Wednesday, July 31, 2013

ESTROGENIC RELATED EVENTS ARE STILL POORLY UNDERSTOOD!

In the life of of women, there is no event that has such profound implications than the onset of the reproductive phase! or the reign of Estrogen!   Clearly, there are 3 phases to women's genetic life in our humble view:
Phase I life before Reproductive life
Phase II life during Reproductive life
Phase III life after Reproductive life

And in each phase, only Estrogen and related proteins make a difference by their absence or presence!
During phase I, the gene life is mostly influenced by the presence of the active X gene and "maturing" of all class of HLA genes as exposure to antigens of all kind occurs!

The rise of Estrogen in the second phase, deeply changes class I HLA expression to prepare the female body to receive a "foreign" body of an eventual infant!  Many genes will be suppressed.  And one of the ways they are suppressed is through hyper-Methylation.  To this day, we do not have a sufficient description of the patterns of methylation that occur at this particular time!  Understanding these epigenetic events has turned out to be critical  Just one example that points to the importance of these events, are the high rates of complications with Lupus (and other autoimmune diseases) in women during this second phase.  And remember, most congenital genetic based cancers express themselves during this period of time, that is why we suspect them to be genetic based (first clue in oncology practice)!  i.e.Triple negative Breast cancer in a 30 Year old! Gives you the aha moment!

The retirement of Estrogen in the IIIrd phase induces so much cardiovascular havoc that books have been written about the devastations of menopause!

Describing patterns of epigenetic events in women in each phase is so critical and complicated we simply run away from it!  But now, taking back courage, we are starting to look at it!

IRON LEVEL MAY BE CRITICAL IN NON SMOKER LUNG CANCERS

Antioxidants may bring rage to the fire!
In communities which depend on Beta-carotene producing food staples ( " Foods rich in beta-carotene include orange fruits and vegetables such as apricots, cantaloupes, and carrots, as well as leafy green vegetables such as broccoli,spinach " etc..) and water supplies lacking iron, the combination of plenty antioxidants and iron deficiency could potentially be a problems particularly for women.   Women in these regions are at increased risk of being Iron deficient because of Menses (Versus Men) and therefore could be at higher risk of developing "non smoker" type of lung cancers.
We are trying to look into this issue because a simple Iron monitoring of serum level of iron could reverse the the trend of lung cancer occurrence in these region.  We should confess that Zinc level could have an impact as it goes hand in hand with Iron level as demonstrated in many studies.

Scientific basis of this suspicion
======================


"Recent studies have shed light on the mechanisms of hypoxia-driven stabilization of HIF-1α protein. Under normal oxygen tension, HIF-1α protein is hydroxylated on two proline residues by a family of oxygen-dependent prolyl hydroxylases (PHD1–3), and the modified HIF-1α becomes a substrate for polyubiquitination by a protein complex containing von Hippel-Lindau proteins (pVHL) and is thus targeted for degradation [1]. The enzymatic activities of PHD proteins are sensitive to oxygen availability. Under low-oxygen conditions, PHD proteins are unable to modify the HIF-1α protein, keeping HIF-1α protein unhydroxylated and allowing it to escape pVHL recognition and subsequent degradation, resulting in the triggering of the hypoxia responses [2]. HIF-1α protein is usually degraded under normal oxygen concentrations (normoxia), but in hypoxic conditions or in the presence of iron chelators, the degradation rate decreases, and HIF-1α protein accumulates and associates with HIF-1β to form a functional transcription complex, triggering the transcription of a host of hypoxia-inducible genes.
HIF-1α protein stabilization, however, is not limited to hypoxic conditions, and the so-called hypoxia responses can occur even with an adequate oxygen supply. This oxygen tension-independent hypoxia response can result from a wide range of possible genetic alterations and signaling malfunctions, including loss of VHL [3], p53 [4], or PTEN (a phosphatidylinositol trisphosphate lipid phosphatase) [5]; or activation of phosphatidylinositol 3-kinase/Akt [6] or Src pathways [7]. Hypoxia-independent HIF-1α protein stabilization is seen in patients with von Hippel-Lindau disease, a genetic disease in which one copy of the VHL gene is either inactivated or deleted. In these patients, when the remaining normal copy of the VHL gene is lost or inactivated, the HIF transcriptional complexes stay constitutively active, even under normal oxygen concentrations, due to faulty, pVHL-dependent degradation pathways. This dysregulated hypoxia pathway is a key factor in the development of multiple neoplasms in patients with von Hippel-Lindau disease [8]. CHI et al!"

You read correctly, in the "presence of iron Chelators" means iron deficiency.
And Iron deficiency is again worse in women who have menses !  The length of exposure to menses is increased in communities with "one child policy" since natural amenorrhea associated with child bearing  is minimal in these society presumably.  Rates of abortions may also play into the amount of iron deficiency in women in these regions.  Length of the iron deficiency state and prolong exposure to antioxidants appear critical.  So, iron deficiency will "protect" HIF-1 alpha protein from Ubiquitin dependent degradation and drive its association with HIF-1beta leading to stimulation or activation of transcription factors, MAPK pathways, and dangerous heterogeneic types of genes in the families of  Rho, and Src.  The direct involvement of the Estrogen cannot be discounted since Estrogen Receptors have been found activated in lung cancer tissue!  Again give weight to the observation that it is indeed non smoker women are indeed the target of this disease.


FURTHER SUPPORTIVE EVIDENCES

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

The role of VEGF and EGFR inhibition: implications for combining anti-VEGF and anti-EGFR agents.

Source

Medical Oncology Service, Vall d'Hebron University Hospital, P. Vall d'Hebron, 119-129, 08035 Barcelona, Spain. jtabernero@vhebron.net

Abstract

Multiple cellular pathways influence the growth and metastatic potential of tumors. This creates heterogeneity, redundancy, and the potential for tumors to bypass signaling pathway blockade, resulting in primary or acquired resistance. Combining therapies that inhibit different signaling pathways has the potential to be more effective than inhibition of a single pathway and to overcome tumor resistance. Vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) inhibitors have become key therapies in several tumor types. Close relationships between these factors exist: VEGF signaling is up-regulated by EGFR expression and, conversely, VEGF up-regulation independent of EGFR signaling seems to contribute to resistance to EGFR inhibition. Therefore, inhibition of both pathways could improve antitumor efficacy and overcome resistance to EGFR inhibition. Preclinical studies have shown that VEGF and EGFR inhibitors can have additive effects and that combined inhibition is effective in EGFR inhibitor-resistant cell lines. Clinical trials have also produced promising data: combining the anti-VEGF monoclonal antibody bevacizumab with the anti-EGFR antibody cetuximab or the EGFR tyrosine kinase inhibitor erlotinib increases benefit compared with either of these anti-EGFR agents alone or combined with chemotherapy. The potential of this novel approach to anticancer therapy will be elucidated by large, ongoing clinical trials.


