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

==============================================================
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.

Too little, too late!

In a living cell, things are constantly happening, nothing is still,  molecules are constantly cross talking
so to believe that lipid deposits from Arteriosclerosis is benign is foolish...the endothelial cell that is covered by this stuff is constantly under pressure and Cytokines are being produced that will come back to hunt us as we plant head in the sand!  When it comes to cholesterol build up "zero tolerance " should be our norm.  But we have no lipase to throw at it we have no easy solution, so we wait that the occlusion be  more that 75% to attempt something...by then Cytokines have done their deeds, irreversible damage may have been done to the blood vessel wall.  Could PGC 1, the master co-activator, have warned us of the real toll on our systesm? or is it the PPARy, the RAR, c-AMP?   What are the true genetic biomarkers of Arteriosclerosis (to be continued)

GENE WORK INVOLVING Breast CANCER SURVIVORS

With significant progress being achieved in cancer therapy, we are finding ourself living with our sisters and few brothers who had gone through the horrific ordeal of Breast Cancer treatments and now live with this doubt on whether or not the disease is going to come back.  While it is true that in most solid tumors, the 5 year survival rule could be applied, and that we can reassure victims of solid tumor disease that once you pass 5 years post treatment, your risk of recurrence is critically decreased and one can venture to call this bench  mark for cure,  Breast cancer remains a mysterious disease that seems to escape this general rule!  Breast Cancer can return when it wants....It seems that for some reasons it can stay dormant, and wake up to disturb its victim once again.  (Clue) What this is reminiscent of, is of course Viral Herpes when it first shows up as chicken Pox and goes to sleep in our nerve roots, and break out as Shingles later on in our peaceful life to disturb and affect it.  (New clue, progress in HIV, it is now a chronic disease)
At gene level, nothing occurs without some genes acting out!  It is time that we answer the questions that survivors need from us.  The genes are there, let take the time to look at them and stop this cancer cell madness of trying to come back in our survivors.  No head in the sand because we don't have an answer, but take the Bull by the Horns and see what happens!  (You know what I mean!)

TRYING OUR BEST TO TALK TO THESE GENES IN BREAST CANCERS: MED1,6 and 12

With the clinical finding that Bicalutamide, a non steroidal anti-androgen, has a role in some of the luminal forms of Breast cancers, genes affecting the Hormones have quickly become the focus of intensive research. So we venture to explores some of the genes having links to Hormone.  At CRBCM we are looking at DAX1 as it interacts with COPS2 and through the thyroid Hormone Receptor alpha gene will affect the MEDs which ultimately the Glucocorticoid Receptors and a slew of other critical receptors and genes (even the BRCA-1) is in the line of fire!
Now how important this observation is in triple negative breast cancer is still a matter of debates.  Proof of concept work is still needed but it is a clear start, join the discussion!

" MED1 has been shown to interact with Thyroid hormone receptor alpha,^[4] Androgen receptor,^[5] Cyclin-dependent kinase 8,^[6][7] Glucocorticoid receptor,^[8][9] BRCA1,^[10] Hepatocyte nuclear factor 4 alpha,^[11][12] Peroxisome proliferator-activated receptor gamma,^[13] PPARGC1A,^[14] P53,^[15][16] Estrogen receptor alpha,^[7][17] TGS1^[18] and Calcitriol receptor".<sup>[6][17] wikipedia


WHERE ELSE COULD THINGS BE HAPPENING BUT HERE!
THE INVOLVMENT IS THE CALCITRIOL RECEPTOR IS ANOTHER AREA OF INTEREST.  THIS MED1 SEEMS LIKE A GIFT THAT KEEP ON GIVING.   THE ANDROGEN RECEPTOR INVOLVEMENT IS A CRITICAL STEP SINCE IT BELONGS TO THE "WILD GENES"</sup>

Proof that target therapy has come in to change things in cancers!

1.Combining Ibrutinib with R-CHOP is not only feasible but yield 100% response in Diffuse Large cell Lymphoma.

