Medtronic's renal denervation system in patients with treatment-resistant hypertension failed

KNOW WHAT WORKS! THIS IS IN THE NEWS, CHECK-IT OUT!

WELCOME COTE D'IVOIRE! (OR IVORY COAST!)

THE CRBCM WOULD LIKE TO ACKNOWLEDGE OUR READERS FROM COTE D'IVOIRE,
REMEMBER SCIENCE DOES NOT BELONGS TO ANYONE, THE CELL IS THERE TO BE DISCOVERED BY ANY OBSERVER PUTTING HIS MIND TO IT!
PROFESSOR FAGNEREY TAUGHT ME THIS BACK IN KINSHASA IN MY BIOLOGY CLASS IN 1974-76 ( YEARS OF BIOLOGY CLASSES IN HIGH SCHOOL).  GRADUATED 1976 AT COLLEGE BOBOTO (EX-ALBERT).  AND NOW HERE WE ARE!
CRBCM, A GOOD FIGHT IS WORTH PUTTING UP!

Avastin, the Hero to beat in Colon Cancer! (aflibercept lurking)

It has made its place and win the argument, in Metastatic Colon cancer, the fight against cancer through the various VEGF receptors cannot be demonstrated better but by what Avastin has achieved.  Avastin has won our heart and the argument, and is now part of standard of care for metastatic Colon cancer.  It is most of the time Given with Folfox.  All Oncologists have had to use this combination of treatment with confidence because it works.  Well, for a while, like most any thing you try to do to a cell, suppression of a pathway is survived by amplification or activation of dormant pathways.  In a normal cell of adult individuals, anything placental has to be "dormant" or clearly "subliminal".   Well think again, if you block the main angiogenic (VEGF1) pathway, you wake up the secondary ones.   Among the one you awake, one is striking, The Placental one called PLGF or Placental Growth factor.  Not only it is awaken, but it is also stealing the show.  If you go to a conference on Colon Cancer these days and no one mention this gene, be assured you went to the wrong conference!   Everyone is talking about this PLGF but be careful, inhibition of this one leave the cell without ability to handle " inflammation".  If you completely inhibit this one, get ready to fight an (give or take) "eclampsia" looking like syndrome  (PLGF is decreased in Pre-eclampsia) .  Handle this one with care!  But scientist have their eyes on this one.  It stole the show from the MTOR inhibitors (MTOR is the other way of developing resistance to VEGF inhibition).(see our previous blogs).  Lack of biomarkers is driving researchers from exhausting all options to their fullest benefit!  We keep hop-here and hop-there! and see what works!

Suffice is to say that Panitumumab (Vectibix) is looking very good right now with Folfiri as a second line, suggestion is that it is  beating Cetuximab (Erbitux) in second line...weigh my word..."suggestion"...
wild type KRAS related of course.

But now the NRAS, we need to dig deep on this one!

In The Kinases, one winner (FDA approved )Regorafenib, we are learning, and patients are waiting!

Activity at CRBCM!

Hello,

This is a courtesy email to let you know that we have processed the yellow fever application and are mailing the stamp this afternoon to the address shown on the application.  Please contact me immediately if there is any problem with this, or if you have any questions. 

Thank you,

Genetic work is fun, Go to town with it! Important questions

*Can disruption at LAT1,2 be achieved through MITF (SLC7A8)
*Is ZFYVE16 a substantial target in Gastric cancers
*should we be monitoring IL-1 in patients with GERD
as a biomarker risk of Gastric cancer
*Inhibition of RFXAP in T cell leukemia,what could be the effect!
*Blocking TOM1 could help in disease where MITF is a driving force (Melanoma).  Are activities at MITF the reason for short duration of BRAF inhibitors?
*What happens when you block CD28 in Ovarian cancer
*Is CD79 a floppase?
*Inhibition of BIRC7 will unleash Apoptosis and could be the way to win over Mutation in MITF
*Should patient with melanoma of the eye avoid Beta Blockers because of effect on the GPC1
*Beta blocker protective or inducer of cancer, what is the state of GPC1 and DAB2 in patient taking this drug
*Role of Beta blocker in Ovarian cancer (connection through DAB2)
*Are the LRP (s) the connection of Fatty food to carcinogenesis?
*Block TOM1 when giving BRAF inhibitor?

Human made lack of progress in cancer research

10 years after the Cancer Genome Atlas project published its findings, some its key findings remain in the closet.  That is very little has reached the bedside of our patients.  Most of the use has benefited research companies that used the information to design drugs most of which remains in clinical trials.   Information that could have benefited the day to day practice of oncology, remains away from the reach of practicing physicians because not fully endorsed by leaders in the field.  For something to be used, approval by the FDA or strong recommendations by leading bodies such as NCCN and the like must occur for Insurance companies to follow, and for practioners to be able to orders pertinent test to use the knowledge.
ie. "Mutation of FOXA1 could be a marker of endocrine sensitivity...Depletion of FOXA1 abolishes Estrogen Receptor binding capacity..." (Cynthia X et al)  That FOXA1 level could predict response to endocrine therapy....This is a major finding.  The lack of endorsement makes this finding insufficiently unused in our community of Oncologist.  In reality this finding should be reported next to the ER positivity to further affirm that success of therapy is more likely, a fact that will further reassure our patients.  In endorsing this fact, technology to make this test will be developed for an easy and more readily use in oncology practice.  To spice things up? well Cyclic AMP should also be reported and monitor over time to predict MTOR activity and resistance build up.  MTOR inhibitor have shown disease free progression advantage when added to AI.  May be we should see resistance coming don't you think?  If not C-AMP, may be CRE...now don't start the polemic...!   HUMAN....  blocking progress....

