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Wednesday, September 25, 2013
just in now!
Genetic going deeper in the Obesity research!
Going deep into Obesity issues and tumor induced cachexia, we stumble upon RIP 140, Sp1, and believe or not E2F1(a wild gene).
"RIP140 is part of the chain by which tumors can cause cachexia.[15][16]
Levels of RIP140 expression in various tissues varies during aging in mice, suggesting changes in metabolic function.[17] RIP140 is implicated in certain human disease processes. In morbid obesity, RIP140 levels are down-regulated in visceral adipose tissue.[18] In breast cancer, RIP140 is involved in regulation of E2F1, an oncogene which discriminates between luminal and basal types of tumours. RIP140 has an influence upon cancer phenotype and prognosis.[19] In addition, RIP140 has a role in inflammation, since it acts as a coactivator for NFkappaB/RelA-dependent cytokine gene expression. Lack of RIP140 leads to an inhibition of proinflammatory pathways in macrophages."
wikipedia
It seems that this is where Obesity becomes a disease by its state of high inflammatory state. The diease process in Obesity is defined or determined by a relatively high level of Growth factor and Cytokines inducing major deleterious consequences on the muscle skeletal system through the activated NF-KB. The RIP 140 (also known as NRIP1) is hard at work. Remember it interacts with DAX1 which involves the COPS2 (nothing to do with the police!),SREBF1 (the bone modulator) and SF1 ("feminization" of the obese individual).
It is clearly important that the understanding and measurement of the obese by clear new biomarkers allow us to establish new guidelines for monitoring. Following BMI, lipid profile and pushing diet is clearly insufficient. Blocking the central Nervous system to force mental rejection of food is not the only answer ...remember RIP-140 modulation is part of cachexia induced by Tumors.
(remember the rule, if it can induce a malformation, it is an important gene (check out DAX1 and SREBF1)
Othre gene in the link TRERF1, CREB-binding protein,EP 300.
Get to work! At CRBCM...the race is on!
"RIP140 is part of the chain by which tumors can cause cachexia.[15][16]
Levels of RIP140 expression in various tissues varies during aging in mice, suggesting changes in metabolic function.[17] RIP140 is implicated in certain human disease processes. In morbid obesity, RIP140 levels are down-regulated in visceral adipose tissue.[18] In breast cancer, RIP140 is involved in regulation of E2F1, an oncogene which discriminates between luminal and basal types of tumours. RIP140 has an influence upon cancer phenotype and prognosis.[19] In addition, RIP140 has a role in inflammation, since it acts as a coactivator for NFkappaB/RelA-dependent cytokine gene expression. Lack of RIP140 leads to an inhibition of proinflammatory pathways in macrophages."
wikipedia
It seems that this is where Obesity becomes a disease by its state of high inflammatory state. The diease process in Obesity is defined or determined by a relatively high level of Growth factor and Cytokines inducing major deleterious consequences on the muscle skeletal system through the activated NF-KB. The RIP 140 (also known as NRIP1) is hard at work. Remember it interacts with DAX1 which involves the COPS2 (nothing to do with the police!),SREBF1 (the bone modulator) and SF1 ("feminization" of the obese individual).
It is clearly important that the understanding and measurement of the obese by clear new biomarkers allow us to establish new guidelines for monitoring. Following BMI, lipid profile and pushing diet is clearly insufficient. Blocking the central Nervous system to force mental rejection of food is not the only answer ...remember RIP-140 modulation is part of cachexia induced by Tumors.
(remember the rule, if it can induce a malformation, it is an important gene (check out DAX1 and SREBF1)
Othre gene in the link TRERF1, CREB-binding protein,EP 300.
Get to work! At CRBCM...the race is on!
Tuesday, September 24, 2013
Breakthrough!
"The U.S. Food and Drug
Administration has granted breakthrough therapy designation to
volasertib for the treatment of patients with previously untreated acute
myeloid leukemia who are ineligible for intensive remission induction
therapy, and who are 65 or older. Volasertib is an investigational
inhibitor of polo-like kinase (Plk)." from Oncology time. go to full article
*Kathy Miller from Indiana University suggests that the best adjuvant chemotherapy in relevent Breast cancer patient is AC Q3weeks followed by weekly Paclitaxel as it has comparative efficacy and better tolerance of the weekly Taxol part!
*Kathy Miller from Indiana University suggests that the best adjuvant chemotherapy in relevent Breast cancer patient is AC Q3weeks followed by weekly Paclitaxel as it has comparative efficacy and better tolerance of the weekly Taxol part!
How long you can live: Determination through the genes! DO YOU KNOW YOUR FOXO3 VARIANT?
Many patients that I meet these days stress during my interview with them that their own parents died of "old age". Meaning that there seems to be a certain finality to life of humans. There will be a time when despite good care and prevention, human life will end. Patients deny their parents died of heart failure, stroke or any other cause but "old age" as if at some point we are doomed to a programmed death. Inquisition into people who live longer (more then a hundred years) point to the existence of a gene, a particular variant FOXO3 (see below). DO YOU KNOW YOUR FOXO3 VARIANT?