Effect of iron supplementation on oxidative stress and antioxidant status in iron-deficiency anemia.

Source

Department of Hematology, Medical School, Selcuk University, Konya, Turkey.

Abstract

The role of VEGF and EGFR inhibition: implications for combining anti-VEGF and anti-EGFR agents.

Source

Medical Oncology Service, Vall d'Hebron University Hospital, P. Vall d'Hebron, 119-129, 08035 Barcelona, Spain. jtabernero@vhebron.net

Abstract

Multiple cellular pathways influence the growth and metastatic potential of tumors. This creates heterogeneity, redundancy, and the potential for tumors to bypass signaling pathway blockade, resulting in primary or acquired resistance. Combining therapies that inhibit different signaling pathways has the potential to be more effective than inhibition of a single pathway and to overcome tumor resistance. Vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) inhibitors have become key therapies in several tumor types. Close relationships between these factors exist: VEGF signaling is up-regulated by EGFR expression and, conversely, VEGF up-regulation independent of EGFR signaling seems to contribute to resistance to EGFR inhibition. Therefore, inhibition of both pathways could improve antitumor efficacy and overcome resistance to EGFR inhibition. Preclinical studies have shown that VEGF and EGFR inhibitors can have additive effects and that combined inhibition is effective in EGFR inhibitor-resistant cell lines. Clinical trials have also produced promising data: combining the anti-VEGF monoclonal antibody bevacizumab with the anti-EGFR antibody cetuximab or the EGFR tyrosine kinase inhibitor erlotinib increases benefit compared with either of these anti-EGFR agents alone or combined with chemotherapy. The potential of this novel approach to anticancer therapy will be elucidated by large, ongoing clinical trials.

. No significant differences existed between treated patients at 6 wk and at the end of the study. The erythrocyte levels of catalase, SOD, and GSH-Px were significantly lower in treated patients relative to controls (p<0.05). These levels increased after 6 wk of supplementation (p<0.05) and showed no significant differences with those at the end of the study.

AND WE THANK RESEARCHERS QUOTED HERE FOR THEIR CONTRIBUTIONS!


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

 CLEARLY IT DOES NOT TAKE A GENIUS TO SEE THE POTENTIAL THREAD OF ASSOCIATION
Iron deficiency (and possibly Zinc amount or serum levels) could have a role.  Remember Sirtuins and Butein uses in these regions are also increased. Src and related membrane located molecules have special sites of attachment for Iron.  And level of iron affect deeply these molecule.  The gene activator Erythropoietin is indeed here also!

one of the gene activated is VEGF which a complicated dance with EGFR.  In some conditions, VEGF inhibits EGFR, in other it drive the activation of EGFR.  And EGFR expression is peculiar in this disease, so much so that it would be illegal no to consider anti -EGFR as first line treatment in this disease!
=================================
NO MATTER THE STRENGTH OF THESE ASSERTIONS, PROOF OF CONCEPT IS NEEDED
REMEMBER A SIMPLE INTERVENTION COULD MAKE SO MUCH DIFFERENCE IN THE LIFE OF MANY!
SUPPORT RESEARCH AT CRBCM, CALL 915-307-3354 AND DONATE!
THE CRBCM IS A NON PROFIT ORGANIZATION RECOGNIZED BY THE IRS!

CAN YOU BEAT 100% IN LYMPHOMA MANAGEMENT?


Ibrutinib/R-CHOP Combination Achieves 100% Response Rate in Non-Hodgkin Lymphoma

Read more >>




Ganetespib-Docetaxel Combination Improves Survival in GALAXY-1 Trial

Read more >>




Proteins Identified as Potential Biomarkers for Response in KRAS-Mutated NSCLC


go to targeted healthcare communications for more!
targetedHC.

STRONG PROPOSED COLLABORATION WITH THE UNIVERSITY OF TEXAS AT EL PASO (UTEP).

PROGRESS AT CRBCM

Dear Dr. Kankonde,

It was nice meeting with you and Peggy!

Please see the attached proposal draft. If you have any comments or suggestions, please let me know.

Best regards,

Jianying Zhang, M.D., Ph.D.

Associate Professor
Department of Biological Sciences
The University of Texas at El Paso
500 West University Avenue
El Paso, Texas 79968
Tel: 915-747-6995 (office); 915-747-5343/5183 (lab)
===================================================

With the University lending its hands and laboratory support, the CRBCM has entered the serious phase of research production.  We will embark on a lung cancer project which was funded partially by MDHonors as previously disclosed.
The laboratory support work will be completed by 
 .DR CHAI YURONG, a visiting scholar from ZHENGZHOU UNIVERSITY IN CHINA.

The CRBCM family would like to take this opportunity to congratulate publicly Professor Jiang Zhang who was made FULL PROFESSOR this month at UTEP.   We thank him for his work!

The CRBCM, working with only the best!

OF NOTE, WE THANK THE EL PASO DEPARTMENT OF HEALTH FOR RECOMMENDING US TO PROFESSOR ZHANG!

Monday, July 29, 2013

CRBCM at the Health Fair of Foundation Surgical Hospital in El Paso

Recruiting volunteers for the National Cancer 3 Study aged between 30 and 65 who have not had a diagnosis of cancer: We are knocking out cancer !
The response was tremendous, the majority of the visitors of the CRBCM's booth took the pledge to participate in the study and to help better understand and better fight cancer, and to finally help put EL PASO back on the map of Cancer research and request funding in proportion of the population and its real and yet chronically unmet needs which are huge!