Mutivitamins' controversy

Vitamin has been defined as an organic molecule that our body needs but cannot synthetasize.  It has got to be provided to our body through food. Today in age most vitamins have been synthetasized and can be sold to us as a pill at various concentrations.  What is peculiar about vitamins, is that generally the body requires these Vitamins at very low amounts. The body has to seek these vitamins hungrily.  Cells have to put out many ways of capturing these vitamin through gene receptors formation.  This is the natural and balanced way of cellular life.  The persistence lack of vitamins or their insufficiency have deleterious effects.  In lung cancer, diets that are deficient in Vitamin C, A, and Beta Carotene have been reported to increase the risk this disease development, However heavy supply of Beta carotene to patient who have had lung cancer did worsen the prognosis because it induced higher risk of lung cancer.  One should stop and wonder what the meaning of this fact is.   Why is it that supply of a needed compound will be linked to deleterious consequences.   The truth is that to any action there is a reaction!
The cell has no clear way of telling our body about its finite needs such as lack of vit D.  It can only do things within the realm of its powers such as increasing its receptors in order to increase its chances to capture Vit D.  This upregulation of receptors will have an impact on downstream pathways when of course the receptor ligand has been supplied particularly if it is provided abundantly!  It is presumed that an exagerated supply of Vitamins may lead to Receptor desensitization at the long run.  (to be continued)

ONE CASE OF EMBRYONAL RHABDOMYOSARCOMA BEING TREATED AT CRBCM!

We are currently treating a 19 year old who presented with a testicular mass
Guess what was the Histopathology: "Embryonal Rhabdomyosarcoma"
at CRBCM, we are looking at the possibility of a MUSK gene mutation
WHAT DO YOU THINK?
DON'T BE SHY NOW, CALL 915-307-3354!
AND THANK YOU

*PDPK1, THIS STUFF GIVING POWER OF RESISTANCE TO CANCER, WONDER IF IT IS ACTIVATED IN TRIPLE NEGATIVE BREAST CANCER?  IT MAKES MELANOMA TOUGH TO TREAT!

Bromocrptine and Colchine could potentially enter the fight against triple negative breast Cancer (maintenance therapy)

Following our first article about Triple Negative Breast cancer as it could be related to the ROLE OF PROLACTIN, It is evident that Medications that depress the secretion of Prolactin will come into play soon in the maintenance therapy of triple negative Breast cancer if proof of concept is maintained.  One of the comment made was that Prolactin and its receptor could not possibly be the culprit despite the fact that the gene for the prolactin receptor is a "wild gene".  We still believe we are on the right path.  Indeed one of the major role of Prolactin is to promote genes related to Casein.  Many Hormones including Glucocorticoids and potentially (or more likely Insulin) do promote Casein related genes.  One of these genes is Casein Kinase, a major source of substrate phosphorylation for critical Compounds

"Casein kinase 2, alpha 1 has been shown to interact with CHEK1,^[4][5] FGF1,^[6] CDC25B,^[7] CREB-binding protein,^[8] Activating transcription factor 2,^[8] C-Fos,^[8] MAPK14,^[9] RELA,^[10] PIN1,^[11] PLEKHO1,^[12] CSNK2B,^{[12][13][14][15][16]} PTEN,^[17] ATF1,^[8] TAF1,^[18] UBTF,^[19] DNA damage-inducible transcript 3,^[20] Basic fibroblast growth factor,^[6] APC,^[21] HNRPA2B1^[22] and C-jun".^[8]wikipedia

if you did not see the wnt listed, read again my blog of yesterday, because between the frizzled and dishevelled, one of them vividly interacts with CK2 gene.  To find inhibitors to this CK2, leave quickly the US and fly to Padua, Italy:

"Selectivity of 4,5,6,7-tetrabromobenzotriazole, an ATP site-directed inhibitor of protein kinase CK2 (‘casein kinase-2’)

Edited by Giulio Superti-Furga

• Stefania Sarno^{a, 1},
• Helen Reddy^{b, 1},
• Flavio Meggio^a,
• Maria Ruzzene^a,
• Stephen P. Davies^b,
• Arianna Donella-Deana^a,
• David Shugar^c,
• Lorenzo A. Pinna^{a, ,}

• ^a Department of Biological Chemistry, University of Padua, and CNR Biomembrane Research Center, viale G. Colombo 3, 35121 Padua, Italy"
• ======================================
•  
•  
• SO, FORGET ESTROGEN, PROGESTERONE, WELCOME   CASEIN RECEPTORS IN TRIPLE NEGATIVE BREAST CANCERS!
• AND IF YOU DID NOT SEE P300 AMONG THE PHOSPHORYLATED by CK2...GO BACK TO THE DRAWING BOARD! and if you did not notice UBTF, please read wikipedia again!
•  
• CRBCM PUSHING RESEARCH IN BREAST CANCER!  WELL KIND OF, THE FINANCIAL INSTITUTIONS THAT CAN HELP US ARE STILL SITTING ON THEIR HANDS FOR POLITICAL REASONS!

Good work recognized

Dear Dr. Kankonde--

How lucky my Mother and sister Lynn were to find your clinic open Christmas Day. Your thorough, thoughtful and appropriate care of my tough but very ill 94-year-old Mother has been more helpful that I can tell you. And the followup of the RX for albuterol without dragging Mother back out and to your office has been a lifesaver for all three of us! I will be returning to my home in Austin today, but even without ever having met you or your wife, you will be in my thoughts and on my "Thank-you" list forever!  That Mother is doing as well as she is is remarkable but would not have been so without your being available and effective!  Thank you!