Evidence abounds now that how long we shall live is encrypted in our genes, but no one seems to rush to offer this option of an approach to care because it is not as simple as that! But I still believe that for proper "advance directives" preparation of this information should be included as we gauge our sens of survival! At the individual cellular level, basically this FOXO3,4,6 upregulates BIM and PUMA (wild animal in us keeping us alive!) and downregulates (FLIP) to slow programmed cellular death (Apoptosis). The interesting thing is this FOX ability to work is very tightly linked to energy! Yes, when you touch the FOXO, Galactose and Insulin metabolisms come right at you! As if telling you if you monitor me closely (as in Biomarkers) you may know what FOXY is doing. In other words, the GALT gene is a good Biomarker of FOXO3. And may tell you the status of cancer cells! (think carefully) during and after treatments!"
A variant of FOXO3 has been shown to be associated with longevity in humans. It is found in most centenarians across a variety of ethnic groups around the world.[7][8] The homologous genes daf-16 in the nematode C. elegans and dFOXO in the fruit fly are also associated with longevity in those organisms."
DAF-16 is the sole ortholog of the FOXO family of transcription factors in the nematode Caenorhabditis elegans.[1] DAF-16 is notable for being the primary transcription factor required for the profound lifespan extension observed upon mutation of the insulin-like receptor daf-2.[2] Moreover, the tractability of C. elegans as a model and interest in teasing out this conserved aging-associated genetic pathway allowed the intricacies of Insulin and Insulin-like growth factor (IGF) Signaling (IIS) to be thoroughly characterized primarily through studies using this model organism.[3]wikipedia
"The expression of GALT is controlled by the actions of the FOXO3 gene. The absence of this enzyme results in classic galactosemia in humans and can be fatal in the newborn period if lactose is not removed from the diet. The pathophysiology of galactosemia has not been clearly defined.[1]wikipedia"
Evidence abounds now that how long we shall live is encrypted in our genes, but no one seems to rush to offer this option of an approach to care because it is not as simple as that! But I still believe that for proper "advance directives" preparation of this information should be included as we gauge our sens of survival! At the individual cellular level, basically this FOXO3,4,6 upregulates BIM and PUMA (wild animal in us keeping us alive!) and downregulates (FLIP) to slow programmed cellular death (Apoptosis). The interesting thing is this FOX ability to work is very tightly linked to energy! Yes, when you touch the FOXO, Galactose and Insulin metabolisms come right at you! As if telling you if you monitor me closely (as in Biomarkers) you may know what FOXY is doing. In other words, the GALT gene is a good Biomarker of FOXO3. And may tell you the status of cancer cells! (think carefully) during and after treatments!"
A variant of FOXO3 has been shown to be associated with longevity in humans. It is found in most centenarians across a variety of ethnic groups around the world.[7][8] The homologous genes daf-16 in the nematode C. elegans and dFOXO in the fruit fly are also associated with longevity in those organisms."
DAF-16 is the sole ortholog of the FOXO family of transcription factors in the nematode Caenorhabditis elegans.[1] DAF-16 is notable for being the primary transcription factor required for the profound lifespan extension observed upon mutation of the insulin-like receptor daf-2.[2] Moreover, the tractability of C. elegans as a model and interest in teasing out this conserved aging-associated genetic pathway allowed the intricacies of Insulin and Insulin-like growth factor (IGF) Signaling (IIS) to be thoroughly characterized primarily through studies using this model organism.[3]wikipedia
"The expression of GALT is controlled by the actions of the FOXO3 gene. The absence of this enzyme results in classic galactosemia in humans and can be fatal in the newborn period if lactose is not removed from the diet. The pathophysiology of galactosemia has not been clearly defined.[1]wikipedia"
Monday, September 23, 2013
Major implication of the Gli-1
I. The Gli-1 gene
affects the following other genes
---PDGFR in mesenchymal tissue
---FOXM1
---Sufu
---SP1, USF1
---Twist1
---CyclinD2
---Plakoglobulin
---Shh
II. PTCH1: Act as a receptor to the Hedgehog ---the contact releases the SMO
Revant Info-Vismodegib
"The substance acts as a cyclopamine-competitive antagonist of the smoothened receptor (SMO) which is part of the hedgehog signaling pathway.[2] SMO inhibition causes the transcription factors GLI1 and GLI2 to remain inactive, which prevents the expression of tumor mediating genes within the hedgehog pathway.[4] This pathway is pathogenetically relevant in more than 90% of basal-cell carcinomas.[5]"wikipedia
link to chondrosarcoma is most puzzling
role in bladder cancer still to be explored, mostly I guess in the squamous type?
in Medulloblastoma?
affects the following other genes
---PDGFR in mesenchymal tissue
---FOXM1
---Sufu
---SP1, USF1
---Twist1
---CyclinD2
---Plakoglobulin
---Shh
II. PTCH1: Act as a receptor to the Hedgehog ---the contact releases the SMO
Revant Info-Vismodegib
"The substance acts as a cyclopamine-competitive antagonist of the smoothened receptor (SMO) which is part of the hedgehog signaling pathway.[2] SMO inhibition causes the transcription factors GLI1 and GLI2 to remain inactive, which prevents the expression of tumor mediating genes within the hedgehog pathway.[4] This pathway is pathogenetically relevant in more than 90% of basal-cell carcinomas.[5]"wikipedia
link to chondrosarcoma is most puzzling
role in bladder cancer still to be explored, mostly I guess in the squamous type?
in Medulloblastoma?