BREAKING THROUGH: ANTIOXIDANTS MAY BE DANGEROUS IN A SETTING OF IRON DEFICIENCY: THE LUNG CANCER STORY

 AT ISSUE: LUNG CANCER IN NON SMOKER, PROMINENT IN WOMEN

According to
"Overall, 10-15% of lung cancers occur in non-smokers. (Another 50% occur in former smokers.)
Two-thirds of the non-smokers who get lung cancer are women, and 20% of lung cancers in women occur in individuals who have never smoked. This percentage is significantly higher in Asian women."
--------------------------------
Now,  the inferences to this statement are:
1. That there is something peculiar in women, particularly of Asian origin, that predispose them to this Cancer.  And what we know about women in general is that they have more Estrogen than men.  And that, in general women tend to be more Iron deficient because of their Menses!  The one child policy increases Estrogen fluctuation exposure and prolonged menses period, and therefore the likelihood of iron deficiency!

2. Asian women are known for their good diet full of Anti-oxidants  (Nuts, Green tea, etc.), and their Beta-carotene based nutrition (Pumpkins, carots, apricots ) exposing them to increased amounts of Vitamin A.

3. "10-15% of lung cancers in non smokers" means in the United States alone where there will be 222,520 new cases, we are talking about 30,000 new cases of lung cancers in non smokers who are  somewhat involved by this hypothetical discussion.

4. WHO: "recent studies have shown that the intakes of Calcium Zinc Magnesium, Potassium and other essential minerals were insufficient and are a traditional problem in the chinese diet" Chen J Gao et al.
This implicates Zinc deficiency which has  documented interactions with Iron.  This implicates the water supply as a poor source of Iron or Zinc for that matter.  WHO has not proposed any guideline values for Iron in drinking water.  "The average iron value in water supplies across Hong Kong is very low (2.2 millions families are affected by this deficiency"(Fox Yi hu)

5. "Beta-carotene supplementation was associated with an increased risk of lung cancer among high risk populations of heavy smokers in 2 out of 3 clinical trials" (David Gerber et al!)

THERE WAS NO OBSERVATION LOOKING AT THE SERUM LEVEL OF IRON OR ZINC IN THE EVALUATION OF THIS RISK!




Saturday, July 27, 2013

ACTIVITY AT THE CRBCM

Good Morning every one, we have completed 2 weeks of work in Fort Wayne IN conducting field work.  Very successful Mission which keeps the CRBCM funded for future endeavors!  We are returning to El Paso for a very active work load.  From Covering Local Hospitals to participating to Community Activity at Physician Hospital of El Paso. (We will put up some Pics when they become available).
This week we will meet again with UTEP staff in order to further reaffirm details of our collaboration on our specific Research program.  The CRBCM will also visit one of the 4 Grifols' Plasma Centers. Work at the Greater East cancer Center also awaits attention.
The CRBCM has been working on several projects which need finalization.
Attending an important Oncology Conference in Miami will help obtain further questions to be explored in our blog.  Contractual agreements limit some disclosures.
Keeping busy, legal and efficient will be the focus at CRBM.

Friday, July 26, 2013

EPIGENETIC PHENOMENA ARE CRITICAL IN GENE EXPRESSION...
It is now clear that the DNA expression is clearly an important parameter in the destiny of the cell, be it normal or cancerous, the cell destiny is determined by its potential forces built in its DNA.  But as the cell live, there are phenotypic influences imposed by postranslational modifications brought on by epigenetic events which ultimately shape further DNA expression.
These events have been described by others
and include:
1.Histones Modification
2.DNA Methylation or lack of!(Hypomethylation)
3."Nucleosome positioning"
4,Activity of MicroRNA
5.Gene to Gene suppression of expression
we will discuss each as it is pertinent.
But please don't believe that this all.  Indeed:
1.Abnormal Splicing (Frame shift)
2.Point Mutations
3.Disabling of DNA repair
4.Gene cross-talking
5.Enzyme deficiency and
6. Alteration of Homeobox Molecule and arrangements therein ...
WILL ALL AFFECT DNA EXPRESSION AND POTENTIALLY BE A DRIVING FORCE TO ABNORMALITY IN THE CELL!


With lack of signs of life at CPRIT,
the Burnt Orange report is news! and juicy (I meant spicy!)

Greg Abbott, CPRIT, And Favors for Friends


by: Lone Star Project

Mon Jul 22, 2013 at 07:17 PM CDT


(Thanks to the Lone Star Project for helping to shine a light on the connections between Abbott and CPRIT.   - promoted by Katherine Haenschen)

(Originally posted at the Lone Star Project)
For voters, it seemed to make sense for the State Attorney General, our top civil law enforcement official, to sit on the board of the newly created Cancer Research Institute of Texas (CPRIT). The promise of new and innovative treatments for cancer was clearly a worthwhile state expenditure, but accountability would be needed. With millions of tax dollars flowing through the agency to private companies, a State official with law enforcement responsibilities diligently conducting oversight would deter improper activity and, if improprieties occurred, could move quickly to investigate and prosecute.

So much for reasonable expectations. It turns out that Texas AG Greg Abbott sitting on the oversight board was a green light rather than a caution sign to many of these key donors. Businesses backed by Abbott contributors - many of whom are partisan Republicans - have received large grants and contracts from CPRIT without fear of any oversight at all.
 (
Read more below the jump.  (please go to the full damaging report)

====================YOU CANNOT LEAD FROM BEHIND!  YOU CAN NOT CONTROL WHAT IS SAID BY HIDING! MEET THE CHALLENGE RIGHT IN FRONT!

Thursday, July 25, 2013

AS OF JULY 25TH, 2013/ VISITORS AT CRBCM


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AS OF JULY 25TH 2013

EntryPageviews
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14874
Russia
1882
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1120
France
417
United Kingdom
385
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278
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244
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144
Sweden
92
Taiwan
80

NEW TARGET THERAPY AT THE HORIZON

When a cell becomes cancerous, one of the thing to ensure survival is to multiply and move away from the original site to find food and ensure to escape immune surveillance. Indeed a localized cell will end-up being reported as it changes its receptors and membrane proteins.  Its neighbors will tell on it as it will escape the consensus required and set in place by the NOTCH.  But a normal cell is well specialized in order to participate to the Notch controlled function of the tissue to which it belongs.  A cell in the liver, will be differentiated to do liver function.  and the more a cell differentiate, the less it can multiply.  For the cell that is now cancerous, one of the way to recuperate its multiplication potential is to de-differentiate, lose the differentiation, becoming more totipotential.   It is known that forcing leukemic cell for example into full differentiation, will control the disease.

