CPRIT/Update from Interim Executive Director - 05/28/2013
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Tuesday, May 28, 2013
CPRIT/Update from Interim Executive Director - 05/28/2013
HYPOMETHYLATION, NEW AREA OF RESEARCH
With the laws of nature described here, we continue to maintain that therapeutic interventions follow the various stages or layers of the cell. That is there are drugs acting at membrane level, cytosolic level, mitochondria, nuclear etc...And combination therapy to be significant, should combine at least 2 different classes following these layers of cell division suggested.
In the Epigenic region, a prominent activity is methylation of genes. This is achieved for promoting or silencing certain genes. The effect is certain when the genes involved are promoters or globally regulators of some function of significant. In Leukemia, we have argued that the mains events are nuclear and epigenic (with a secondary lymphokine effect) putting center Hypomethylation as a therapeutic intervention. Indeed, other than induction chemotherapy using drugs inducing Nuclear havoc (Cytarabine and Daunorubicin), Decitabine and related Hypomethylating drugs have been the significant main intervention, particularly in the adult population because of perceived poor tolerance of standard induction approaches.
With the advance of target therapy, Hypomethylation has entered the microscopy of researcher. It is now combined to standard induction in clinical trial. Decitabine treatment has now been 10 days with better results, and much more is being done to further dissect how this group of drug works. In fact, the knowledge that these medications are at risk of Deamination, has prompted studies of Anti-deaminasation (Plerixafor-an anti-CXCR4). The challenge remains though! which gene is actually being methylated and when. Methylation gene is a quick evolving history in a living cell and can quickly change however under effect of Core-binding like molecules, neoplastic processes, and or drug treatments! Scientists are hard at work.
With the laws of nature described here, we continue to maintain that therapeutic interventions follow the various stages or layers of the cell. That is there are drugs acting at membrane level, cytosolic level, mitochondria, nuclear etc...And combination therapy to be significant, should combine at least 2 different classes following these layers of cell division suggested.
In the Epigenic region, a prominent activity is methylation of genes. This is achieved for promoting or silencing certain genes. The effect is certain when the genes involved are promoters or globally regulators of some function of significant. In Leukemia, we have argued that the mains events are nuclear and epigenic (with a secondary lymphokine effect) putting center Hypomethylation as a therapeutic intervention. Indeed, other than induction chemotherapy using drugs inducing Nuclear havoc (Cytarabine and Daunorubicin), Decitabine and related Hypomethylating drugs have been the significant main intervention, particularly in the adult population because of perceived poor tolerance of standard induction approaches.
With the advance of target therapy, Hypomethylation has entered the microscopy of researcher. It is now combined to standard induction in clinical trial. Decitabine treatment has now been 10 days with better results, and much more is being done to further dissect how this group of drug works. In fact, the knowledge that these medications are at risk of Deamination, has prompted studies of Anti-deaminasation (Plerixafor-an anti-CXCR4). The challenge remains though! which gene is actually being methylated and when. Methylation gene is a quick evolving history in a living cell and can quickly change however under effect of Core-binding like molecules, neoplastic processes, and or drug treatments! Scientists are hard at work.
THE RETURN OF GEMTUZUMAB.
Here is a drug that was the FDA dis-approved believing it has closed the coffin on it. But straight from the cemetery, an uproar is coming to rattle the FDA door once again! The point is while the door closed on Gemtuzumab here in the USA, the European have continued using the drug at least at clinical trial basis. Evidence suggesting that when added to Cytarabine, Gentuzumab could double or triple 2 year survival and increase by 10 months overall survival, is hard to conceal or reject. This has forced Americans to reconsider, new clinical trial has been re-completed here, and soon the FDA has to convene for these new indications!
Here is a drug that was the FDA dis-approved believing it has closed the coffin on it. But straight from the cemetery, an uproar is coming to rattle the FDA door once again! The point is while the door closed on Gemtuzumab here in the USA, the European have continued using the drug at least at clinical trial basis. Evidence suggesting that when added to Cytarabine, Gentuzumab could double or triple 2 year survival and increase by 10 months overall survival, is hard to conceal or reject. This has forced Americans to reconsider, new clinical trial has been re-completed here, and soon the FDA has to convene for these new indications!
GENES VERSUS CHROMOSOME ABNORMALITY
AS WE MOVE FORWARD, ABNORMALITY IN GENES WILL BE MORE IMPORTANT AS FAR AS CLINICAL RELEVANCE IS CONCERNED. ONCE UPON A TIME CHROMOSOME ABNORMALITY WAS RELEVANT BUT WITH THE NOW RISING INTEREST IN TARGET THERAPY, THE GENE IS THE FOCUS OF ATTENTION.
IT IS TRUE KNOWING THAT ABNORMALITY OF THIS AND THAT CHROMOSOME WAS RARELY RELEVANT FROM THERAPEUTIC STAND POINT UNTIL YOU DISSECT THE GENES INVOLVED. DEL OF 5q IN MYELODYSPLASIA WAS THE MOST CITED EXAMPLE OF HOW REVLIMID HELPED THE CHROMOSOMAL DETECTION EXAMPLE, BUT THE FACT IS, IT IS STILL UNCLEAR WHAT GENES IN THIS SCENARIO ARE AT PLAY. AND THE NEED TO DO BETTER AT TARGETING CALL FOR GENE IDENTIFICATION RATHER THAN GLOBAL CYTOGENETIC STUDIES!
LOOKING AT THIS CLOSER, EUROPEAN INVESTIGATORS ARE NOW THE TRUE MECHANISM OF ACTION OF SOME WELL ESTABLISH MEDICATIONS. AZACITIDINE FOR EXAMPLE IS NOW INCREASING RECOGNIZED AS A IMMUNE-MODULATOR BECAUSE OF ITS EFFECT ON T-CELL. IT IS ACTUALLY TRUE THAT IF YOU FOLLOW THE NF-kB, C-JUN AND FOS (INVOLVEMENT OF GROWTH FACTORS), YOU QUICKY WILL ARRIVE IN THE EPIGENIC REGION WHERE HYPOMETHYLATION, SPLICING, m-ARN TRANSFERASE AND OTHER RELEVANT ACTIVITY CO-MINGLE AND CO-ACTIVATE AT RAPID PACE MAKING DISSECTION AND ATTRIBUTION OF ROLE DICEY OR TRICKY.
ON OTHER FRONT, STILL LOOKING INTO MECHANISM OF ACTION OF KNOWN DRUG, THE THALIDOMID STORY GOT A NEW DEVELOPMENT WITH THE ANNOUNCEMENT THAT FDF8 WAS THE TERATOGENIC BASIS OF THALIDOMID ACTIVITY! IF BY TERATOGENESIS, WE MEAN MORPHOLOGIC ABNORMALITY, THIS WILL BE A SIGNIFICANT DEVELOPMENT. HOW IS FDF8 RELATED TO ANGIOGENESIS? IS FDF8 RELEVENT ONLY TO THALIDOMID OR SHOULD ALTERATION HERE BE BROADLY APPLIED TO CHECK ALL DRUGS FOR TERATOGENIC POTENTIAL? HOW IS FDF8 RELATED TO MESENGIAL TRANSFORMATION...MUCH IS TO BE LEARNED YET! SUFFICE IS TO SAY THAT A GENE INVOLVING SIGNIFICANT MORPHOLOGIC CHANGES IS DEFINITELY AN IMPORTANT GENE!
AS WE MOVE FORWARD, ABNORMALITY IN GENES WILL BE MORE IMPORTANT AS FAR AS CLINICAL RELEVANCE IS CONCERNED. ONCE UPON A TIME CHROMOSOME ABNORMALITY WAS RELEVANT BUT WITH THE NOW RISING INTEREST IN TARGET THERAPY, THE GENE IS THE FOCUS OF ATTENTION.
IT IS TRUE KNOWING THAT ABNORMALITY OF THIS AND THAT CHROMOSOME WAS RARELY RELEVANT FROM THERAPEUTIC STAND POINT UNTIL YOU DISSECT THE GENES INVOLVED. DEL OF 5q IN MYELODYSPLASIA WAS THE MOST CITED EXAMPLE OF HOW REVLIMID HELPED THE CHROMOSOMAL DETECTION EXAMPLE, BUT THE FACT IS, IT IS STILL UNCLEAR WHAT GENES IN THIS SCENARIO ARE AT PLAY. AND THE NEED TO DO BETTER AT TARGETING CALL FOR GENE IDENTIFICATION RATHER THAN GLOBAL CYTOGENETIC STUDIES!
LOOKING AT THIS CLOSER, EUROPEAN INVESTIGATORS ARE NOW THE TRUE MECHANISM OF ACTION OF SOME WELL ESTABLISH MEDICATIONS. AZACITIDINE FOR EXAMPLE IS NOW INCREASING RECOGNIZED AS A IMMUNE-MODULATOR BECAUSE OF ITS EFFECT ON T-CELL. IT IS ACTUALLY TRUE THAT IF YOU FOLLOW THE NF-kB, C-JUN AND FOS (INVOLVEMENT OF GROWTH FACTORS), YOU QUICKY WILL ARRIVE IN THE EPIGENIC REGION WHERE HYPOMETHYLATION, SPLICING, m-ARN TRANSFERASE AND OTHER RELEVANT ACTIVITY CO-MINGLE AND CO-ACTIVATE AT RAPID PACE MAKING DISSECTION AND ATTRIBUTION OF ROLE DICEY OR TRICKY.
ON OTHER FRONT, STILL LOOKING INTO MECHANISM OF ACTION OF KNOWN DRUG, THE THALIDOMID STORY GOT A NEW DEVELOPMENT WITH THE ANNOUNCEMENT THAT FDF8 WAS THE TERATOGENIC BASIS OF THALIDOMID ACTIVITY! IF BY TERATOGENESIS, WE MEAN MORPHOLOGIC ABNORMALITY, THIS WILL BE A SIGNIFICANT DEVELOPMENT. HOW IS FDF8 RELATED TO ANGIOGENESIS? IS FDF8 RELEVENT ONLY TO THALIDOMID OR SHOULD ALTERATION HERE BE BROADLY APPLIED TO CHECK ALL DRUGS FOR TERATOGENIC POTENTIAL? HOW IS FDF8 RELATED TO MESENGIAL TRANSFORMATION...MUCH IS TO BE LEARNED YET! SUFFICE IS TO SAY THAT A GENE INVOLVING SIGNIFICANT MORPHOLOGIC CHANGES IS DEFINITELY AN IMPORTANT GENE!
When finished printing this certificate, click here to go to your CME Tracker »
CONTINUING MEDICAL EDUCATION CERTIFICATE
certifies that
Mutombo Kankonde, MD
2400 Trawood Drive
Suite 303
El Paso, TX 79936
2400 Trawood Drive
Suite 303
El Paso, TX 79936
has participated in the enduring material titled
Acute Myeloid Leukemia and Myelodysplastic Syndromes in Older Patients
May 28, 2013
and is awarded
2.25
AMA PRA Category 1 Credit(s)™.
Medscape, LLC designates this enduring material for a maximum of 2.25 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.
Medscape, LLC is accredited by the Accreditation Council for
Continuing Medical Education (ACCME) to provide continuing medical
education for physicians.
