RANDOM NEWS FROM ASCO

1.  For first line Metastatic Pancreatic Cancer:
        3 options Tarceva + Gemzar
                      FOLFIRINOX
and the new Abraxane-Gemzar
---------------------------------------------------and the winner is FOLFORINOX according to Michigan Researcher DR Philip Philip.
BUT ABRAXANE-GEMZAR is with less side effects and could be better tolerated by elderly patients

2.The point made by researcher that Treating early Breast cancer with adjuvant chemotherapy should be justified by Oncotype DX  (MammaPrint and now EndoPredict score, Breast Cancer Index (BCI))  findings is appreciated because about 0.5 % of women exposed to Chemotherapy  may develop Leukemia.  The risk was confirmed in a retrospective study reviewing data from the NCCN data base for 10 years.

3. Daratumumab, a monoclonal antibody used in myeloma showed a 47% mostly partial response and stable diseases.  But this is to follow very closely as it add a modality of treatment to be considered in refractory ahere nd late stage of disease, particularly in patient who had undergone most of the standard treatments. Keep an eye on this one, it may be a life savior in patients who have exhausted many options!

4.Predicting Oral Mucositis by Saliva source DNA could help us predict who will benefit from Palifermin (kepivance).  This remind me that Taxotere and Selumetinib gave much Mucositis, Just wonder if the nature of the drugs used is more important but who really knows how much predisposition plays into this!  will wait to hear more about this.

5 An eye catcher, BLINATUMOMAB, an anti-CD-19 bispecific T-cell engager (BiTE) could have a role in a disease where there is limited competition, Refractory ALL.  follow this one too...

6.  In triple negative Breast cancer, adding Bevacizumab did not make much difference.  I still wonder if our focus is wrong, it is not the anti-VEGF but the  anti-MEK that we need to use more to achieve.  OK LET'S TRY COMPARE THESE APPROACHES IN A CLINICAL TRIAL!  YES WHEN YOU THINK ABOUT IT, AN ANTI-MEK PRECEEDS THE ANTI-VEGF THING AND WILL HAVE HAVE OTHER IMPLICATIONS ON ADDITIONAL SIGNAL TRANSDUCTION PATHWAYS!

7.

A PEEK INTO THE FUTURE!

The article published in the Lancet about Taxotere combined to Selumetinib in 2nd line treatment of lung cancer, opens the door to future therapy to come.  It marks the increasing trend of incorporating Target therapy to standard good old chemotherapy.  Selumetinib is a MEK inhibitor downstream from KRAS.
Already the results are impressive with the doubling of progression free survival and Overall survival.
Already, we have a peek to a new set of toxicity because these are new combinations and the outlook is grim now with almost half of the patients having Nausea, diarrhea, severe Neutropenia and stomatitis.
Not only is MEK down stream from RAS-RAF-MEK-ERK (MAPK) signaling pathway; it is the revolving door between epidermal presentation which should block Metastatic spread and Endodermal transformation that the Cancer chooses to metastasize.
Another question that will rise immediately is if we have a driver mutation, when should we stop inhibiting such target, when do we stop closing this revolving door? The rising need of maintenance therapy follows.  In lung cancer, Alimta, Tarceva and Taxotere have all shown to be beneficial in maintenance setting.  So the choice here would be Taxotere maintenance, or should we continue to push closed MEK with Selumetinib?
This article emphasized the fact that this was the first time that KRAS was used as a biomarker for  Target therapy.  Very true, but mesenchymal transformation and angiogenesis play a role in almost every cancer.
THE FIGHT IS ON.

(LAST POINT: WE HAVE NOT LEARNED ENOUGH ABOUT HOW TO PREVENT THESE SIDE EFFECTS, WE NEED TO STEP UP!)

OUTRAGEOUS THINGS!

I AM IN WARSAW INDIANA/ US/ IN CASE YOU WONDER.
I TRAVELED THROUGH CHICAGO AIRPORT, WAS ACTUALLY SURPRISED THAT THE FAUCETS THERE WERE NOT MODERNIZED, YOU STILL HAVE TO SPIN THE FAUCET KNOB AND YOU KNOW, WITH MY ARTHRITIS, THAT IS NOT A FAIR DEAL.

YOU WOULD THINK THAT WITH THE NAME OF CHICAGO, THINGS WILL BE UP TO DATE!
COME ON LEADERS, WAKE UP!

IT IS THE SAME SURPRISE I HAD A FEW DAYS AGO WHEN I LEARNED THAT THE UNIVERSITY MEDICAL CENTER IN EL PASO DID NOT HAVE A PET SCAN !?  WHY KEEP YOUR RESEARCHERS BEHIND PURPOSELY! ?  WITH ALL THE GIST BEING MONITORED BY PET SCAN, IT IS JUST SCANDALOUS NOT TO HAVE A PET SCAN IN A UNIVERSITY MEDICAL CENTER IN THE UNITED STATES.  LOOKING BACK, IT SHOULD NOT BE TOLERATED!

THIS ONLY HAPPENS WHEN OUR LEADERS ARE EQUIVOCATING INSTEAD OF DOING THE RIGHT THING!

WAKE UP AND SMELL THE COFFEE.  THE STORY OF DDR2

ONE OF THE MOST POWERFUL PAPERS

« ASCO issues Provisional Clinical Opinion on EGFR testing in Non-Small-Cell Lung Cancer | Main | Systems biology for studying cancer »

May 06, 2011

DDR2 Kinase Mutations in Lung Squamous Cell Carcinoma

Yes--you read that right!
The journal Cancer Discovery reports in a publish ahead-of-print article (abstract) the discovery of mutations in the discoidin domain receptor 2 tyrosine kinase (DDR2) gene in a series of lung squamous cell carcinomas (SQC) that may identify a  potential therapeutic target similar to those described for lung adenocarcinomas.  Interestingly, DDR2 is a receptor kinase that normally binds collagen as its ligand and has been shown to promote cell migration, proliferation, and survival when activated by ligand binding and phosphorylation.
While subtypes of lung adenocarcinoma (ADC) have been increasingly better defined and characterized on multiple levels with respect to identifying therapeutic targets/responses, minimal progress has been made with squamous cell carcinoma.
The authors of this study used conventional Sanger sequencing of 201 genes, including the entire tyrosine kinome, in an initial set of 20 primary lung SQC and matched normal controls and identified 2 samples with DDR2 mutations; a secondary screen of 48 lung SQC samples identified an additional 4 DDR2 mutations.  Following this, the authors sequenced DDR2 in a validation cohort of 222 primary lung SQC samples and identified 5 additional samples with mutations.  Excluding samples from lung SQC cell lines, there was an overall frequency of 3.2% of DDR2 mutations in primary lung SQC samples--about the same frequency reported for ALK fusion mutations in lung ADC.
The authors analyzed the TKIs imatinib and dasatinib, previously reported to inhibit DDR2, to evaluate whether targeting DDR2 mutated in SQC might be a potential therapeutic strategy.  Dasatinib showed particular efficacy in inhibiting proliferation and promoting cell death through apoptosis in SQC cell ines with DDR2 mutations.  In addition, they report one of 7 subjects from an early-phase trial of dasatinib or combination dasatinib and erlotinib with advanced stage lung SQC cancer who exhibited significant shrinkage in tumor size while receiving the dasatinib/erlotinib combination.  The authors were able to perform direct sequencing of DDR2 in a pretreatment tumor specimen from this individual and identified a novel DDR2 kinase mutation.
This is an intriguing paper that you might well keep in mind.  Hopefully, this may stimulate other investigators to not only look for other potential genomic alterations that either drive SQC and/or represent targetable proteins but also go back and scrutinize histological and other clinicopathological characteristics of lung SQC that may have therapeutic or prognostic importance.

