Potential future collaboration lead at CRBCM!

"Thanks Peggy for your quick response,

As I mentioned to you last week, there was a potential collaboration with an oncologist in China. The story was that I met a clinical oncologist, Dr. Baofa Yu, who used be a research assistant professor at UCSD. When I was in Scripps Res. Institute in San Diego, I have known him quite well. He has returned to China about 10 years ago to establish private tumor hospitals using a therapeutic approach he developed to treat cancer patients (He has US and China Patents) . It was very successful. Currently, he has owned four tumor hospitals in China (in Beijing and other cities). He has interest in collaborating with an oncologist in US to use his novel approach to treat cancer patients. I have introduced our research collaboration to Dr. Yu on phone last week. He has great interest in collaborating with Dr. Kankonde. Dr. Yu may come to US for a visit in this coming July. Maybe we can meet here at El Paso. Dr Yu let me tell you that if it is possible, Dr. Yu would also like to invite you to China to visit his cancer hospitals in the near future."

The CRBCM will be honored to learn from DR Yu...

The future will be bright!And only the future will tell!

CRBCM, on the move again

Flying today to LAS VEGAS for a major hematology conference
for our reader this is the annual update in certain Hematologic conditions
a report will follow I am sure, but its our ways to watch what is driving the mood in Hematology!
Be patient, the news will come to you...If I am not back....I just may have won in Vegas!
And if I don't say a thing!  well what happens in Vegas, stay in Vegas......
We are reviewing in the meantime all these good genes  HHEX,KCNJ11,PPARG, TCF7, MTNR1, TRAF1....Is there a crystal ball in these?

A critical Function down the neoplastic transformation : NPM1

As we test gene mutations with the UTEP team, one of the Mutation detected in the sera of lung cancer patients was Mutation or over expression of NPM1.  The literature suggested that this gene is a critical path to closing of natural ways to apoptosis while exacerbating cell division.
Indeed we all know that cancer is  characterized by cellular persistence, and longer life relative to normal cell.  This fact is more seen with Leukemic cells and NPM1 will be more present in these diseases as a matter of  facts.   To escape cellular programmed death, cancer will use NPM1 and related molecules to escape normal death particularly in the presence of abnormal genetic alteration often present in cancer cells!
It is not by mistake that NPM1 will have interactions with
1. BRCA that affect gene repair
2.P53 to close that reflex cellular arrest
3.Runx genes in hematopoietic malignancies  (proof of promoters'activities)
ARF, etc...   for some, RUNX is a part of CBFs
The activities into suppression of programmed death can even be measure by drop in Caspase 3,8 as reported by bright scientists!
  The second fold is of course promotion of cell division mainly through the Nucleoli and division of centromeres.   NPM1 expression appears bad prognostic indicators but has been cited in some leukemia of the young as a good prognosis indicator?   And that is most likely because it is a secondary events rather than truly a driver mutation?
Clearly it was striking to find it sitting there in Lung cancers!

And progress continues on CRBCM Blog! More than 40,000 reviews....

Coalition for the Reversal of Breast Cancer Mortality in African American Women  ·  Stats  ›  Overview

May 2007 – April 2014

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More than 40.000 reviews in less than 2 years! The CRBCM!

With over 40,000 reviews, the CRBCM is advancing slowly but deliberately
our cause is just that is why we are still alive,
will stay alive long enough until enemies become irrelevant!
We are still advancing as more is being done,
and somehow we keep staying alive by the grace of God!
40,000 reviews and counting in less than 2 years ...we can be proud and the need is there!
we will keep on progressing until we get to the promised "land"....

Ramucirumab, FDA approved in Metastatic GE Junction and gastric cancer, but is-it all?

May be Ramucirumab will work
At CRBCM we have a patient who has Angiosarcoma in the liver who had a rapid progression on Gem-Taxane (in fact she had a very powerful allergic reaction to Taxane) and again progressed on MAID
She was switched to Avastin alone since the reaction to Taxane was strong. The disease remains stble for 1 year.  She has now vaginal bleed and acute SOB that responded only to steroid, Avastin has benn on hold
It is unclear if she will tolerate it again.
Alternative Pazopanib?
?Trabectedin (unavailable in the US?)
Cediranib?
or is-it the new Ramucirumab?  will try with Lilly!

The process of Neoplasia in lung cancer, potential for screening through blood!

Lung cancer, one of the leading deadly cancers for which screening has not clearly be established, has been one of the target of many researches.  To this day, only radiological evaluations have creeped up to a level of screening.   With the advance of technology, we have gone from Chest Xray to low-dose cat scans for this indication.  And this despite our progress in the knowledge of genetics.

Quite frankly it seems that much of preliminary genetic knowledge has been developed.  The amount of information available on genes of cancer is impressive.  What is missing is boldness of our scientists to form theories of progression of this disease which kill many victims each year.  The neoplastic process however continues to occur steadily, and year after year, new lung cancers are being brought to light through detection that is characteristically late.  There are many lung cancers and none appears to have the same pathophysiologic occurrence mechanism.   So in this maze of mechanisms, finding a steady gene abnormality that does vary very much through stages of cancer appears a significant fact!  Indeed the MDM-2 Mutation appears steadily throughout the stages of certain lung cancers, particularly the Adenocarcinomas.  Mouse double minute 2 homolog (MDM2) also known as E3 ubiquitin-protein ligase is the gene in question!  In our sample, this gene was the highest present and its presence seemed to vary little both on cancer tissues and in the serum of diseased patients.  These specimen were provided to CRBCM and the UTEP biologic research laboratory by LCBRN -VA university tissue bank (under MDHONORS funding).