For information on
applicability and acceptance of continuing education credit for this
activity, please consult your professional licensing board.
| Certificate Number: 43110741 |  Cyndi Grimes Director, Continuing Medical Education Medscape, LLC |
BONE MARROW TRANSPLANTERS ARE NOW COMING UP WITH A FLEXIBLE ARGUMENT. THEY HAVE COME TO THE REALIZATION THAT THE CUT OFF POINT OF 65 YEARS OF AGE IS NOT WORKING OUT TOO GOOD FOR THEM! MYELODYSPLASIA AND LEUKEMIAS ARE DISEASES OF AN EVER GROWING POPULATION. AND THE ELDERLY ARE THE BULK OF THE PATIENTS. AND 65 YEARS OF AGE IS NOT ENOUGH IN THE DEFINITION OF ELDERLY.
THE NEW WORD NOW IS "COMORBIDITY INDEX" AND INCLUDE
1. PERFORMANCE STATUS
2. ALBUMIN LEVEL
3. CREATININE LEVEL
4. AGE
5. PLATELET COUNT
6. BLAST COUNT
7. PRIMARY versus SECONDARY AML
YES MDS/AML ARE ON THE INCREASE
AND THERE MORE AND MORE ADULTS OVER 65 YEAR OF AGE UNDERGOING SOME FORM OF TRANSPLANT!
THE NEW WORD NOW IS "COMORBIDITY INDEX" AND INCLUDE
1. PERFORMANCE STATUS
2. ALBUMIN LEVEL
3. CREATININE LEVEL
4. AGE
5. PLATELET COUNT
6. BLAST COUNT
7. PRIMARY versus SECONDARY AML
YES MDS/AML ARE ON THE INCREASE
AND THERE MORE AND MORE ADULTS OVER 65 YEAR OF AGE UNDERGOING SOME FORM OF TRANSPLANT!
WHILE IT IS TRUE THAT UNIVERSITIES ARE BY DEFINITION LEADERS IN SCIENCE
IT IS ALSO TRUE THAT SCIENCE PROVIDE ENOUGH OPPORTUNITIES FOR RESEARCH TO PROVIDE ONE WHO IS WILLING A CHANCE TO CREATE ORIGINAL. TESTING AND EVALUATION OF RESULTS IS THE ONLY CONCRETE ADVANCES THAT PROVIDE THE FRAME WORK OF FUTURE WORK, GIVE US A CHANCE OR CLEAR THE WAY, AND LET FREEDOM OF THINKING REIGN WITHOUT HINDRANCE!
IT IS GOOD TO HAVE CONSENSUS ON WHAT IS IMPORTANT AND TRUE, BUT IN RESEARCH, LET IMAGINATION REIGN BECAUSE WHAT IS TRUE TODAY MAY NOT BE TOMORROW, AND UNTIL IMAGINATION IS FREED, NO NEW LEADS WILL BE CREATED, AND WHAT IS TRUE TODAY BUT FALSE TOMORROW WILL NOT BE CORRECTED. WHEN IT COMES TO RESEARCH, FOLLOWING OUR LEADERS IS NOT THE ONLY WAY TO THE TRUTH OR THE CURE! ONE HAS TO CONTINUOUSLY QUESTION THE PREMISES. IT IS WHY THE SUPREME COURT EXISTS DESPITE THE DICTATES OF A CONSTITUTION WHICH HAS WITHSTAND THE TIME.
TO WIN, YOU CAN FOLLOW FOR A WHILE, BUT AT A CERTAIN TIME IN THE PATH, YOU HAVE GOT TO DEMARCATE, TAKE A DIFFERENT TANGENT AND BREAK FREE, AND THIS DESPITE THE UPROAR. AND WHILE YOU ARE FOLLOWING, KNOW THE OPPONENT WELL AND WHAT HE IS UP TO!
BUT REMEMBER, YOU CAN NOT WIN BY STRICTLY FOLLOWING!
IT IS ALSO TRUE THAT SCIENCE PROVIDE ENOUGH OPPORTUNITIES FOR RESEARCH TO PROVIDE ONE WHO IS WILLING A CHANCE TO CREATE ORIGINAL. TESTING AND EVALUATION OF RESULTS IS THE ONLY CONCRETE ADVANCES THAT PROVIDE THE FRAME WORK OF FUTURE WORK, GIVE US A CHANCE OR CLEAR THE WAY, AND LET FREEDOM OF THINKING REIGN WITHOUT HINDRANCE!
IT IS GOOD TO HAVE CONSENSUS ON WHAT IS IMPORTANT AND TRUE, BUT IN RESEARCH, LET IMAGINATION REIGN BECAUSE WHAT IS TRUE TODAY MAY NOT BE TOMORROW, AND UNTIL IMAGINATION IS FREED, NO NEW LEADS WILL BE CREATED, AND WHAT IS TRUE TODAY BUT FALSE TOMORROW WILL NOT BE CORRECTED. WHEN IT COMES TO RESEARCH, FOLLOWING OUR LEADERS IS NOT THE ONLY WAY TO THE TRUTH OR THE CURE! ONE HAS TO CONTINUOUSLY QUESTION THE PREMISES. IT IS WHY THE SUPREME COURT EXISTS DESPITE THE DICTATES OF A CONSTITUTION WHICH HAS WITHSTAND THE TIME.
TO WIN, YOU CAN FOLLOW FOR A WHILE, BUT AT A CERTAIN TIME IN THE PATH, YOU HAVE GOT TO DEMARCATE, TAKE A DIFFERENT TANGENT AND BREAK FREE, AND THIS DESPITE THE UPROAR. AND WHILE YOU ARE FOLLOWING, KNOW THE OPPONENT WELL AND WHAT HE IS UP TO!
BUT REMEMBER, YOU CAN NOT WIN BY STRICTLY FOLLOWING!
Sunday, May 26, 2013
- RETINOBLASTOMA
- "One function of pRb is to prevent excessive cell growth by inhibiting cell cycle progression until a cell is ready to divide. It is also a recruiter of several chromatin remodeling enzymes such as methylases and acetylases.
pRb belongs to the pocket protein family, whose members have a pocket for the functional binding of other proteins.[2][3] Should an oncogenic protein, such as those produced by cells infected by high-risk types of human papillomaviruses, bind and inactivate pRb, this can lead to cancer."
REPORTEDLY THIS EFFECT OF Rb GENE GO THROUGH CDKs
"
Cyclin-dependent kinases (CDKs) play essential roles in cell proliferation and gene expression. Although distinct sets of CDKs work in cell division and transcription by RNA polymerase II (Pol II), they share a CDK-activating kinase (CAK), which is itself a CDK-Cdk7-in metazoans."FISHER ET AL
"
- cholera toxin - increase cAMP levelsIn a cAMP-dependent pathway, the activated Gs alpha subunit binds to and activates an enzyme called adenylyl cyclase, which, in turn, catalyzes the conversion of ATP into cyclic adenosine monophosphate (cAMP).[2] Increases in concentration of the second messenger cAMP may lead to the activation of
- cyclic nucleotide-gated ion channels[3]
- exchange proteins activated by cAMP (EPAC)[4] such as RAPGEF3
- an enzyme called protein kinase A (PKA).[5]
- enzymes that convert glycogen into glucose
- enzymes that promote muscle contraction in the heart leading to an increase in heart rate
- transcription factors, which regulate gene expression
(cyclin-dependent kinase 7 (CDK7) has essential roles in both the cell-division cycle and transcription, as a CDK-activating kinase (CAK) and as a component of the general transcription factor TFIIH,") FISHER
Cyclic AMP inhibits the proliferation of thyroid carcinoma cell lines through regulation of CDK4 phosphorylation.(Rocha)
AND
Rb inactivation in cell cycle and cancer: the puzzle of highly regulated activating phosphorylation of CDK4 versus constitutively active CDK-activating kinase.(Paternot et al!)
LINKING cyclic-AMP to Rb
-------------
activators of c-AMP
Paternot S, Bockstaele L,- forskolin - a diterpene natural product that activates adenylyl cyclase
- caffeine and theophylline inhibit cAMP phosphodiesterase, which leads to an activation of G proteins that result in the activation of the cAMP pathway
- bucladesine (dibutyryl cAMP, db cAMP) - also a phosphodiesterase inhibitor
- pertussis toxin, which increase cAMP levels by inhibiting Gi to its GDP (inactive) form. This leads to an increase in adenylyl cyclase, therefore increasing cAMP levels, which can lead to an increase in insulin and therefore hypoglycemia (WIKIPEDIA)
take Theophylline for that matter!
DO NOT DRINK COFFEE WITH MTORC1 DRIVEN CONDITION?
YOU BE THE JUDGE!
ALK GENE
Involvement with Neoplasia
although ALK can be involved by amplification and mutation, but it is its fusion to other genes that is the most remarkable determinant to a neoplastic transformation of the involved cell. Also the type of splicing it undergoes in some tissues will be somewhat specific in that certain Axons will be prevalent in some tissues.
"ALK, itself activates both the PI3K and the MAPK cascades"
Amplification of genes involved in Metastatic processes (Catenins) and events at P53 further exacerbate the aggressivenes of the cancer. And so does involvement of the c-MET cascade which fortunately is easily blocked by Crizotinib. (Crizotinib also inhibits the c-Met/Hepatocyte growth factor receptor (HGFR) tyrosine kinase, which is involved in the oncogenesis of a number of other histological forms of malignant neoplasms.[9]wikipidia) Of note, HGFR is the only known path to c-MET suggesting it is the revolving door mentioned in early blogs!
AMPLIFICATION OF THE MAPK IS EQUIVALENTLY MATCHED BY A DROP IN EXPRESSION OF c-JUN AND FOX, AT LEAST IN THYROID CANCER, SUGGESTING POSSIBLY THAT IN THIS DISEASE CYTOKINE ARE UPREGULATED AND THAT MOST LIKELY THE INITIAL EVENT MAY HAVE NOT BEEN HSP90 DRIVEN!
THE ACTIVITY OF CRIZOTININB IN ALK POSITIVE LYMPHOMA COULD INTUITIVELY MORE RELATED TO THE COEXISTENCE OF ROS-1, AND SHOULD MORE LIKELY BE RE-EMPHASIZED BY A CLINICAL TRIAL IF ANY EXIST BECAUSE ALTHOUGH ROS-1 IS PART OF THE SONS OF THE SEVENLESS (PUTTING ITS ACTION SQUARELY AR THE RAS RECEPTOR, ROS-1 IS THE PASS TO ACTIVATION OF PTPN6 WHICH ENLISHES A STRONG CASCADE:
" PTPN6 has been shown to interact with Lymphocyte cytosolic protein 2,[4][5] Janus kinase 2,[6][7] Lck,[8][9][10] PTK2B,[11][12] CD117,[13][14] CD31,[15][16] CD22,[17][18][19][20][21] FCRL3,[22] Homeobox A10,[23] Signal-regulatory protein alpha,[24][25] Tyrosine kinase 2,[26] CTNND1,[27] Grb2,[11][28][29] LILRB2,[30][31] Syk,[11][32] ROS1,[33] Epidermal growth factor receptor,[34][35] Erythropoietin receptor,[36] BCR gene,[37] PRKCD,[38] LAIR1[24][39][40][41][42] and LILRB4." (LIST OF ALL TARGETABLE GENE IN THE ALK POSITIVE LYMPHOMA. AND AS DISCUSSED GRB 2 IS THE FOCUS OF OUR ATTENTION AT CRBCM. THESE GENES ARE CRITICAL IN THE Lyn-CD22-SHP-1 pathway WHICH COULD BE ALL YOU NEED TO CONTROL (ANTI CD 22).