The finding that an epigenetic phenomena can return totipotentiality to the cell marks a significant discovery
XU et al :" that expression of microRNA-145 (miR-145) is low in self-renewing human embryonic stem cells (hESCs) but highly upregulated during differentiation. We identify the pluripotency factors OCT4, SOX2, and KLF4 as direct targets of miR-145 and show that endogenous miR-145 represses the 3' untranslated regions of OCT4, SOX2, and KLF4." "Yamanaka factors (Oct3/4, Sox2, Klf4, c-Myc) are highly expressed in embryonic stem (ES) cells,"LIU ET AL
This means cancer cell have to suppress mi-145 to recoup self renewal...this is a powerful pathways that need to be absolutely tampered with particularly in hematologic malignancies!

GET BACK TO WORK WITH THE CRBCM!  PROOF OF CONCEPT NEEDED!
The CRBCM is proud to announce that work funded BY MDHonors is taking shape.  Our consultation and collaborative setting with UTEP is in place.  The CRBCM  is encouraged by the mighty help it will get from DR Prof Zhang on this work.  We thank also the University of Virginia Tissue Bank for all its help.  Work is before us.  Let's go for it!

Osegueda, Roberto A.
12:54 PM (5 hours ago)

to me, Renato, Robert, Jianying
Jul25Thu
Lung Cancer Research w/ Dr. Zhang
WhenThu Jul 25, 2013 3:30pm – 4:30pm (MDT)
WhereDr. Oseguedas Office
WhoZhang, Jianying, Aguilera, Renato, Kirken, Robert, osegueda@utep.edu*

Yes

Maybe
No

When: Thursday, July 25, 2013 3:30 PM-4:30 PM (UTC-07:00) Mountain Time (US & Canada).

Where: Dr. Oseguedas Office
Note: The GMT offset above does not reflect daylight saving time adjustments.
*~*~*~*~*~*~*~*~*~*
Dear All,
Dr. Osegueda and Dr. Zhang will be meeting with Peggy today. 
Dr. Aguilera, they will be meeting without you today.
Thank you,
Ana
=================================
A FOLLOW-UP MEETING IS SCHEDULED FOR THIS COMING TUESDAY
THE CRBCM IS UPBEAT, WE ARE IN PLAY...
THERE IS A BUZZ OF EXCITEMENT
DOORS ARE OPENING 
Folic Acid

It is said to increase Methylation of Homocystein,  what can it also methylate particularly taken at higher doses!  Can it impact significantly epigenetic events?

The Notch once again!

"Migraine with Aura often precede the strokes by several years.The responsible gene on chromosome 19 results in Mutations of the Notch3 Receptor protein."...(Zivin)

DON'T FIX IT IF IT IS NOT BROKEN

An 84 year man saw on TV an advertising about a new molecule in the nutritional supplement  (not FDA approved).  The molecule was said to "bust" blood clot and unclog circulation.  He figured that this new medicine must be better then Aspirin he was taking for clotting prevention.   He stopped Aspirin, and while waiting for the new drug, he developed a stroke.  The new medication failed to reverse the stroke induce hemiplegia....lesson to learn from...better prevent things, and keep on doing what works!


Wednesday, July 24, 2013

CRBCM, moving mountains

We were right not to give up.  We seem to have a match.  The University of Texas at El Paso seems to have finally responded...It appears they will work with us on the Research project. Now watch our enemies go to work to stop progress.  The CRBCM is advancing ever since we understood we can not lead from behind!  We have found the right match, progress is with us, on our side.

Still in Fort Wayne Indianna for another CRBCM contract, will be back in El Paso this week-end.   Then will prepare a trip for Miami...The CRBCM, Advancing in the face of adversity but building collaboration all the way...CRBCM, an engine of progress toward the cure ...  We submitted new conceptual research projects for review today...breaking new ways in a path of stone...

FORCES AGAINST PROGRESS TO THE CURE

We continue to maintain that political forces are the best ally to cancer,
to search for and reach the  cure, one needs support, financial resources, and political muscles.  And none of these involve the actual research that will be needed to reach the cure.  The CRBCM was close to obtaining the PCR machine that would have put us as an independent contender in the race for the cure of cancer.  But political forces worked in the dark to stop the acquisition.  Indeed we did not know that the who's who we were dealing with WERE CONNECTED TO OUR COMPETITORS...suffice is to say that phone calls and meetings in the dark of the night occurred and the plug has been pulled on this acquisition...the CRBCM has lived another setback in this political world and our intended research received another setback...cancer in the meanwhile is still killing...but we are a Coalition and the fight continues...
After a fall, stand up to fight yet another day...people would rather keep a valuable instrument (PCR machine) bought with public money in a closet unused rather than lending it to CRBCM.  In the closet, with no use, it is rotting and soon will become obsolete...  but that what happen in a small world full of politics!
The CRBCM meanwhile continues its road because we believe our cause is just...and we will not fail in our commitment to realize our mission.  The CRBCM is a mission driven company...will continue our path until our enemies become irrelevant...

Monday, July 22, 2013

PROGRESS IN TARGETING THERAPY IN UVEAL MELANOMA

ADDING  INTERFERON WOULD MAKE MORE SENSE THAN ADDING AVASTIN TO SIROLIMUS IN UVEAL MELANOMA.

Uveal Melanoma has been now extensively studied and has been associated in up to 50% of cases, to GNAQ/GNA11 genes, these is basically a G-protein, a switch that stays on in patient amplifying permanently the MAPK pathways, and therefore the MTOR.  This fact amplifies the role of MTOR inhibitors in this disease's treatment.
Although Avastin could have a role by involving another target, it seems that intervening at epigenic level by using Dasatinib or by using a known effective agent such as interferon would add more.  The caveat here is that epigenic intervention could tamper with MTOR expression proper and Mitigate the role of its inhibitor.  Suffice is to say that intervention at epigenic level could prove additive to MTOR inhibitors.   It is still to be established whether purified Hamartin, a derivative from TCS1 gene (in combination or not with Tuberin-TSC2) may prove  synergestic to MTOR inhibitors...