Frizzled hair post chemotherapy, a tell-tell sign! ("CURLY HAIR", I AM INSTRUCTED TO ADD)

One of the reality faced by cancer survivors is that they come to need hair treatments because the hair comes back but not the same.  Cancer survivors most of the time report wrinkled hair.  Treatment aimed at straightening the hair is often required.   The Wnt is often involved in cancer, and most chemotherapy will affect it to be effective.  Down the wnt pathway is the Frizzled gene which through the dishevelled gene will affect the the Axin maze of genes which could result on derangement of the AXIN (ACTIN).

If you can describe your hair as "disrupted", think first of the Frizzled and the Dishevelled gene"
wikipidia :"The frizzled (fz) locus of Drosophila coordinates the cytoskeletons of epidermal cells, producing a parallel array of cuticular hairs and bristles"  There is some truth to that!

How this is linked to deeper disturbances is under intense research
remember this pathway involve the Wnt, a versatile gene that can follow canonical and non canonical pathways.  Meaning it can reach the GSK-3B and therefore the Lef-TcF transcription gene or go non canonical on you and reach the MEKK/JNK  with different peculiar downstream transformations.

Currently in Oncology practice, we do not pay attention enough to the resulting hair transformation.  But it is there for us to see.  Dismissing it as a potential message the body of the survivor is telling us...is totally missing the point!

FUTURE IMMUNOTHERAPY IN SOLID TUMORS

From the San Antonio meeting this year, we are having echos that are of interest to the CRBCM
There is a great interest in immunotherapy, that is, how to recruit the innate immunity to the fight against cancer.  The finding that there are lymphocytes that infiltrate the tumor has been observed and further, the presence of Lymphocytes in the tumor seems to confer, most of the time, a better prognosis.
Speculation is that if an effective autoimmune reaction is mounted, metastatic cells could be destroyed at distance from the primary tumor and seeding of metastasis could be delayed or precluded, therefore delaying disease progression.   The question is how to make such autoimmunity directed againt the tumor more effective.  Data collected in Prostate Cancer (Sipuleucel/Provenge) and Melanoma have been encouraging in terms of encouraging this line of research.

Furthermore, the inefficiency of infiltrated lymphocyte in cleaning the site of the tumor, has been attributed to a tumorkine secreted by the cancer to annihilate   the lymphocyte attack.  Tumorkine Receptors on the lymphocyte (and tissue itself for that matter) are now target therapy site potential.

It is of interest that various treatments given to the patient may alter his genes and some of the structure of the cancer cell could become immunogenic.  Studies looking at these changes after neoadjuvant therapies are now being conducted.  The point is that if they were not sufficiently immunogenic, rendering them immunogenic by conjugation with known compounds of immunogenic potential could be an interesting objective that will lead to the use of innate defense against cancer cell...this is a rapidly growing field!

THE CYTOKINE QUAGMIRE!

Times and times again we land in this soft land of unknown, with the future of our patient potentially irreversibly compromised, despite a great response to therapy. And we know or suspect the Cytokines without knowledge of clearly which, and what to do about it.  And wonder if we should have seen it coming by more sophisticated measurements (if the insurance covered it!).  This has happened with Bleomycin use, and now with modern therapies, it is happening again!
You find this great target therapy, you give to a patient, the tumor responds, everybody is happy, there it comes by way of proteinuria, abnormal liver functions and worse this dry cough and ultimately shortness of Breath (SOB !-please take this professionally, not as you please) that impairs our patients despite response to therapy!  Interstitial Bronchitis they call it.  And you know it is the Cytokines. At least the response to steroids strongly suggests it...Then the curve ball is thrown at you.  Did you just affect the response by bringing in the steroids? are they going to mitigate response to therapy, do they compromise future therapy, can you resume the treatment with the now known effective drug.  Warning boxes stop you though!  And how we ended up here without scrutiny? how we are cornered to be sleeping at the wheel?  head in the sand again?  In this environment of limited therapeutic options, it is a true Quagmire we found ourselves in.

CRBCM working on better Bio-markers for predicting side effects!

Oncologist of today must be "MR Clean"

The Beauty of target therapy is that you know exactly, at least you feel like you know, what you have done, and could possibly predict the response.  You can predict what will happen and deviations are expected but within the realm of our understanding.  You could make adjustment and make a somewhat rational decision.  You know you gave Avastin, and you know the escape mechanism can be by way of MTOR (biomarkers needed! don't be surprised and hurt my feelings!).  You know you can use MTOR inhibitor (sequentially) just as the cell as reacted and started resisting.  There is a logical thinking!

On the other hand when Adriamycin or Etoposide, you have your eyes on the DNA, when indeed the action is somehwere in the in the epigenetic events. And BOMMM! you are surprised by a resistance at Mitochondrial level (BCL-2).  In short, you just don't know what to expect.  You are left with the only Inconsequential strategy, the kill all spraying with a combination chemotherapy approach from the dungeons of Oncology.   Beside, the side effects of non specific attacks on cancer cells have manged to give the bad rep to Oncology.  We have to move fast away from these drugs and come back to them in desperate situations.  Oncologists of today must become "Mister clean", with specific target and hit only at will after a careful search of targets for our specific patients.  No collateral damages!  And for that, we need to tease every gene, and know who it is talking to and how to mend the message incognito!