THE EXISTENCE OF CTNND1 IN THIS RENDITION OF GENES IS NOTABLE, THAT IS THAT SOMEWHERE ALONG THE LINE IMMUNOTHERAPY OR ANTI-ROS-1 MAY HAVE A ROLE IN ANAPLASTIC CANCERS WHICH OVER EXPRESS THE ROS-1 MUTATION! IN ITS METASTATIC PHASE THAT IS. "activation of β-catenin could represent another mechanism leading to the ATC (THYROID) phenotype. Indeed in one study, such mutations were found in 61% of the lesions but not in the precursor lesions" (HEBRANT ET AL)
ASSOCIATION WITH TWIST ONE IS BAD!
"Twist1 has been shown to be involved in evading apoptosis, making the tumour cells resistant against chemotherapeutic drugs like cisplatin.[12] Moreover, Twist1 has been shown to be expressed under conditions of hypoxia, corresponding to the observation that hypoxic cells respond less to chemotherapeutic drugs.[11]
Another process in which Twist 1 is involved is tumour metastasis. The underlying mechanism is not completely known yet, but at least implicates the upregulation of matrix metalloproteinases[13] and inhibition of TIMP.[14]" WIKIPIDIA
ROCHA ET AL
"However, cAMP differentially inhibited the pRb-kinase activity and T172-phosphorylation of CDK4 complexed to cyclin D1 or cyclin D3, whereas CDK-activating kinase activity remained unaffected".
OPENING AN OPPORTUNITY FOR INTERVENTION! (BY BLOCKING TGF-BETA1 WHICH SEEMS TO FIGHT c-AMP) AGAIN REMEMBER THAT c-JUN IS SUPPRESSED, AN EVIDENCE THAT CYTOKINS AND TGF ARE WILDLY OVER EXPRESSED IN THESE DISEASES!
Involvement with Neoplasia
although ALK can be involved by amplification and mutation, but it is its fusion to other genes that is the most remarkable determinant to a neoplastic transformation of the involved cell. Also the type of splicing it undergoes in some tissues will be somewhat specific in that certain Axons will be prevalent in some tissues.
"ALK, itself activates both the PI3K and the MAPK cascades"
Amplification of genes involved in Metastatic processes (Catenins) and events at P53 further exacerbate the aggressivenes of the cancer. And so does involvement of the c-MET cascade which fortunately is easily blocked by Crizotinib. (Crizotinib also inhibits the c-Met/Hepatocyte growth factor receptor (HGFR) tyrosine kinase, which is involved in the oncogenesis of a number of other histological forms of malignant neoplasms.[9]wikipidia) Of note, HGFR is the only known path to c-MET suggesting it is the revolving door mentioned in early blogs!
AMPLIFICATION OF THE MAPK IS EQUIVALENTLY MATCHED BY A DROP IN EXPRESSION OF c-JUN AND FOX, AT LEAST IN THYROID CANCER, SUGGESTING POSSIBLY THAT IN THIS DISEASE CYTOKINE ARE UPREGULATED AND THAT MOST LIKELY THE INITIAL EVENT MAY HAVE NOT BEEN HSP90 DRIVEN!
THE ACTIVITY OF CRIZOTININB IN ALK POSITIVE LYMPHOMA COULD INTUITIVELY MORE RELATED TO THE COEXISTENCE OF ROS-1, AND SHOULD MORE LIKELY BE RE-EMPHASIZED BY A CLINICAL TRIAL IF ANY EXIST BECAUSE ALTHOUGH ROS-1 IS PART OF THE SONS OF THE SEVENLESS (PUTTING ITS ACTION SQUARELY AR THE RAS RECEPTOR, ROS-1 IS THE PASS TO ACTIVATION OF PTPN6 WHICH ENLISHES A STRONG CASCADE:
" PTPN6 has been shown to interact with Lymphocyte cytosolic protein 2,[4][5] Janus kinase 2,[6][7] Lck,[8][9][10] PTK2B,[11][12] CD117,[13][14] CD31,[15][16] CD22,[17][18][19][20][21] FCRL3,[22] Homeobox A10,[23] Signal-regulatory protein alpha,[24][25] Tyrosine kinase 2,[26] CTNND1,[27] Grb2,[11][28][29] LILRB2,[30][31] Syk,[11][32] ROS1,[33] Epidermal growth factor receptor,[34][35] Erythropoietin receptor,[36] BCR gene,[37] PRKCD,[38] LAIR1[24][39][40][41][42] and LILRB4." (LIST OF ALL TARGETABLE GENE IN THE ALK POSITIVE LYMPHOMA. AND AS DISCUSSED GRB 2 IS THE FOCUS OF OUR ATTENTION AT CRBCM. THESE GENES ARE CRITICAL IN THE Lyn-CD22-SHP-1 pathway WHICH COULD BE ALL YOU NEED TO CONTROL (ANTI CD 22).
THE EXISTENCE OF CTNND1 IN THIS RENDITION OF GENES IS NOTABLE, THAT IS THAT SOMEWHERE ALONG THE LINE IMMUNOTHERAPY OR ANTI-ROS-1 MAY HAVE A ROLE IN ANAPLASTIC CANCERS WHICH OVER EXPRESS THE ROS-1 MUTATION! IN ITS METASTATIC PHASE THAT IS. "activation of β-catenin could represent another mechanism leading to the ATC (THYROID) phenotype. Indeed in one study, such mutations were found in 61% of the lesions but not in the precursor lesions" (HEBRANT ET AL)
ASSOCIATION WITH TWIST ONE IS BAD!
"Twist1 has been shown to be involved in evading apoptosis, making the tumour cells resistant against chemotherapeutic drugs like cisplatin.[12] Moreover, Twist1 has been shown to be expressed under conditions of hypoxia, corresponding to the observation that hypoxic cells respond less to chemotherapeutic drugs.[11]
Another process in which Twist 1 is involved is tumour metastasis. The underlying mechanism is not completely known yet, but at least implicates the upregulation of matrix metalloproteinases[13] and inhibition of TIMP.[14]" WIKIPIDIA
ROCHA ET AL
"However, cAMP differentially inhibited the pRb-kinase activity and T172-phosphorylation of CDK4 complexed to cyclin D1 or cyclin D3, whereas CDK-activating kinase activity remained unaffected".
OPENING AN OPPORTUNITY FOR INTERVENTION! (BY BLOCKING TGF-BETA1 WHICH SEEMS TO FIGHT c-AMP) AGAIN REMEMBER THAT c-JUN IS SUPPRESSED, AN EVIDENCE THAT CYTOKINS AND TGF ARE WILDLY OVER EXPRESSED IN THESE DISEASES!
Saturday, May 25, 2013
GOVERNMENT AND ITS REACH!
Mutombo Kankonde has been included in the list
of Do Not Forward as notified by the Multi Carrier System (MCS).
This means Mutombo Kankonde may not receive the FFS EHR incentive payment.
Please contact your Medicare Administrative Contractor (MAC) to resolve this.========================================================
THIS IS AN OFFICIAL GOVERNMENT MESSAGE
"I AM INCLUDED IN A LIST, NO SPECIFICATION AS TO WHAT LIST
NO MENTION AS TO WHY
BUT I AM TARGETED, BANNED FROM BENEFIT FROM THE MEDICARE ADMINISTRATION
CAN'T REPLY AS YOU SEE
THE OBAMA ADMINISTRATION IS GETTING AS OBSCURE AS THE GESTAPO
SOME ARE TARGETED WITHOUT CAUSE!
POLITICIANS HAVE THIS REFLEX OF TRYING TO "PLAY POLITIC UNTIL THEY GET CAUGHT! IT HAPPENS AT THE IRS, NOW MEDICARE IS NEXT! IT'S A VIRUS, THEY ALL GET INFECTED, SO SURE OF THEM SELF UNTIL THEY SELF-INFLICT WOUNDS TO NO SURVIVAL! YOU THINK THEY WILL LEARN BY NOW BUT NO! THEY CAN CROSS ME AND PASS BUT IN THEIR VICIOUS HUNGER TO RUIN PEOPLE, THEY WILL TACKLE SOMEONE WITH MUSCLE AND WILL NOT SURVIVE THE FEAST!
POLITICIANS FULL OF THEMSELVES ALWAYS SUCCUMB BECAUSE THEY NEVER LEARN WHEN TO STOP! CRBCM IS A HARD ROCK TO SWALLOW!
|
11:11 PM (3 hours ago)
| | ||
| ||||
of Do Not Forward as notified by the Multi Carrier System (MCS).
This means Mutombo Kankonde may not receive the FFS EHR incentive payment.
Please contact your Medicare Administrative Contractor (MAC) to resolve this.========================================================
THIS IS AN OFFICIAL GOVERNMENT MESSAGE
"I AM INCLUDED IN A LIST, NO SPECIFICATION AS TO WHAT LIST
NO MENTION AS TO WHY
BUT I AM TARGETED, BANNED FROM BENEFIT FROM THE MEDICARE ADMINISTRATION
CAN'T REPLY AS YOU SEE
THE OBAMA ADMINISTRATION IS GETTING AS OBSCURE AS THE GESTAPO
SOME ARE TARGETED WITHOUT CAUSE!
POLITICIANS HAVE THIS REFLEX OF TRYING TO "PLAY POLITIC UNTIL THEY GET CAUGHT! IT HAPPENS AT THE IRS, NOW MEDICARE IS NEXT! IT'S A VIRUS, THEY ALL GET INFECTED, SO SURE OF THEM SELF UNTIL THEY SELF-INFLICT WOUNDS TO NO SURVIVAL! YOU THINK THEY WILL LEARN BY NOW BUT NO! THEY CAN CROSS ME AND PASS BUT IN THEIR VICIOUS HUNGER TO RUIN PEOPLE, THEY WILL TACKLE SOMEONE WITH MUSCLE AND WILL NOT SURVIVE THE FEAST!
POLITICIANS FULL OF THEMSELVES ALWAYS SUCCUMB BECAUSE THEY NEVER LEARN WHEN TO STOP! CRBCM IS A HARD ROCK TO SWALLOW!
Friday, May 24, 2013
NOW TIME FOR SURPRISING NEWS!
Patients With Macular Degeneration at Increased Death Risk
Cataract Surgeons See Laser's Potential in a New Light
FDA Approves Trulign Intraocular Lens
AREDS2: Insights Into Optimal Supplements for AMD
Glucosamine Linked to Increased Intraocular Pressure
Drug & Reference Information
Glucosamine supplementation was linked to
significant, reversible increases in intraocular pressure (IOP) in a
small, retrospective study published online May 23 in JAMA Ophthalmology.
However, the investigators, led by Ryan K. Murphy, DO, from the
University of New England College of Osteopathic Medicine, Biddeford,
Maine, and colleagues, could not exclude the potential for permanent
damage.