Saturday, July 20, 2013

Transplant

Hematopoietic stem cell transplantation (HSCT) is the transplantation of multipotent hematopoietic stem cells, usually derived from bone marrow, peripheral blood, or umbilical cord blood. It is a medical procedure in the fields of hematology and oncology, most often performed for patients with certain cancers of the blood or bone marrow, such as multiple myeloma or leukemia. In these cases, the recipient's immune system is usually destroyed with radiation or chemotherapy before the transplantation. Infection and graft-versus-host disease is a major complication of allogenic HSCT.
Hematopoietic stem cell transplantation remains a dangerous procedure with many possible complications; it is reserved for patients with life-threatening diseases. As the survival of the procedure increases, its use has expanded beyond cancer, such as autoimmune diseases.[1][2] wikipedia
==================================================================

Around the World over 50,000 Bone marrow transplants occur now each year.  Bringing cure to many lives.  When it is allogeneic, the graft-versus tumor effect prolongs the cancer killing...yielding better cure rates, sometime at the risk of graft versus host disease that requires careful management.  In most leukemia, Allogeneic transplant is the only curative option (CML).  Transplant can also restore immuno-deficiency in congenital syndromes such as the Wiskott-Aldrich Syndrome and the severe combined deficiency-immunodeficiency syndrome.
When the risk is reasonable, transplant has been indicated to:
1.Restore defectuous Red Blood Cells (Aplastic Anemias, Thalassemias,
2.Restore deficient enzymatic and metabolic diseases (Gaucher disease)
3.fight malignancies by allowing to use high doses of both Radiation and chemotherapy when Marrow rescue is assured.

Bone marrow Transplantation leads to 5 year survival of 50 to 70% when used in first remission of AML, and ALL.  This result is better than the best conventional chemotherapy.  It is therefore standard of care in the United States.  In Non Hodgkin Lymphoma, transplantation is most indicated when there is evidence of Marrow involvement.

Autologous transplantation is primarily used with Myeloma in the United States, although it is also used in
1.Non Hodgkin lymphoma and in recurrent germ cell cancers (Testicular) and in Neuroblastoma,
2.Myeloma.
3. but also AML and ALL.

Depletion of T cell in the marrow is used decrease graft-Vesus Host effect in allogeneic BM transplantation, while the use of Automated direct sequencing allow the discovery of more secondary HLA mismatch which improves unrelated donor selection.

Tumor contamination and lack of GVHD makes autologous transplant less effective.  Researchers are looking to better detect contamination and may be develop eradication methods to improve results of Autologous transplant!

Relapse after transplant can respond to
1.Cessation of immuno-suppressant if it was on them in Hematologic cancers
2.Reinfusionn of donor lymphocytes (often after reinduction chemotherapy)
3.Reduce-intensity allogeneic retreatment
4.or 2nd full transplant if the progression free survival was over a year
5.some new target therapy!

GVHD, Veno-Occlusive Hepatic disease and infections plague transplantation, particularly the allogeneic type, makes this procedure risky !  (read also Frederic Appelbaum)

(The CRBCM is in the process of acquiring a PCR  light Cycler...research will advance at CRBCM)

JUST A LITTLE PEARL!

We eat sugar to grow and get energy.  Energy production occurs within the cell. How do sugars get into the cell? Mostly through a door opens and that one guy called "insulin" !  For insulin to work, it has to attach to a Receptor called "Insulin receptor".  If enough sugar has entered and the cell has used the sugar it needs, it figures that we need to have an energy reserve, and makes fat for energy reserve.  While doing the build up of fat, it also figures that we do not need so many doors for insulin to bring in more sugar...so it closes some doors or better, removes some of these insulin receptors (desensitization).  The end result is that outside the cell, there is a relatively high number of Insulin  Molecules.  Well, without their regular doors/receptors the Insulin starts looking for other receptors to stimulate, and stimulation will occur at doors that look like Insulin, which unfortunately, once stimulated will go downstream and stimulate MAPK AND STRESS LIKE c-JUN/fos LEADING TO INCREASED CYTOKINES  with Interferons and interleukins leading to diseases caused by Obesity!   That's how a simple fact gets rapidly complicated at the cellular level!
THIS MAKES OBESITY A CONDITION OF PROFOUND ENDOCRINE AND CYTOKINE DISTURBANCES! A TRUE DISEASE STATE!
THE POWER OF THE NOTCH PATHWAYS IS IN ITS INTRINSIC RELATION WITH THE WNT PATHWAYS.

Globally, the most powerful pathways in the cell, the Wnt and the Notch pathways, control the most important functions in the cell from cell differentiation and tissue formation and delineation, to commitment to the assigned function (Notch).  The Wnt completes the differentiation by directing the differentiation to its appropriate place through cell adhesion manipulation and migration.  But this influence of the 2 pathways does not stop there !  The Notch interacts with ADAMS 10, 17 liberating Metalloproteases while disintegrins act or are  Cyclins (including Cyclin D1) with known impact on cell division while Metalloproteases helps in cell migration but could also initiate inflammatory processes as well as attack unprepared cells (cells without a relevant inhibitor of those specific Metalloproteases).  Portions of the transmembrane proteins belonging to the Notch, once lysed by SECRETASES are quickly transported to the nucleus where they induce transcription factor production.  The effect does not stop here Notch and Wnt affect Sodium channel, calcium dependent function, Immunoglobulin and their receptors (IgCAM), and totipotentiality of cells.   Stem cells would not be without these pathways.  In fact, Teratoma is an expression of significant disturbances of these 2 gene pathways!
One other poorly understood or underestimated functions, is the "cellular consensus" function which not only commits to a specific life of tissue...but also to death, or time to die.  You can stay alive even hidden underground, or you can stay irreversibly dead even hooked to supportive machines...if the Notch and Wnt say so!

DO NOT MINIMIZE THE ROLE OF SECRETASES MENTIONED HERE, THEY ARE AT THE SOURCE OF ALZHEIMER DEMENTIA...MORE IS TO COME ABOUT THESE SECRETASES AS THEIR INHIBITION IS BEING OFFERED AS A TREATMENT STRATEGY!

Thursday, July 18, 2013

WHAT DO WE LEARN FROM AGING /the future of medical practice!

Our knowledge has been increasing at a rapid pace, and day after day, we are increasingly convinced that medicine practiced today will not be practiced in the future.  Most of our current recommendations leading medical practices will be modified if not abandoned.  There is a lot of ignorance still going around and most likely some of our conclusions are either short sighted or clearly wrong.
Some of the major potential areas of Mistakes:

1.We ignore the fact that our current major tested parameters are related to a corrected physiology:  we check a normal calcium in the blood, sometimes ignoring that this normal in the blood is achieved by an increase in PTH such as in secondary parathyroidism.  We know well that a persistent elevation of PTH means bone stability is impaired.  In this case, the normal Calcium is not a status of health.