Focus on Peroxisome
Peroxisomes IPA: [pɛɜˈɹɒksɪˌsoʊmz][1] (also called microbodies) are organelles found in virtually all eukaryotic cells.[2] They are involved in the catabolism of very long chain fatty acids, branched chain fatty acids, D-amino acids, polyamines, and biosynthesis of plasmalogens, i.e. ether phospholipids critical for the normal function of mammalian brains and lungs.[3] They also contain approximately 10% of the total activity of two enzymes in the pentose phosphate pathway, which is important for energy metabolism.[3] It is vigorously debated if peroxisomes are involved in isoprenoid and cholesterol synthesis in animals.[3] Other known peroxisomal functions include the glyoxylate cycle in germinating seeds ("glyoxysomes"), photorespiration in leaves,[4] glycolysis in trypanosomes ("glycosomes"), and methanol and/or amine oxidation and assimilation in some yeasts.(Wikipedia)
============================================
with our discussion on the PEX26 and Sufu, we are working on opportunities of interventions through the peroxisome!
============================================
with our discussion on the PEX26 and Sufu, we are working on opportunities of interventions through the peroxisome!
Sunday, September 22, 2013
"Bigger is better"
New York
— Memorial Sloan-Kettering Cancer Center has launched a transformative
initiative to improve the quality of cancer care and the lives of cancer
patients. Hartford HealthCare, a multi-hospital health care system in
Connecticut, was selected as a pioneering member of the newly formed
Memorial Sloan-Kettering Cancer Alliance.
The MSK Cancer Alliance is designed to enable an ongoing, living, breathing dynamic partnership between the comprehensive cancer center and community oncology providers, in order to bring the newest knowledge into the community setting.
The critical need for such an Alliance can be found in a report recently issued by the Institute of Medicine (IOM) that described the challenge of delivering high-quality cancer care as a national “crisis” and noted advances in treatment may be unavailable to patients who lack access to sophisticated genetic tests or clinical trials.
The MSK Cancer Alliance is designed to enable an ongoing, living, breathing dynamic partnership between the comprehensive cancer center and community oncology providers, in order to bring the newest knowledge into the community setting.
The critical need for such an Alliance can be found in a report recently issued by the Institute of Medicine (IOM) that described the challenge of delivering high-quality cancer care as a national “crisis” and noted advances in treatment may be unavailable to patients who lack access to sophisticated genetic tests or clinical trials.
“Currently,
the vast majority of cancer care in the United States is delivered by
community oncologists, but cancer advances can take years to be adopted
in a community setting,” said José Baselga, MD, Physician-in-Chief of
Memorial Sloan-Kettering, who notes that ongoing, interactive real-time
relationships are needed to effectively close this gap. “We want to
rapidly accelerate the pace of integrating the latest advances of cancer
care into a community setting. This unprecedented approach will
demonstrate real value to both organizations and most importantly will
improve the lives of cancer patients,” he added.
=======================================================
BUT HERE AT THE CRBCM WE BELIEVE :
THE MORE VERSATILE, COST EFFICIENT SMALLER CLINIC IS THE ANSWER FOR BETTER STREAMLINING OF CANCER RESEARCH AND APPLICATION OF NEW KNOWLEDGE. THE PROBLEM IS NOT THE COMMUNITY ONCOLOGIST'S LACK OF WILLINGNESS TO LEARN, BUT INDEED THE MEANS OF COMMUNICATION WITH RESEARCHERS IN THE FIELD.
Researchers are taking over main Oncology publications by publishing non readily useable information while support for conferences is dwindling. It is amazing how many Oncologists do not read Blood or JCO because the immediate relevancy of information/articles are perceived as relevant to day to day practice. Among oncologists, FDA approval and whether a randomized phase III trial has demonstrated benefits, seems to be the overwhelming standard for adoption of new therapeutics. Of course the input from trusted authors and opinions from their local referral center also drives the practice.
Larger Institutions could serve a purpose of streamlining referrals if carefully orchestrated, however something may be lost in quality of care (may be because staff there lose a bit of compassion) and money and administrative weight increase dramatically to impair the quick delivery of care they mean to better!
The weight of overheads, the number of meetings, size of committees and political infighting, tends to slow the process by the nature of the beast! These larger institutions attract more research money for a relatively poor output. The CPRIT experience proves this case. Over half of the money given to date went to large institutions in Texas, we are still waiting for the return on investment, and communities overall have still to see lingering effects.
At the CRBCM we like the idea of smaller, more versatile organizations with more effect and efficiency. We believe that science does not belong to any particular institution, and that we can not lead from behind and that we absolutely need to create new paths. This is driving how we perceive new scientific progress results, and most of all how readers will note that our interpretation of facts may be at odds, but that is deliberate and ready to open new approaches! And at least open the debate! If we have not progressed as fast as wished, it is because of political elephants in the room!