"Frequently, patients are being told that while studies give conflicting data as to whether glucosamine and chondroitin sulfate are effective in reducing arthritic pain, there does not appear to be any risk in trying these supplements," Andrew L. Sherman, MD, professor and vice chair of clinical rehabilitation medicine at the University of Miami Leonard M. Miller School of Medicine in Florida, told Medscape Medical News when asked for comment on the study. "This study, if [the findings are confirmed], attacks that premise."
US prevalence of osteoarthritis is 27 million, and for open-angle glaucoma, it exceeds 2 million, according to the Centers for Disease Control and Prevention.
"Although it is [unclear] what the implications of having increased IOP would be for individual patients, the risk is...that ocular damage could possibly occur from what were previously thought to be 'benign' supplements," said Dr. Sherman, who was not involved in the study.
A keen observation by coauthor Edward Hall Jaccoma, MD, clinical associate professor of ophthalmology at the University of New England College of Osteopathic Medicine, provided the impetus for this study.
"A family member I was following as a glaucoma suspect suddenly had a sharp rise in...IOP, and the only change in his life was adding glucosamine supplements for arthritis," Dr. Jaccoma told Medscape Medical News. "I made a tentative connection based on the molecular biology and potential kinship to steroid glaucoma. When he stopped the supplement, his IOP returned to baseline levels. Subsequent observations of...patients on these supplements appear to show an interaction similar to what [happened] in this index patient."
Study Design and Findings
The investigators retrospectively studied 6 men and 11 women, with a mean age of 76 years, who had a history of glucosamine supplementation and ocular hypertension (IOP > 21 mm Hg) or diagnosed open-angle glaucoma, a willingness to discontinue glucosamine, 3 or more IOP measurements within 2 years, and no associated changes in glaucoma medications or eye surgery. Group A (n = 11) had 1 to 3 baseline IOP measurements before starting glucosamine, and group B (n = 6) had no baseline IOP measurements.
IOP increased in group A after starting glucosamine supplementation (P = .001). After glucosamine discontinuation, IOP decreased in group A (P = .002), group B (P = .008), and groups A and B combined (19.5 ± 0.4 to 16.7 ± 3.0 mm Hg in the right eye and 20.3 ± 2.9 to 17.3 ± 2.4 mm Hg in the left eye; P < .001). For any categories or comparisons, the left and right eyes in each patient did not differ significantly.
"Many questions are raised by glucosamine supplementation–associated IOP changes," the study authors write. "This study shows a reversible effect of those changes, which is reassuring. However, the possibility that permanent damage can result from prolonged use of glucosamine supplementation is not eliminated."
Study Limitations and Implications
"Glucosamine supplements are a billion dollar business, and as the baby boom generation looks for ways to stave off their arthritis, more and more of them [turn] to what has been billed as a 'safe supplement,' " said Dr. Jaccoma, who is also director of Southern Maine Eye Associates in Sanford and of New England Dry Eye Center in Kennebunk, Maine. "My concern is that some...of them may end up with glaucomatous damage that could have been prevented or...medicating (or having laser and other surgical interventions) for a disease...that might have been avoided in the subset of 'glucosamine responders.' "
Dr. Jaccoma recommends that at the very least, people at risk for glaucoma have their IOP more closely monitored during glucosamine supplementation.
"I do have a small subset of patients who find glucosamine so helpful to their arthritis that they would prefer to treat the IOP [rather than] give up the supplements," he said. "The large [National Institutes of Health] study on glucosamine suggested there could be a group of arthritic patients who do benefit from this supplement, but the majority did not show much, if any, benefit. Given that data, it appears that many may be taking this supplement needlessly, if not dangerously."
Study limitations noted by the investigators and Dr. Sherman include its retrospective design and the very small sample with limited generalizability because it consisted of patients who were at least glaucoma suspects. The study did not account for glucosamine dosage, duration, brand, or compliance.
"[M]y personal observations suggest that the response is very similar to what we see with steroids, in that the average patient will have little IOP effect..., but that there is a higher risk group who must be identified to avoid harm from their steroid treatment," Dr. Jaccoma said. "I believe...we will find a similar...group that reacts this way to glucosamine..., but more research is needed."
Coauthor Mona Doss, MA, also from the University of New England
College of Osteopathic Medicine, suggests larger, randomized clinical
trials are needed to assess dose-dependent increase in IOP with
glucosamine supplementation in different patient groups.
"At this point in time more research is required to definitively change current management," she said. "The clinical implications may indicate consideration by primary care or other providers in recommending such supplementation for arthritis in patients with known risk of elevated IOP or glaucoma."
"These results will need to be replicated in a larger population of patients to be felt to be entirely reliable," Dr. Sherman concluded. "{After confirming] these results with a larger study, [they should] study the real clinical implications of this increase in IOP for...those with and without glaucoma."
The study authors and Dr. Sherman have disclosed no relevant financial relationships.
JAMA Ophthalmol. Published online May 23, 2013. Extract
"Frequently, patients are being told that while studies give conflicting data as to whether glucosamine and chondroitin sulfate are effective in reducing arthritic pain, there does not appear to be any risk in trying these supplements," Andrew L. Sherman, MD, professor and vice chair of clinical rehabilitation medicine at the University of Miami Leonard M. Miller School of Medicine in Florida, told Medscape Medical News when asked for comment on the study. "This study, if [the findings are confirmed], attacks that premise."
US prevalence of osteoarthritis is 27 million, and for open-angle glaucoma, it exceeds 2 million, according to the Centers for Disease Control and Prevention.
"Although it is [unclear] what the implications of having increased IOP would be for individual patients, the risk is...that ocular damage could possibly occur from what were previously thought to be 'benign' supplements," said Dr. Sherman, who was not involved in the study.
A keen observation by coauthor Edward Hall Jaccoma, MD, clinical associate professor of ophthalmology at the University of New England College of Osteopathic Medicine, provided the impetus for this study.
"A family member I was following as a glaucoma suspect suddenly had a sharp rise in...IOP, and the only change in his life was adding glucosamine supplements for arthritis," Dr. Jaccoma told Medscape Medical News. "I made a tentative connection based on the molecular biology and potential kinship to steroid glaucoma. When he stopped the supplement, his IOP returned to baseline levels. Subsequent observations of...patients on these supplements appear to show an interaction similar to what [happened] in this index patient."
Study Design and Findings
The investigators retrospectively studied 6 men and 11 women, with a mean age of 76 years, who had a history of glucosamine supplementation and ocular hypertension (IOP > 21 mm Hg) or diagnosed open-angle glaucoma, a willingness to discontinue glucosamine, 3 or more IOP measurements within 2 years, and no associated changes in glaucoma medications or eye surgery. Group A (n = 11) had 1 to 3 baseline IOP measurements before starting glucosamine, and group B (n = 6) had no baseline IOP measurements.
IOP increased in group A after starting glucosamine supplementation (P = .001). After glucosamine discontinuation, IOP decreased in group A (P = .002), group B (P = .008), and groups A and B combined (19.5 ± 0.4 to 16.7 ± 3.0 mm Hg in the right eye and 20.3 ± 2.9 to 17.3 ± 2.4 mm Hg in the left eye; P < .001). For any categories or comparisons, the left and right eyes in each patient did not differ significantly.
"Many questions are raised by glucosamine supplementation–associated IOP changes," the study authors write. "This study shows a reversible effect of those changes, which is reassuring. However, the possibility that permanent damage can result from prolonged use of glucosamine supplementation is not eliminated."
Study Limitations and Implications
"Glucosamine supplements are a billion dollar business, and as the baby boom generation looks for ways to stave off their arthritis, more and more of them [turn] to what has been billed as a 'safe supplement,' " said Dr. Jaccoma, who is also director of Southern Maine Eye Associates in Sanford and of New England Dry Eye Center in Kennebunk, Maine. "My concern is that some...of them may end up with glaucomatous damage that could have been prevented or...medicating (or having laser and other surgical interventions) for a disease...that might have been avoided in the subset of 'glucosamine responders.' "
Dr. Jaccoma recommends that at the very least, people at risk for glaucoma have their IOP more closely monitored during glucosamine supplementation.
"I do have a small subset of patients who find glucosamine so helpful to their arthritis that they would prefer to treat the IOP [rather than] give up the supplements," he said. "The large [National Institutes of Health] study on glucosamine suggested there could be a group of arthritic patients who do benefit from this supplement, but the majority did not show much, if any, benefit. Given that data, it appears that many may be taking this supplement needlessly, if not dangerously."
Study limitations noted by the investigators and Dr. Sherman include its retrospective design and the very small sample with limited generalizability because it consisted of patients who were at least glaucoma suspects. The study did not account for glucosamine dosage, duration, brand, or compliance.
"[M]y personal observations suggest that the response is very similar to what we see with steroids, in that the average patient will have little IOP effect..., but that there is a higher risk group who must be identified to avoid harm from their steroid treatment," Dr. Jaccoma said. "I believe...we will find a similar...group that reacts this way to glucosamine..., but more research is needed."
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"At this point in time more research is required to definitively change current management," she said. "The clinical implications may indicate consideration by primary care or other providers in recommending such supplementation for arthritis in patients with known risk of elevated IOP or glaucoma."
"These results will need to be replicated in a larger population of patients to be felt to be entirely reliable," Dr. Sherman concluded. "{After confirming] these results with a larger study, [they should] study the real clinical implications of this increase in IOP for...those with and without glaucoma."
The study authors and Dr. Sherman have disclosed no relevant financial relationships.
JAMA Ophthalmol. Published online May 23, 2013. Extract
The behavior of Penile cancer is peculiar because of the trigger that set off the neoplastic process
but also because of the extent of pertubations/Mutations of dangerous suppressors genes with impact on major pathways in the the cell. we did discuss about the Human Papilloma Virus (HPV) incriminated in almost half of the penile cancers. And mentioned in passing Herpes II. We did elaborate about E6 and E7.
Here we would like to expand on Genes essentially and particularly bring to the attention of the readers the dangerous involvement of critical genes with significant developments and implications.
Aside from the involvement of E-cadherin (CTNNB1), CCND1 and BIRC5, today we chose to comment on DAPK1 which principally interacts with MITF. MITF will knock down RUNX3 a suppressor gene favoring apoptosis to hyperplasia. It suppression there for favor Hyperplasia and decreases Apoptosis mainly by suppressing the BIM, a pro-apoptotic gene. Suppression of the RUNX3 does not stop there, it unfortunately Activate the TLE gene with 2 dangerous development
1. Activation of the Glycoprotein 130 which could eventually block JAK at the receptor, inducing receptor failure for TGF and IL6 receptor, We have discussed what happen with TGF receptor failure caused while discussing triple negative Breast Cancers (go to article).
2.TLE actions will affect a cross-road GENE called SIX3
SIX3 is a bad gene to bother! (SOME IDENTIFY SIX3 WITH THE SONIC HEDGEHOG PROPER!