Coming back to the MDM-2:
------------------------------

When one lean on this finding in depth, the puzzle for the involvement of the MDM-2 runs deeper than first suspected.  And clearly lays in the dawn of the neoplastic process.  And as we lean further, new suspicions rise that the onset of the neoplasia for some cancers is here! Several facts contribute to this perception.  We all know that cigarette smoking is a common cause of lung cancer, and now this known fact...
Dr Yurong Chai, our investigator stressed that Cigarette smoke "increase the risk of alternative MDM-2 splicing" a fact that establishes the initial event that will trigger so much subsequent genetic calamities.   MDM-2 happens to be the regulator of P53.  It also has a competitive partner, the FKBP25,
OCHOKA"
"The p53 tumour suppressor protein is tightly controlled by the E3 ubiquitin ligase, mouse double minute 2 (MDM2), but maintains MDM2 expression as part of a negative feedback loop. We have identified the immunophilin, 25kDa FK506-binding protein (FKBP25), previously shown to be regulated by p53-mediated repression, as an MDM2-interacting partner. We show that FKBP25 stimulates auto-ubiquitylation and proteasomal degradation of MDM2, leading to the induction of p53. Depletion of FKBP25 by siRNA leads to increased levels of MDM2 and a corresponding reduction in p53 and p21 levels. These data are consistent with the idea that FKBP25 contributes to regulation of the p53-MDM2 negative feedback loop."   The impact on a member of the FK506 family has deep implications both on the disease process and therapeutically as we may discuss.
The involvement of disturbances of the MDM-2 has even deeper consequences, because of independent MDM-2 activity directly on initiation of  DNA replication and through its activity on Cyclin-depedent Kinases!   The MDM-2 rise quickly as a biomarker of Cancer initiation and therefore a major Biomarker of the danger of smoking!  And its presence no matter the stage of disease has several implications including that of how you appreciate curability!  (to be continued)

We had our last meeting with DR CHOI at UTEP!

Yes yesterday was our last face to face meeting with DR Choi a brilliant scientist working at UTEP
with DR Zhang. She is returning to China within a week.  She transformed our world of suspicions into real events.  She has been a dominant force and a matter of facts woman who has key to our project on lung cancer detection kit  development project.
She did the PCR work needed and open us up to new perspective on the 3 genes looked at that not only confirms our suspicions, but opened new perspectives for future research questions related to the 3 genes.
Her findings have reaffirmed that we are in the right path and raises significantly the importance of target therapy, strengthen the notion that Ubiquitylation is critical in the initiation of lung cancers (and other cancers)
and could probably be a potent biomarker ( by its disturbances) to smoking danger to initiate lung cancers.
In the sera of patients  with lung cancers, her findings have been just as stunning and intriguing.  From high Cyclin presence to the presence of antibody for NPM1, p16 and even in minutes amount the presence of 14-3-3  (the same found in Creutzfeld Jacob disease ?).  All these findings were captivating and raising new questions about the specificity and sensitivity of some of our tests.
The level of amplification of these abnormal genes certainly call for a cut of point for amplification that could be primary and be suspected to be neoplastic, or secondary that could be an unintended event subsequent to other gene's amplification whether malignant or not.
When it comes to Antibody, what we suspected was confirmed.  Indeed since the antibody secretion is function of fluctuating lymphocyte reaction, or cellular use of genes involved in raising attraction of the white cells, the levels of antibody is fleeting or not correlating with the presence of gene amplification.   But our findings is that in cancer the presence of antibody is confirmed.  This may help in early detection...
Our discussion also brought to mind the difficulty of perceiving or detecting gene suppression unless your sets include normal tissue (we were offered biopsies of surrounding tissue luckily).  Finding genes that are less expressed is critical.  The example would be the suppression of PTEN in lung cancer, a well published event.  Unless you are comparing with surrounding tissues in the same individual, establishing repressed gene could elude your observation.  And we know how important such an observation represents as in major neoplasia, regulator genes could be suppressed!  Our work is still preliminary, and may be revisiting, but clearly new perspectives have been open and our work will continue no matter what!
CRBCM is progressing deliberately.  Please wait for the publication as it is being finalized!

Dangerous precedent about VIAGRA, its connection to Melanoma!

The risk association of Melanoma with Viagra raises significant fear for those who have no genetic background because Melanoma is still one of the most dangerous and untreatable cancer at advanced stage.  For the scientist, this open the door to further research into gene interactions.
Melanoma is a disease that raises fear in the community given its fatality in advanced stage. In the Untited states it kills close to 9000 lives yearly or more than 10% of affected individual globally.  The gene involved is p16/CDKN2A which encodes for both p16 and p14ARF.   It is worth mentioning that Xeroderma pigmentosum and BRCA2 predispose to this disease.  Also loss of PTEN has been cited for association with Melanoma.    GNAQ/GNA11 has been associated with Uveal Melanoma.  c-KIT has been cited in Lentigo maligna Melanoma.

Viagra, suppressor of the enzyme phosphodiesterase type 5 (PDE5),will block degradation of Cyclic GMP necessary for Erection performance.  What this has to do with PTEN. CDKN2A, and may be p14ARF or BRCA2 becomes of interest.  Other then standard Erection dysfunction, Viagra has been used more chronically in patients who have Pulmonary Hypertension, a silently deadly condition.

This elevated risk of melanoma does not come as a surprise however and more discoveries are upcoming for certain since the Cyclic GMP, like Cyclic AMP are "second messengers" affecting many pathways given their position early in these pathways.  The observation also point to the danger of chronic exacerbations of genes in any pathways.  The reactions occurring in a cell to adjust to excited gene could be deleterious as it can either exacerbate or suppress compensatory pathways, leading to cancers.  Another independent fact is the fact that "second messengers" have been used in the past for Biomarker of chemical molecule activity...and Cyclic GMP is a "messenger", a clear Biomarker of event to come in a cell!

Hyperlipidemia "under the microscope", REDUCING RISK OF CORONARY AND BLOOD VESSEL DISEASES

-does Xanthelasma, Corneal arcus, provide clues in triglyceride deposition in the artery
-does minimal pancreatitis and similar induced inflammatory disease induced by hyperlipidemia contributes to Coronary disease
-what type of inflammatory process are produced by free fatty acids and related lipid molecules
-?associated Pulmonary hypertension
-Dysbetalipoproteinemia provides more clues to pathophysiology?
-Cytokines involved in Neurologic syndrome of Chylomicronemia or is it direct disruption of lipogenesis/lysis
-What is the role of IL-6 in all this mess, can controlling IL-1 & 6 help (ie preserve elasticity of blood vessel)  could vascular cellular preservation slow down Arteriosclerotic phenomena (preservation of elastin and related compounds)
-what is the role of cytokines in vascular transformations (AS CYTOKINES INDUCED BY FFA)
-should closer elective follow-up of the pancreas serve as a biomarker of hyperlipidemia
-should early xanthoma be allowed to alert of Coronary event due to hyperlipidemia, FFA levels?
-what is the role of TSH, and the thyroid?
-what in the urine analysis predict a coronary events (as it relates to lipid)
-What Vitamins have to do with this?  Vitamin D role?
-Eruptive Vs tuberous XANTHOMAS (FAT VS CHOLESTEROL) WHY AND WHEN?
-how to consume debris of lipolysis without causing a "Cytokine storm" or an autoimmune disease
is it through IL-6
-how does specific  medicines works to minimize cytokine storm?
-How does Ileal bypass affect the cytokines, vascular transformation, should it be routine at a certain age to reduce Coronary risk
-can sonogram of the pancreas, specific artery gives a clue on coronary disease due to lipid disruption