IT WILL MAKE US BETTER FOR IT!

CRBCM, SEEING A BIGGER PICTURE!

AN EXCITING HIDDEN PEARL in triple negative breast cancers.

Hidden beneath the mantle of "triple negative breast cancer", one wonder if there is still to be discovered a sensitivity to Estrogen to be unveiled and used for therapeutic intentions.  One thing for sure there no one but many triple negative breast cancers.  Nothing is always the same when it comes to cancer, There is always and always will be a caveat!  Because of the variety of genes and their isoforms, and the heterogeneity of not only the isoforms but also their mutations.  But for the inquisitive mind, the suspicion that Estrogen can still work is a legitimate inquiry.
That is until you meet the Glucanase, Pectinase, and Polygalaturonases.
Before you start to wonder what in hell these have to do with anything. Let remind ourselves That Estrogen to be important has to meet its receptor.  The Receptor is made mostly of Protein but never forget the GLYCAN moiety that covers it.  For a receptor function, a glycan must be present.  And remember it is this Glycan moiety that triggers immunity (Primary/innate immunity in particular).  Then come the Glucanases that the cell send in the extracellular matrix to destroy the described functionally important covers of receptor and thereby annihilating their (receptor) very existence (CELLULAR DESENSITIZATION MECHANISMS).

In other words the lack of a receptor can be because they are not present enough to be detected by our measurements,  But if you find Pectinases and glucanases, the receptors' absence is deeper or I should say more radical.
There is something peculiar about this radical way of shutting down receptor by destruction through the Glucanases, That is, it is carefully engineered genetically and lead to disturbance of target protein vesicular transport.  ie Estrogen will be hard to travel the cell and will eventually be whisked away for Lysosomal degradation and related ESTROGEN GENE production will be shut down through the miRNA (the gene DND1 is at play here) or through the RUNX1- (interplay with Nuclear Receptor co-repressor1).  But shutting down these genes at production level, triple negative breast cancer cells make sure giving specific hormones will not work.  The noted hormone transport is disrupted, and its destruction assured.

NOW IF YOU ARE STILL IN DOUBT OF THESE PRECEPTS, AND YOU SHOULD BE SINCE IF YOU HAVE THAT RESEARCH INCLINED MIND, JOIN THE CROWD.  AND CHANG FR ET AL...IS A GOOD READING!

CRBCM, ENCOURAGING INTUITIVE MINDS! AND TEASING YOUR BRAIN ALWAYS!

BY THE WAY YOU KNOW WHO KNOWS MORE ABOUT THE GLUCANASES ? BEER MAKERS OF COURSE, THEY FERMENT GLUCOSES ALL DAY!  SMOKERS USE GLUCANASES TO DESTROY QUIETLY THEIR RECEPTORS ALL DAY, LOOK IT UP I AM NOT KIDDING! 

Tankyrase, an important target in triple negative breast cancer!

If the concept is right
and with the advent of the importance of vesicular formation and displacement of cellular protein as a major disturbance in this disease, the role of Tankyrase genes (TNKS1,2) is rapidly growing as target in triple negative Breast cancers.   How can someone come up empty?
Tankyrases are involved in:

1.Telomere length
2.Insulin resistance
3.Spindle assembly and formation
4.Molecular trafficking (AXIN)
5.Catening degradation  (hell the involvement of GSK1 get MUC1,NOTCH, and WNT in this)
6.Cancer cell resistance (Through activity with with MCL1, a BCL-2 family member)
7.Cellular deformation (theses genes through their connection with TERF1 and SALL1 can lead to the famous "Anal-ear syndrome" (so to speak))
8.through the FNBP1 gene, its reach expands exponentially to reach the Grb2 and MITF (through UBE2I)

Just remember our belief that a gene capable of inducing malformation, is a potent oncogene, and that reaching a "wild gene" such as Gerb2 or UBE2I is a dangerous development for all mutation driven processes.

FARNESYLATION, FRIEND OR FOE

The ascent of KRAS as a therapeutic biomarker in Metastatic Colon cancer has increased the interest in Farnesylation as cellular process because is closely linked with Prenylation, if it is not the same process.
And from wikipedia:

"Proteins that undergo prenylation include Ras, which plays a central role in the development of cancer. This suggests that inhibitors of prenylation enzymes (e.g., farnesyltransferase) may influence tumor growth. In the case of the K- and N-Ras forms of Ras, when cells are treated with FTIs, these forms of Ras can undergo alternate prenylation in the form of geranylgeranylation.^[5] Recent work has shown that farnesyltransferase inhibitors (FTIs) also inhibit Rab geranylgeranyltransferase and that the success of such inhibitors in clinical trials may be as much due to effects on Rab prenylation as on Ras prenylation. It should be noted that inhibitors of prenyltransferase enzymes display different specificity for the prenyltransferases, dependent upon the specific compound being utilized." wikipedia

Meaning wild type Ras which benefit from Cetuximab and Panitumumab could be affected if farnesylation is compromised.  Indeed logically, FTI could limit the effect of anti-EGFR because the kind of indrectly "mutate" or disable RAS by making it inattrative to its protein co-activator.  Remember prenylation increases protein-protein interaction.  By the same token, use of statins needs to be carefully reviewed in thiese circumstances since it may impact or block prenylation and there.

Interactions on calcium/ phosphate ratios can impact rate of Alzheimer disease? can we ask if Prenylation has something to do with rates of dementia...a good question to explore fully?

Perturbance of Farnesylation has been linked to Blindness, somewhat contribution to Avastin use in treating some ophthalmic condition (an honest question)?