At least 4 new genes and pathways are automatically disturbed when SIX3 IS ACTIVATED
1. SOX3
SOX (SRY-related HMG-box) family of transcription factors involved in the regulation of embryonic brain development and in determination of cell fate. The encoded protein acts as a transcriptional activator.[3] Mutations in this gene have been associated with X-linked hypopituitarism (XH) and X-linked mental retardation. Patients with XH are male, have short stature, exhibit a mild form of mental retardation and present pan-hypopituitarism. [2] [4]wikipidia
WE HAVE MADE QUITE CLEAR THE IMPORTANCE OF GENE CAUSING "SHORT STATURE" AND WAY THEY OPEN THE DOOR TO USE OF IMMUNOMODULATOR AS A THERAPEUTIC INTERVENTION. TELLING US THERE IS A ROLE FOR tHALIDOMIDE AND VELCADE IN THIS DISEASE!
2. SIX3 ACTIVATE THE Wnt PATHWAY AND THE SONIC HEDGEHOG
OPENING THE DOOR TO VISMODEGIB
====================================================================================
BETHESDA, MD 30 January 2012—Genentech
and FDA today announced the approval of vismodegib, or Erivedge, for the
treatment of adults with locally advanced basal cell cancer who are not
candidates for surgery or radiotherapy or whose cancer has
metastasized.
PLEASE NOTE THE INVOLVEMENT OF FOXO1, A POTENTIAL DOOR TO APOPTOSIS WHICH IN THIS CASE IS CLOSE.
4. FINALLY AND NOT THE LEAST
SIX3 INTERACTS WITH NOR1
-----------------------------------------------------------------------------------------------------
(NOR1) also known as NR4A3 (nuclear receptor subfamily 4, group A, member 3) is a protein that in humans is encoded by the NR4A3 gene.[1] NOR1 is a member of the nuclear receptor family of intracellular transcription factors.
NOR1 plays a central regulatory role in cell proliferation, differentiation, metabolism[2][3] and apoptosis[4]WIKIPIDIA
------------------------------------------------------------------------------------------------------------------
ENSURING PLENTY OF PROLIFERATION OF PENILE CANCER!
AND THIS IS JUST FOR A START, WAIT UNTIL YOU HERE ABOUT THE EZRIN, S100A4, SCCA, KAI-1, MKI67, PCNA,RASSFIA AND OTHERS AND YOU WILL KNOW WHAT WE ARE UP AGAINST!
but also because of the extent of pertubations/Mutations of dangerous suppressors genes with impact on major pathways in the the cell. we did discuss about the Human Papilloma Virus (HPV) incriminated in almost half of the penile cancers. And mentioned in passing Herpes II. We did elaborate about E6 and E7.
Here we would like to expand on Genes essentially and particularly bring to the attention of the readers the dangerous involvement of critical genes with significant developments and implications.
Aside from the involvement of E-cadherin (CTNNB1), CCND1 and BIRC5, today we chose to comment on DAPK1 which principally interacts with MITF. MITF will knock down RUNX3 a suppressor gene favoring apoptosis to hyperplasia. It suppression there for favor Hyperplasia and decreases Apoptosis mainly by suppressing the BIM, a pro-apoptotic gene. Suppression of the RUNX3 does not stop there, it unfortunately Activate the TLE gene with 2 dangerous development
1. Activation of the Glycoprotein 130 which could eventually block JAK at the receptor, inducing receptor failure for TGF and IL6 receptor, We have discussed what happen with TGF receptor failure caused while discussing triple negative Breast Cancers (go to article).
2.TLE actions will affect a cross-road GENE called SIX3
SIX3 is a bad gene to bother! (SOME IDENTIFY SIX3 WITH THE SONIC HEDGEHOG PROPER!
At least 4 new genes and pathways are automatically disturbed when SIX3 IS ACTIVATED
1. SOX3
SOX (SRY-related HMG-box) family of transcription factors involved in the regulation of embryonic brain development and in determination of cell fate. The encoded protein acts as a transcriptional activator.[3] Mutations in this gene have been associated with X-linked hypopituitarism (XH) and X-linked mental retardation. Patients with XH are male, have short stature, exhibit a mild form of mental retardation and present pan-hypopituitarism. [2] [4]wikipidia
WE HAVE MADE QUITE CLEAR THE IMPORTANCE OF GENE CAUSING "SHORT STATURE" AND WAY THEY OPEN THE DOOR TO USE OF IMMUNOMODULATOR AS A THERAPEUTIC INTERVENTION. TELLING US THERE IS A ROLE FOR tHALIDOMIDE AND VELCADE IN THIS DISEASE!
2. SIX3 ACTIVATE THE Wnt PATHWAY AND THE SONIC HEDGEHOG
OPENING THE DOOR TO VISMODEGIB
====================================================================================
Pharmacy News
FDA Approves First Drug Treatment for Metastatic Basal Cell Carcinoma
The drug, FDA said, is the first one that
the agency has approved specifically for the treatment of metastatic
basal cell carcinoma.
According to vismodegib's labeling (PDF), the dosage is one 150-mg oral capsule daily until the disease progresses or an unacceptable toxicity occurs.
There is no contraindication to therapy with vismodegib.
The drug inhibits the so-called hedgehog
pathway, which, FDA and Genentech said, is active in most basal cell
tumors but also is important to the development of embryos.
A boxed warning in the drug's labeling calls
on health care professionals to advise all patients that vismodegib can
severely harm or kill an embryo or fetus. All women of reproductive
potential and all men are supposed to undertake measures to prevent
pregnancy during vismodegib therapy. Even men who have had a vasectomy
are supposed to use a condom with a spermicide during sex with female
partners. The drug's medication guide addresses these issues.
During the clinical trials of vismodegib in
patients with advanced basal cell carcinoma, the most frequent adverse
reactions were muscle spasms, hair loss, a bad taste in the mouth, and
weight loss. These reactions occurred at a rate of more than 40%.
Diarrhea occurred in 29% of the patients.
FDA said it approved the application to
market vismodegib on the basis of the results of a study of 96 patients,
34% of whom had metastatic basal cell carcinoma. All the patients took
the drug. The cancerous lesions shrank in 30% of the patients with
metastatic disease. Among the patients with locally advance disease, the
lesions shrank or disappeared in 43%.
Genentech, a member of Roche Group, said Erivedge will be available within two weeks.
The company said specialty pharmacies will distribute the product.
==================================================================
3. SIX3 ACTIVATES PAX3
INCREASING METASTASIS TO BONE MARROW AND FAILURE RATES
"A PAX3/FKHR fusion gene is often associated with the alveolar type of rhabdomyosarcoma,[4]
a kind of cancer arisen from striated muscle cells. Translocation
between chromosomes 2 & 13 produce fusion protein PAX3/FKHR which
serves as a tumor marker in this type of RMS.Also in ARMS expressing
PAX3/FKHR increased risk of metastasis to bone marrow and hence
increased rate of failure and death were seen."WIKI
" Note: The gene
represented in this entry is involved in disease pathogenesis. A
chromosomal aberration involving PAX3 is found in rhabdomyosarcoma.
Translocation (2;13)(q35;q14) with FOXO1. The resulting protein is a
transcriptional activator.
A chromosomal aberration involving PAX3
is a cause of rhabdomyosarcoma. Translocation t(2;2)(q35;p23) with
NCOA1 generates the NCOA1-PAX3 oncogene consisting of the N-terminus
part of PAX3 and the C-terminus part of NCOA1. The fusion protein acts
as a transcriptional activator. Rhabdomyosarcoma is the most common soft
tissue carcinoma in childhood, representing 5-8% of all malignancies in
children."UNIPROTKBPLEASE NOTE THE INVOLVEMENT OF FOXO1, A POTENTIAL DOOR TO APOPTOSIS WHICH IN THIS CASE IS CLOSE.
4. FINALLY AND NOT THE LEAST
SIX3 INTERACTS WITH NOR1
-----------------------------------------------------------------------------------------------------
(NOR1) also known as NR4A3 (nuclear receptor subfamily 4, group A, member 3) is a protein that in humans is encoded by the NR4A3 gene.[1] NOR1 is a member of the nuclear receptor family of intracellular transcription factors.
NOR1 plays a central regulatory role in cell proliferation, differentiation, metabolism[2][3] and apoptosis[4]WIKIPIDIA
------------------------------------------------------------------------------------------------------------------
ENSURING PLENTY OF PROLIFERATION OF PENILE CANCER!
AND THIS IS JUST FOR A START, WAIT UNTIL YOU HERE ABOUT THE EZRIN, S100A4, SCCA, KAI-1, MKI67, PCNA,RASSFIA AND OTHERS AND YOU WILL KNOW WHAT WE ARE UP AGAINST!
Colleagues:
As
you know, smoking is the leading cause of preventable death and
disease, killing nearly 9,700 Hoosiers each year. For every person who
dies from tobacco use, another 20 are suffering
from one or more serious smoking-related illnesses. Reducing smoking is
one proven way we can help people live healthier lives and is a 2013
strategic priority of the Indiana State Department of Health.
Not
smoking while pregnant is also critical for reducing Indiana’s high infant mortality rate, also a priority of ISDH.
This spring, the Centers for Disease Control and Prevention (CDC) launched the second
Tips From Former Smokers national tobacco education campaign (Tips
2013) to raise awareness about the suffering caused by smoking and
secondhand smoke exposure, and to encourage smokers to quit. As a
health care provider, you know smoking has
a negative impact on your patient’s health.
Next week, the media campaign will highlight a “Talk With Your Doctor”
effort by including the tagline: “You Can Quit. Talk with Your Doctor
for Help.” This will provide a great
opportunity for you to ask your patients about their tobacco use and
encourage them to make a quit attempt. You are one of the most important
sources of health information for your patients and their families.
Tobacco users are more likely to make a quit
attempt if advised by their doctor.
I
am reaching out to ask that you use your influence as a health care
provider to help your patients quit smoking! Please see attached letter
that contains links to information that
will assist you.
William C. VanNess II, MD
State Health Commissioner
NEW DRUGS IN HEMATOLOGIC MALIGNANCIES
1.ABT-199 A BCL-2 INHIBITOR
2.DASATINIB (SRC-ABL INHIBITOR)
3.FOSTAMATINIB (SYK INHIBITOR)
4.IDELALISIB (PI3K INHIBITOR) IN RELAPSED CLL
5.REVLIMID (IMMUNOMODULATOR)
6.OBINUTUZUMAB (ANTI-CD20)
7 IBRUTINIB inhibitor of Bruton's tyrosine kinase (Btk). CANNOT COMMENT ENOUGH ABOUT IBRUTINIB, WORKS EVERYWHERE IN HEMATOLOGIC MALIGNANCIES!
1.ABT-199 A BCL-2 INHIBITOR
2.DASATINIB (SRC-ABL INHIBITOR)
3.FOSTAMATINIB (SYK INHIBITOR)
4.IDELALISIB (PI3K INHIBITOR) IN RELAPSED CLL
5.REVLIMID (IMMUNOMODULATOR)
6.OBINUTUZUMAB (ANTI-CD20)
7 IBRUTINIB inhibitor of Bruton's tyrosine kinase (Btk). CANNOT COMMENT ENOUGH ABOUT IBRUTINIB, WORKS EVERYWHERE IN HEMATOLOGIC MALIGNANCIES!