Genes to Eternal life

According to the US Government on Aging (at least seems to suggest)

to have eternal life you have to have or know some of the genes for these functions:

-Gene(s) to avoid unhealthy choices (ie. blocking Glucogen,controlling lipid,MTOR, CRE gene)

-Genes to keep life sparks (hormones,cytokine,physical exercise,what to eat)

-Gene(s) to keep eternal  youth (Telomeres,MTOR)

-Genes to stay spunky (hormone,routines, MTOR

-Genes that keep you fun (Hormones, cytokines)

-Genes to keep magical transformation (rejuvenating) (Cytokines,

-Genes to avoid physical decline (Exercice under cytokine control

-Genes to avoid vulnerability to disease (Flyn,Lyn directions for looking)

let's go find them!

related questions? Personal record mind you!

*Can use of Atra/retinoic acid improves Nexavar?
*could decreasing Zinc by a chelator increase or decrease Metastic progression in the liver
*Could blocking Prostaglandins affect metastatic progression in the liver
*can inflammatory parameters be useful in measuring progression of metastatic disease in the liver?
*defining role of Anti-Adenyl CYCLASE in both inflammatory and neoplastic disease in the liver
*and now what is the exact role of Protein Kinase C
*N-Acetyl cystein? what may be other roles...
*What is more important in TBI, IL-1 or IL6?
what is it again ----Arylhydrocarbon?let's dwelve into these

What I got from the literature, if you didn't get it, you did not get it!

That Inflammatory forces will

1. Increase
-Fibrinogen/Fibronectin
-alpha-Antitrypsin
-Serum Amyloid A
-C-Reactive Protein
-Complement protein factor B
- C3
-ESR
and may Be Adenyl-Cyclase

2.Decrease
-Albumin
-Transferrin
-?P450
-AHH

3.Major forces
Zinc level---and level of EGF?
activity of kinase-C
PMA
Prostaglandins (E)
EGF
ICAM1
Neurotensin

look into these
C-Met, EGF, HGFR,GLP1R, NOD-1,P2Y,C5a,NF4R,ASGP-Receptors

something is here, got to find it! if you didn't get it, you didn't get it!

search for the "OBLONG" pill.

"Oblong man" rather than "circle man" infers less obesity
Obesity is a growing issue in the United States and many want to find an answer to obesity by coming up with a "pill" that will make people lose weight...the "Oblong Pill" is such a pill.
while many reports "fighting" against obesity, few patients with autoimmune diseases are reporting to us for inability to gain weight!  In Autoimmune diseases, we surmise that cytokines induced in this disease significant perturbation of both glucogenesis and lipogenesis-lysis.  The logical conclusion is that isolating the cytokines involved may help with weight management.  But in autoimmune disease we could also localize relevant biomarkers that mark the increase in cytokines.   We could also test why cellular proliferation does not occur (is it through FOXO3), and measure transformation in lymphoproliferative disorders (is it through the LYN, RELA etc?). Should we avoid these types of development and what would be the type of warning that these mechanisms are elicited .

Bani-Sadr et al "Weight loss is reported by more than 20% of hepatitis C virus (HCV)-monoinfected patients treated with the peg-interferon (peg-IFN) and ribavirin combination."  and indeed chronic use of interferon is accompanied by weight loss.  Interferon belong to the Cytokines, another proof that Cytokine may be an answer to Obesity if controlled and managed carefully!

Mechanism of targeting for therapy

*Receptor Inhibitor
*ATP competitor inhibitor
*DNA repair
*Amplification of certain gene or proteins (EMSY)
*Hypermethylation of certain gene
*Inhibition of critical enzymes
*Inhibition of pathways'genes

Be There! from PER

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	Joyce A. O’Shaughnessy, MD     Dear Colleague, I invite you to attend the 13th Annual International Congress on the Future of Breast Cancer® to be held from Thursday, July 17, 2014, through Saturday, July 19, 2014, at the Hyatt Regency in Huntington Beach, California. This event has become a yearly highlight for the community oncologist specializing in breast cancer. Our faculty includes very talented experts in medical, surgical, and radiation oncology, as well as translational scientists, all of whom are firmly dedicated to advancing patient care in breast cancer. The 13th Annual International Congress on the Future of Breast Cancer® is a 3-day international meeting that will serve as an update on advances in the field with a focus on the clinical implications of breast cancer genomic and phenotypic subtyping, as well as novel agents, strategies, and improved regimens changing the future of breast cancer therapy. This year will place an even greater emphasis on the clinical questions and challenges facing community oncologists in their daily practice. Lectures will focus on emerging data that directly impacts patient care, with leaders in the field addressing practical implications and evolving management paradigms. More time will be devoted to in-depth discussion of the application of the data to real-world patient cases, including 2 new case presentation sessions entitled “Exceptional Responders with Metastatic Breast Cancer” and “Breast Cancer Molecular Tumor Board.” Physicians’ Education Resource®, LLC (PER®), the ACCME-accredited provider and Congress sponsor, plans and develops more than a dozen annual live conferences, in conjunction with leading experts in oncology, to advance cancer care. Through certified continuing medical education, we are improving patient lives. The International Congress on the Future of Breast Cancer® is one that I am thrilled to be a part of, as it elicits very positive feedback from the attendees each year. For more information or to register, please visit www.gotoper.com. As a special offer to you, register before May 1, 2014, and save $100 off the price of registration. Use code: B14CLE upon registration. Sincerely, Joyce A. O’Shaughnessy, MD Co-Director, Breast Cancer Research Baylor Charles A. Sammons Cancer Center Texas Oncology The US Oncology Network Dallas, TX
	Physicians’ Education Resource®,LLC, is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. Physicians’ Education Resource®, LLC, designates this live activity for a maximum of 19.25 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. This activity is supported by an educational grants from Celgene Corporation, EISAI, Inc., and Lilly. For further information concerning Lilly grant funding visit www.lillygrantoffice.com. PER® complies with the Physician Payments Sunshine Act as part of the Affordable Care Act. Accordingly, we may be required to collect information on transfers of value provided to any covered recipient under the Act.
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role of TPI gene in cancers