Posted at 11:40 AM in Lung Cancer, Lung Squamous Cell Carcinoma, Molecular Pathology, Prognostic/Predictive Cancer Markers | Permalink

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AT CRBCM WE BELIEVE

ONE OF THE MOST POWERFUL TREATMENT AGAINST A DISEASE IS TO FIND THE TARGET THAT INITIATED IT.  THE STRONGEST EVIDENCE THAT A TARGET MOLECULE IS A CRITICAL MOLECULE IS WHEN ITS MUTATION SHORTENS A LIMB IN INDIVIDUALS AND DDR2 MUTATION DOES EXACTLY THAT !!!!
It reminds me of the story of Thalidomide.  And the 2 can be linked.  I am only 50% of this! And whenever a limb is missing, your Angiogenesis and Differentiation are not very far and sure enough, Dasatinib, Imitanib and most likely Thalidomid are not far, lurking in the neighborhood!

SPONDYLO META EPIPHYSEAL DYSPLASIA (SMED) IS THE CONDITION OF SHORT STATURE AND SMALL LIMBS THAT IS RELATED TO DDR2 MUTATION!
SCIENTISTS DID NOT SLEEP, THEY LOOKED IN LUNG CANCER WHAT DASATINIB WOULD DO IN THESE PATIENTS WITH DDR2 MUTATION AND SURE ENOUGH, DASATINIB WORKS. The proof of concept is there in the pudding.

Now don't go out hunting for any short stature individual to test their gene.  But nature has given us a clue that all short stature gene found in a cancer cell, should not only tell us that the gene is targetable by an anti-VEGF and related kinase.  WE SHOULD BE TESTING ALL CANCER FOR DDR2, AND TREAT WITH DASATINIB. CURE IN THOSE CASES IS REACHABLE!  And may be we can prevent all stature with these drug.   One thing for sure, let's find DDR 2 in triple negative breast cancer, and we know what to give pronto now!

ACTIVITIES AT CRBCM

*Flying today to Indiana,  WARSAW!
New prospects await
life is short
CRBCM is still on the move
There is still hope
we will survive
Interested in their plan to develop a cancer center
will talk and explore their meaning
This is exciting!  let's catch United 3736

*Today will e-mail our PI for the DOD project
It is Amazing how much a determined leader Vs a hesitant one can make a difference.
Sometimes life of people, a city, a country can rest in the will of one person, this is the scenario.
The PI is one of the "Quadrons" at Fort Bliss.
His involvement is the only requirement we have to fulfill to get this grant!
And he does not know us from ADAM !
How do you convince a guy!?
CRBCM is going to try.

*Follow-up on Request for Medications for indigent and un-insured patients
for Xeloda and Avastin today.
It is amazing how much paper work and phone calls are required
absolute poverty is some times hard to prove when the eye of the beholder is full of suspicion and doubts!
We keep trying at CRBCM. Never giving up. Never.

Let's catch that plane!

GENES INVOLVED IN THE  6th LAW.
REPROGRAMMING OR MESENCHYMALIZATION.
=======================================

1. MET
---------------It is center to cancer preparing for Metastasis.
Once the initial cause of cancer have hit the cell, and the cancer cell wants to migrate because of several reasons such as stress in that location, lack of Oxygen or nutrients, the cancer cell is ready to find another location to increase its chance of survival.  Most cancer develop within the lining of ducts of tube like part of the organs (Bowel, breast ducts,  pancreatic duct, endometrial cancer etc) therefore they are epithelial.  But epithelial cell do not migrate well, they are  tied up to neighboring cell to make somewhat of a seal.  That is they use plenty of adhesion molecule to anchor down the basal membrane and the immediately surrounding cell.   To start moving, they have to rejuvenate and try to re-acquire the early version that brought them there in the first place.  They came from MESENCHYMAL cells.  AND THE DOOR TO GO FROM MESENCHYMAL TO EPITHELIAL CELL PASS THROUGH MET!  MET IS THE REVOLVING DOOR.   IT IS ONLY THROUGH MET THAT METASTASIS CAN OCCUR, ESTAHLISH ITSELF, AND STABILIZE IN NEW LOCATIONS.    REMEMBER MET CAN AMPLIFY VEGF FOR NEW BLOOD SUPPLY TO THE NEW TUMOR LOCATION!
TO FIND OUT MORE, Please go to:

Published in Volume 119, Issue 6 (June 1, 2009) J Clin Invest. 2009;119(6):1429–1437. doi:10.1172/JCI36183. Copyright © 2009, American Society for Clinical Investigation Review Series Biomarkers for epithelial-mesenchymal transitions Michael Zeisberg1 and Eric G. Neilson2

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



c-RET
c-ROS
2. c-MYC
Role of Rho-GTPase
PARAXIS
Resistance to EGFR
Oct 4
Klf4
SOX 2  Vs SOX 9(in Chorndrosarcoma)
Nanog
E-cadeherin,
syndecan-1
Claudins
B-catenin
Occludin-1 (Zo-1)
Other EpCam
Crumbs
homolog-3
Snails (Slug)
Zeb
-----------
FSP-1
SRC
RAS
fos
HSP47
Fibrobalaste transcrition site
CBF-A
Carg Box Binding Factor
-----------
TGF beta
NT-3
Sonic Hedgehop
alpha 5 beta 1 Integrin
----------------------
alpha SMA stress fibers,
DDR2
------------------------
cell spindle shape
AXL
---------------------------
Collagen, Vimentin, laminin, fibronectin

UPDATE on the CRBCM BLOG

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THIS BLOG OFFERS A UNIQUE PERSPECTIVE , THAT IS AT TIMES UNDER THE HYPOTHESIS RUBRIC, IT SOMETIMES CHALLENGES COMMON UNDERSTANDING.  PARTICULARLY AS IT PERTAINS TO THE NOTION OF LAWS OF NATURE, AND LOGICAL CONCLUSIONS ON TREATMENT STRATEGIES.   OUR AUDIENCE IS CHALLENGED IN VARIOUS WAYS!

TTP

THROMBOTIC THROMBOCYTOPENIC PURPURA (HYPOTHESIS CONTINUES)

Here is the example of a metastatic mechanism going bad when it hits the right ADAM.  Remember that ADAM are made of 2 basic domains, one an integrin and one a metalloproteinase domain.  The Metalloproteinase enters the Flippase-floppase (or sometimes scramblase)-like structure and is destined to be rejected outside, the Integrin is sent inside the cell.
Metalloproteinases are sent outside and attack collagen-like molecules to open the way to cell migration and allow Metastatic processes to move forward.  However, the cell membranes have a collagen-like structure, too.  So potentially the released Metalloproteinases could attack the cell.  The cell is not stupid and knows what metalloproteinase it has put out.  So it shields itself with Inhibitors and Decoy receptors from that specific metalloproteinase and the cell goes about its migration.