Lemon derived product are at the source of Farnesol,  is it safe to eat Lemon while with KRAS driven disease?
Many questions to tease our readers!

do remember a gene called PGC1 which interacts
with Farnesoid X Receptor as well as PPARy and the Retinoic X Receptor alpha
PGC1 interect and is down stream from NRF1

All this put Farnesylation at the center of  PI3K pathways in a way!

(IF YOU DON'T REACT TO THIS BLOG, ARE YOU FRIEND OR FOE?)  YOU GOT TO REACT!

Dupplicity of MITF( microphthalmia-associated transcription factor)

One of the gene that tells us that we are still at the dawn of big genetic discoveries is MITF.
The NCBI tells us "This gene encodes a transcription factor that contains both basic helix-loop-helix and leucine zipper structural features. It regulates the differentiation and development of melanocytes retinal pigment epithelium and is also responsible for pigment cell-specific transcription of the melanogenesis enzyme genes."
But this is just the beginning  of a complex set of interaction that lead to cancers
from Melanoma (TRPM1)to Hodgkin (IKKa, CHUK) disease to various lung cancers (DYNLL1)
Wikipedia tells us this is an example of a gene that can induce malformation
and a "wild gene"
Careful now don't jump in with inhibition
because in activating TRPM1, it blocks the aggressiveness of Melanoma by decreasing its Metastatic potential.  So don't get overexcited here.
But by playing the RAB27A card, MITF could impact on removal the inhibition that drives NF-kB expansion, fueling Hodgkin disease.
Through ZPYVE16/TOM1, MITF could impact lysosomal degradation of Growth factors...
Through its Catenin Connection (CHUK-CTNNB1), it can affect the overall shape of the cell affecting epidermal differentiation.
MITF interacts also with UBE2I, another known target gene
So be careful approaching this gene as a target, patient hair will go "silver gray" on you (MyO5A)...

Current treatment of Gastric cancer (New patient at GECC)

Local disease

Surgery cure rates in node negative diseases 75 to 20%
for stage III (node positive)  5 year survival  20-25%  (the reverse)

In the US, post-operative 5-FU-Leucovorin --RT--5-FU/LV (sandwish) has been standard of care

Neoadjuvant Chemotherapy  (rarely +RT) is used particularly when lesion is obstructive...but certainly not standard.   Most of the time Neoadjuvant chemotherapy is given to shrink the lesion to allow better surgery. Decision to offer this option is made after consultation with the surgeon.


With the results of the DUTCH study, D2 surgery has won the argument and should be offered to our patients!You don't have to be Asian to call for it as a patient

In Metastatic disease

1.DCF is still the main option in good performance patient
but brace yourself for the 30% Febrile Neutropenia rate and use growth factors
otherwise use EOX  (we still use in hospital ECF for poor folks that can't afford Xeloda or can't afford PO medications) I am facing this situation now with an uninsured patient.

2.Her-2 positive patients, will get Trastuzumab and chemotherapy-standard of care now(ToGA trial)

Lapatinib, Panitumumab and Cetuximab (and Irinotican) have a role, particularly in 2nd line therapy,

AT CRBCM, further targets are being actively investigated.
(ASCO-reference)

Biomarkers' controversy in Medicine

As we see our volume of patients expand by overtaking other Doctor's business, there is this growing notion that we will be alright if we can stick to already defined standards of care, and make sure that patient main diseases have been monitored through current defined and recognized biomarkers.  Yet as an investigator, we live in an environment that we know to be in a transition to better biomarkers as modern medicine and technology continue to advance us rapidly.  As a physician, we are aware that disease biomarkers are very important in determining the cause of the disease that will initiate our patient condition, that some biomarkers will determine the disease status of activity, that some biomarkers will gives us the patient prognosis or clinical outcome in terms of disability or ultimately, fatality.   Level of patient participation in current recommended  prevention endeavors is held today by government institutions as a premier "biomarker" of patient's health.  Yes indeed across the country, the government is monitoring participation in immunization, glaucoma check, colonoscopy, mammogram and bone density screening for patients in defined age. The PSA (Prostate Specific Antigen) and rectal exploration for prostate size have sent us in a world of controversy because of the inadequacy in predicting Prostate cancers that really need to be screened!  Indeed, as it turned out, knowing that Prostate cancer is present is not enough because it is now clear that early detection did not give us clear and palpable benefit in survival.  That what happens when our biomarkers are insufficiently tested.  (new genetic biomarkers are in the work to come to the rescue).

Monitoring level of Testosterone and Vitamin D level has entered current practice and correction measures are being aggressively taken in a world of predominant frequency of cases of associated Hypertension without a clear balance of diseases' related risk.  To make the matter worse, our patients do not have have one single diagnosis.  Most patient carry up to 10 diagnosis to navigate in terms of clinical biomarkers...which biomarker set is important in each individual patient may be a matter of determinant symptoms or perception of medical risk for each individual patient and relevant clinical background as perceived by his doctor who uses insufficient standards of care but best under current circumstances and state of technology.

One area of Puzzling observation that need to be mentioned is the use of anti-inflammatory drugs.  Aspirin has entered the routine medical prevention....to be continued...