OROSZ et al:
"One of these, triosephosphate isomerase (TPI) deficiency, is unique among the glycolytic enzyme defects since it is associated with progressive neurological dysfunction and frequently with childhood death. The physiological function of TPI is to adjust the rapid equilibrium between dihydroxyacetone phosphate and glyceraldehyde-3-phosphate produced by aldolase in glycolysis, which is interconnected to the pentose phosphate pathway and to lipid metabolism via triosephosphates."

*SABiosciences Regulatory transcription factor binding sites in the TPI1 gene promoter:
         c-Fos   PPAR-gamma1   AP-1   ATF-2   PPAR-gamma2   c-Jun   c-Ets-1 
         Other transcription factors

*development of Giardiasis is a potent sign of this disturbance
*Is TPI involved in salivary gland cancers
*does supplying G3P +DHAP resulting product correct this disease?
*what is the expression of REB1,RAP1,GCR1 in salivary gland cancers?
stephens et al: on Adenoid Cystic Cancer ( fusions of the MYB-NFIB genes)
"We identified multiple mutated genes that, combined, implicate chromatin deregulation in half of cases. Further, mutations were identified in known cancer genes, including PIK3CA, ATM, CDKN2A, SF3B1, SUFU, TSC1, and CYLD. Mutations in NOTCH1/2 were identified in 3 cases, and we identify the negative NOTCH signaling regulator, SPEN, as a new cancer gene in ACC with mutations in 5 cases. Finally, the identification of 3 likely activating mutations in the tyrosine kinase receptor FGFR2, analogous to those reported in ovarian and endometrial carcinoma, point to potential therapeutic avenues for a subset of cases."

Delayed Response to Ipilimumab

This case of delayed Melanoma response to Ipilimumab is clearly puzzling and raises the question of the appropriateness of our measurement of disease response to treatment in solid cancers being treated with Immune approach.  The need for "Immune Response Criteria" or Biomarker is clearly here!
We block CTLA4, a lymphocyte related molecule but we stick to the mass volume criteria to assess response when indeed activation of lymphocytes should be the criteria.  One would think that Adenyl Cyclase activation would be the first proof of Medication activity since most pathways will pass by this?
gene activation would be best bio-markers and attraction to the tumor would be best quantified here (by certain gene activation)
Dampening of B7, particularly with closure of  related downstream genes would make a stronger indication of disease response...And we know suppression of receptors is marked when this happens.
The awakening of the Lymphocyte theoritically should raise the possibility of inducing Inflammatory  process in some patients based on genetic heterogeneity (which is the question behind this possibility), in the case presented, an inflammatory bowel disease was reactivated...did the patient present such an genetic atopy or background?  does use of steroids contribute to the delayed response or is-it the other way? that is genetic back ground actually drives the delay in response?  which background? IBD? (the fact is that in the case presented, one of the metastatic Melanoma mass involved the Colon provide further clue as to further link of this Melanoma with the GI tract could be surmised!)   The resection of this mass is an heroic activity that struck me !  most clinical settings would not have tried this exercise deemed futile in most American institutions...a paper should be provided just on what prompted this resection...please tell us what prompted the resection of a metastatic Melanoma lesion?it is puzzling but at the end a good thing for this patient!

few investigation questions in various diseases

What testosterone gene has to do with Hairy cell leukemia
What HLA has to do with Hairy cell leukemia (why the incidence in black is lower?)
Weight loss is linked to Cytokine discharges which interfere with Gluconeogenesis?
Organomegaly is linked to disturbances in the Catenins, protein mobility in the cells, or "cellular flagellation" ? but why?
Interesting this hairy cell, leads to hypocholesterolemia? what cytokine does this again? should it enter therapeutic trial?
Is it the Annexin A1,  what TRAP has to do, BRAF-V600E (activity of Vemurafenib in Hairy cell)
what cytokine lead to collagen or reticulin expression in this disease?
High dose interferon works in this disease!   Yes a Cytokine works (where is my Cytokine bank!)
The disease brings back a fundamental question, why susceptibility to infection, is it weakness in the mitochondria?is it the LYN gene, c-MYB or disturbance in the Ig.
Why vasculitis in this disease?  disturbance of G-proteins?

ALL STROKE PATIENTS UNDERGO A CYTOKIN STORM AND SHOULD EXPECT PTSD!

And once again we tremble to recognize that all stroke patients will suffer PTSD or post traumatic stress syndrome even though it is the basic principle and process that will and have happened
and will fluctuate based on our genetic heterogeneity, location in the brain, and intensity of cytokine.   The reaction of cytokines could actually be predicted for each of us prior to event as we can test Macrophage reaction before hand!  And knowing the genes,
and Early administration of MTOR inhibitor and interferon  (or Sirtuins) like products could indeed dampen the Cytokine storm and minimize maximally the effect of a stroke!  But we still wait to test what we know !
Here we stress  the need to know our inflammatory index as age or status of our vascular status. we also stress the need for a camera deep in  vessel to check our thrombus stratus and status. and report which thrombi are on the "brink" of collapse. Forget measuring by EEG, we are past Aspirin and plavix, the treatment of stroke is on the cytokine and the Macrophage! (what is Adenyl cyclase doing?)  An "homocystein" and related gene system system will tell us if a thrombus somewhere is about to break!  And gene activation (ie "cytokines or growth factor index") will tell physician how hard our blood vessel is!  Are they ready to break?!   Following blood pressure alone is not enough and has failed us!  medicine of tomorrow is just genes!  genes and genes!  25000 only and we can't read them despite all our computers!  Lets go back to work!