Thursday, May 23, 2013
CHALLENGES IN DRUG THERAPY
As we look for the cure, we aim at specific genes as target for our therapy
The challenges are multiple
1-which gene to take up
2-which receptor or cluster of differentiation (CD) to block
3.which pathway to tone down or amplify
while it appears that blocking is evidently easier achieved, amplifying a gene continue to pose a challenge in vivo. It requires knowing some of the normal inhibitor (s) (or regulator) to the gene, finding a promoter gene or globally amplify the genome such as done by c-MYC.
ONE GENE WE HAVE NOT TALKED ABOUT ENOUGH I BELIEVE IS THE CTNNB1
WE TEND TO ONLY LOOK AT ITS ROLE AS AN ADHESION MOLECULE AND THEREFORE IMPORTANT ONLY IN THE METASTATIC PROCESS, IN FACT IT IS THE DOOR TO THE Wnt AND ENDO/MESODERMAL TRANSFORMATION.
JUST LOOKAT WHAT IS SAID ABOUT IT!
As we look for the cure, we aim at specific genes as target for our therapy
The challenges are multiple
1-which gene to take up
2-which receptor or cluster of differentiation (CD) to block
3.which pathway to tone down or amplify
while it appears that blocking is evidently easier achieved, amplifying a gene continue to pose a challenge in vivo. It requires knowing some of the normal inhibitor (s) (or regulator) to the gene, finding a promoter gene or globally amplify the genome such as done by c-MYC.
ONE GENE WE HAVE NOT TALKED ABOUT ENOUGH I BELIEVE IS THE CTNNB1
WE TEND TO ONLY LOOK AT ITS ROLE AS AN ADHESION MOLECULE AND THEREFORE IMPORTANT ONLY IN THE METASTATIC PROCESS, IN FACT IT IS THE DOOR TO THE Wnt AND ENDO/MESODERMAL TRANSFORMATION.
JUST LOOKAT WHAT IS SAID ABOUT IT!
| "CTNNB1 a regulator of cell adhesion and a key downstream effector in the Wnt signaling pathway. Implicated early embryonic development and tumorigenesis. Phosphorylated and destabilized by CK1 and GSK-3beta. Stabilized cytoplasmic beta-catenin is a hallmark of a variety of cancers. Stabilized beta-catenin translocates to the nucleus, where it acts as a transcriptional activator of T-cell factor (TCF)-regulated genes. Interacts with the PDZ domain of TAX1BP3, inhibiting its transcriptional activity. Two alternatively spliced human isoforms have been described. Note: This description may include information from UniProtKB. | |
| Protein type: Actin binding protein; Nuclear receptor co-regulator; Motility/polarity/chemotaxis; Cell adhesion; Transcription factor | |
| Cellular Component: desmosome; centrosome; basolateral plasma membrane; fascia adherens; intercellular junction; zonula adherens; cytosol; beta-catenin destruction complex; transcription factor complex; cell-cell adherens junction; membrane; lamellipodium; perinuclear region of cytoplasm; cytoplasm; synapse; dendritic shaft; lateral plasma membrane; spindle pole; internal side of plasma membrane; catenin complex; cell cortex; Z disc; cell-substrate adherens junction; adherens junction; microvillus membrane; apical part of cell; plasma membrane; nucleus; cell junction | |
| Molecular Function: protein C-terminus binding; identical protein binding; transcription coactivator activity; protein phosphatase binding; transcription factor binding; protein kinase binding; ionotropic glutamate receptor binding; signal transducer activity; protein binding; enzyme binding; androgen receptor binding; cadherin binding; double-stranded DNA binding; estrogen receptor binding; chromatin binding; SMAD binding; structural molecule activity; kinase binding; transcription factor activity; alpha-catenin binding; nuclear hormone receptor binding | |
| Biological Process: skin development; regulation of myelination; regulation of centriole-centriole cohesion; positive regulation of apoptosis; positive regulation of transcription, DNA-dependent; regulation of fibroblast proliferation; negative regulation of chondrocyte differentiation; cell maturation; T cell differentiation in the thymus; positive regulation of fibroblast growth factor receptor signaling pathway; Wnt receptor signaling pathway through beta-catenin; osteoclast differentiation; cell-cell adhesion; positive regulation of endothelial cell differentiation; positive regulation of mesenchymal cell proliferation; embryonic foregut morphogenesis; male genitalia development; synapse organization and biogenesis; ectoderm development; cell adhesion; embryonic limb morphogenesis; hindbrain development; bone resorption; response to drug; positive regulation of neuroblast proliferation; tongue morphogenesis; positive regulation of I-kappaB kinase/NF-kappaB cascade; regulation of smooth muscle cell proliferation; transcription, DNA-dependent; hair cell differentiation; genitalia morphogenesis; patterning of blood vessels; muscle cell differentiation; midgut development; smooth muscle cell differentiation; positive regulation of transcription from RNA polymerase II promoter; embryonic digit morphogenesis; negative regulation of transcription, DNA-dependent; oocyte development; negative regulation of apoptosis; negative regulation of osteoclast differentiation; glial cell fate determination; endodermal cell fate commitment; apoptosis; cell-matrix adhesion; neuron migration; dorsal/ventral axis specification; cell fate specification; determination of dorsoventral asymmetry; negative regulation of transcription from RNA polymerase II promoter; embryonic hindlimb morphogenesis; response to estradiol stimulus; negative regulation of cell proliferation; central nervous system vasculogenesis; positive regulation of MAPKKK cascade; pancreas development; forebrain development; fallopian tube development; proximal/distal pattern formation; cell structure disassembly during apoptosis; Wnt receptor signaling pathway; hair follicle morphogenesis; thymus development; in utero embryonic development; cytoskeletal anchoring; embryonic axis specification; regulation of T cell proliferation; synaptic vesicle transport; gastrulation with mouth forming second; liver development; regulation of angiogenesis; odontogenesis of dentine-containing teeth; negative regulation of oligodendrocyte differentiation; myoblast differentiation; positive regulation of osteoblast differentiation; Schwann cell proliferation; response to cadmium ion; ureteric bud branching; response to cytokine stimulus; androgen receptor signaling pathway; positive regulation of muscle cell differentiation; epithelial to mesenchymal transition; embryonic heart tube development; lens morphogenesis in camera-type eye; anterior/posterior axis specification | |
| Reference #:
P35222 (UniProtKB)'" HOW DO YOU AMPLIFY A GENE YOU WANT AMPLIFIED IN VIVO CASE IN POINT THE FHIT GENE ONE OF THE REASON CANCER MUTATES THIS GENE IN A HURRY IS BECAUSE IT WANT TO REMOVE ITS REPRESSION ON HER-2 DRIVEN EVENTS, AND CONTROL OVER THE BRCA (s). RESTORING ITS FUNCTION IS A CRITICAL ACTIVITY AND WILL GO ALONG WAY TO IMPROVE THE SITUATION IN MANY CANCER AND MOST IMPORTANTLY LUNG CANCER! THE NUMBER ONE KILLER CANCER. THIS IS WHY THE DRUG RESTORING P53 IS BEING OF PRIMARY INTEREST AS SUGGESTED IN OUR PREVIOUS BLOG. RESTORING THE FUNCTIONS OF A SUPPRESSOR GENE THAT HAS BEEN MUTATED WOULD BE A FEAST IN SOME CANCERS AND A CRITICAL CORRECTION IN SOME OTHERS! |
GENES IN PENILE CANCER
1. KAI-1
BEAUTIFULLY SUMMARIZED BY
"KAI-1/CD82, the molecule and clinical implication in cancer and cancer metastasis.
SUPPRESSOR OF METASTASIS
SUPPRESSOR OF SECONDARY TUMORS
ONDITSOVA ET AL ADDED
" We show here that the CD82/KAI-1 tetraspanin is directly associated with the EGF receptor (EGFR), and that ectopic expression of CD82/KAI-1 in epithelial cells specifically suppresses EGF-induced lamellipodial extensions and cell migration. In cells expressing CD82/KAI-1, the initial activation of EGFR is not affected, but subsequent desensitization of EGF-induced signaling occurs more rapidly. This attenuation is correlated with an increased rate of receptor endocytosis. These results identify CD82/KAI-1 as a new regulator of EGF-induced signaling and show that the association of EGFR with the tetraspanin is critical in EGFR desensitization."
TAKAHASHI ET AL "
CD82-c-Met complex inhibits HGF-induced cancer cell migration! OR
Signaling adapter proteins for c-Met, such as Grb2 and p85, exhibited reduced association with c-Met in cells that ectopically expressed CD82. These results indicate that the CD82-c-Met complex inhibits HGF-induced cancer cell migration by the inactivation of small GTP-binding proteins of the Rho family via c-Met adapter proteins."
TODESHINI ET AL
Ganglioside GM2, but not GM3 or globoside, interacted specifically with tetraspanin CD82, and such a complex inhibited hepatocyte growth factor (HGF)-induced activation of Met tyrosine kinase in a dose-dependent manner.
SI ET AL
"These inhibitory effects are enhanced when GM3 or GM2 are in complex with specific tetraspanins (TSPs) (CD9, CD81, CD82). Processes (i)-(iii) occur through specific organization of GSLs with key molecules (TSPs, caveolins, GFRs, integrins) in the glycosynaptic microdomain. Some of these processes are shared with epithelial-mesenchymal transition induced by TGFbeta or under hypoxia, particularly that associated with cancer progression."
" this gene has been shown to be downregulated in tumor progression of human cancers and can be activated by p53 through a consensus binding sequence in the promoter. Its expression and that of p53 are strongly correlated, and the loss of expression of these two proteins is associated with poor survival for prostate cancer patients" WIKIPIDEA
========================================================================
2.S100A4 A
BEAUTIFULLY SUMMARIZED BY
"KAI-1/CD82, the molecule and clinical implication in cancer and cancer metastasis.
Source
Department of Surgery, Cardiff University School of Medicine, Cardiff, UK.Abstract
CD82, also known as KAI-1, structurally belongs to tetraspanin family while categorised as metastasis suppressor gene on functional grounds. KAI1/CD82 is localized on cell membrane and form interactions with other tetraspanins, integrins and chemokines which are respectively responsible for cell migration, adhesion and signalling. In recent years apart from its significant involvement in the suppression of secondary tumours it has also been observed that KAI1/CD82 plays a vital role in virus binding and its entry inside the cell. Decreased expression of KAI1/CD82 molecule results in aggravating cancer progression. Altered expression levels of KAI1/CD82 molecule in different types of human cancer have been implicated as having prognostic value and linking to the long term survival of the patients. Increased level of KAI1/CD82 also results in the suppression of secondary tumour growth. Increased expression of this molecule results in reduced cell invasion and cell migration due to endocytosis of epidermal growth factor receptors (EGFR). Thus,"SUPPRESSOR OF METASTASIS
SUPPRESSOR OF SECONDARY TUMORS
ONDITSOVA ET AL ADDED
" We show here that the CD82/KAI-1 tetraspanin is directly associated with the EGF receptor (EGFR), and that ectopic expression of CD82/KAI-1 in epithelial cells specifically suppresses EGF-induced lamellipodial extensions and cell migration. In cells expressing CD82/KAI-1, the initial activation of EGFR is not affected, but subsequent desensitization of EGF-induced signaling occurs more rapidly. This attenuation is correlated with an increased rate of receptor endocytosis. These results identify CD82/KAI-1 as a new regulator of EGF-induced signaling and show that the association of EGFR with the tetraspanin is critical in EGFR desensitization."