2. We tend to ignore some evidences because we do not know what to do about them:  It is known for quite sometime now that aging is related to high levels of growth factors and Cytokines." THE LEVELS OF INFLAMMATORY CYTOKINES INTERLEUKIN-6, IL-1 BETA, C-REACTIVE PROTEIN, TGF-beta ALL INCREASE WITH AGE" (MORTIMER )." Yet we do not intervene despite our current means!  No elderly comes out of his or her Docteur's office with a level of Cytokine or Metalloproteases for that matter.
We have a consensus that obesity is a disease, but no patient comes out yet with IGF levels.  Metformin is good for you, but so far no indications as to what BMI needs to prompt metformin prescription (and at what age: 30 when the decline is reportedly starting?  What level of IGF Receptor desensitization is critical in cancer development, how to measure this?

3. We are at the wee hours of pathway amplification or repression measurements.  Is it the length of exposure, or a critical level of influence on pathways that starts a neoplastic process?  Or is it a sense of cellular polarity? Is it the mere level of cytokines or is it a ratio that is important (ie. IL-6/IL2  or IL12/IL-4) ? This is where the future will be...

4.  What kills post synaptic neurons after a stroke? Cytokines!  Do we do something to stop it? not yet!

5. We know the Wnt and the Notch are critical in the determination of our survival, but how do we know to actually measure this?

6. We know Interferon 1 dysregulates our immune system, insurance will not let measure this but in the future of course, this will be routine!

7. Telomere length...routine

The routine lab test chart will be completely different from the current CBC and CMP.  What is the state of your thymus by the way?  These are the kinds of information that will be routine then!

Add to it the types of virus that have invaded your genome chart and you know the feeling!  Medicine has more room to advance for the benefit of our patients!

Echinacea

Echinacea

 from Wikipedia

"The immunomodulatory effects of echinacea preparations are likely caused by fat-soluble alkylamides (alkamides), which occur mostly in E. angustifolia and E. purpurea but not in E. pallida.[22] Alkylamides bind particularly to human CB2 and to a much lesser degree to CB1 cannabinoid receptors; as a result they are implicated in a variety of modulatory functions, including immune suppression, induction of apoptosis, cell migration and inhibition of tumor necrosis factor α TNF-alpha[23] These Alkylamides have similar potency to that of THC at the CB2 receptor, with THC being around 1.5 times stronger (~40 nm vs ~60 nm affinities). However, potency is dramatically less than that of THC at the psychoactive CB1 receptor (~40 nm vs ~ >1500 nm affinities).
As with any herbal preparation, individual doses may vary significantly in active chemical composition. In addition to poor process control which may affect inter- and intra-batch homogeneity, species, plant part, extraction method, and contamination or adulteration with other products all lead to variability between products.[24][25]"
 Echinacea extracts inhibited growth of three species of trypanosomatids: Leishmania donovani, Leishmania major, and Trypanosoma brucei.[35]
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Like the CB1 receptors, CB2 receptors inhibit the activity of adenylyl cyclase through their Gi/Goα subunits.[9][10] Through their Gβγ subunits, CB2 receptors are also known to be coupled to the MAPK-ERK pathway,[9][10][11] a complex and highly conserved signal transduction pathway, which critically regulates a number of important cellular processes in both mature and developing tissues.[12] Activation of the MAPK-ERK pathway by CB2 receptor agonists acting through the Gβγ subunit ultimately results in changes in cell migration[13] as well as in an induction of the growth-related gene Zif268 (also known as Krox-24, NGFI-A, and egr-1).[11] The Zifi268 gene encodes a transcriptional regulator implicated in neuroplasticity and long term memory formation.[14]
At present, there are five recognized cannabinoids produced endogenously throughout the body: Arachidonoylethanolamine (anandamide), 2-arachidonoyl glycerol (2-AG), 2-arachidonyl glyceryl ether (noladin ether), virodhamine,[9] as well as the recently-discovered N-arachidonoyl-dopamine (NADA).[15] Many of these ligands appear to exhibit properties of functional selectivity at the CB2 receptor: 2-AG preferentially activates the MAPK-ERK pathway, while noladin preferentially inhibits adenylyl cyclase.[9] Like noladin, the synthetic ligand CP-55,940 has also been shown to preferentially inhibit adenylyl cyclase in CB2 receptors.[9] Together, these results support the emerging concept of agonist-directed trafficking at the cannabinoid receptors." wikipedia
===============================comments to follow!

More studies needed for Barrett Esophagus!

BARRET ESOPHAGUS
*Characterized by a Metaplastic epithelium
*Risk factors include "GERD, white, Hispanic race,male sex, advancing age, smoking and obesity"
*Although low grade is still associated with cancer, preventive resection is indicated only in high grade dysplasia, the other needs to be observed!? go figure.  Likely enough P53 Mutation presence will force the hand of the surgeon no matter the level of dysplasia!
* It is still unlear if medical management of GERD decreases occurrence of malignancy!? and 10-20% of symptomatic GERD have Barrett Esophagus (scoped population)
*One thing for sure HPV is more associated with the Squamous kind of Esophageal cancers!

Wednesday, July 17, 2013

Notions on Cervical cancers: Push for Immunization

NOTIONS ON CERVICAL CANCERS

Cervical cancers provide an opportunity for researchers to explore the pathophysiology of cellular interaction with a virus, and is a good example as to how a virus could lead to Cancer, and how, with a vaccine, one can eradicate or at least influence the prevalence of diseases including a specific cancer.  World wide, 1 million people have cervical cancer and almost half that number will die of Cervical cancer.  This point to an aggressive disease as compared to prostate cancer for example.  The HPV related Cervical cancer is sexually transmitted, and in the United state up to 45% of women 25-29 year of age have tested positive in a particular study.   There are over 100 types of HPV with the 16, 18 serotypes  being the most cited as particularly prevalent.  Their  E6, E7 genes has been shown to incorporate themselves in Cervical cell genome.  Other factors of causal nature include Smoking (which increases the risk of dysplastic changes at the Cervix), short interval between Coitarhe and Menarche, multiple sexual partners etc...Clearly use of condoms decreases exposure.  Immunization is recommended for girls 9-26 years of age.  Quadrivalent Vaccine has been advocated for boys to decrease frequency of Genital Warts and Anal cancers!

to be continued!   NOW THE QUESTION IS SHOULD A BOOSTER SHOT BE ADVISED TO INCREASE COMPLIANCE?