(This article should be read by "scientists"only, or open minded person)

New areas of investigation in cancer research

Can Cisplatin be used to stop recalcitrant Viral hepatitis load  ?
or a combination of Cisplatin and Sunitinib or Imatinib
what is the relationship with RFX-1

" treatment with retinoic acid induces both MIBP1 and RFX1 protein, as well as their DNA-binding activity,"Z-Kaye et al.     (Is there promotion of c-MYC in APL by retinoic Acid use)
Lubelsky"derepression of the RFX1 gene is only partially blocked by inhibiting Chk1, the DNA checkpoint kinase."...." Rfx1 binds and represses its own promoter. Furthermore, Rfx1 binding to its promoter is reduced upon induction of a DNA replication block by hydroxyurea," A dangerous gene by its ability to self promote and repress.  Mutation here could have cataclysmic consequence, worth while checking number of this mutation in CML, and whether this would be a clone responding better to Hydrea?

how frequently Testicular cancer present with this Mutation
Is an indication that Hydrea could replace the bad, dangerous Bleomycin?

What is its (RFX1 mutation) presence in Thyroid cancer
Can Hydrea work there?
should Anaplastic thyroid cancer therapeutic combination include Hydrea when RFX-1 is over expressed?
Is RFX1 a biomarker for Hydrea activity?  Can Cisplatin be associated to booster the effect?
==========================
do not confuse with NFX-1 implicated in Papilloma Virus but acting strangely the same as it come to penetrating the Nucleus? or may be they are both epigenetic, but this one linked to p109 according to the Seattle People!


To read more?

Go to:  "

Study of FoxA Pioneer Factor at Silent Genes Reveals Rfx-Repressed Enhancer at Cdx2 and a Potential Indicator of Esophageal Adenocarcinoma Development

Jason A. Watt et al....

Questions in Diabetes

Importance of measuring residual Insulin by weight, how that affect control of DM type2
how does the level insulin affect the need for Insulin supply to patient
Is there level of insulin predictive of the need for insulin
how to you gauge vascular age in DM
how do you gauge Neurologic age in DM
Is it necessary to obtain G-protein profile at diagnosis, plasminogen activator inhibitors
can Mitochondrial data help predict the course of therapy
IMPORTANCE OF LISTING ALL ENDOCRINOPATHY, AUTOIMMUNE DISEASES AT ONSET!
GLUCOKINASES, with the highest glucose output  (heterogenity in HNF-1-alpha) can it predict Insulin use/need.
rate of lipolysis?
rate of Hepatic glucose production
impact of free fatty acid ?are they predictive or prognosis
role of presence of Antibody to Insulin receptor, clinical use?
GLUT1,4 gene expression, TCF7L2,PPAR-gamma,calpain, Beta-adrenergic receptors,secretion of insulin ,amylin level, leptin, adiponectin
deficiency in glucogen synthesis
does level of cortisol impact prognosis in DM-2

TNF level
resistin
TGF

few questions on Sarcoidosis?

What's wrong with Macrophages in sarcoidosis?
why cells are so incited to become multinucleated (epithelioid)giant cells?
Could blocking of any of the cytokine stops the process
is it mandatory an intervention
and how to monitor this activity
can persistent low Vit D suggests activity of the disease
or Urine calcium level
Can Anergy suggests disease activity?
can frequent SPE be biomarker to test
should we test KatG protein in every case, BTLN2, ANXA11
how do you follow pulmonary hypertension in these patient
does ACE affects Blood Pressure in these patients
?serial EKGs
FEV
response to inhalers

With every case, some twists (Seminoma)

At CRBCM,
A 40 year old prisoner was referred to us after an Orchiectomy.
there is still a residual 10.6 cm retroperitoneal mass now know encasing the Aorta and major blood vessel
and invading the L4, L5.  Threatening the spine stability in this area.  The pain ihere is controlled with Medication.   HCG 159.  PET obtained show extension of the mass laterally, Nephrostomy bilaterally in place. Hct 27%, Hx of HTN
===========================================
some of the considerations and consulted Published notes follow:
will admit for the 1st Cycle of BEP

please contact us with questions;
1.how much we will reduce Cisplatin?
2.should attempt to resection be proposed?
3.or do you think RT after 4 cycles of BEP should do?
4.Is this patient at higher risk for secondary AML?
5.do we need a MRI of the brain?
 ===========================


"Urology was consulted and recommended induction chemotherapy and consideration of surgical consolidation after chemotherapy. The case was discussed extensively at tumor board. The consensus was that cisplatin-based chemotherapy is an essential component of potentially curative treatment, so the planned treatment included reduced-dose etoposide and cisplatin with aggressive IV hydration along with renally dosed allopurinol given the bulk of the tumor."
 Tim McCarthy.

A randomized trial of cisplatin, etoposide and bleomycin (PEB) versus carboplatin, etoposide and bleomycin (CEB) for patients with 'good-risk' metastatic non-seminomatous germ cell tumors.

Bokemeyer C¹, Köhrmann O, Tischler J, Weissbach L, Räth U, Haupt A, Schöffski P, Harstrick A, Schmoll HJ.

Author information

Abstract

BACKGROUND:

Cisplatin-based combination chemotherapy will cure 70% to 80% of patients with metastatic non-seminomatous germ cell tumors but is associated with the possibility of severe neuro-, oto- and nephro-toxicities. Carboplatin, a cisplatin analogue, is an active drug in testicular cancer with a more favourable spectrum of side effects. In a randomized trial, the German Testicular Cancer Study Group compared a combination regimen of carboplatin, etoposide and bleomycin (CEB) to standard cisplatin, etoposide and bleomycin (PEB) chemotherapy for patients with 'minimal-' and moderate-disease' non-seminomatous germ cell tumors, according to the Indiana University classification.

PATIENTS AND METHODS:

PEB was given for three cycles at standard doses (given days 1-5), and the CEB regimen consisted of carboplatin (target AUC of 5 mg/ml x min) on day 1, etoposide 120 mg/m2 on days 1 to 3 and bleomycin 30 mg on days 1, 8 and 15. Four cycles of CEB were given, with the omission of bleomycin in the fourth cycle. Thus, the cumulative doses of etoposide and bleomycin applied in the two treatment arms were comparable. Fifty-four patients were entered on the trial, 29 were treated with PEB and 25 with CEB chemotherapy. Patients were stratified according to disease extent (minimal versus moderate) and the degree of tumor marker elevation. Thirty-two patients (59%) belonged to the group with minimal disease and low markers.