Friday, September 20, 2013
The Crux of Tumorgenesis
The secret of cancer proliferation and persistence lays in phenomena at the membrane, where the NOTCH, Wnt and Hedgehog are located. These functions of the membrane start and drive the cancer with help from the ABCG2, MRp1, Pgp gene; it gives it resistance to powerful medications (Adriamycin, CPT11), with SuFu/PEX it reaches a gene capable of inducing malformation, with FOXM1, proliferation is guaranteed, through GLI1, Cyclin D2 is reached. Differentiation is reached though the MEK and failure of control is assured by dysregulation at the FAK. The Cancer's mind set is driven by the FOXM1 for sure. Other genes involve the NANOG, the PTCH1, The SOX and the OCT, CDH1, Shh,Twist, Plakoglobulin...
Profiling through at the CRBCM!
At the CRBCM something is coming through:
1. Deterioration at membrane receptor by lack of stimulation or "false or abnormal stimulation" could not only alter the nature of the "glycan" covering the protein portion of the receptor, but also induce stress like molecules.(HSP)
2. As a result of receptor failure new cytokines and TGFs are secreted which unfortunately fail at the initial receptor, but induce other receptors, amplifying standard pathways like RAS or PIK
3. Certains TGFs have an intrinsic power to maintain life of cells no matter what and induce metastasis.
4. Certain genes have an auto-phosphorylation or self-limiting mechanism that can easily go wrong (RAS, FAK) driving to neoplastic process
5. FAK plays a larger role in aggressive prostate cancer than it has been recognized!
6. FAK has a closer relation to Androgen than recognized
7. NOTCH has closer relation with MEK and "stem cell potential" than recognized.
8. FAK disturbance prominence in cancer explains its sensitivity to Taxanes! That is on top of Microtubule disturbances induced by the drug!
9. Metalloproteases are the ultimate Biomarkers of membrane events !
10. Epigenetic methylation and its patterns are one of the largest mystery still to be elucidated!
1. Deterioration at membrane receptor by lack of stimulation or "false or abnormal stimulation" could not only alter the nature of the "glycan" covering the protein portion of the receptor, but also induce stress like molecules.(HSP)
2. As a result of receptor failure new cytokines and TGFs are secreted which unfortunately fail at the initial receptor, but induce other receptors, amplifying standard pathways like RAS or PIK
3. Certains TGFs have an intrinsic power to maintain life of cells no matter what and induce metastasis.
4. Certain genes have an auto-phosphorylation or self-limiting mechanism that can easily go wrong (RAS, FAK) driving to neoplastic process
5. FAK plays a larger role in aggressive prostate cancer than it has been recognized!
6. FAK has a closer relation to Androgen than recognized
7. NOTCH has closer relation with MEK and "stem cell potential" than recognized.
8. FAK disturbance prominence in cancer explains its sensitivity to Taxanes! That is on top of Microtubule disturbances induced by the drug!
9. Metalloproteases are the ultimate Biomarkers of membrane events !
10. Epigenetic methylation and its patterns are one of the largest mystery still to be elucidated!
Thursday, September 19, 2013
QUESTIONS IN PROSTATE CANCER
1. INDOLENT Vs AGGRESSIVE CANCER
2. Belief that the older you get, the less important to detect the disease yet 2/3 of deaths is in patients older than 75 years of age.
3.Aggressiveness of this disease in the black race mimick exposure to different inducer (the dutasteride experience)
4.does sensitivity to androgen increase FAK, NOTCH, Wnt
2. Belief that the older you get, the less important to detect the disease yet 2/3 of deaths is in patients older than 75 years of age.
3.Aggressiveness of this disease in the black race mimick exposure to different inducer (the dutasteride experience)
4.does sensitivity to androgen increase FAK, NOTCH, Wnt
surprise, surprise! AND THE NOTCH DANCE CONTINUA!
Arsenic trioxide inhibits the proliferation of myeloma cell line through notch signaling pathway
wonders of the NOTCH
Aberrant Activation of Notch Signaling in Human Breast Cancer
"Notch signaling prevents induction of the p53 target genes Puma and Noxa following mitoxantrone treatment. Western blot analysis for JNK activation, Thr81 phosphorylation of p53, Puma, Noxa, and cleaved caspase-3 levels in parental (lane 1), vector control (lane 2), MCF 10A/RBP-Jκ (lane 3), and MCF 10A/NICD (lane 4) cells treated with mitoxantrone for 16 hours. Activation of JNK and Thr81 phosphorylation of p53, leading to the up-regulation of Puma and Noxa and cleavage of caspase-3, were observed in parental and vector control cells but not in cells stably expressing RBP-Jκ/VP16 or NICD. Puma, Noxa, and cleaved caspase-3 were undetectable in untreated cells.
=====================================================
THAT'S HOW THE NOTCH ENSURE CELLS DO NOT DIE!
====================================================
Crosstalk Between Vascular Endothelial Growth Factor, Notch, and Transforming Growth Factor-β in Vascular Morphogenesis
- Matthew T. Holderfield,
- Christopher C.W. Hughes
- "
The formation of a new capillary involves endothelial cell activation, migration, alignment, proliferation, tube formation, branching, anastomosis, and maturation of intercellular junctions and the surrounding basement membrane. Each of these stages is either known or suspected to fall under the influence of the vascular endothelial growth factor, notch, and transforming growth factor-β/bone morphogenetic protein signaling pathways. Vascular endothelial growth factor is essential for initiation of angiogenic sprouting, and also regulates migration of capillary tip cells, proliferation of trunk cells, and gene expression in both." - ===========================================
- NO NEW BLOOD VESSELS WITHOUT THE NOTCH!