Tuesday, July 16, 2013

ALL THE GOOD REASONS FOR A CANCER SURVIVOR PROGRAM!

Cancer: The Newest Chronic Disease (FROM MEDSCAPE)


Hello. I'm Dr. Sandra Fryhofer. Welcome to Medicine Matters.
The topic: achieving high-quality cancer survivorship care and the American Society of Clinical Oncology's (ASCO®) new blueprint for improving care for cancer survivors, published in the Journal of Clinical Oncology.[1] Here's why it matters.
More and more patients are living with cancer and they're living longer. Right now, more than 13.5 million people are cancer survivors. The 3 most prevalent cancers for men are prostate, colorectal, and melanoma; for women they are breast, uterine, and colorectal cancers.[2]
Review summaries of articles on clinical issues in Type 1 Gaucher disease and gain understanding of patient concerns.
Information from Industry
Over the next 10 years, by 2022, the number of cancer survivors is expected to increase to nearly 18 million.[2] The Centers for Disease Control and Prevention (CDC) points out that about two thirds of people with cancer are expected to live at least 5 years after diagnosis.[3] These are patients who have had cancer and they've survived it. They've completed cancer treatments and now need continued follow-up care for cancer and other chronic diseases. ASCO has issued a new set of recommendations to help improve this care and to keep cancer survivors from falling through the cracks. Achieving this goal will require enhanced communication and coordination of care.
First, ASCO wants cancer to be considered a chronic disease. This is because the Affordable Care Act calls for Accountable Care Organizations (ACOs) and patient-centered medical homes to promote coordinated care for chronic diseases. Calling cancer survival a chronic disease would promote patient-centered coordinated care based on shared care models and would enhance collaboration.
Section 1 of 2

where is CPRIT!

CRBCM is still looking for signs  of life at CPRIT!  we will advise our partnes as soon as we learn!
will send a camera to Houston/Austin.
all we could find in the media is this interesting statement:

" What I found particularly interesting, however, is how, in spite of a really nasty, disillusioning scandal like CPIRT having a largely happy ending for Texas taxpayers — the reformers got everything they wanted, from considerably more transparency to radical changes to avoid conflicts of interest — the Texas media largely downplayed Governor Perry’s signing of the bill. In this way, a scandal that started with an indignant outcry from the media and Texas residents ended as a footnote." (Bionews-tex).

A camera has been sent to record if indeed people are still at work!  Silence is just too heavy!  The involved journalists are just as silent!

Lymphoepithelioma

From Wikipedia, the free encyclopedia
Jump to: navigation, search
Lymphoepithelioma
Classification and external resources

Nasopharyngeal lymphoepithelioma in a lymph node. Note the small, blue lymphocytes between the larger cancer cells.
ICD-O: M8082/3
For more information on this topic, see Nasopharyngeal carcinoma
Lymphoepithelioma is a type of poorly differentiated nasopharyngeal carcinoma characterized by prominent infiltration of lymphocytes in the area involved by tumor. Lymphoepithelioma is also known as "class III nasopharyngeal carcinoma" in the WHO classification system. It has a high tendency to metastasize and is responsive to radiotherapy. Most cases are associated with Epstein-Barr virus infection.[1]
Lymphoepithelioma may also be referred to as Schmincke-Regaud tumor, after the German pathologist Alexander Schminke and French radiologist Claude Regaud.
Lymphoepithelioma-like carcinomas are carcinomas that arise outside of the nasopharynx, but resemble a lymphoepithelioma histologically. Lymphoepithelioma-like carcinomas may be found in almost any epithelial organ, including the lung, thymus, breast, colon, endometrium, prostate, and skin,[1] as well as urinary bladder, trachea, esophagus, stomach, salivary glands, vulva.[2]wikipedia
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These tumors are of interest because of their
1. possible viral induction or association: leading to believe that genes associated with the Virus are either imbedded in the normal tissue pathways inducing the transformation and therefore specific targets will be those that can block such incorporation.  That indeed a different vaccine can be tried for the EBV virus in endemic regions once drivers of incorporation can be identified.  Is it the DNA-ase, RNA-ase or CDK or just the cyclins...Here it appears that epigenetic events involving splicing molecules will be important.  There got to be splicing and reconnection of Nuclear materiat, juxta-position to promoters and regulator factors for this disease to progress.   Is there a Core binding factor like molecule driving this condition?  I believe a genetic study is in order here to tell us!
What is the status of the NF-kB and what are the specific Cytokine (interon1, IL-2,4,6, 11,12,23) TNF and TGF-Beta.  Role of some Known integrins (avB) and prominent Metaloproteases.

2.  The response to concurrent Radiation and chemotherapy tends to suggest DNA breakdown is critical in this disease 
emphasizing that P53 must be amplified (mostly secondarily), that DNA repair potential will have  prognosis significance and Microsatellite  instability will also have prognosis significance.  MDM2, E, Rb genes would be important.  Begin a question, can Velcade and the Aurora add something in Maintenance settings in this disease...Certainly an interesting approach!  
can Vincristine and others Methotrexate like agents targeting the lymphoid component be given in maintenance setting, have a value in terms of prolonging survival or progression free survival?

A good study should include both the endemic and the non endemic portion to clearly see the importance of viral impact !
CRBCM is still alive!

We can go on

combining Cisplatin, Velcade and Aurora B as a new Induction therapy in Endemic Nasopharyngeal cancer....

 

Sunday, July 14, 2013

MURKY STATEMENT IN LUNG CANCER PREVENTION

Diets deficient in vitamin A and C and Beta-carotene have been associated with increased risk of lung cancer!  However "there is no role for Beta-Carotene, Vitamin A or any other derivatives for the chemoprevention of lung cancer".  The truth is Beta-carotene  is associated with an increased risk of lung cancer among heavy smokers!  A protective role of against lung cancer by Beta-carotene vitamin A or their derivatives, was not found in prospective trials.   Briefly if you diet misses it, it is bad,  but if you happen to take it, there is no purpose!  Go figure!  To ask question about such an unresolved issue is clearly dishonest, don't you think...!