RESULTS:

No significant difference in response to chemotherapy was seen between the two arms, with CR rates of 81% for the PEB arm and 76% for CEB treatment. However, more patients treated with CEB (32% versus 13%) have relapsed after therapy, and 4 patients (16%) have died of disease progression after CEP in contrast to 1 (3%) after PEB therapy. The first interim analysis of negative events (relapse, vital tumor at secondary resection, death from disease and therapy-associated death) showed a significantly higher rate after CEB than after PEB therapy, and the trial was terminated early. After a median follow-up of 33 months for all patients, the calculation of negative events is still significantly in favour of PEB-treated patient, particularly since three late relapses > 2 years have been observed in the CEB arm (P = 0.03).

CONCLUSION:

This randomized trial demonstrates that even with the use of adequate doses of etoposide and full-dose bleomycin, carboplatin cannot altogether replace cisplatin in patients with testicular cancer. Treatment with the PEB regimen remains the standard approach in patients with 'good-risk' non-seminomatous germ cell tumors.



BEP
Regimen 1 (5-day schedule)
Bleomycin 30 U or 30 mg iv bolus d1, 8, 15 or d2, 9, 16
Etoposide (VP-16) 100 mg/m2/d iv over 1 h d1-5
Cisplatin (CDDP) 20 mg/m2/d iv over 1 h d1-5
Q3w x 3-4 cycles
Culine S et al. Randomized trial comparing bleomycin/etoposide/cisplatin with alternating cisplatin/cyclophosphamide/doxorubicin and vinblastine/bleomycin regimens of chemotherapy for patients with intermediate- and poor-risk metastatic nonseminomatous germ cell tumors: Genito-Urinary Group of the French Federation of Cancer Centers Trial T93MP. J Clin Oncol 2008; 26:421 (link to the article).    
de Wit R et al. Equivalence of three or four cycles of bleomycin, etoposide, and cisplatin chemotherapy and of 3- or 5-day schedule in good-prognosis germ cell tumor: a randomized study of the European Organization for Research and Treatment of Cancer Genitourinary Tract Cancer Cooperative Group and the Medical Research Council. J Clin Oncol 2001; 19:1629 (link to the article).  
Nichols CR et al. Randomized comparison of cisplatin and etoposide and either bleomycin or ifosfamide in treatment of advanced disseminated germ cell tumors: an Eastern Cooperative Oncology Group, Southwest Oncology Group, and Cancer and Leukemia Group B study. J Clin Oncol 1998; 16:1287 (link to the article).    
Williams, SD et al. Treatment of disseminated germ-cell tumors with cisplatin, bleomycin, and either vinblastine or etoposide. N Engl J Med 1987; 316:1435 (link to the article).
 ===================================

R.Miller et al!   Cisplatin induced Nephrotoxicity!
==================================

1.Acute Renal failure
2.Hypomagnesemia
3.Hypocalcemia
4.Fanconi like Syndrome
5.Distal RTA
6.Renal salt wasting
7.Renal Concentration defect
8.Hyperuricemia
9.Erythropoietin deficiency
10Thrombotic Micro-angiopathy
11.Chronic Renal Failure

what is in store
----------------------
" Testicular Cancer
Initial chemotherapy
Salvage chemotherapy


Initial chemotherapy
Carboplatin (for stage I seminoma)
Carboplatin (Paraplatin) AUC 7 x 1 dose
Oliver RT et al. Radiotherapy versus carboplatin for stage I seminoma: updated analysis of the MRC/EORTC randomized trial (ISRCTN27163214). 2008 ASCO annual meeting. Abstract 1 (link to the abstract).
Oliver RT et al. Radiotherapy versus single-dose carboplatin in adjuvant treatment of stage I seminoma: a randomized trial. Lancet 2005; 366:293 (link to the article).
BEP
Regimen 1 (5-day schedule)
Bleomycin 30 U or 30 mg iv bolus d1, 8, 15 or d2, 9, 16
Etoposide (VP-16) 100 mg/m2/d iv over 1 h d1-5
Cisplatin (CDDP) 20 mg/m2/d iv over 1 h d1-5
Q3w x 3-4 cycles
Culine S et al. Randomized trial comparing bleomycin/etoposide/cisplatin with alternating cisplatin/cyclophosphamide/doxorubicin and vinblastine/bleomycin regimens of chemotherapy for patients with intermediate- and poor-risk metastatic nonseminomatous germ cell tumors: Genito-Urinary Group of the French Federation of Cancer Centers Trial T93MP. J Clin Oncol 2008; 26:421 (link to the article).    
de Wit R et al. Equivalence of three or four cycles of bleomycin, etoposide, and cisplatin chemotherapy and of 3- or 5-day schedule in good-prognosis germ cell tumor: a randomized study of the European Organization for Research and Treatment of Cancer Genitourinary Tract Cancer Cooperative Group and the Medical Research Council. J Clin Oncol 2001; 19:1629 (link to the article).  
Nichols CR et al. Randomized comparison of cisplatin and etoposide and either bleomycin or ifosfamide in treatment of advanced disseminated germ cell tumors: an Eastern Cooperative Oncology Group, Southwest Oncology Group, and Cancer and Leukemia Group B study. J Clin Oncol 1998; 16:1287 (link to the article).    
Williams, SD et al. Treatment of disseminated germ-cell tumors with cisplatin, bleomycin, and either vinblastine or etoposide. N Engl J Med 1987; 316:1435 (link to the article).
Regimen 2 (3-day schedule)
Bleomycin 30 U or 30 mg iv bolus d1, 8, 15
Etoposide (VP-16) 165 mg/m2/d iv d1-3
Cisplatin (CDDP) 50 mg/m2/d iv d1-2
Q3w x 3-4 cycles
de Wit R et al. Equivalence of three or four cycles of bleomycin, etoposide, and cisplatin chemotherapy and of 3- or 5-day schedule in good-prognosis germ cell tumor: a randomized study of the European Organization for Research and Treatment of Cancer Genitourinary Tract Cancer Cooperative Group and the Medical Research Council. J Clin Oncol 2001; 19:1629 (link to the article).   
EP
Etoposide (VP-16) 100 mg/m2/d iv over 1 h d1-5
Cisplatin (CDDP) 20 mg/m2/d iv over 1 h d1-5
Q3w x 4 cycles
Kondagunta, GV et al. Etoposide and Cisplatin chemotherapy for metastatic good-risk germ cell tumors. J Clin Oncol 2005; 23:9290 (link to the article).
VIP (for patients with underlying lung disease)
Etoposide (VP-16) 75 mg/m2/d iv over 1 h d1-5
Ifosfamide 1.2 g/m2/d iv d1-5
Cisplatin (CDDP) 20 mg/m2/d iv over 1 h d1-5
Mesna 120 mg/m2 iv bolus d1 before ifosfamide, followed by 1.2 g/m2/d civi d1-5
Filgrastim (Neupogen) 5 mcg/kg sc qd d7-16
Q3w x 4 cycles
Nichols, CR et al. Randomized comparison of cisplatin and etoposide and either bleomycin or ifosfamide in treatment of advanced disseminated germ cell tumors: an Eastern Cooperative Oncology Group, Southwest Oncology Group, and Cancer and Leukemia Group B study. J Clin Oncol 1998; 16:1287 (link to the article).
Hinton, S et al. Cisplatin, etoposide and either bleomycin or ifosfamide in the treatment of disseminated germ cell tumors: final analysis of an intergroup trial. Cancer 2003; 97:1869 (link to the article).