- SEE IMPLICATIONS FOR STROKE AND TUMOR METASTASIS========
- ========================================
- " The Jagged/Notch signaling pathways control cell fate determination and differentiation, and their dysfunction is associated with human pathologies involving cardiovascular abnormalities."(LINDNER ET AL!)
- ===================================ARRHYTHMIA AND SUDDEN DEATH IS AN AREA WHERE THE NOTCH IS IMPORTANT (OF COURSE DON'T FORGET THE DYSTROPHIES, CHANNELOPATHIES AND VARIOUS MITOCHONDRIAL DISTURBANCES (MCARDLE DISEASES)
WHERE NOTCH PLAYS, THE Wnt /cADHERIN IS NOT VERY FAR
===================================================
FOR ANY ACTIVE MOLECULE, THERE IS ONE THAT TAMPERS IT, SLOW IT DOWN...FOR THE NOTCH IT IS THE "NUMB" MOLECULE THAT "COOLS" IT!
Wednesday, September 18, 2013
so you know!
 |
 |
SUBJECT: Risks associated with the use of XGEVA® (denosumab 120 mg)
August 27, 2013
Dear Health Care Professional,
This
letter is issued to notify healthcare providers about risks associated
with
Severe symptomatic hypocalcemia, including fatal casesthe use of Xgeva; severe symptomatic hypocalcemia, including fatal cases, and hypersensitivity, including anaphylactic reactions. Xgeva is indicated for the prevention of skeletal-related events in patients with bone metastases from solid tumors and for the treatment of adults and skeletally mature adolescents with giant cell tumor of bone that is unresectable or where surgical resection is likely to result in severe morbidity. Xgeva is not indicated for the prevention of skeletal-related events in patients with multiple myeloma.
In
the postmarketing setting, in patients with cancer receiving Xgeva for
prevention of skeletal-related events, severe symptomatic hypocalcemia, including fatal cases, has been reported. Signs and symptoms of these cases include altered mental status, tetany, seizures and QTc prolongation, which were temporally associated with Xgeva use and decreased serum calcium levels. The calculated reporting rate of severe symptomatic hypocalcemia suggests that the incidence in the postmarketing setting is similar to the rate observed in clinical trials. During clinical trials, severe hypocalcemia (corrected serum calcium < 7 mg/dL or < 1.75 mmol/L) occurred in 3.1% of patients receiving treatment with Xgeva and 1.4% of patients had hypocalcemia reported as a serious adverse event.
Action being taken by Amgen
To communicate this important safety information, changes have been madeto the US prescribing information (USPI) as described below:
The risk of severe symptomatic hypocalcemia among patients receiving Xgeva can be minimized by the following:
In the postmarketing setting, two spontaneously reported cases of anaphylactic reactions were identified and were considered causally related to Xgeva. The calculated reporting rate of anaphylactic reaction is 5.4 per 100,000 patient-years, which classifies anaphylactic reaction as a very rare event. Action being taken by Amgen To communicate this important safety information, changes have been made to the US prescribing information (USPI) as described below:
Patients with clinically significant hypersensitivity to Xgeva should not receive Xgeva. Further Information These are not the only risks associated with the use of this product. Please see the full prescribing information for more information about the risks associated with the use of this product. This information is also available at www.xgeva.com. Contact details for adverse event reporting or to request further information Any suspected adverse reactions should be reported to FDA’s MedWatch Adverse Event Reporting Program:
use of Xgeva, please contact Amgen’s Medical Information Department at 1-800-77-AMGEN. Sincerely,  Michael Severino, MD Senior Vice President, Global Development, and Chief Medical Officer Amgen
Amgen, Inc. | PO Box 681308 | Indianapolis, IN 46268
74864-R1-V1 |
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Multiple Sclerosis would fit
Multiple sclerosis would fit the model of pathology prompted by failure at the receptor of Interleukins
with resulting increase of Cytokines. In this model the initial insult will be destruction of Glycans at the IL-2,7 receptor resulting in the increase of these cytokines. Although they will fail at the receptors, they will still attract T cell and other relevant inflammatory cell. This is confirmed by the scenario of Traumatic brain injury in which lack of post-synaptic stimulation also result in post synaptic neuron destruction. Failure at the receptors stays the most dangerous cellular event. The triple negative Breast cancer is another example.
The effect of Interferon as a therapeutic intervention confirms that increase of Interleukins is the most significant driving event in the disease! It is driving even the coexisting gliosis found in the disease...
with resulting increase of Cytokines. In this model the initial insult will be destruction of Glycans at the IL-2,7 receptor resulting in the increase of these cytokines. Although they will fail at the receptors, they will still attract T cell and other relevant inflammatory cell. This is confirmed by the scenario of Traumatic brain injury in which lack of post-synaptic stimulation also result in post synaptic neuron destruction. Failure at the receptors stays the most dangerous cellular event. The triple negative Breast cancer is another example.
The effect of Interferon as a therapeutic intervention confirms that increase of Interleukins is the most significant driving event in the disease! It is driving even the coexisting gliosis found in the disease...