This year the American Society for Hematology (ASH) took place in New Orleans
and no one participant has left without hearing about CARs
CURRAN et al defines these:
"One promising strategy entails the introduction of genes encoding artificial receptors called chimeric antigen receptors (CARs), which redirect the specificity and function of immune effectors. CAR-modified T cells targeted to the B cell-specific CD19 antigen have demonstrated promising results in multiple early clinical trials, supporting further investigation in patients with B-cell cancers. However, disparities in clinical trial design and CAR structure have complicated the discovery of the optimal application of this technology. Recent preclinical studies support additional genetic modifications of CAR-modified T cells to achieve optimal clinical efficacy using this novel adoptive cellular therapy."
This technology is just another example  of use of our immune system against cancer
It has been made more feasible with the new ability to transfer gene into cells to give them more fighting powers.

"FDA Approval for Sipuleucel-T," was just another example of such manipulation.

* A telomerase inhibitor showed up finally, Imetelsat (geron) at ASH to rock the world of Myelofibrosis, while Obinutuzumab was shaping the CLL world, it could replace Rituxan reportedly.  We know that cd20 expression in CLL is weak, therefore may be a more potent immune based agent is needed in combination with other therapy.  This will be even more important in those cases where Rituxan is used alone!

R PAZDUR:

"

On November 1, 2013, the Food and Drug Administration (FDA) approved obinutuzumab (Gazyva™ injection, for intravenous use, made by Genentech, Inc.; previously known as GA101) for use in combination with chlorambucil for the treatment of patients with previously untreated chronic lymphocytic leukemia (CLL).
The approval was based on demonstration of an improvement in progression-free survival (PFS) in a randomized open-label multicenter trial that compared obinutuzumab in combination with chlorambucil (GClb) with chlorambucil (Clb) alone in patients with previously untreated  CD20-positive CLL. The study also compared rituximab in combination with chlorambucil (RClb) with obinutuzumab in combination with chlorambucil (GClb). The results of the comparison of RClb with GClb will be available at a later stage.
Patients randomly assigned to be treated with obinutuzumab in combination with chlorambucil received 1000 mg doses of obinutuzumab intravenously on day 1 (later divided into 100 mg on day 1, followed by 900 mg on day 2), day 8, and day 15 of the first cycle. Chlorambucil, 0.5 mg/kg, was administered on days 1 and 15.  During treatment cycles 2-6, patients received obinutuzumab, 1000 mg intravenously only on day 1 in combination with chlorambucil, 0.5 mg/kg, on days 1 and 15. Patients received pre-medication with a glucocorticoid, acetaminophen, and antihistamine prior to initial obinutuzumab infusions and subsequently as needed. Patients assigned to be treated with single-agent chlorambucil received 0.5 mg/kg on days 1 and 15 of all treatment cycles (cycles 1 to 6). Cycles were repeated every 28 days.
A total of 356 patients were  randomly assigned (2:1) to receive obinutuzumab plus chlorambucil (n=238) or chlorambucil alone (n=118). The median age was 73 years (range 39 years-88 years). The independent review committee-assessed median PFS was 23.0 months for patients treated with obinutuzumab plus chlorambucil and 11.1 months for patients treated with  chloramucil alone [HR 0.16 (95 percent CI: 0.11, 0.24), log-rank p-value <0.0001].
The most common adverse reactions (at least 10 percent) with obinutuzumab plus chlorambucil (with a higher frequency than in the control arm) were infusion-related reactions, neutropenia, thrombocytopenia, anemia, pyrexia, cough, and musculoskeletal disorder. The most common grade 3-4 adverse reactions (at least 10 percent) were infusion-related reactions, neutropenia, and thrombocytopenia.
Infusion reactions occurred in 69 percent of patients receiving obinutuzumab; 21 percent experienced grade 3 or 4 reactions. Symptoms (greater than 10 percent) included dyspnea, hypotension, nausea, vomiting, chills, flushing, and pyrexia.
Obinutuzumab is approved with a BOXED WARNING regarding Hepatitis B virus reactivation and Progressive Multifocal Leukoencephalopathy. Patients should be advised of these risks and assessed for Hepatitis B virus and reactivation risk. Infusion reactions are included in the WARNING and PRECAUTIONS section of the label.
The recommended dose and schedule for the approved regimen is:
Obinutuzumab:
Cycle 1: 100 mg intravenously on day 1, 900 mg on day 2, and 1000 mg on days 8 and 15 
Cycles 2-6: 1000 mg administered intravenously every 28 days
Chlorambucil:
0.5 mg/kg orally on days 1 and 15 of each cycle"

THIS MEANS ELDERLY PATIENTS WITH POOR PERFORMANCE MAY SEE THIS DRUG COMING TO THEM .

2010 

*Mylotarg (gemtuzumab ozogamicin): Market Withdrawal, adding Myelotarg to Acute Leukemias seem to prolong disease free survival,calling for an FDA second look!

*Wake up to the Calreticulin gene,

remember when we used to ask for JAK-2 to prove the existence of Myeloproliferative diseases, well now it's not just the JAK-2, but also MPL Mutation, and the latest the CALR gene!