2 conclusions:

1. Insufficient inhibitors and decoy receptors to Metalloproteinases (and others such as Hydroeicosatetraenoic Acid) will have devastating effects.  If genetically the inhibitors are insufficient, and metalloproteinases are expressed massively, and this happens at the endothelial cell, massive and extensive destruction of endothelial cells throughout the body happens, exposing collagen like structures of the blood vessel walls.  This of course trigger extensive activation of platelets and the Thrombosis of TTP-like syndrome.  So in TTP, it is the inhibitor that is lacking.  (ie Von Willebrand cleaving protease inhibitors have also been cited).  And plasmapheresis removes the the Metalloproteinases (and microbial Antigens/toxin when relevent), stopping the onslaught.

2.What is in the Integrin domain is critical, in ADAM-17, the integrin domain is occupied by TNF-alpha, converting enzyme (TACE) which will free and activate the devastating Tumor Necrosis Factor.  Released massively, TNF can not only induce Apoptosis like certain other Cyclins (interleukine and Interferon ), but also leads directly to NECROSIS.  A massive uncontrolled septic-like syndrome kills rats after infusion of TNF.

ADAM 10, the disintegrin there gives you Amyloid structures of Alzheimer's.  TO BE SHORT, PICK THE ADAM AND SEE THE CONSEQUENT DISEASE ON YOUR OWN!

ADAM! A FLIPPASE, FLOPPASE AND/OR A SCRAMBLASE-LIKE MOLECULE !

HYPOTHESIS : WHERE DO CYCLINS COME FROM?

There is increasing evidence that Cyclins are integrins and so are Tumor growth factors, Tumor Necrosis factors, interleukins and interferons.
All these are membrane proteins with a particularity to be released from Metalloprotease and related adhesion molecules depending on the nature of stimuli.  The discovery and description of ADAMs as type I membrane protein containing Metalloproteinase and an integrin domain locate the growth factors and Cyclins squarely at the membrane  (surface and reticulum membrane).  These proteins, once released, go straight to the Nucleus to unveil their might by activating transcription factor.  In their track to the nucleus they can amplify and activate signal transduction pathways as well as either molecules. The cyclins find cytoplasmic and protein substrates (mostly enzymes)  which have their specific domains and link to the site to activate them most of the time, changing their shapes so as to expose hidden electrons or atomic groups (such SH) to cause downstream chain activation.

Now as the pathway unfolds at light speed (or electronic speed) it may overwhelm the cell, protection has to be assured to hide death domains (which also are integrins and therefore at the membrane) and pathways to Apoptosis.  Protection at the membrane seems to be offered by the INK while the CIP/Kip.  But deep in the cell are the Bcl-like proteins. The CIP/Kip seems to work like Decoy specific proteins since the have Cyclin domain to stop them from stimulating their respective CDKs (Cyclin dependent Kinases).  Some CDKs need 2 or more different stimulations to accomplish their deed. And with the number of stimulations comes the consequent activation of various substrates.  The Retinoblastoma substrate governs the G1 progression phase in the cell cycle, but it needs at least 2 activations, first by Cyclin D followed by activation by Cyclin E in order for it to free E2F that light up tarnscrptions genes which control the path to S-phase.  This Cyclin E also activates processes leading to Histone Biosynthesis, Centrosome activity and DNA replication.  And in fact, Cyclin E is the one that leads to gene instability that characterize many triple negative breast cancers

(E2F AND CYCLIN E, ARE POWERFUL TARGETS FOR CANCER CURE)

One of the CIP/Kip(s) is the P21 which plays a role in the cell cycle arrest due to P53 activation.
I should note that the Kinase itself may be mutated.  CDK4 is mutated in Melanoma, it renders the INK4 protein unable to occupy its domain and therefore is free to affect the nuclear transcription factor.  Therefore the solution is to increase the ligand to INK4 so as to increase its ubiquitination and and degradation through the proteasome (Ipilimumab/CTLA 4 in T cell/ does not do this unfortunately, so there is more room for you to research).  YES, LIKE FOR MERCEDES, WE NEED THE E CLASS OF PROTEINS TO FURTHER UBIQUITINATION.  A MUTATION IN E CLASS (WHICH INCLUDES MDM2) WILL BE BAD IN MELANOMA!

Suffice is to show that what starts at the membrane moves quickly to the nucleus in a milli-milli second in a flash and turn the life of the host around!

It is worth noting that not only Cyclins can be blocked from entering the Nucleus where they trigger transcription factor formation, but sometimes the Decoy (Cip/Kip) is stopped from entering the nucleus and cannot stop Cyclins which have entered the nucleus: this happens in breast cancer (p27 mislocation)
-----------------------------------------------------------------------------------------
THE INTEGRINS, PRESUMED SOURCE OF CYCLINS!

NEWS FROM EXJADE  SURVEYS

"Exjade is dosed based on weight with an initial recommended dose of 20 mg/kg/day
 with later adjustments every 3 – 6 months in steps of 5 or 10 mg/kg/day as needed
 to control serum ferritin levels.  In patients at a dose of 30 mg/kg/day with serum ferritin
levels persistently above 2,500 μg/L, doses up to (but not beyond) 40 mg/kg/day may be
 considered.

In an open-label, noncomparative trial of efficacy and safety of Exjade, 184 patients
 (including 47 MDS patients) were treated for up to 1 year at doses of 5, 10, 20,
or 30 mg/kg/day based on baseline liver iron content (LIC).  The reduction in absolute
LIC from baseline to end of study at 1 year was 4.2 mg-Fe/g-dry weight.

In the primary study of Exjade efficacy – an open-label, randomized, active comparator
 study vs.deferoxamine, 586 patients with β-thalassemia and transfusional hemoiderosis
 were randomized with 296 patients receiving Exjade at doses of 5-30 mg/kg/day and
 treated up to 1 year.
 The following figure summarizes the changes in liver iron content and serum ferritin between
 baseline and end of study at 1 year for Exjade patients at doses of 5, 10, 20, and
30 mg/kg/day."