Tuesday, September 17, 2013
ANTI-EGFR, what is the inside story (full story)
Could anti-EGFR effect be simply an intra-tumoral Vasculitis blocking vascular Oxygenation? Can ANCA be a significant Biomarker particularly in those with Dermatitis? Is FAK and Metalloproteases be better biomarkers
text to follow!
"The fact is that anti-EGFR activity is associated with a significant dermatitis. And the dermatitis is associated or has been linked to drug activity. Indeed the more severe the rash, the more the activity of the drug. At skin level, we know as a result of the drug, toxic chemical are liberated to induce the reaction.
Myeloperoxidase (MPO) is a peroxidase enzyme that in humans is encoded by the MPO gene.[2] Myeloperoxidase is most abundantly expressed in neutrophil granulocytes (a subtype of white blood cells).[3] It is a lysosomal protein stored in azurophilic granules of the neutrophil. MPO has a heme pigment, which causes its green color in secretions rich in neutrophils, such as pus and some forms of mucus.
As part of the respiratory burst that neutrophils use to kill bacteria, myeloperoxidase converts hydrogen peroxide (H2O2) into hypochlorous acid (HOCl). HOCl is the most potent oxidant generated by neutrophils, and can cause significant tissue damage during inflammation. Dapsone arrests myeloperoxidase in an inactive intermediate form, reversibly inhibiting the enzyme. This prevents accumulation of hypochlorous acid, and reduces tissue damage during inflammation" wikipedia
Antibody " against MPO have been implicated in various types of vasculitis, most prominently crescentic glomerulonephritis and Churg-Strauss syndrome. They are detected as perinuclear ANCAs (p-ANCAs), as opposed to the cytoplasmic ANCAs (c-ANCAs) against proteinase-3 (PR3), which are strongly associated with Wegener's granulomatosis. Recent studies have reported an association between myeloperoxidase levels and the severity of coronary artery disease.[8] It has been suggested that myeloperoxidase plays a significant role in the development of the atherosclerotic lesion and rendering plaques unstable."wikipedia
The above discussion bring to mind that dermatitis seen with use of Drugs aiming at epithelial covering of blood vessel could indeed lead to secretion of molecules such as Cyclo-oxygenease (target of NSAID), MPO such as in this case Dapsone but Anti EGFR dose liberate from other affected cells cytokines of similar products that induced rash as a secondary effect. Should study confirms that MPO is our guy, then ANCA would be a legitimate candidate Bio-Marker.
Certainly during the activity of anti-EGFR, there is significant mambranes activity in terms of shedding proteins/Cytokines, FAK will be over express as a function of this activity and high FAK will be expected, liberations of Metalloproteases and the ADAMS such as 12 will follow the same logic and could join biomarkers of EGFR activity. Elevated stress at the membrane could be associated with HSP 90 amplification...let's go get them in a trial!
text to follow!
"The fact is that anti-EGFR activity is associated with a significant dermatitis. And the dermatitis is associated or has been linked to drug activity. Indeed the more severe the rash, the more the activity of the drug. At skin level, we know as a result of the drug, toxic chemical are liberated to induce the reaction.
Myeloperoxidase (MPO) is a peroxidase enzyme that in humans is encoded by the MPO gene.[2] Myeloperoxidase is most abundantly expressed in neutrophil granulocytes (a subtype of white blood cells).[3] It is a lysosomal protein stored in azurophilic granules of the neutrophil. MPO has a heme pigment, which causes its green color in secretions rich in neutrophils, such as pus and some forms of mucus.
As part of the respiratory burst that neutrophils use to kill bacteria, myeloperoxidase converts hydrogen peroxide (H2O2) into hypochlorous acid (HOCl). HOCl is the most potent oxidant generated by neutrophils, and can cause significant tissue damage during inflammation. Dapsone arrests myeloperoxidase in an inactive intermediate form, reversibly inhibiting the enzyme. This prevents accumulation of hypochlorous acid, and reduces tissue damage during inflammation" wikipedia
Antibody " against MPO have been implicated in various types of vasculitis, most prominently crescentic glomerulonephritis and Churg-Strauss syndrome. They are detected as perinuclear ANCAs (p-ANCAs), as opposed to the cytoplasmic ANCAs (c-ANCAs) against proteinase-3 (PR3), which are strongly associated with Wegener's granulomatosis. Recent studies have reported an association between myeloperoxidase levels and the severity of coronary artery disease.[8] It has been suggested that myeloperoxidase plays a significant role in the development of the atherosclerotic lesion and rendering plaques unstable."wikipedia
The above discussion bring to mind that dermatitis seen with use of Drugs aiming at epithelial covering of blood vessel could indeed lead to secretion of molecules such as Cyclo-oxygenease (target of NSAID), MPO such as in this case Dapsone but Anti EGFR dose liberate from other affected cells cytokines of similar products that induced rash as a secondary effect. Should study confirms that MPO is our guy, then ANCA would be a legitimate candidate Bio-Marker.
Certainly during the activity of anti-EGFR, there is significant mambranes activity in terms of shedding proteins/Cytokines, FAK will be over express as a function of this activity and high FAK will be expected, liberations of Metalloproteases and the ADAMS such as 12 will follow the same logic and could join biomarkers of EGFR activity. Elevated stress at the membrane could be associated with HSP 90 amplification...let's go get them in a trial!
