates an enzyme called adenylyl cyclase, which, in turn, catalyzes the conversion of ATP into cyclic adenosine monophosphate (cAMP).^[2] Increases in concentration of the second messenger cAMP may lead to the activation of
  
• cyclic nucleotide-gated ion channels^[3]
• exchange proteins activated by cAMP (EPAC)^[4] such as RAPGEF3
• an enzyme called protein kinase A (PKA).^[5]

The PKA enzyme is also known as cAMP-dependent enzyme because it gets activated only if cAMP is present. Once PKA is activated, it phosphorylates a number of other proteins including:^[6]

• enzymes that convert glycogen into glucose
• enzymes that promote muscle contraction in the heart leading to an increase in heart rate
• transcription factors, which regulate gene expression

Specificity of signaling between a GPCR and its ultimate molecular target through a cAMP-dependent pathway may be achieved through formation of a multiprotein complex that includes the GPCR, adenylyl cyclase, and the effector protein.<sup>[7]WIKIPEDIA

 (</sup>cyclin-dependent kinase 7 (CDK7) has essential roles in both the cell-division cycle and transcription, as a CDK-activating kinase (CAK) and as a component of the general transcription factor TFIIH,") FISHER

Cyclic AMP inhibits the proliferation of thyroid carcinoma cell lines through regulation of CDK4 phosphorylation.(Rocha)

AND 

 

Rb inactivation in cell cycle and cancer: the puzzle of highly regulated activating phosphorylation of CDK4 versus constitutively active CDK-activating kinase.(Paternot et al!)

LINKING  cyclic-AMP to Rb

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

activators of c-AMP

Paternot S, Bockstaele L,

• forskolin - a diterpene natural product that activates adenylyl cyclase
• caffeine and theophylline inhibit cAMP phosphodiesterase, which leads to an activation of G proteins that result in the activation of the cAMP pathway
• bucladesine (dibutyryl cAMP, db cAMP) - also a phosphodiesterase inhibitor
• pertussis toxin, which increase cAMP levels by inhibiting Gi to its GDP (inactive) form. This leads to an increase in adenylyl cyclase, therefore increasing cAMP levels, which can lead to an increase in insulin and therefore hypoglycemia (WIKIPEDIA)

drink coffee while on treatment with Melanoma ? or Rb driven disease?
take Theophylline for that matter!

DO NOT DRINK COFFEE WITH MTORC1 DRIVEN CONDITION?
YOU BE THE JUDGE!