Salvage chemotherapy (back to top)
VIP
Etoposide (VP-16) 75 mg/m2/d iv over 1 h d1-5
Ifosfamide 1.2 g/m2/d iv d1-5
Cisplatin (CDDP) 20 mg/m2/d iv over 1 h d1-5
Mesna 120 mg/m2 iv bolus d1 before ifosfamide, followed by 1.2 g/m2/d civi d1-5
Filgrastim (Neupogen) 5 mcg/kg sc qd d7-16
Q3w x 4 cycles
Loehrer, PJ Sr et al. Salvage therapy in recurrent germ cell cancer: ifosfamide and cisplatin plus either vinblastine or etoposide. Ann Intern Med 1988; 109:540 (link to the article).
McCaffrey, JA et al. Ifosfamide- and cisplatin-containing chemotherapy as first-line salvage therapy in germ cell tumors: response and survival. J Clin Oncol 1997; 15:2559 (link to the article).
VeIP (for patients who received prior etoposide)
Vinblastine 0.11 mg/kg/d iv over 1 h d1-2
Ifosfamide 1.2 g/m2/d iv d1-5
Cisplatin (CDDP) 20 mg/m2/d iv over 1 h d1-5
Mesna 400 mg/m2 iv 15 min before first ifosfamide dose, followed by 1.2 g/m2/d civi d1-5
Q3w x 4 cycles
Loehrer, PJ Sr et al. Salvage therapy in recurrent germ cell cancer: ifosfamide and cisplatin plus either vinblastine or etoposide. Ann Intern Med 1988; 109:540 (link to the article).
Loehrer PJ, Sr et al. Vinblastine plus ifosfamide plus cisplatin as initial salvage therapy in recurrent germ cell tumor. J Clin Oncol 1998; 16:2500 (link to the article).
TIP
Paclitaxel (Taxol) 250 mg/m2 iv over 24 hrs d1
Ifosfamide 1.5 g/m2/d iv over 1 h d2-5
Cisplatin (CDDP) 25 mg/m2/d iv over 30 min d2-5
Mesna  500 mg/m2 iv before ifosfamide, and at 4 and 8 hrs after ifosfamide daily, d2-5
Filgrastim (Neupogen) 5 mcg/kg sc qd d7-18
Q3w x 4 cycles
Kondagunta, GV et al. Combination of paclitaxel, ifosfamide, and cisplatin is an effective second-line therapy for patients with relapsed testicular germ cell tumors. J Clin Oncol 2005; 23:6549 (link to the article).

Cisplatin + Epirubicin
Cisplatin (CDDP) 20 mg/m2/d iv d1-5
Epirubicin 90 mg/m2 iv over 15-30 min d1
Filgrastim (Neupogen) 5 mcg/kg sc qd d7-16, or pegfilgrastim 6 mg sc d7
Q3w x 4 cycles
Bedano P et al. Phase II study of cisplatin plus epirubicin salvage chemotherapy in refractory germ cell tumors. J Clin Oncol 2006; 24:5403 (link to the article).
Paclitaxel + Gemcitabine (for platinum-refractory disease)
Paclitaxel (Taxol) 100-110 mg/m2 iv over 1 h d1, 8, 15
Gemcitabine (Gemzar) 1000 mg/m2 iv over 30 min d1, 8, 15
Q4w x 6 cycles
Einhorn LH et al. Phase II study of paclitaxel plus gemcitabine salvage chemotherapy for germ cell tumors after progression following high-dose chemotherapy with tandem transplant. J Clin Oncol 2007; 25:513 (link to the article).
Hinton, S et al. Phase II study of paclitaxel plus gemcitabine in refractory germ cell tumors (E9897): a trial of the Eastern Cooperative Oncology Group. J Clin Oncol 2002; 20:1859 (link to the article)."

Body Surface Area Calculator for medication doses

Calculates Body Surface Area for medication doses and includes descriptive statistics.

Step 1. Enter Height & Weight then click "Calculate". Weight: can  convert lbs to kg Height:    or       using Formula: click for info re: Body Surface Area formulas Body Surface Area = m2

Step 2.  Safety Check.  Set Age and Gender, then re-Calculate. Age:  years or  Gender:   Body description:   Step 3. Optional Medication Dose Calculator Multiply BSA m2  x Dose/m2 equals

Additional Statistics: Height is at: Compared to others of same Age Weight is at: Weight is at: Compared to others of same Height

Other formulas: Body Mass Index: kg/m2 Lean Body Weight: Ideal Body Weight:

for default units ( lbs/kg, in/cm) and calculation formula.

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LOOKING DEEPER INTO THIS

IS IT THE CYTOKINES AGAIN?
how to detect vascular health?
objective 130/80
biomarkers for detecting risk of stroke, A-fib, ESRD,peripheral
and how that correlate with BMI and age, and level of HTN

Cytokine Bank!