"Gattermann et al. [Haematologica, 2012; 97(9): 1364-1371] have recently published
 data on the impact of chelation therapy with deferasirox (Exjade) on hemoglobin levels,
 platelet counts, and neutrophil counts in patients with transfusion-dependent MDS.
To be included in the trial, patients must have:

1. Been diagnosed with iron overload (serum ferritin > 1,000 μg/L or LIC > 2 mg-Fe/g-dw)
2. Had a history of multiple blood transfusions (> 20 transfusions or > 100 ml/Kg
3.  of RBCs)
4. Not be on a concomitant disease modifying agent for MDS (e.g., Vidaza, Dacogen,
5.  Revlimid)

Recruited patients were treated with deferasirox for 1 year of active treatment – there
was no control arm in the trial design.  The following table summarizes the main study findings:"

	Erythroid analysis	Platelet analysis	Neutrophil analysis
Eligible patients	247	100	50
Inclusion criteria	Pre-treatment HB < 11 g/dl, OR RBC transfusion requirements > 4 units per 8 weeks	Pre-treatment platelets < 100 x 109/L	Pre-treatment ANC < 1.0 x 109/L
Definition of response	HB increase > 1.5g/dL, OR reduction of ≥ 4 RBC transfusions per 8 weeks	Increase > 30 x 109/L for patients below 20 x 109/L, or > 100% increase	> 100% increase, AND absolute increase > 0.5 x 109/L
Response rate	21.5%	13%	22%
Median days to response	109	169	226
Mean actual deferasirox dose, mg/kg/day	~19.3	~19.5	~18.8

DRUGS IN THE PIPELINE PER "ONCOLOGY LIVE"

1. POMALIDOMIDE APPROVED FOR CML (EVEN T315I POSITIVE),  A.L.L.   PHILADELPHIA POSITIVE

2.T-DM 1 FOR HER-2 POSITIVE BREAST CANCERS.

3.APF530   FOR ACUTE AND DELAYED CHEMOTHERAPY INDUCED VOMITING

4 LYMPHOSEEK, TECHNETIUM, WILL SEEK SENTINEL NODES 

5. CHEMOSAT FOR OCULAR MELANOMA METASTATIC TP THE LIVER, MELPHALAN BASED

6. TIVOZANIB ANTI-VEGF FOR METASTATIC RENAL CANCERS

7 AFATINIB  FOR ADVANCED LUNG CANCER EGFR, ERB4 INHIBITOR

8. DABRAFENIB ANTI-BRAF IN MELANOMA

9. TRAMETINIB -ANTI MEK FOR ADVANCED MELANOMA

10 RADIUM-223 DICHLORIDE ALPHA PARTICLE EMISSION,  IN BONE METASTASIS IN PROSTATE CANCER

ETHICAL ISSUES IN CANCER THERAPY USED IN CLINICAL TRIALS.
----------------------------------------------------------------------------------

In desperate times and in situations where there is no known standard therapy left or existing, patients are involved in various phases of clinical trials and off label use of medications occurs.  One difference between off label use with On label use is that early on, people had been willing to put their life at risk, and consented to participate in a clinical trial aimed at proving a point or concept.. These trials often are with a limited scope of objectives to reduce specific biases. But once proof of concept is established, can we extrapolate  these findings to other parallel situations?  Or do we need to do clinical trials even though similar situations, concepts, mechanisms and possible responses apply?  Several scenarios can be asked:

1. If A leads to B and B leads to C, can we conclude without a trial that A leads to C?
2. If A=B and B=C, can we conclude that A=C ?
3. If A-B=C can we conclude the A-C=B?
4. If A using B gets C, therefore A using C gets B?

While some of the scenarios are clearly true, some are not fully true and some conclusions are completely wrong. And resulting consequences could be devastating. The variables are what happens between the letters. And the intensity of the quality of the conclusion depends very much on these various variables.  Ethicists around the world struggle with these Issues all the time.

When it comes to Humans, the variables become endless: Gene differences, gender, age, previous exposures, set of circumstances, state of main organs, and susceptibilities are just a few known and unknown variables.   Reaction to something known will depend on the mentioned variable.  And even though the drug and side effects are known, these variables still question or challenge us because they can change the outcome.  The safety or acceptability of the outcome determines or influences the ethical nature of the outcome.  The moral nature of the outcome is another dimension that is part of the Ethical decision and is a tall order that also nees do be met.
------------------------
Case in point:

3 decades ago a young researcher was working with a drug that was banned because pregnant women who took the drug had babies with short limbs. The drug was Thalidomide of course.  He was trying to know why this drug led to this calamity.  History taught us that restricted growth of blood vessels in the embryo was one of the main reasons; of course we know now.  But as he worked with Thalidomide, he fell ill.  He was diagnosed with Myeloma.  He wanted to learn more about his disease and soon learned about the pathways in Myeloma and quickly concluded that based on what he knew about Thalidomide, it could help in Myeloma.  He also knew that it would take time for the drug manufacturer to allow the use of the drug for his condition.  Off label use was authorized by someone in this desperate situation and the rest is history!
Now that we know the drug used is effective, was it ethical to try or allow the use of thalidomide without having the results of a clinical trial?  This situation judged today brings out the notion that what is not ethical today may not be unethical tomorrow. The ethical nature of a practice is relative to time, place and culture and? you think it, it's good!

Case in point 2:

Dr Maurie Markman commented on a case about the possible use of Bexarotene, a medication approved for treatment of Cutaneous T-cell lymphoma, in Alzheimer dementia.  Based on what target and mechanisms, one may conclude it can work in this disease.  But a physician says "NO" to recommending it off label.
Who should decide, the desperate, but informed patient, or the Doctor?
And what are the possible reasons this Doctor makes that decision?
At what threshold is a trial needed to allow us to conclude that the OFF-LABEL USE IS WORTH WHILE? IS OUR IGNORANCE ENOUGH OF A REASON TO NOT TRY SOMETHING CONSENTED? IS AN ETHIC PANEL ENOUGH PROOF TO ALLOW SUCH A USE?
Or both patient consent and an ethical panel decision need to reach the threshold together?
YOU TELL ME!
SHOULD WE LEARN SOMETHING FROM THE FIRST CASE? 

ACTIVITY AT CRBCM

*Steady stream of patients good for business,
but Medicare and Medicaid payments still not coming in
and they accuse physicians for not wanting to take these patients;
but how can you dedicate your time fully to the complexity of taking care of patients without being paid!
It is just a shame!

*we are meeting this coming week the UTEP biostatistic lab for possible Collaboration on future research projects.
The Dept of Defense is calling for submissions. Please Rush and participate!  Closing door Feb 27, 2013.

*There are only 2 PET scan Machines in El Paso. Population 750,000, 4th city in Texas!   Price range per study from $1,500 to 4,000 according to your insurance!  Investors contact me. I will help!  Even the University Medical Center does not have (one from sure source)!

*The Great State of Indiana is UP! we will be traveling there tomorrow to take the Pulse!

*Survivorship program for cancer survivors in Indiana, coming soon!  We keep working Hard!

JOIN THE CLINICAL TRIAL
A PHASE III OF ONARTUZUMAB (METMAB) WITH TARCEVA AGAINST TARCEVA ALONE FOR ADVANCED OR METASTATIC LUNG CANCER!
THIS IS A FIRST LINE TREATMENT
NCT01456325, OAM4971g

LBK-1 GENE AND CAVEOLIN DISRUPTION

Some women have a clear tendency to have Multiple calcifications or  Microcalcifications in the Breast.  And we know that clusters of calcifications found on mammograms, call for a Biopsy of the involved area.  Disruption of the shape of the epithelium is known to be associated with Mutation of LBK-1 as stated in our previous blog.