FOR THOSE OF US WHO FOLLOW CPRIT LIFE CLOSELY

GO TO THE ARTICLE BY JAMES DREW TO BE FULLY INFORMED (DALLAS NEWS)

Ex-official indicted over $11 million Texas cancer-fund grant

 BY JAMES DREW

TO FIND THE ARTICLE
GOOGLE CPRIT,COBBS
AND READ UNDER COMMUNITY  CRIME

ACTIVITY AT CRBCM 2013

MERRY CHRISTMAS TO ALL
This was the first year of CRBCM
AND WE REGISTERED OVER 33,000 REVIEWS OF OUR BLOG
WHICH NEEDED TO BE CREATED TO FURTHER OUR MISSION.
We did not expect to find an easy road nor did we fool ourselves.
Four our various project, donor institutions have been reluctant to help.   We thank MDHonors for rising above the doubt, and investing in our project.  This led to  a great collaboration with the Local University (UTEP) which is providing us with the scientific support we needed to actually perform molecular research at PCR level.  We thank the University of Virginia tissue Bank for providing samples.  Our project on lung cancer is advancing at deliberate pace.  We intend to develop a KIT and look into why Avastin may fail in cancers.   This year we participated in 2 conferences held in El Paso, with 4 posters accepted at the first ever conference 4 Posters at 1st BIOMED Symposium, El Paso 10/26/2013


AND EVEN BETTER, WE WERE INVITED AS SPEAKER AT

14th Annual Rio Grande Trauma Conference & Pediatric Update - December 5-6, 2013.

our poster was so good, it got stolen!

 

Now we are taking over the practice of DR Ray Lundy who we will miss greatly, this step will mark a dramatic expansion of Greater East cancer center.  A few patients are now streaming from  the University Medical Center, and we are finally on the roster for call at more hospital.

The year has not been pink.  Our failure to convince donor institutions such as CPRIT and the NIH for our committment to research remain the biggest hurdles.  These are big time political institutions.  They are a myth for little guys.  Their leaders, mostly politicians, are tied to games.  Our mission is clear, we move forward deliberately and will work with this knowledge that CPRIT and the NIH are just a side show.  We have gone international where funding institutions are not under local politics.  Science awaits to be teased.  And science is where the answer is...

This year we took over the directorship at the El paso 2 Plasma center (Talecris/Grifols).  Working as a Director required a special training (Certification by CLIA) and now applying the rigorous knowledge of checks and more checks to ensure quality in lab work.

We look forward to an exciting 2014 at the CRBCM and Greater East Cancer Center.

happy holidays, Merry Christmas, happy new year 2014 to all!

FOR THE CURE, PROMOTE APOPTOSIS!

For cancer cell killing, no one can do it best but the cell itself through it's programmed death process we come to know as Apoptosis.  The killing here is efficient, long time choreographed as if a dance to death, and without mambo jambo!  No side effects and proper noticia to surrounding cells:"we are dying for this potential reason".  When the BIM, FASL and the BAX role in Apoptosis  has been sufficiently documented, the role of the PAX6, ELK1, MEF2, ATF1...or even ETS/Er81, has not been fully investigated or rephrasing, fully elaborated....I should say MAX is here somewhere....(to be continued)

IN BRAIN CANCER, THE INTRICACY OF THE RAC AND RICS GENES, THEIR DANCE WITH THE TIAM1

There is no underdog gene or gene not fully recognized for its power than RAC-1. yet it is a pivotal gene.  RAC-1 belongs to the Rho family of GTPases and therefore is a Protein kinase activators or enabling molecule.  RAC-1, like any powerful gene, will get its power through its interactions.  Through PAK1, it talks to Raf (Vemurafenib's target ) but it is through RICS and TIAM1 that it reaches its full metastasis potentials in virulent cancers.  Of course I am not going to Hide my penchant for the Wnt and the NOTCH genes, but this RAC-1 puzzles me  (to no end, they say) when it comes to Brain tumors! tell me if I am on the right track...of course you also know about this gene that help (lipid) layers to go to their exact locations in the brain, it intrigues me also...let reconvene on this soon now!  We are zeroing in!

WHAT VITAMIN D GOT TO DO WITH c-MYC ANYWAY?

Yes it is true that there is a potential link between Calcitriol (the active form of Vitamin D) and  the master genetic amplifier c-MYC, a bad prognosis factor in some cancers such as small cell lung cancers. And  in this type of lung cancers, the expression or activation of c-MYC is one the driving forces.  And it is not the only virulent cancer to borrow the power of c-MYC.

"Amplification and expression of the c-myc oncogene in human lung cancer cell lines
Cameron D. Little, Marion M. Nau, Desmond N. Carney, Adi F. Gazdar & John D. Minna
NCI-Navy Medical Oncology Branch, National Cancer Institute, National Institutes of Health, and Naval Hospital, Bethesda, Maryland 20814, USA
Genetic changes involving the c-myc oncogene have been observed in human tumours. In particular, the c-myc gene is translocated in Burkitt's lymphoma^1–3 and is amplified in the human promyelocytic leukaemia cell line...."
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(If you happen not to find a target for therapy, call CRBCM, immediately!) today VITAMIN D is given at 50,000 IU weekly.
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Calcitriol acts through its receptor, the Calcitriol receptor of course, will eventually interact with a Zinc finger and BTB domain-containing protein 16, encoded by the ZBTB16, a popular gene that will engage events in the epigenetic areas which include many receptors (watch out because even the Angiotensin receptor is engaged).  But ultimately the RUNX and the GATA2 are also engaged. The involvement of SN3A and MDX1 however will have the most importance when it comes to c-MYC since these gene impact the Mad-Max complex.  And you know what c-MYC needs to be active (association with MAX),

let Wikipedia tell you:

MXD1

From Wikipedia, the free encyclopedia

Jump to: navigation, search

MAX dimerization protein 1
PDB rendering based on 1nlw.
Available structures PDB Ortholog search: PDBe, RCSB [show]List of PDB id codes
Identifiers
Symbols	MXD1; BHLHC58; MAD; MAD1
External IDs	OMIM: 600021 MGI: 96908 HomoloGene: 1767 GeneCards: MXD1 Gene
[show]Gene Ontology
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	4084	17119
Ensembl	ENSG00000059728	ENSMUSG00000001156
UniProt	Q05195	Q8K1Z8
RefSeq (mRNA)	NM_001202513	NM_010751
RefSeq (protein)	NP_001189442	NP_034881
Location (UCSC)	Chr 2: 70.12 – 70.17 Mb	Chr 6: 86.65 – 86.67 Mb
PubMed search	[1]	[2]