Nothing will produce such a bounce in medicine
there no parallel in progress in medicine
but constitution of a cytokine bank will have the most benefit both financially and medically without precedent!  Its touch will be wide, unprecedent and a marvel in science.   With genetic know how of current days, an amplification of minimally present cytokine could have unpredictable effect. A cytokine storm kill the host, there is no increment or change in our cells that is more likely cytokine driven, it leads to scar and every major complicated syndrome includes somewhere cytokine release or activity.  From PTSD to diarrhea, from treatment of cancers (IL-2 for renal cell cancer including the rare cures in this disease come from IL-2), from lung fibrosis to why CD4 drops in HIV, you name you got it in medicine, from being young to becoming old, all phenomena are affected by Cytokines.  We know this and the cytokines know they exist, but we keep our heads in the sand.  But I know this, medicine of the next century will be made by how much a condition needs in term of cytokine to be treated.

We got to start a cytokine Bank Now!

HOW CAN WE GO WRONG?

WIKIPIDEA FOR EXAMPLE:

"

• Immunoglobulin (Ig) superfamily, which are ubiquitously present throughout several cells and tissues of the vertebrate body, and share structural homology with immunoglobulins (antibodies), cell adhesion molecules, and even some cytokines. Examples: IL-1 receptor types.
• Hemopoietic Growth Factor (type 1) family, whose members have certain conserved motifs in their extracellular amino-acid domain. The IL-2 receptor belongs to this chain, whose γ-chain (common to several other cytokines) deficiency is directly responsible for the x-linked form of Severe Combined Immunodeficiency (X-SCID).
• Interferon (type 2) family, whose members are receptors for IFN β and γ.
• Tumor necrosis factors (TNF) (type 3) family, whose members share a cysteine-rich common extracellular binding domain, and includes several other non-cytokine ligands like CD40, CD27 and CD30, besides the ligands on which the family is named (TNF).
• Seven transmembrane helix family, the ubiquitous receptor type of the animal kingdom. All G protein-coupled receptors (for hormones and neurotransmitters) belong to this family. Chemokine receptors, two of which act as binding proteins for HIV (CD4 and CCR5), also belong to this family.^{[citation needed]}
• Interleukin-17 receptor (IL-17R) family, which shows little homology with any other cytokine receptor family. Structural motifs conserved between members of this family include: an extracellular fibronectin III-like domain, a transmembrane domain and a cytoplasmic SERIF domain. The known members of this family are as follows: IL-17RA, IL-17RB, IL-17RC, IL17RD and IL-17RE.^[12]
• Interleukin-12 (IL-12), secreted by macrophages and act on T_H0 (T-helper cell 0) and convert into T_H1 (T-helper cell 1)which produce IFN γ. IFN γ activates macrophages, thus starting cell mediated immune response."

AND THIS IS JUST A START!

ZERO-ING ON MEMBRANE PHENOMENA

*Metastatic processes are facilitated with depression of E-Cadherin
but are PKP2 also depressed or overexpressed
does the processes of metastatic diseases different than base line natural cellular displacement in terms of Vimentin, plakoglobin, and desmoplakin expression.  Or are these proteins behaving the same way no matter the cellular process.
*Can these parameters translate well the activity of Taxotere.
*Can level of methylated Vimentin coincide with Taxotere resistance or susceptibility, or level of side effects in the patient being treated.
*Can these genes reliably predict Adriamycin toxicity!
*can tightening Microtubule -Vimentin interaction by Antibody slow down cancer metastatic potentials?
*Is Tuberin/Hamartin more easily evaluated in the peripheral sera
*

Human Papillomavirus 16 E6 Oncoprotein Interferences with Insulin Signaling Pathway by Binding to Tuberin

Zheming Lu ET AL!

NOW DOES LEVEL OF TUBERIN REFLECT LEVEL OF ACTIVITY OF E6, TRANSFORMATION IN CERVICAL CANCER, OR RESPONSE TO PLATIN BASED CHEMOTHERAPY, OR SIDE EFFECT LINKED TO INVOLVEMENT OF INSULIN, CNS DISEASES OR SIDE EFFECTS

looking into new targets

Casolaro et al

" Recently Polo-Like Kinase 1 (PLK1) has emerged as a new candidate drug target in AML."
but evidence is imposing PLGC1 because of its critical interactions with Gerb2 and DVL1, the FLT
and may be more importantly with ETS.

*Anti-NHE1/CHP could have a larger impact in resistant Thyroid cancers theoritically, or diseases where the Calcineurin/NFAT have a stronger role?

from those who know the regulators of major pathways!

"Nde1, Lis1, and Brap regulates the dynamic MAPK signaling threshold in a spatially dependent fashion. Brap, a mitogen-activated protein kinase (MAPK) signaling threshold modulator,"
what more, we need to find out!

Careful what you read

In cancer reading, one should be careful because so much remains unknown
most of the time, the reader is exposed to the writer interpretation of facts.
One may suggest that a gene amplification, mutation or repression is bad for the cancer as if that gene presentation is notoriously bad for the patient.  The statement tends to suggest the presence of this gene variation from the norm to be either predictive or prognosis.   But little is said on whether that gene happens to be bad because the use of the current therapy ensure a poor response!   What is bad is not the gene presence, it is the use of a poor therapy that worsen the situation.   This is why target therapy is warranted!  Now it is true that at current time, we don't know it all, but one thing is for sure, as we progress with medicine, and as we know more, our therapy is improving sharply...our patient are noticing the difference.  Our Colon cancer patients have ripped the benefit...and so do those with Multiple Myeloma.

But there are recalcitrant cancers such as the Gliomas in which we are still struggling!  But so we intensify our research...

One other area of caution is the weight loss in our cancer patients.  We like the idea that there is associated production of cytokine or growth factors that accompany cancers and causes the cachexia or marked weight loss in these diseases.  Cachectins and other cytokines have been thrown at our faces as a reason for the phenomena.  We fail to recognize that deep in the belly of genes draining the cancers, these unique perturbations of genes actually directly affect other genes compromising the Glucolysis or Glucogenesis.  ie TPI genes (G3P combination to DHAP). And that may be supplying the end result to this combination to these patient should be a therapeutic intervention to be incorporated in the therapeutic strategy (if the failure is diagnosed).  We could use Giardia infection as a sign this is actually happening!  wake up folks we see this all the time!

(to be continued)