SRC-3Delta4 mediates the interaction of EGFR with FAK to promote cell migration.
Source
Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030 USA.Abstract
EGF induces signal transduction between EGFR and FAK, and FAK is required for EGF-induced cell migration. It is unknown, however, what factor mediates the interaction between EGFR and FAK and leads to EGF-induced FAK phosphorylation. Here, we identify SRC-3Delta4, a splicing isoform of the SRC-3 oncogene, as a signaling adaptor that links EGFR and FAK and promotes EGF-induced phosphorylations of FAK and c-Src.OTHER TARGETS! WHAT IN HELL IS LEUKEMEIA INHIBITOR FACTOR?
THE LIST OF TARGET IS ENDLESS
EVERYWHERE IN THE CELL THERE IS MUCH TO FIND OUT
AND SCIENTISTS ARE SPEECHLESS
LETS DELVE ON THIS ONE
IN MATTER OF INTRODUCTION LET'S GO TO SHARKEY ET AL!
"Transcripts encoding the receptor for c-fms, the receptor for colony-stimulating factor-1 (CSF-1), and c-kit (the receptor for stem cell factor [SCF]) were expressed throughout preimplantation development. Other growth factor ligand and receptor transcripts were expressed in a stage-specific manner: these included receptors for interleukin (IL)-6 (IL-6R), leukemia inhibitory factor (LIFR), tumor necrosis factor alpha (TNF alpha) (TNFRp80 and TNFRp60), and gp130."
THIS STATEMENT UNVEIL gp130 AND ITS VARIOUS CO-FACTOR LOOMING IN THE DARK
DOING ITS THINGS, BUT IMPORTANT IN THE CYTOKINES LIBERATION AND ACTIVITY OF INTERLEUKINS. LEUKEMIA DRIVEN BY INTERLEUKIN-6 CAN BE MODULATED BY ACTING ON ITS RECEPTOR AND TARGETING TO gp130 AND ITS SLEW OF CO-FACTORS!
EVERYWHERE IN THE CELL THERE IS MUCH TO FIND OUT
AND SCIENTISTS ARE SPEECHLESS
LETS DELVE ON THIS ONE
IN MATTER OF INTRODUCTION LET'S GO TO SHARKEY ET AL!
"Transcripts encoding the receptor for c-fms, the receptor for colony-stimulating factor-1 (CSF-1), and c-kit (the receptor for stem cell factor [SCF]) were expressed throughout preimplantation development. Other growth factor ligand and receptor transcripts were expressed in a stage-specific manner: these included receptors for interleukin (IL)-6 (IL-6R), leukemia inhibitory factor (LIFR), tumor necrosis factor alpha (TNF alpha) (TNFRp80 and TNFRp60), and gp130."
THIS STATEMENT UNVEIL gp130 AND ITS VARIOUS CO-FACTOR LOOMING IN THE DARK
DOING ITS THINGS, BUT IMPORTANT IN THE CYTOKINES LIBERATION AND ACTIVITY OF INTERLEUKINS. LEUKEMIA DRIVEN BY INTERLEUKIN-6 CAN BE MODULATED BY ACTING ON ITS RECEPTOR AND TARGETING TO gp130 AND ITS SLEW OF CO-FACTORS!
Monday, September 16, 2013
Key advances
*Microtubule Inhibitors (Taxanes, Ixabepilone, Erubilin)
*Signs of cellular death (Shrinkage of cell, membrane bleb formation, DNA fragmentation)
Pro-Apoptotic BCL-2 are Bax, Bak and Bim. whereas Anti-Apoptotic are BCL ( 2, XL,w)
*BH3 mimiking agents affecting BCL-XL led to significant thrombocytopenia
can this agent be used in Essential thrombocytopenia,
what is the status of BCL-XL in Essential thrombocytopenia, is it amplified?
*Does side effect of chemotherapy due to the drug itself or to cell killed
what cell was killed during the process, are there lymphokines that were liberated and could induce the side effects. Which receptor to target.
for skin reaction a panoply of of receptors could be crossed to steroid affected Receptors to find which one to block.
FDA approved anti JAK
-Tofacinib (anti JAK 1 and 3)
-Ruxolitinib (Anti JAK 1 and 2)
what is the link NOTCH1 and blockage of apoptosis, is it the BCL2, blockage of death receptor, the MTOR or the Telomerase.
or iit the MYC for amplification of genes
Are pro-apoptotic BCL2 increased in MDS, and are they under the influemce of the NOTCH
Does FAK over expression induce Fibroblast growth factor 2 to explain chemoth resistance in patient treated with chemotherapy? how does Fibroblast growth factor2 induce drug resistance?
Meaning of reduction of splenomegaly, ?decreases infltrate of abnormal cells
or Fibroblast growth factor induces fibrosis and transfusion independence is more space for normal producing cell, decrease of opposing (inhibitor ) growth factor effects or reduction of cell death.
Are Neuropathy associated to membrane phenomenon (metalloproteases) in the blood vessel, or fibroblast growth factor like activity inside the neuron, or death of the neuron
*Signs of cellular death (Shrinkage of cell, membrane bleb formation, DNA fragmentation)
Pro-Apoptotic BCL-2 are Bax, Bak and Bim. whereas Anti-Apoptotic are BCL ( 2, XL,w)
*BH3 mimiking agents affecting BCL-XL led to significant thrombocytopenia
can this agent be used in Essential thrombocytopenia,
what is the status of BCL-XL in Essential thrombocytopenia, is it amplified?