TAKAHASHI ET AL "
CD82-c-Met complex inhibits HGF-induced cancer cell migration! OR
Signaling adapter proteins for c-Met, such as Grb2 and p85, exhibited reduced association with c-Met in cells that ectopically expressed CD82. These results indicate that the CD82-c-Met complex inhibits HGF-induced cancer cell migration by the inactivation of small GTP-binding proteins of the Rho family via c-Met adapter proteins."
TODESHINI ET AL
Ganglioside GM2, but not GM3 or globoside, interacted specifically with tetraspanin CD82, and such a complex inhibited hepatocyte growth factor (HGF)-induced activation of Met tyrosine kinase in a dose-dependent manner.
SI ET AL
"These inhibitory effects are enhanced when GM3 or GM2 are in complex with specific tetraspanins (TSPs) (CD9, CD81, CD82). Processes (i)-(iii) occur through specific organization of GSLs with key molecules (TSPs, caveolins, GFRs, integrins) in the glycosynaptic microdomain. Some of these processes are shared with epithelial-mesenchymal transition induced by TGFbeta or under hypoxia, particularly that associated with cancer progression."
" this gene has been shown to be downregulated in tumor progression of human cancers and can be activated by p53 through a consensus binding sequence in the promoter. Its expression and that of p53 are strongly correlated, and the loss of expression of these two proteins is associated with poor survival for prostate cancer patients" WIKIPIDEA
========================================================================
2.S100A4 A
ASKED THE RIGHT QUESTION TO THE WRONG MAN!
DURING A SURVEY/STUDY, I ASKED A MAN IF HE HAD TROUBLE SLEEPING.
HIS ANSWER CAUGHT MY ATTENTION:
"I OWN A BUSINESS! AND IF YOU OWN A SMALL BUSINESS AND YOU SLEEP EASY, SOMETHING IS WRONG"!
YOU BE THE JUDGE !
------------------------------------------------------------------------------------
ALSO,
YOU KNOW NEW THERAPY IS IN WHEN YOU ARE DEALING WITH A NEW SET OF SIDE EFFECTS. THIS STUFF ABOUT RESURRECTING TUBERCULOSIS WAS NOT IN MY CUP OF SIDE EFFECTS OF DRUGS UNTIL RECENTLY! THEN I KNEW SOMETHING IS UP! BACK IN THE DAYS, IT WAS ALLERGY, NAUSEA AND SO FORTH, BUT INDUCING LYMPHOMA, THAT'S A NEW ONE ON ME!
HIS ANSWER CAUGHT MY ATTENTION:
"I OWN A BUSINESS! AND IF YOU OWN A SMALL BUSINESS AND YOU SLEEP EASY, SOMETHING IS WRONG"!
YOU BE THE JUDGE !
------------------------------------------------------------------------------------
ALSO,
YOU KNOW NEW THERAPY IS IN WHEN YOU ARE DEALING WITH A NEW SET OF SIDE EFFECTS. THIS STUFF ABOUT RESURRECTING TUBERCULOSIS WAS NOT IN MY CUP OF SIDE EFFECTS OF DRUGS UNTIL RECENTLY! THEN I KNEW SOMETHING IS UP! BACK IN THE DAYS, IT WAS ALLERGY, NAUSEA AND SO FORTH, BUT INDUCING LYMPHOMA, THAT'S A NEW ONE ON ME!
MITOCHONDRIAL TARGETS
BESTWICK et al
"The human genome comprises large chromosomes in the nucleus and mitochondrial DNA (mtDNA) housed in the dynamic mitochondrial network. Human cells contain up to thousands of copies of the double-stranded, circular mtDNA molecule that encodes essential subunits of the oxidative phosphorylation complexes and the rRNAs and tRNAs needed to translate these in the organelle matrix. Transcription of human mtDNA is directed by a single-subunit RNA polymerase, POLRMT, which requires two primary transcription factors, TFB2M (transcription factor B2, mitochondrial) and TFAM (transcription factor A, mitochondrial), to achieve basal regulation of the system."
DO YOU REALIZE THAT ATTACKING ELECTIVELY FACTOR A OR /AND B COULD RIG THE ALL RESPIRATORY SYSTEM OF THE CELL?DAMN!
WHAT ABOUT DIABETES?
------------------------------
GABALLA et al.
BESTWICK et al
"The human genome comprises large chromosomes in the nucleus and mitochondrial DNA (mtDNA) housed in the dynamic mitochondrial network. Human cells contain up to thousands of copies of the double-stranded, circular mtDNA molecule that encodes essential subunits of the oxidative phosphorylation complexes and the rRNAs and tRNAs needed to translate these in the organelle matrix. Transcription of human mtDNA is directed by a single-subunit RNA polymerase, POLRMT, which requires two primary transcription factors, TFB2M (transcription factor B2, mitochondrial) and TFAM (transcription factor A, mitochondrial), to achieve basal regulation of the system."
DO YOU REALIZE THAT ATTACKING ELECTIVELY FACTOR A OR /AND B COULD RIG THE ALL RESPIRATORY SYSTEM OF THE CELL?DAMN!
WHAT ABOUT DIABETES?
------------------------------
GABALLA et al.
"
In addition, eccentric left ventricular geometric patterns,
detected by echocardiography, and renal hypertrophy, revealed by
ultrasonography, are promising new markers predicting DN development.
Serum and urinary markers are still invaluable elements, including
serum uric acid, microalbuminuria, macroalbuminuria, urinary liver–type
fatty acid–binding protein (u–LFABP), and urinary nephrin.
Moreover, studies have illustrated a tight relationship between obstructive sleep apnea and the development of DN.
Wednesday, May 22, 2013
LOOKING FOR ANSWERS? HERE ARE THE QUESTIONS! THESE ARE NOT THE CRBCM QUESTIONS, THE NCI IS ASKING!
Group A covered by RFA-CA-12-015 and RFA-CA-12-016 (using the R01 and R21 funding mechanisms, respectively). PQs in this group seek answers to specific unsolved problems in cancer prevention and risk. The following PQs are included:
PQA1: What is the molecular mechanism by which a
drug (such as aspirin or metformin) that is chronically used for other
indications protects against cancer incidence and mortality?
PQA2: How does obesity contribute to cancer risk?
PQA3: How do cognitive processes such as memory
and executive function interact with emotional or habitual processes to
influence lifestyle behaviors and decisions, and can we use this
knowledge to design strategies to change behaviors that increase cancer
risk?
PQA4: As modern measurement technologies improve, are there better ways to objectively ascertain exposure to cancer risk?
PQA5: How does the level, type or duration of physical activity influence cancer risk and prognosis?
PQA6: How does susceptibility of exposure to cancer risk factors change during development?
Group B covered by RFA-CA-12-017 and RFA-CA-12-018 (using the R01 and R21 funding mechanisms, respectively). PQs in this group are focused on perplexing problems in mechanisms of tumor development or recurrence. The following PQs are included:
PQB1: Why do second, independent cancers occur
at higher rates in patients who have survived a primary cancer than in a
cancer-naïve population?
PQB2: As we improve methods to identify
epigenetic changes that occur during tumor development, can we develop
approaches to discriminate between "driver" and "passenger" epigenetic
events?
PQB3: What molecular and cellular events
determine whether the immune response to the earliest stages of
malignant transformation leads to immune elimination or tumor
promotion?
PQB4: What mechanisms of aging, beyond the accumulation of mutations, promote or protect against cancer development?
PQB5: How does the order in which mutations or
epigenetic changes occur alter cancer phenotypes or affect the efficacy
of targeted therapies?
PQB6: Given the difficulty of studying
metastasis, can we develop new approaches, such as engineered tissue
grafts, to investigate the biology of tumor spread?
Group C covered by RFA-CA-12-019 and RFA-CA-12-020 (using the R01 and R21 funding mechanisms, respectively). PQs in this group concentrate on improving tumor detection, diagnosis, and prognosis. The following PQs are included:
PQC1: Can we determine why some tumors evolve to aggressive malignancy after years of indolence?
PQC2: How can the physical properties of tumors,
such as the cell's electrical, optical or mechanical properties, be
used to provide earlier or more reliable cancer detection, diagnosis,
prognosis, or monitoring of drug response or tumor recurrence?
PQC3: Are there definable properties of
pre-malignant or other non-invasive lesions that predict the likelihood
of progression to metastatic disease?
PQC4: How do we determine the significance of
finding cells from a primary tumor at another site and what methods can
be developed to make this diagnosis clinically useful?
PQC5: Can tumors be detected when they are two to
three orders of magnitude smaller than those currently detected with
in vivo imaging modalities?
PQC6: What molecular events establish tumor dormancy after treatment and what leads to recurrence?
Group D covered by RFA-CA-12-021 and RFA-CA-12-022 (using the R01 and R21 funding mechanisms, respectively). PQs in this group are focused on problems in cancer therapy and outcomes. The following PQs are included:
PQD1: How does the selective pressure imposed by
the use of different types and doses of targeted therapies modify the
evolution of drug resistance?
PQD2: What molecular properties make some cancers curable with conventional chemotherapy?
PQD3: What underlying causal events - e.g.,
genetic, epigenetic, biologic, behavioral, or environmental - allow
certain individuals to survive beyond the expected limits of otherwise
highly lethal cancers?
PQD4: What properties of cells in a pre-malignant
or pre-invasive field - sometimes described as the result of a cancer
field effect - can be used to design treatments for a tumor that has
emerged from this field or to block the appearance of future tumors?
PQD5: Since current methods to predict the
efficacy or toxicity of new drug candidates in humans are often
inaccurate, can we develop new methods to test potential therapeutic
agents that yield better predictions of response?
PQD6: What mechanisms initiate cachexia in cancer
patients, and can we target them to extend lifespan and quality of
life for cancer patients?
THERE IS MORE TO CRIZOTINIB THAN MEETS THE EYES!
"Crizotinib significantly enhanced the cytotoxicity of chemotherapeutic agents which are also ABCB1 substrates, in MDR cells with no effect found on sensitive cells in vitro and in vivo. Additionally, crizotinib significantly increased intracellular accumulation of rhodamine 123 and doxorubicin and inhibited the drug efflux in ABCB1-overexpressing MDR cells. Further studies showed that crizotinib enhanced the ATPase activity of ABCB1 in a concentration-dependent manner."
Crizotinib (PF-02341066) reverses multidrug resistance in cancer cells by inhibiting the function of P-glycoprotein.
Zhou WJ, Zhang X ET AL."Crizotinib significantly enhanced the cytotoxicity of chemotherapeutic agents which are also ABCB1 substrates, in MDR cells with no effect found on sensitive cells in vitro and in vivo. Additionally, crizotinib significantly increased intracellular accumulation of rhodamine 123 and doxorubicin and inhibited the drug efflux in ABCB1-overexpressing MDR cells. Further studies showed that crizotinib enhanced the ATPase activity of ABCB1 in a concentration-dependent manner."