For decades, CHOP had remained King of treatment of diffuse large cell lymphoma
Elaborate combinations of chemotherapy drugs failed to improve on CHOP, until the targeting of CD20 by Rituxan.  And now with the arrival of the almighty powerful Ibrutinib, response rates seem to be overwhelming although not all seems to be complete Responses, at least not yet since analysis of data is still ongoing!

Dr. Kankonde MD the new physician and custodian for Dr. Lundy's patients in El Paso Texas

The CRBCM,
expanding its foot print in El Paso.  We are in the right fight because our cause is just!

Collaboration at the CRBCM, good progress in our lung cancer research! We thank MDHonors, UTEP, LCBRN/Univ. of Virginia tissue Bank!

12/16/2013

"Hi Peggy,

Attached is your invoice for the 45 RNA samples and 50 serum samples that you recently requested from the LCBRN.  Once payment has been received, I can set up a shipment date."
=======================================
We thank MDHONORS, funding organization.
We thank UTEP (UNIVERSITY OF TEXAS AT EL PASO) PERFORMING PCR WORK FOR the CRBCM.
and We thank the LCBRN/ UNIVERSITY OF VIRGINIA for their support
and We thank the GREATER EAST CANCER CENTER, our SECONDARY FUNDING ORGANIZATION

PROGRESS IS PAINSTAKING AND SLOW, BUT IT IS THE INGREDIENT OF SUCCESS.
OUR EARLY DETECTION OF LUNG CANCER PROJECT IS ON ITS WAY FOR A SECOND PHASE  (FIRST PHASE WAS COMPLETED ON 5 TISSUE SPECIMENS TO TEST OUR PCR WORK FOR TARGETED GENES).
WITH THIS FIRST PHASE COMPLETED, the CRBCM is deliberately moving forward!
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DON'T WORRY, THE RNA SAMPLES WILL BE QUICKLY PROCESSED (WITHIN 48 HOURS) c-DNA FOR LONGER STABILITY (YOU GET MY DRIFT!).

PIM1, a powerful target in Cytokine dependent diseases

No gene is deep in the bowel of the cellular Beast having such powerful interactions that leads to cytokine production as this one.  Its relation with the NF-KB and the NFATs is a testimony to how critical a gene it is.
Under the management of NUMA1....(to be continued!)

The secret of triple negative breast cancer

Common sense tells us that events happening in your women when they acquire childbearing age contribute significantly to the happening of triple negative breast cancer.   The young woman has gone through infancy when events here are more related to the setting of class I HLA antigens first for self tolerance, then comes exposure to the outside world and the building of defense mechanisms.  Implying development of class II HLA Antigens which we know by now are very much linked in their variations to racial disparity.  Then the young woman enters puberty which brings in the reign of the Estrogen with its extensive methylation of genes dampening the Class I HLA to prepare the young lady's body to receive the foreign "body" of the potential infant.  We have touched in one of our precedent writings about the effects of Estrogen on the immune system.   We have extensively discussed the interaction of Interferon and TNF /TGFs on receptors of Estrogen (Activation followed by desensitization or lack thereof.  The female individual with autoimmune disease will be much more affected by the surge of cytokines above.  Then come the menses with their resulting Iron deficiency which prones the body to the danger of Reactive Oxidative species.  But as far as genes are a concern, the most important event is the development of the breasts.  It is the reign of the PROLACTINS.....
Indeed, it is Prolactins that will happen on this background of Estrogen/Cytokines effects.   Don't think of Prolactin as a hormone, it is a Cytokine!  Yes, it comes in to not only have a direct effect on the Janus Kinase 2 and induce the JAK-2-STAT pathways, but through its Dopamin Receptor, it will pound on the c-MET effect and exert numerous pounding on the PIK (effect include on its regulators (AGAP2) pathway....If you happen to have another genetic abnormality such as BRCA, or too much free Iron stimulating the HIF or any other failure....something wrong is bound to happen....such as ...triple negative breast cancer.....The point is, don't forget the Prolactin reign!!!

IN THE "EL PASO TIMES"

There is an announcement for the last 2 Sundays,
reporting the Retirement of DR RAY LUNDY, a Dr who has been a pillar in this community.
DR Lundy has chosen the Greater East Cancer Center  (and the CRBCM) to continue the care of his patients.
We are pleased by is careful choice, and promise to continue what he started.  We will make sure patients receive the kind of excellent care they expect from us!