MAD protein is a protein that in humans is encoded by the MXD1 gene.^[1][2]
MAD-MAX dimerization protein belongs to a subfamily of MAX-interacting proteins. This protein competes with MYC for binding to MAX to form a sequence-specific DNA-binding complex, acts as a transcriptional repressor (while MYC appears to function as an activator) and is a candidate tumor suppressor.^[2] The MAD-MAX protein dimer may be a reference to the popular cult classic film Mad Max (1979)."wikipedia

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FOR A CAREFUL PREVENTION PROGRAM USING VITAMIN D, OR ASSOCIATION OF VITAMIN D IN TREATMENTS OF MENTIONED CANCERS, LET'S WORK HARD! (whenever focusing on c-MYC, don't forget the FUSE or FUBP1)

PONATINIB, A COMEBACK KID!

GOOD THERAPIES ARE DIFFICULT TO DIE

A DRUG JUST RECENTLY STOPPED BY THE FDA, IS RETURNING TO THE MARKET FOR SPECIFIC INDICATIONS WITH A WORD OF CAUTION.  ACCORDING TO MEDSCAPE :
"The indications are now limited to 2 groups of patients: adults with T315I-positive chronic myeloid leukemia (chronic phase, accelerated phase, or blast phase) or T315I-positive Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL); and adults with chronic-phase, accelerated-phase, or blast-phase chronic myeloid leukemia or Ph-positive ALL for whom no other tyrosine kinase inhibitor therapy is indicated.
The FDA has also revised the Warnings and Precautions section of the label to describe vascular occlusion events, including the observed arterial and venous thrombosis and occlusions that have occurred in at least 27% of patients treated with this drug."

Description of Spindel Cell Sarcoma and why inflammation and injuries can lead to spread of malignant cells

Spindle cell sarcoma

From Wikipedia, the free encyclopedia

Jump to: navigation, search

Spindle cell sarcoma is a type of connective tissue cancer in which the cells are spindle-shaped when examined under a microscope. The tumors generally begin in layers of connective tissue such as that under the skin, between muscles, and surrounding organs, and will generally start as a small lump with inflammation that grows. At first the lump will be self-contained as the tumor exists in its stage 1 state, and will not necessarily expand beyond its encapsulated form. However, it may develop cancerous processes that can only be detected through microscopic examination. As such, at this level the tumor is usually treated by excision that includes wide margins of healthy-looking tissue, followed by thorough biopsy and additional excision if necessary. The prognosis for a stage 1 tumor excision is usually fairly positive, but if the tumors progress to levels 2 and 3, prognosis is worse because tumor cells have likely spread to other locations. These locations can either be nearby tissues or system-wide locations that include the lungs, kidneys, and liver. In these cases prognosis is grim and chemotherapy and radiation are the only methods of controlling the cancer.
Spindle cell sarcoma can develop for a variety of reasons, including genetic predisposition but it also may be caused by a combination of other factors including injury and inflammation in patients that are already thought to be predisposed to such tumors. Spindle cells are a naturally occurring part of the body's response to injury. In response to an injury, infection, or other immune response the connective tissues will begin dividing to heal the affected area, and if the tissue is predisposed to spindle cell cancer the high cellular turnover may result in a few becoming cancerous and forming a tumor.

Determined to lead to the recognition of the CRBCM! Promoting standard Care!

We are not the only ones looking into Sirtuins and how to reduce cellular stress response in the Brain:

Cellular stress response, sirtuins and UCP proteins in Alzheimer disease: role of vitagenes

Carolin Cornelius¹, Angela Trovato Salinaro¹, Maria Scuto¹, Vincenzo Fronte¹, Maria Teresa Cambria¹, Manuela Pennisi², Rita Bella², Pietro Milone³, Antonio Graziano³, Rosalia Crupi⁴, Salvatore Cuzzocrea⁴, Giovanni Pennisi² and Vittorio Calabrese^1*

• * Corresponding author: Vittorio Calabrese calabres@unict.it

Author Affiliations

For all author emails, please log on.

Immunity & Ageing 2013, 10:41  doi:10.1186/1742-4933-10-41
Published: 17 October 2013

Abstract

Alzheimer’s Disease (AD) is a neurodegenerative disorder affecting up to one third of individuals reaching the age of 80. Different integrated responses exist in the brain to detect oxidative stress which is controlled by several genes termed Vitagenes. Vitagenes encode for cytoprotective heat shock proteins (Hsp), as well as thioredoxin, sirtuins and uncouple proteins (UCPs). In the present study we evaluate stress response mechanisms in plasma and lymphocytes of AD patients, as compared to controls, in order to provide evidence of an imbalance of oxidant/antioxidant mechanisms and oxidative damage in AD patients and the possible protective role of vitagenes.

We found that the levels of Sirt-1 and Sirt-2 in AD lymphocytes were significantly higher than in control subjects. Interestingly, analysis of plasma showed in AD patients increased expression of Trx, a finding associated with reduced expression of UCP1, as compared to control group.

This finding can open up new neuroprotective strategies, as molecules inducing this defense mechanisms can represent a therapeutic target to minimize the deleterious consequences associated to oxidative stress, such as in brain aging and neurodegenerative disorders.