GUANGWEN CAO ET AL STATED:
"Caveolin-1 (Cav1) is a major structural protein of caveolae, small membrane invaginations of the cell membrane that play a cell and context-dependent role in potocytosis, transcytosis, molecular transport, and signal transduction. ^1,2 Specific molecules from four major signaling pathways have been detected in caveolae, G-protein mediated signaling, calcium-mediated signaling, tyrosine kinase/mitogen-activated protein kinase signaling, and lipid signaling. Caveolae appear to be a focal point for compartmentalizing, organizing, and modulating signal transduction activities that begin at the cell surface and Cav1 may function not only as a structural molecule but also to modulate the function of signal transduction pathways. ²'

CALVEOLIN-1 HAS BEEN ASSOCIATED WITH URINARY STONES.

Are disruptions at LBK-1 and Cav-1 associated with benign multiple calcification in the breast?  And is their presence a predictor of DCIS and/or early breast cancer?

HURTHLE CELLS:  Thyroid MALIGNANCY SHOULD BE A PART OF THE VON HIPPEL LINDAU SYNDROME.
It all makes basic sense.  There are significant disturbances in the Mitochondria of cells of patients with VHL syndrome.  These disturbances involve Mitochondrial DNA and Cytochrome Oxidase.  Multiplication of Mitochondria results, with the abnormal content giving the appearance of "Hurthle" cells!  This just hit me as I was looking into a new case of Hurthle cells, the patient had a History of VHL!

Curcio-Morelli et al. (Harvard institute) also described how VHL protein affects Thyroid hormone activation through de-Ubiquitination of regulating enzymes.

RANDOM NEWS

*Data released from the CDC 's Office on Smoking and Health were rather sobering.   between 2010 and 2011, the prevalence of Smoking did not drop despite a 58% quitting attempt rate recorded. People just smoke a little less as the proportion of those who reported smoking less than 30 packs per year dropped. In the United states, 19% of the Adult population smoke despite all the warning. This lead to 443,000 or half a million deaths related to smoking related illnesses in the United States alone (latest Jama pg 539).  Of these, approximately 165,000 will die of lung cancer (37%).
Carcinogens in cigarettes, ability to detoxify oneself, and presence of Estrogen receptor Beta in the lung seems to contribute.  Amount, length,and nature  of smoking exposure are recognized variables and influence the type of cancer found.    exposure to Radon, Arsenic, Chromium and others such as Nickel have also been implicated.  Host variations include Cytochrome P450, Glutathione S transferase and DNA repair enzymatic system.  Deficiency of Vitamin A, C beta-carotene, fruit and vegetable consumption have all be recognized to be associated with lung cancer risks.

Kidney, bladder, uterine cervix, head and neck cancers have all been linked to smoking.

*Up to 75% of patients with Bladder Cancer who are of European descent may have rs2294008, making this a significant Biomarker to be understood and targeted.

* A device approved by the FDA can recognize existence of cancer cells at the Margins of surgery to help the surgeon delineate his surgical Margin.  The Margin Probe uses an eletromagnectic recognition system to identify a "signature" of malignancy to tell the presence of Malignant cells.  This device can tell 3 times better reportedly where the cancer tissue ends!

*OFF AGAIN, ON AGAIN, MULTIVITAMIN SUPPLEMENTATION IS GOOD FOR YOU TO REDUCE RISK OF CANCER PER THE PHYSICIAN HEALTH STUDY II DESPITE THE LACK OF SIGNIFICANT DIFFERENCE IN MORTALITY.  THE DIFFERENCE WAS IN NUMBER OF CANCERS.  

RANDOM NEWS with updates for Letrozole

*BIG 1-98 showed that LETROZOLE was more effective in post-menopausal patient with any histology of breast cancer that is ER positive and Her-2 Negative, with the effect being greater in lobular type of Carcinoma.  And in Luminal B versus Luminal A.

* In HER-2 positive, one year Vs 2 Years.
"2 year long treatment not recommended",
finding of the HERA trial remains the standard of care.

In the study of 6 months Vs 12 months of Herceptin, there was a trend toward better results with 12 months also statistically no difference was detected.

*In Early Breast cancer, High Baseline of Vitamin D level was a predictor of 3 things:
1. better prognosis
2. low risk bone relapse
3. better outcome with use of Zometa.

recommendation is to measure Vit D at diagnosis and to replenish it!

*In triple negative breast cancer, the disease would be amenable to new type combinations of medications such as
A/  Cisplatin /PARP (olaprib) and Vandetanib (EGFR/VEGF).
B/  Cisplatin/PARP inhibitor and   Vorinostat (Histone deacetylase inhibitor)
C/  Androgen Inhibitors and MTOR

*PD 0332991, an oral Cyclin dependent Kinase (CDK 4/6) inhibitor added to Letrozole  increased the progression free from 7.5 months to 26.1 months.  This is an impressive performance if confirmed. 
 *PIM-1 may be a surrogate of c-MYC  amplification, and is being targeted.

* Routine Breast MRI still not recommended

*32mg IV Ondansetron  can cause Arrhythmia and has been withdrawn.

GENES INVOLVED IN PERIPHERAL NEUROPATHY

Many chemotherapy and target therapy drugs leave behind devastating peripheral neuropthy.  Most prominently mentioned are Cisplatin, Vincristine, Navelbine Taxanes, Thalidomid, Velcade, Revlimid to name a few.  The level and extent of the induced Neuropathy varies with the specific drug.
We try to look into the genetic abormalities that underly some of the common peripheral neuropathies to see if a common thread may be picked up to explain the many variation in presentation, and whether there would be a way to predict who is the most susceptible patient given a known drug.

A preliminary review revealed the followng genes for further observation:

1. PMP22:     (Peripheral Myelin Protein 22) located on chromosome 17, this gene and related  in an essential component Myelin the covering sheath of the neuronal axon.  Parallel to Histone covering the gene, Myelin is not only there to cover the Axon.  It participate in its development, growth and function.  It helps maximize the neuronal function by increasing the efficient of the motor and sensory traffic.    Death of the neuron follows generally Myelin degeneration particularly in trauma.
Disease results generally from Mutation in the genes but also from alterations in the many regulators of this genes (which include P53, AP-1, and Sox 9 and 10, Luciferase and ERG-2).  Frame shift Mutyation leads to many clinical Syndromes which have been well Characterized.
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2. MPZ: this is the major component (in number) of the Myelin sheet, these proteins make a glue like substance that link the Neuron to Schwann cells, has a transmembrane  formation allowing easy transfer of signals, and in effect maximizing axonal transduction.   Myelin Protein Zero is linked to PMP22.
----------------------------------------------------------------------------------------------------
3.GjB-1
4. NEFL
5. GAN
6, dynactin GENE
7. LITAF/SIMPLE
8. RAB-7
9. MFN-2
10. GDAP-1
11.EGF-2
12.GARS
13.MTMR
14.CMT4B2
15.KIA-A1985
16.NDRG-1
17.PRX  Gene maker of Periaxin, a protein protecting and maintening Myelin
-------------------------------------------------
18.DCTN-1
--------------------------------------------------------------------------
19.SPTLC-1 : ENCODE FOR SILENCING ENZYME OF LIPID HOMEOSTATSIS
-----------------------------------------------------------------------------------------------------
20.IKBKAP
IKBKAP (inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase complex-associated protein) is a human gene that provides instructions to make the IKAP protein, which is found in a variety of cells throughout the body, including brain cells. Although the exact function of the IKAP protein is not clearly understood, it probably plays a role in transcription, which is the process of making a blueprint of a gene for protein production. Researchers have identified the IKAP protein as part of a six-protein complex (called the holo-elongator complex) that interacts with enzymes necessary for transcription. The IKAP protein probably performs other functions in the cell as well, such as responding to stress. Its homolog in fly (D-elp1) has RNA-dependent RNA polymerase activity and is involved in RNA interference.^[1]
The IKBKAP gene is located on the long (q) arm of chromosome 9 at position 31,wikipedia:  