CRITICAL POTENTIAL NOTIONS IN UNDERSTANDING TRIPLE NEGATIVE BREAST CANCERS

It all makes sense that Hypoxia induced by respiratory failure in a predominantly obese population will contribute to generation of Reactive Oxidative Species and that Over eating of sugar based products will worsen the events that will lead to HIF-1 gene excitation and probable amplification, which eventually involve the VHL (justifying the correlation of clear cell Renal cancer with obesity), and eventually amplify angiogenic genes (EGFR,VEGF).  This will end-up through Gerb2 connection gene, amplify the G proteins connected MAPK and could drive to a neoplastic process.  When p38-MAPK is involved there appears that the process will be accompanied by a significant cytokine release leading to an associated inflammatory process.  This is why anti-p38 is more looked into for its anti-inflammatory consequences rather than anti-neoplastic processes. For this inflammatory process to be successful, stimulation of the CREB must be suppressed, which it is in hypoxia. The level of Cyclic-AMP is also dampened as a result.

In the epigenic zone, amplification of the MAPK will ultimately amplify the MIFT (MIFT was first described under these conditions of amplified MAPK) with consequences that lead to dampening of Androgen activity if the MIFT interacts with PATZ1.

 If  MIFT interaction is mediated via PIAS3 binding^,, ER will be next to be knocked out


Wikipedia: "This interaction is mediated via PIAS3 binding to the STAT3 DNA binding domain. Hence, STAT3 transcriptional activity is inhibited by the physical prevention of its binding to target genes. Subsequently, PIAS3 was also found to be a regulator protein of other key transcription factors, including MITF,^[6] NFκB,^[7] SMAD ^[8] and estrogen receptor.^[9] PIAS3 protein also functions as a SUMO (small ubiquitin-like modifier)-E3 ligase"

Pretty soon, you have yourself a triple negative breast cancer!!!
(leading to the question is IL6 elevated in this disease?

MIFT involvement with TFE3 will engage HMGA-2 and prop the metastatic propensity in this disease (triple negative breast cancer).

The involvement of MIFT is obligatory since it will unlock the chromatin to allow access to nuclear material by chromatin modulation

TO BE CONTINUED

An interesting Observation

 Contact QIAGEN OUR SOURCE FOR QUESTIONS!

 A study on a  BRAF(V600E) melanoma cell line treated with RAF, MEK, ERK or combined RAF-MEK inhibitors revealed a cAMP-dependent melanocytic signaling network not previously associated with drug resistance, including G-protein-coupled receptors (GPCRs), adenyl cyclase, protein kinase A (PKA) and cAMP response element binding protein (CREB).
" histone-deacetylase inhibitors suppressed MITF expression and cAMP-mediated resistance (Nature, December 2013" QUIAGEN


This observation from journal nature reported to us by QIAGEN
tells us
1. a second look at a old story does not hurt
BRAF INHIBITION IS A NEW THING HAPPENING TO A OLD STORY
AND LOOK WE HAVE BEEN SITTING ON OUR HANDS IN MELANOMA UNTIL IT SUNK ON US TO TARGET THERAPY! NOW LET'S ENJOY THE SUCCESS OF VEMURAFENIB IN OUR FIGHT FOR THE CURE!
2.THIS IDEA THAT  MITF AND c-AMP MAY HAVE THE POWER IN THEM TO CAUSE DRUG RESISTANCE IS EXTREMELY IMPORTANT, IT MAY BE THE JUSTIFICATION OF 2 IMPORTANT PHENOMENA
2.1 THAT EGFR/VEGF INHIBITION IS TEMPORARY, THAT ULTIMATELY AVASTING WILL FAIL BECAUSE OF THESE ACTORS (OR ARE THEY BYSTANDERS?)
2.2 THAT MTOR INHIBITION CAN STOP THIS RESISTANCE ONCE IT IS DOCUMENTED BY AMPLIFICATION OF THESE 2 GENES.  SO YOU GIVE AVASTIN, AND WATCH THESE 2 GENES, AND IF THEY CREEP UP, YOU KNOW AVASTIN RESISTANCE IS IN PLACE, AND HOP! YOU GIVE MTOR INHIBITOR!  WHAT'S THIS FOR A CONCEPT TO BE PROVEN!