GENES IN PENILE CANCER
One of the particularity of Penile cancer is that, at least in half of the patients, the trigger is infectious and Papilloma virus (HPV) primarily, and Herpes-2 secondarily. And with the Viral cause comes the assumption that insertion of the viral genome in the Human genome will occur to take over the machinery of the human genome and use it to viral purposes! First, not all types of HPV achieve this. Those with E6 and E7 will however lead to neoplastic transformation. You would think that like any infection, stimulation of the immune system and awakening of NF-kB would be the predominant events. The literature does not deny these roles, however, stray away to P14arf/MDM2/P53 and P16/INK4a /Cyclin D, and Retinoblastoma . These paths will lead to the activation of Ras, MYC, Telomerases, MMP, PGE and COX. E-Cadherin is decreased. To come up to what is going on, let's review these factors in order to clarify these opportunities for targeting this cancer.
HPV ASSOCIATED CANCER:
In August 2012, the Medscape website released a slide presentation about HPV and cancer risk. The following table shows the incidence of HPV associated cancers in the period of 2004-2008 in the US.[14]
(wikipidia)
HPV RELATED ONCOGENES"
E6 and E7, are known to act as oncogenes that promote tumor growth and malignant transformation. Oral infection with HPV increased the risk of HPV-positive oropharyngeal cancer independent of tobacco and alcohol use.[17] In the United States, HPV is expected to replace tobacco as the main causative agent for oral cancer.[18]
The p53 protein prevents cell growth and stimulates apoptosis in the presence of DNA damage. The p53 also upregulates the p21 protein, which blocks the formation of the Cyclin D/Cdk4 complex, thereby preventing the phosphorylation of RB and, in turn, halting cell cycle progression by preventing the activation of E2F. In short, p53 is a tumor suppressor gene that arrests the cell cycle when there is DNA damage.
E6 has a close relationship with the cellular protein E6-AP (E6-associated protein). E6-AP is involved in the ubiquitin ligase pathway, a system that acts to degrade proteins. E6-AP binds ubiquitin to the p53 protein, thereby flagging it for proteosomal degradation."
CONSEQUENTLY, P53 IS REMOVED FROM THE EQUATION, p21 IS DEPRESSED, CYCLIN D BOOSTED AND RB, A SUPPRESSION GENE, IS PHOSPHORYLATED WHILE APOPTOSIS IS BLOCKED EVEN IN THE PRESENCE OF A DERANGED HUMAN GENOME! TOLERANCE THAT IS NEEDED FOR NEOPLASIA TO PROSPER.
AND THIS IS HOW THE INTEGRATION GOES DOWN:
" E6/E7 proteins:
The two primary oncoproteins of high risk HPV types are E6 and E7. The “E” designation indicates that these two proteins are expressed early in the HPV life cycle, while the "L" designation indicates late expression.[15] The HPV genome is composed of six early (E1, E2, E4, E5, E6, and E7) ORFs, two late (L1 and L2) ORFs, and a non-coding long control region (LCR).[59] After the host cell is infected viral early promoter is activated and a polycistronic primary RNA containing all six early ORFs is transcribed. This polycistronic RNA then undergoes active RNA splicing to generate multiple isoforms of mRNAs.[60] One of the spliced isoform RNAs, E6*I, serves as an E7 mRNA to translate E7 protein.[61] However, viral early transcription subjects to viral E2 regulation and high E2 levels repress the transcription. HPV genomes integrate into host genome by disruption of E2 ORF, preventing E2 repression on E6 and E7. Thus, viral genome integration into host DNA genome increases E6 and E7 expression to promote cellular proliferation and the chance of malignancy. The degree to which E6 and E7 are expressed is correlated with the type of cervical lesion that can ultimately develop.[56]" WIKIPIDIA
HSU ET A
" E6 proteins of both low-risk and high-risk human papillomavirus (HPV) interact with three coactivator HMTs, CARM1, PRMT1 and SET7, and downregulate their enzymatic activities in vitro"
THE E6 AND E7 OTHER ROLE IS EPISOMAL MAINTENANCE
(DICTIONARY)
TO BE CONTINUED
HPV ASSOCIATED CANCER:
In August 2012, the Medscape website released a slide presentation about HPV and cancer risk. The following table shows the incidence of HPV associated cancers in the period of 2004-2008 in the US.[14]
| Cancer area | Average Annual Number of cases | HPV Attributable (Estimated) | HPV 16/18 Attributable (Estimated) |
|---|---|---|---|
| Cervix | 11,967 | 11,500 | 9,100 |
| Vulva | 3,136 | 1,600 | 1,400 |
| Vagina | 729 | 500 | 400 |
| Penis | 1,046 | 400 | 300 |
| Anus (woman) | 3,089 | 2,900 | 2,700 |
| Anus (men) | 1,678 | 1,600 | 1,500 |
| Oropharynx (woman) | 2,370 | 1,500 | 1,400 |
| Oropharynx (men) | 9,356 | 5,900 | 5,600 |
| Total (women) | 21,291 | 18,000 | 15,000 |
| Total (men) | 12,080 | 7,900 | 7,600 |
HPV RELATED ONCOGENES"
E6 and E7, are known to act as oncogenes that promote tumor growth and malignant transformation. Oral infection with HPV increased the risk of HPV-positive oropharyngeal cancer independent of tobacco and alcohol use.[17] In the United States, HPV is expected to replace tobacco as the main causative agent for oral cancer.[18]
The p53 protein prevents cell growth and stimulates apoptosis in the presence of DNA damage. The p53 also upregulates the p21 protein, which blocks the formation of the Cyclin D/Cdk4 complex, thereby preventing the phosphorylation of RB and, in turn, halting cell cycle progression by preventing the activation of E2F. In short, p53 is a tumor suppressor gene that arrests the cell cycle when there is DNA damage.
E6 has a close relationship with the cellular protein E6-AP (E6-associated protein). E6-AP is involved in the ubiquitin ligase pathway, a system that acts to degrade proteins. E6-AP binds ubiquitin to the p53 protein, thereby flagging it for proteosomal degradation."
CONSEQUENTLY, P53 IS REMOVED FROM THE EQUATION, p21 IS DEPRESSED, CYCLIN D BOOSTED AND RB, A SUPPRESSION GENE, IS PHOSPHORYLATED WHILE APOPTOSIS IS BLOCKED EVEN IN THE PRESENCE OF A DERANGED HUMAN GENOME! TOLERANCE THAT IS NEEDED FOR NEOPLASIA TO PROSPER.
AND THIS IS HOW THE INTEGRATION GOES DOWN:
" E6/E7 proteins:
The two primary oncoproteins of high risk HPV types are E6 and E7. The “E” designation indicates that these two proteins are expressed early in the HPV life cycle, while the "L" designation indicates late expression.[15] The HPV genome is composed of six early (E1, E2, E4, E5, E6, and E7) ORFs, two late (L1 and L2) ORFs, and a non-coding long control region (LCR).[59] After the host cell is infected viral early promoter is activated and a polycistronic primary RNA containing all six early ORFs is transcribed. This polycistronic RNA then undergoes active RNA splicing to generate multiple isoforms of mRNAs.[60] One of the spliced isoform RNAs, E6*I, serves as an E7 mRNA to translate E7 protein.[61] However, viral early transcription subjects to viral E2 regulation and high E2 levels repress the transcription. HPV genomes integrate into host genome by disruption of E2 ORF, preventing E2 repression on E6 and E7. Thus, viral genome integration into host DNA genome increases E6 and E7 expression to promote cellular proliferation and the chance of malignancy. The degree to which E6 and E7 are expressed is correlated with the type of cervical lesion that can ultimately develop.[56]" WIKIPIDIA
HSU ET A
" E6 proteins of both low-risk and high-risk human papillomavirus (HPV) interact with three coactivator HMTs, CARM1, PRMT1 and SET7, and downregulate their enzymatic activities in vitro"
THE E6 AND E7 OTHER ROLE IS EPISOMAL MAINTENANCE
TO BE CONTINUED
FUTURE OF TARGETING THERAPY
The advent of T-DM1 and its success in delivering chemotherapy specifically to cells that are engaged in neoplastic transformation while posting relevant receptor (in this case the receptor is to Herceptin), open the door to possibility of doing the same for therapy that will target genes! And this will minimize the impact on normal cells!
T-DM1, a conjugate of Herceptin and Emtansine, a powerful chemotherapy that cannot be infused theoritically in living human because it is so potent (theoritically), is now being delivered to cell that express the Herceptin receptor (wait to see this drug used in those 10% of Gastric cancer that have Herceptin receptors). If we conjugate this with PSA, we could theoritically deliver Emtansine to prostate cancers! To CEA may be to colon cancer, well it does not need to be Emtansine, how about the delivery of some more powerful Doxorubicin related compounds!
Beyond this "game" with more powerful chemotherapy drugs, let' replace the powerful drug by a driver gene. We know some leukemia are characterized by immortality, and TIAF1 may be the gene driving this. Leukemia is known to have some typical CD, cluster of differentiation, why not combine Anti-TIAF1 and that particular CD to ensure delivery of the anti-gene to specifically that cell. Where we have a Wnt activated in triple negative breast cancer, we send in anti-CREB attached to TGF beta or other positive receptor. You know that cancer with c-MET amplification you got to go to the Hepatic Growth factor because it is the only known ligand to this receptor. A cancer with over-expression of RNA polymerase that we discussed earlier, we will send in an anti-TAF 15 or anti-POLR2C of some sort! Commanding this conjugate technology is a must and is the future in Oncology! Game is on! Increasing effect of Taxotere, try anti ARHGEF2. In all disease where cyclins play a major role, targeting the JAKs will be the answer! NF-kB amplified...you know the answer!
The advent of T-DM1 and its success in delivering chemotherapy specifically to cells that are engaged in neoplastic transformation while posting relevant receptor (in this case the receptor is to Herceptin), open the door to possibility of doing the same for therapy that will target genes! And this will minimize the impact on normal cells!
T-DM1, a conjugate of Herceptin and Emtansine, a powerful chemotherapy that cannot be infused theoritically in living human because it is so potent (theoritically), is now being delivered to cell that express the Herceptin receptor (wait to see this drug used in those 10% of Gastric cancer that have Herceptin receptors). If we conjugate this with PSA, we could theoritically deliver Emtansine to prostate cancers! To CEA may be to colon cancer, well it does not need to be Emtansine, how about the delivery of some more powerful Doxorubicin related compounds!
Beyond this "game" with more powerful chemotherapy drugs, let' replace the powerful drug by a driver gene. We know some leukemia are characterized by immortality, and TIAF1 may be the gene driving this. Leukemia is known to have some typical CD, cluster of differentiation, why not combine Anti-TIAF1 and that particular CD to ensure delivery of the anti-gene to specifically that cell. Where we have a Wnt activated in triple negative breast cancer, we send in anti-CREB attached to TGF beta or other positive receptor. You know that cancer with c-MET amplification you got to go to the Hepatic Growth factor because it is the only known ligand to this receptor. A cancer with over-expression of RNA polymerase that we discussed earlier, we will send in an anti-TAF 15 or anti-POLR2C of some sort! Commanding this conjugate technology is a must and is the future in Oncology! Game is on! Increasing effect of Taxotere, try anti ARHGEF2. In all disease where cyclins play a major role, targeting the JAKs will be the answer! NF-kB amplified...you know the answer!
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