REMEMBER MUTATION HERE CAUSED FAMILIAL DYSAUTONOMIA, A MOVEMENT DISORDER.  THIS PARTICIPATE IN THE CYTOSKELETON!
------------------------------------------------------------------------
21.NTRK-1  :  In Neuroblastoma, The Neurotropic Tyrosine Kinase Receptor 1 is good for you
                          Receptor 2 is the "bad Guy".  There are other NTKR of undefined implications
------------------------------------------------------------------------------------------------------

ASCORBIC ACID
ANTI-PROGETERONE
INJECTIONS OF NEUROTROPHIN 3.

GENETIC CHANGES IN HURTHLE CELL CANCER

1.  RAS AMPLIFICATION, SEEN IN 40% OF CASES
2.  RET, PREDICTIVE OF SPREAD OF DISEASE, PRESENCE OF RET/PTC REARRANGEMENT
(NEGATIVE RET EXPRESSION SPRESD MORE)
3.OVEREXPRESSION OF P53
4. LOSS OF E-CADHERIN
5. AMPLIFICATION OF MYC
6. INCREASED TGF ALPHA
7. INCREASED INSULIN LIKE GROWTH FACTOR
8. INCREASED THYROTROPIN RECEPTOR AND ALPHA SUBUNIT OF G PROTEIN
9. OVEREXPRESSION OF P27 AND CYCLIN D3
10. PRESENCE OF GRIM 19

WATCH TRABECULAR PATTERN
WATCH FOR LEVEL OF INVASION OF BOTH CAPSULE AND BLOOD VESSEL

LOOK FOR  FAMILY HX
                     MASS, PAIN, DYSPNEA DYSPHAGIA, CHOKING SPELLS, HOARSENESS,
                     HORNER SYNDROME

OBTAIN
TSH, T3,T4, FREE T4
ANTI-PEROXIDASE ANTIBODY
ANTITHYROGLOBULIN ANTIBODY
THYROGLOBULIN LEVEL PARTICULARLY POST SURGERY
THYROID UPTAKE AND SCAN
U/S TO DETECT ADENOPATHY
OCTREOTIDE SCAN OR MORE RECENTLY PET SCAN

5 YEAR SURVIVAL  8-10%
10 YEAR SURVIVAL 18-20 %
10 YEAR SURVIVAL  30%

TREATMENT
1.SURGERY
2. IODINE BASED RADIATION
3. SOMETIME STANDARD RT
4. REPEAT IODINE RT FOR RECURRENCE AFTER UPTAKE BOOSTER
5. ROLE OF ANTI-VEGF +/- TAXANES

STAT-1 DEPRESSION COULD PREDICT SUSCEPTIBILITY TO  HISTONE DEACYLASE AND KILLING THROUGH UPREGULATION OF Fas PATHWAY.

We have recently presented a case of a 38 YOF diagnosed with an unresectable Angiosarcoma
Her tumor was positive for factor 8, CD31, CD34 ad Ki-67.   This immunostaining profile was used to support the reading of the pathologist,  CD31, a platelet adhesion molecule (PECAM-1) is extensively found on the endothelial cells.  But the presence of factor 8 raises the possibility of Interferon Regulated Factor 8 (IRF8),   Therapeutically this would be interesting because not only it raises the possibility of Using Interferon gamma in this woman, but also Histone Deacetylators.

Our question, DOES EXPRESSION OF FACTOR 8 SUGGESTS SUSCEPTIBILITY TO HISTONE DEACETYLASE AND KILLING THROUGH UPREGULATION OF Fas IN PATIENT WITH STAT-1 DEPRESSION.

IT IS ESTABLISHED THAT INTERFERON HAS SOME ACTIVITY IN ANGIOSARCOMA, AND SO DOES ALL ANTI-VEGF AND POTENTIALLY ALL ANTI-MEK

ACUTE MYELOID LEUKEMIA : SOME NOTES FROM DR FREDERICK APPELBAUM COMMENTS

* classification under the FAB was abandoned because it did not give prognosis information

* 4 groups based on Cytogenetics
1. No significant Cytogenetic abnormality : considered the INTERMEDIATE GROUP
2. Unfavorable group with 5q - 7(Monosomy)
3. Favorable group Inv 16, (15,17), (8,21)
4. Unclassified

The favorable have 55% 5 Year survival
Intermediate have 38% 5 year survival
Unfavorable had 11% 5 year survival

ADD NPM1 as good prognosis
ADD CEBPA as good
BUT  FLT-3 as bad despite favorable basic category
C-KIT positive is also bad in Adult only

other cytogenetic of interest N-RAS, NPM and IDH1 Mutation

15 other Mutations for our BUFF in genetic

KIT          MLL             CBL       PTEN      JAK2         DNMT3A      EZHZ      TET2      WT-1
IDH-1      N-RAS        P53         RUNX-1     ASXL-1    PHF-6
--------------------------------------------------------------------------------------------------
IF YOU FINISH LOOKING AT THE 15
WELL LOOK ALSO   ERG   MN1    EVI-1   BAALC   CD34
---------------------------------------PLUS MICRO--RNA, METHYLATION

ADD TO DNA SEQUENCING , TRANSPTOSOME SEQUENCING TO SEE FURTHER


ELN 2012
CATEGORIES OF AML

1. favorable include Inv 16,( 8,21), NPM1, CEBPA and wild type FLT-3

2. Int-1   NPM1 Mutated and FLT3 Mutation
3.  int-2   t(9,11) and NOS
4. Unfavorable   inv 3  (3,3)   t(6,9)   -5  -7  17p  and complex abnormalities

remember good or favorable is not good or favorable anymore if noted after chemotherapy for another primary.

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

In all patients, obtain  (I will send you an angry letter if H&P not completed in EMR!) OK!