LET'S GO TO WORK!

GENES IN MELANOMA

ERCC6
DDB2
POLH
RAD2
p16/CDKN2A, p14ARF
CDK4
MCIR
NRAS
BRAF
KIT
MITF
PTEN
GNAQ
GNA11
XPA
BRCA
miRNA

1.does amplification of Grb2 influence c-KIT biomarker function...or response to Imitanib/Dasatinib
is Mutation or amplification of Grb2 necessary to predict response to treatment.
2.what is the therapeutic, prognosis roles of Cytokines in triple negative breast cancers and Melanoma for that matter.  We know CyclinD is involved,  But are theyr other Cytokine, Status of Ornithin?  Polygluthamine, Melanine derivative?level of Ketoacids in both serum and Urine?

Words of caution!

Be careful when targeting these genes, some of them are "wild genes", meaning that they could be leading to the activation of many more genes. As we discussed, handle these with care because you will not be able to control their side effects....Other genes are just critical to so many functions ie. the ELK-1 gene.  You may use it for pro-apotosis, but it is a gene that, once knocked down, can lead to Alzheimer dementia and many more neurologic disturbances.  So read carefully before targeting these genes.  Some could lead to seizures or sudden Neurologic dysfunction, so pick and choose carefully and be prepared to handle Neurologic or cardiac complications...and always start with Phase I as per standard....Indeed you are in the belly of the beast, tread carefully!

Deep in the belly of the beast, ARE HIDDEN NICE THERAPEUTIC TARGETS!

As we examine deeper for possible targets for therapy, we are not swayed by media or political pressures which are mounting, but we look at real facts that are scientific and based on real data and deep studies of pathways: 6 targets come out either because they are at the intersection of pathways or because they are critical, obligatory steps to either DNA proliferation or cytokine production.   They are: JNK, P38, ERK, SRF, c-fos, CRE, ELK-1, NLK, oh hell did I say 6...my mistake  but depending on the neoplasia under consideration, the list can be prolonged. 
It will include: Sap1a, NFAT, JUN-D,atf2,p53,GADD53,PRAK,MAX,HSP27/72,PP3C,
GOOD HUNTING!
 SNIFF THE BEST AND TAKE YOUR PICK!  AND GUESS WHAT: THE DEVIL IS NOT VERY FAR (I MEAN THE DVL GENE) !

Interesting genetic concepts

* Immediately post brain trauma,  Blocking DISC1 --- GSK-3 INTERACTION
could affect post traumatic brain disorder.  I wonder if early administration of Cyclosporin can have this effect by affecting the NFAT pathway?

* In small cell, I wonder if the YWHAE and CDK5 should be the focus of our attention?   Definitively looking into the Noonan disease gene since it induces malformation.
Inhibitor of the CDK5 should be the focus since the experience with the Melanoma has brought light on these inhibitors (p16/CDK2A/CDK4)!

* Could Disturbance of DISC1 explain post Radiation syndrome or "chemo-Brain"?
* Could Cyclosporin and various interventions decrease post Radiation encephalopathy?

*Is there a surge in peripheral blood cytokines post Radiation as experienced in Traumatic brain injury? And what cytokine is being observed?

CELLULAR PLAY

I strongly believe the cell has multiple plays to hide from us its intrinsic play when it comes to neoplastic process.  I believe we have the cards and each of us has a hand of cards to play with. I believe we have before us confused facts, we need just to make the next step.  yes we have the basic facts, we just need to read them correctly. We know all the genes, and know most of their main roles.  And we have solid leads...

We know that stress leads to Gastric cancer, and we know the NF-kB is wild at play but so far our examination has been incomplete, and clearly we would benefit by looking at this pathway deliberately and completely since that approach would yield various culprit genes and potential targets to treat the ailment.