Saturday, July 13, 2013

HERE THE WNT COMES AGAIN TO SHOW ITS MIGHT!

WNT, A MAJOR PATHWAY

The Wnt is one of the major pathway involved in many neaoplastic procell.  Quite frankly we cannot emphasize enough the value of this patways.   And one of the main reason we tend to minimize its importance is that, unlike the the RAS/MAPK, and fascinating PI3K which we can see flowing down the Cytosol, the Wnt occurs deep down the thickness of the Membrane and through  the Reticulum Endothelium, reaching the Nucleus in a flash!
Disturbance at the Wnt affect Cellular polarity with severe folllowing consequence
1. Loss of sense of shape for the cell, cellular hyperplasia seems to be linked directly or indirectly to the Wnt.
2. Disturbance at the Wnt involves the E-Cadherin/Beta-Catenin system, leading to loss sanse of Adhesion,  A cell that lost the sense and input from its neighbor trigger proliferation as if seeking the fill a perceived GAP! there is a reflex proliferation.  With the lack of Adhesion, cellular consensus is impaired and the NOTCH is excited or otherwise profoundly disturbed.  The cell find itself with a choice
1.0  Proliferate to fill the GAP
2.0  Activate the Polycystins and make a CYST filled with liquid.(See physio-pathology)
The stimulation of polycystins actually activates the JAK/STAT pathways increasing the proliferation risk.  There is a related risk of fibrosis as in Myelofibrosis and Capsular formation for Cystic diseases!
Remember through the Polycystins, there is an influx of Calcium blocking Adenyl Cyclase and activation of cAMP phosphodiesterase.  Consumption or Mutations at Polycystins leads to c-AMP build-up favoring Proliferations.  All this to stress that Wnt disturbance leads to obligatory loss of cellular adhesion, shape and proliferation.
Remember close by is the RHOC gene
which " cycles between inactive GDP-bound and active GTP-bound states and function as molecular switches in signal transduction cascades. Rho proteins promote reorganization of the actin cytoskeleton and regulate cell shape and motility. RhoC can activate formins such as mDia1 and FMNL2 to remodel the cytoskelton.[3]
It is prenylated at its C-terminus, and localizes to the cytoplasm and plasma membrane. It is thought to be important in cell locomotion. Overexpression of this gene is associated with tumor cell invasion and metastasis. RhoC-deficient mice can still develop tumors but these fail to metastasize, arguing that RhoC is essential for metastasis.[4]"wikipedia

and also remember  the MTA-1, Ap-1, and HDAC-1 to unleash the rest of the neoplastic and metastatic transformation.

Silencing MTA1 by RNAi reverses adhesion, migration and invasiveness of cervical cancer cells (SiHa) via altered expression of p53, and E-cadherin/β-catenin complex.

 
" It was speculated that the decreased migration and invasion capability by inhibiting the MTA1 expression in the SiHa cell line may be mediated through the altered expression of p53, and E-cadherin/β-catenin complex. MTA1 could serve as a potential therapeutic target in cervical cancer."  
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THE WNT, PATHWAY TO CELL PROLIFERATION AND INVASIVENESS/METASTASIS
======================================================
DO NOT FORGET THE WISP3This gene encodes a member of the WNT1 inducible signaling pathway (WISP) protein subfamily, which belongs to the  (PATWAY TO BONE METS) / WITH BMPR

connective tissue growth factor (CTGF) family. WNT1 is a member of a family of cysteine-rich, glycosylated signaling
proteins that mediate diverse developmental processes. The CTGF family members are characterized by four conserved
cysteine-rich domains: insulin-like growth factor-binding domain, von Willebrand factor type C module, thrombospondin
domain and C-terminal cystine knot-like domain. This gene is overexpressed in colon tumors. It may be downstream in
the WNT1 signaling pathway that is relevant to malignant transformation. Mutations of this gene are associated with
progressive pseudorheumatoid dysplasia, an autosomal recessive skeletal disorder, indicating that the gene is
essential for normal postnatal skeletal growth and cartilage homeostasis. Multiple transcript variants encoding
different isoforms have been found for this gene. (provided by RefSeq, Jul 2008)



 
FROM Hem/Onc today
*recent study suggests that the survival is not affected by Breast cancer diagnosed during pregnancy.
*IMRT offers lesser local adverse effects than standard RT in patients with early breast cancer
*Maintenance therapy with Gemzar-Taxol  improves Progression free and overall survival in patient with metastatic breast cancer (32.3 Vs 25.5 months)

*A study at Baylor suggested circulating tumor DNA to be an "effective Biomarker in Breast cancer".
*Bendamustine and Rituxan appears to be an effective regimen in relapse Diffuse large B-cell lymphoma  with ORR 67% and CR 37%, patients received a large dose of Bendamustine (120mg/m2) on day2,3 with  great frequency of marrow toxicity.

*21 day R-CHOP (instead of 2weeks) remains the recommended standard in Lymphoma.
*As expected, Tivozanib received a thumb down by the FDA for Renal Cell Cancer,  and DARATUMUMAB (Anti-CD 38) RECEIVED "the one to watch status" or Breakthrough status in Myeloma.  FDA also approved  Tafinlar,Mekinist for Melanoma.
*There is such thing as "an inappropriate Colonoscopy" by age of patients!
*OF SIGNIFICANCE, ZIBOTENTAN/TAXOTERE FAILED TO IMPROVE  OVERALL SURVIVAL IN PATIENT WITH HORMONE REFRACTORY PROSTATE CANCER,  AND REMEMBER A CANADIAN STUDY SUGGESTED THAT CETUXIMAB FAILED TO DO THE SAME DESPITE AN INCREASING RATE OF EGFR IN ADVANCING HRPC
*Once again Duloxetine works in Chemotherapy induced peripheral Neuropathy...
*don't run out of name,and not making it up!, Nintedamib good for Renal cell cancer, as good as Sunitinib,they say!
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CAN PATIENT WITH WITH E.COLI POSITIVE TEST SHOW AN AMPLIFIED NF-kB AND HIGHER LEVEL OF CYCLINS (INTERFERON OR INTERLEUKINES) IN THEIR PERIPHERAL BLOOD CELLS AND SERUM (PICK THE RIGHT MEDIA FOR YOUR TESTING)?
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