1.  CBC DIFF and Comprehensivve Metabolic panel
2. Uric acid level ---not high, start Allopurinol
                           ---high start Rasburicase
3.PT and PTT if DIC start ATRA
4. Bone marrow Biopsy
5.Immunophenotyping
to detect the 1% of Mixed phenotype which is of poorer prognosis
and to be able to detect persistence of disease with PCR better accomplished through this method
6.Cytogenetic   which should include CEBPA, FLT-3, and NPM-1, C-Kit

7.HLA typing NOW  NOW   NOW!
-------------------------------------------------------------------------

Please note  age (65) and comorbidities as you ponder if patient can sustain high dose treatment
----------------------------------------------------------------------------------------

Treatment

-start Hydration and Alkalinization
-Allopurinol Vs Rasburicase based on Uric Acid level
-DIC start ATRA no matter what
-start Antibiotic, antiViral and antifunga Coverages NOW
-Consider Fertility Issue now
-speak to family
and start Induction
and consider consolidation based on circumstances per standard of care


In elderly >65,   or >60 with significant comorbidity
Death occurs during induction
so please consider
1.LOW DOSE ARAC-C
2. 5-AZACYTIDINE
3. DECITABINE
4. CLOFARABINE
5. FOR 5q- TRY REVLIMID!
-----------------------these are my notes------------

MA-27 NO SUPERIORITY OF AROMASINE OVER ARIMIDEX IN ADJUVANT SETTING

MA-27
NO SUPERIORITY OF AROMASINE OVER ARIMIDEX IN ADJUVANT SETTING.
NO SUPERIORITY EXTENDS EVEN TO BONE EFFECT FEARED TO BE WORSE WITH ARIMIDEX.
GOOD THING TO KNOW EVEN IF IT DOES NOT CHANGE PRACTICE!  IT IS JUST A GOOD THING TO KNOW AS WE TALK TO WOMEN WITH ER  POSITIVE BREAST CANCER.
THIS IS AN EXAMPLE OF A GOOD NEGATIVE STUDY.  IT HELPS CLEAR THE AIR!

GENES OF CELLULAR DEATH.

1.  BIM or BCL2-L11

BCL2L11

From Wikipedia, the free encyclopedia

Jump to: navigation, search

BCL2-like 11 (apoptosis facilitator)
Rendering based on PDB 2K7W.
Available structures PDB Ortholog search: PDBe, RCSB [show]List of PDB id codes
Identifiers
Symbols	BCL2L11; BAM; BIM; BOD
External IDs	OMIM: 603827 MGI: 1197519 HomoloGene: 7643 ChEMBL: 5777 GeneCards: BCL2L11 Gene
[show]Gene Ontology
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	10018	12125
Ensembl	ENSG00000153094	ENSMUSG00000027381
UniProt	O43521	O54918
RefSeq (mRNA)	NM_001204106.1	NM_009754.3
RefSeq (protein)	NP_001191035.1	NP_033884.1
Location (UCSC)	Chr 2: 111.88 – 111.92 Mb	Chr 2: 128.13 – 128.16 Mb
PubMed search	[1]	[2]

Bcl-2-like protein 11 is a protein that in humans is encoded by the BCL2L11 gene.^[1][2]
The protein encoded by this gene belongs to the BCL-2 protein family. BCL-2 family members form hetero- or homodimers and act as anti- or pro-apoptotic regulators that are involved in a wide variety of cellular activities. The protein encoded by this gene contains a Bcl-2 homology domain 3 (BH3). It has been shown to interact with other members of the BCL-2 protein family, including BCL2, BCL2L1/BCL-X(L), and MCL1, and to act as an apoptotic activator. The expression of this gene can be induced by nerve growth factor (NGF), as well as by the forkhead transcription factor FKHR-L1, which suggests a role of this gene in neuronal and lymphocyte apoptosis. Transgenic studies of the mouse counterpart suggested that this gene functions as an essential initiator of apoptosis in thymocyte-negative selection. Several alternatively spliced transcript variants of this gene have been identified.^[3]
Interactions BCL2L11 has been shown to interact with DYNLL1,^[4][5] MCL1,^[1][6][7] BCL2-like 1,^[1][2][6][8] BCL2L2^[1][2] and Bcl-2.<sup>[1][2][6]
======================================================================================== 
COMMENTS:

BIM IS IN FACT CONSIDERED A MEMBER OF THE BCL FAMILY ONLY BECAUSE IT HAS A BH3
IN FACT AS STATED IT INITIATES APOPTOSIS.  IT ACTUALLY BINDS BCL FAMILY MEMBER AND DESACTIVATES THEM OR VICE VERSA.  MEANING THE MORE IT IT IS ATTACHED TO OTHER MEMBERS IF THERE IS ENOUGH BCL2 LEFT THE CELL IS PROTECTED.  BUT IF NOT, THE CELL IS OPEN TO DEATH.   IT IS DEGRADED THROUGH THE PROTEASOME.  IT IS THEREFORE UPREGULATED BY VELCADE.  TAXANE DOWNREGULATES BIM THEREFORE BIM IS PART OF TAXANE INEFFICIENCY LEADING RESEARCHER TO BELIEVE TO THE VALUE OF TAXANE VELCADE COMBINATION.

LEVEL OF BIM COULD THEREFORE BE A SURROGATE FOR MEASUREMENT ON WHETHER DRUGS ARE ADDITIVE  OR COUNTERPRODUCTIVE IN LABORATORY WHEN IT COMES TO THE CURE.</sup>

2. BID


3.BAD
4.NOXA
5.PUMA (HIDING BEHIND FOXO3 AND THE MTOR ALREADY DISCUSSED)
6.BH3 UPREGULATION
7.DEPRESSION OF Bcl-XL
8.BAX
9.Fas PLUS FASL FORM DISC
10.Death Receptor

SCIENCE DOES NOT BELONG TO ANY ONE:

One thing about Biological Sciences is that it does not care if you are rich or poor.  It just there to be discovered and understood.  Of course the more the observer, the more you can understand it.  But it is a function of what cards you are given, what chances you have and once in a while what luck you have.  Perseverance comes in handy so never give up.  And in research, no road should remain unturned because you just don't know where it may lead.  And no road should be left unchallenged.  Even a negative study established a fact suspected or unsuspected.  It warns to those who come after us not to repeat the mistake our predecessors made.

Basic principle are the same but cells have shown adaptation to the environment.  It got to since our environment is randomly and constantly changing, with at time coordinated progression.  The key is in the work, working hard and long leads to success whatever success means!
From a scientific point of view, life emerges from an incredible amount of chains of reactions which apparently are following a certain logic which makes the law of nature.  These reactions are contained within a controlled environment capable of migration, differentiation, proliferation, angiogenesis, embryogenesis and  energy production and consumption, senescence and programed death.

With the arrival of new stimuli created in the environment,  membrane receptors constantly expand the panoply of their ligands.  And cells solicit their NF-kB and C-jun to adapt and offer an adaption response.  The cell solicits it genes and creates  transcription factors to formulate and express the response.  When it potentials are exhausted, program death is initiated,  Death traps are hidden through out the cell from the membrane where are located Death Receptors, to the Cytosol where various caspases and capsaicins.  Cellular death can happen also with Necrosis and Anoikis. AUTOPHAGIA CAN KILL CELLS BUT MOST OF THE TIME IT IS PROTECTIVE, OCCURS WITH STRESS!