We know that in triple negative breast cancer the NF-kB must be implicated with disruption at hormone receptors.  BRCA and its full pathways of co-factors and downstream molecules (ie.BABAM-1, HTATIP and  ETV-6). And now the role of Androgen in luminal form of this cancer, the WISP3 in inflammatory Breast.  All these messages have not resounded in our head enough to excite us to cross the bridge...

We have the "wild genes" CRE,Gerb,Lyn,MyH or MyB, Flyn, Ep300, AR, etc.. Basically we know when things reach here, everything goes!

We know full differentiation requires the NOTCH, and MEK is the door to de-diferentiation (under the NOTCH control of the MAPK through the ADAMS10).  We know Ubiquitination is also under NOTCH influence...But we don't still use fully the Info!

Using the "master integrator" to its full potential too in cancer prevention to dampen Reactive Oxide species and reduce EGFR positive lung cancer in non smokers would be a significant new approach.
All this is on the desk at CRBCM as we start 2014.   Wish us luck, the fight is still ahead.

Looking at an earlier find in Melanoma!

For the longest time in Melanoma therapy, only DTIC and interferon were cited in Melanoma therapy.  Interferon was given in adjuvant setting Mostly and DTIC in Metastatic diseases from Melanoma.             Despite our understanding of the working of Interferon, there no clear biomarker that would predict which melanoma would be more snsitive to Interferon.  Therefore integration of Interferon into new combinations with new Target therapies such as Ipilimumab and Vemurafenib, remains a hot topic of investigation.
Interferons can act on tumor cell through the direct JAK-STAT pathway, but for some other reasons, go through the ISGF/GAS/PE-1/p91 pathways.  The interferon can recruit stimulation of the IRF pathways as well as activating the MHC class I to immunologically block progression in Melanoma.   How this will impact the effects of newly found pathways of Ipilimumab and Vemurafenib is anybody guess and a matter of current trials.  It appears that we now have to play catch-up, since earlier investigations to define predictive biomarkers for interferon/DTIC responses were not timely completed.  Turning and returning a old stone needs once again to be completed!

BURNING QUESTIONS!

1. OH! let me come out and say it!
Don't you believe by now that there is this suspicion that interfering with Iron Receptors could decrease the rate of metastatic disease to the lungs?  Would it be grand to actually prove you could slow down Hepatoma or breast cancers from moving to the lungs by sending an Antibody against Iron receptor?  Let's look closer into the data!  and reconvene in the coming year to get an update!  At the CRBCM, we are working overtime!

2. Could gene interference with EP300 boost anti-VEGF Medication?  It is after all a co-Activator of HIF-1, isn't it?

3. Cataract prevention: what is the standing of the CRYAB gene? What about the RPGRIP-1 gene in retinal damage?

DANCING WITH A GIANT NAMED: "THE SMALL HETERODIMER PARTNER"

There are 25000 genes in human cell approximately or give and/or take they say!
and only 20% are active at one given time they estimate.   But make no mistake about it, the rule of "company you keep" has not been as strong at play as it has in genes!   The Small Heterodimer PARTNER (SHP) really in the thick of it.  See it plays with one of the gene involved with a tissue which, once cancerous, lead to incurable cancer.   SHP interacts with non other than Hepatocyte nuclear factor 4 alpha (HNF4A).  And through this gene, it will reach a "wild gene" called "CREB-binding" which affects in its dealing to close to 50 genes ( Hell! all genes since it it is involved in the "breathing" of the cell!)  This small Heterodimer Partner is a misnomer, it is a GREAT Partner important in the function of all major Hormone from Androgen to Estrogen!  Touch this one, and you will feel the vibe!  If you know What I imply...

ACTIVITY AT CRBCM

ONE COULD NOT STAND THE BEAUTY OF OUR POSTER, WE CAME BACK WITHOUT OUR POSTER ON TRAUMATIC BRAIN INJURY PROJECT, STOLEN AT THE CONFERENCE.
 I GUESS IT IMPRESSED A HECK OUT OF SOMEONE!  STOLEN POSTER, THAT'S JUST IMPRESSIVE AN ACHIEVEMENT FOR ANY POSTER!  LUCKILY, WE STILL HAVE IT ON A MEMORY CHIP!