GENENTEC REPORTED ALSO!
"

Apoptotic pathways

Apoptosis is triggered through 2 signaling pathways²:
Intrinsic pathway

Extrinsic pathway

Intrinsic pathway

As its name suggests, the intrinsic, or mitochondrial, pathway is initiated from within the cell (Figure 3.1).³
This pathway is often activated in response to signals resulting from DNA damage, loss of cell-survival factors, or other types of severe cell stress. Normally, pro-apoptotic proteins are released from the mitochondria to activate caspase proteases and trigger apoptosis.³

Enlarge this image When these pro-apoptotic signals are not released, the cell cannot die.¹ The intrinsic pathway hinges on the balance of activity between pro- and anti-apoptotic signals of the Bcl-2 family.¹⁴ Preclinical studies indicate that members of the Bcl-2 family regulate the permeability of the mitochondrial membrane and determine whether a pro- or anti-apoptotic signal will be released inside the cell.¹⁵
Research implies that in this cascade, the anti-apoptotic proteins (eg, Bcl-X_L) antagonize Bax and Bak by binding to their BH3 domains. This antagonism is relieved by BH3-only, pro-apoptotic proteins (eg, BIM, BID, BAD, NOXA, PUMA), which alternately bind to anti-apoptotic proteins, like Bcl-X_L. In normal cells, cellular stress would result in an upregulation of these BH3-only proteins in order to initiate apoptosis via the intrinsic apoptotic pathway.³
Currently, the intrinsic pathway is more widely implicated as a blockade to tumorigenesis.²

Extrinsic pathway

The extrinsic pathway begins outside the cell through activation of pro-apoptotic receptors on the cell surface. These are activated by molecules known as pro-apoptotic ligands.¹²
Preclinical studies show that ligand binding causes receptors to cluster and ultimately form a death-inducing signaling complex (DISC).¹²
Upon DISC activation, the extrinsic pathway has been seen to adopt the same effector caspase machinery as the intrinsic pathway.^12"
  ==========================================

   WHATEVER YOU RESEARCH CURE OF CANCER MAINLY HAPPENS WHEN CANCER CELL DEATH OCCURS. KEEP YOU EYES ON THE BALL.

FDA WATCH LIST

4 Medications are back on the watch list of the FDA:
1. VIMPAT which could cause Neutropenia, meaning it has bone marrow suppression
2. Ampyra resported to cause Anaphylactic reaction
3. ARZERRA use can reactivate viral infections
4. Banana Boat sunscreen which can light up before it is dried on the skin if exposed to light 
(the manufacturer has pulled this one from the Market.)

FREE CPRIT/ CPRIT IS ON ITS WAY BACK !

We learned today that The Health and Human Services passed a preliminary bill suggesting measures that will offer a tighter Oversight at CPRIT.  The bill goes to the full chamber for approval.  CPRIT represents the largest opportunity for fight against cancer in Texas primarily, but also the United States given the sparsity of available funds for cancer research and PREVENTION.
In general chances to obtain a grant is around 10% in the United States according to professors at the University of Texas in El Paso (UTEP) .  According to the Audit conducted at CPRIT, the MD Anderson was reported to have received  42% of the approximated one billion so far distributed by CPRIT.  This money comes from all Texans.  Most of them will never see the doors of the MD Anderson when they will need care because they can not afford it!  In El Paso, when you are found with a rare cancer such as a liver Angiosarcoma found recently in a 38 year old woman with no health insurance.  Her chance to participate in a MD Anderson study is more likely  less than 10 percent also if that.  Likely enough, drug company are looking to provide some help for the Avastin we recommended as part of her treatment.
We are also currently fighting to locate funds for another man, also with lack of insurance with metastatic penile cancer with positive pathology in inguinal nodes.  For these patients the prospect of going to Houston, live in a hotel to take part to a trial and afford it, is non-existent despite their participation to CPRIT funding.
For these reason alone CPRIT should not continue the current pattern of funding.  El Paso has received 0.2% of funding so far despite being the 4th city in Texas.  A cry for fairness is being conveyed here at CRBCM.

We look at CPRIT for fair leadership, we look at CPRIT to save life today and more in the future.
Somebody at CPRIT answer the call and fund projects that will help here, today!  Help us put together programs and infrastructure to fight cancer today for a better tomorrow and for the Cure in EL Paso.  Not every one can afford the trip to Houston!

FDA APPROVED THE GENERIC DOXIL IN REPONSE TO SHORTAGE AND ITS CONSEQUENCES ON ONCOLOGY PRACTICES ACROSS THE UNITED STATES.
The Generic version is manufactured by SUN PHARMA GLOBAL FZE.
Shortage was first believed to be a commercial ploy to increase the price until it became real.   This approval will limit chances of new shortage and will help patients with Myeloma, Kaposi sarcoma and Ovarian Cancers who need this medication the most.

PLATELET DERIVED GROWTH FACTOR, A DEADLY MISNOMER
====================================================

By naming this compound PDGF, the scientist who described this cytokine not only picked the wrong name,
but also sent researchers on the wrong path to understanding just how important this growth factor is.  As a result, some people are probably dying because the emphasis brought by the name was not clearly defined.
First of all, PDGF does not come solely from Platelets alone. It is made by a number of cells including Muscle cells, Endothelial cells and even Macrophages.
And when you think of Platelets, Coagulation comes to mind, weakening of platelets and the like.  If this PDGF does this, it is at a strictly minimal or insignificant level.  The effect on Platelets is only mentioned by those who clearly have been fooled and kept looking for rare effects which eventually can be found.  This PDGF works on Mesenchymal cells since creation.  It participates in Embryogenesis, cell survival, proliferation, angiogenesis and differentiation. In adults, its main effect is on Fibroblast and Glial cells.
When you think Platelet, platelet Aggregation, adhesion and so forth.  PDGF kills by Fibrosis in cirrhosis of the liver and Pulmonary hypertension, one of the worse silent killers of our time.  Pulmonary Hypertension is a deadly killer because physicians don't know how to best monitor it.  AND BECAUSE WE CLEARLY DO NOT TREAT IT AGGRESSIVELY.  HOW MANY PHYSICIAN GIVE CIALIS TO THEIR PATIENT FOR PULMONARY HYPERTENSION?   If you raise your hand, you are my hero!
The point is that by misnaming the PDGF, people will assume Aspirin would be the more likely inhibitor.  Think again.  There are almost 20 inhibitors of PDGF listed on the SELLECHEM list.  Believe me it starts with Nexavar and Sutent. Aspirin is not on the list!
HOW MANY PEOPLE THINK OF NEXAVAR IN THEIR TREATMENT OF SCLERODERMA, A DISEASE KNOW TO HAVE PROMINENCE OF PDGF ACTIVITY?    HOW MANY ONCOLOGISTS GIVE GLEEVEC TO TREAT THEIR GLIOBLASTOMA.  (CLUE, AVASTIN IS INDICATED IN REFRACTORY BRAIN DISEASE-YOU THINK AVASTIN-ANGIOGENESIS, THINK NEXAVAR, TELLS SELLECHEM).

In a short study, 11 out of 12 GLIOBLASTOMAS had amplification of PDGF.  This is one of the drivers of GBM.  Forget Platelet, think Mesenchymal derived growth factor, and let us put the right emphasis on this Cytokine!