*Does side effect of chemotherapy due to the drug itself or to cell killed
what cell was killed during the process, are there lymphokines that were liberated and could induce the side effects. Which receptor to target.
for skin reaction a panoply of of receptors could be crossed to steroid affected Receptors to find which one to block.
FDA approved anti JAK
-Tofacinib (anti JAK 1 and 3)
-Ruxolitinib (Anti JAK 1 and 2)
what is the link NOTCH1 and blockage of apoptosis, is it the BCL2, blockage of death receptor, the MTOR or the Telomerase.
or iit the MYC for amplification of genes
Are pro-apoptotic BCL2 increased in MDS, and are they under the influemce of the NOTCH
Does FAK over expression induce Fibroblast growth factor 2 to explain chemoth resistance in patient treated with chemotherapy? how does Fibroblast growth factor2 induce drug resistance?
Meaning of reduction of splenomegaly, ?decreases infltrate of abnormal cells
or Fibroblast growth factor induces fibrosis and transfusion independence is more space for normal producing cell, decrease of opposing (inhibitor ) growth factor effects or reduction of cell death.
Are Neuropathy associated to membrane phenomenon (metalloproteases) in the blood vessel, or fibroblast growth factor like activity inside the neuron, or death of the neuron
THEORY IN CANCER PATHOLOGY
Based on pathology findings in Bladder cancer and the progressive genetic abnormalities proclaimed to be happening in colon cancer it appears that cancer pathology starts with an abnormal persistent stimulation of Receptors (FGFR3, FGF2, EGFR) which eventually under persistent stimulation will be eventually destroyed in an effort to to "desensitize" the cells from further stimulation. The Receptor destruction however could induce alterations of glycans covering the surface of receptors but could also cause immediate demise of the cell through death receptors found in the submenbrane layer of the cell. These Death Receptors are associated with Caspase 3. As the stimulation persists and some of the stimulation going through will solicit normal pathways with internalization of the stimuli-Receptor and solicitation of normal pathways such as the RAS leading to transduction of the signal. It also be perceived as stress triggering HSP and the NF-kB / c-JUN. (this pathway can also be stimulated by cytokine altered Receptors) According to the nature of the stimuli and the nature of the tissue, the HRAS (more epidermal-squamous than Adeno) or KRAS (more adeno then epidermal-squamous) pathway will be engaged. As aggression at the membrane continue The FAK, the Wnt and NOTCH induce membrane events as well as epigenetic events to escape the stimulation leading to liberation of further cytokines and growth factors (c-MYC stimulation) that will allow cellular survival and cellular desensitization. But it is not until repair (BRCAs), and regulator/modulators mechanisms failure that the cell becomes engaged in an irreversible proliferative process. Potentially under the these growth factor the p21,p16, MDM2 etc. are knock down. When the process reaches the P52,P53 AND Rb1, Malignancy is declared. (to be edited further) these events could happen concurrently and at various sites.
Stimulation of the MEK /c-MET Vs Epidermal...to come
Stimulation of the MEK /c-MET Vs Epidermal...to come
Sunday, September 15, 2013
Another BAD ACTOR ; a MET derivative!
If you followed our fight for the cure, we are increasingly suggesting that, nature has given us
its laws that we need to harvest and follow to win the cure, yes you need to follow the cellular pathways and select a point of intervention to stop or amplify in order to kill bad cells. We also have to know the nature of the environment of pathways which contain facilitators (enzymes),substrates(Homeobox) and Breakers (Rb1), repair mechanisms (BRCA), CBF(leukemias) or point of traffic signal orienting the reactions(Homeobox/CBF), and amplifiers (c-MYC, growth factor).
Bad cancers are those that:
1-Recruit genes that leads to malformations (DDR2) (FAK) (VEGF)
2-Recruit genes that restore embryonic potentials (c-MET) (STEM CELLS)
3-Recruit genes Regulating reactions or Homeobox (CBF)
4-Recruit the NOTCH, AND THE Wnt
5-KNOCKS OUT Breakers, repair and regulators, induce transcription factors or affect the miRNA or the polymerases.
6-Recruit and command Ubiquitilation machinery or the Helicases.
7-Recruit the Bcl (s)
8-recruit omnipresent co-factors ("wild gene") such as Gerb2. GAB1
It is quite apparent that genes that are associated with a growth factor will be imitating a chronic stimulation (exposure), or a driver situation. The c-MET is a gene that encodes a growth factor, and not just any growth factor,
"c-Met (MET or MNNG HOS Transforming gene) is a proto-oncogene that encodes a protein known as hepatocyte growth factor receptor (HGFR).[1][2] The hepatocyte growth factor receptor protein possesses tyrosine-kinase activity.[3] The primary single chain precursor protein is post-translationally cleaved to produce the alpha and beta subunits, which are disulfide linked to form the mature receptor."
This GROWTH FACTOR will affect all major "wild gene" and amplify them like the "CAPS LOCK" button of your computers!
The like of FGF2, HGFR is another dangerous trigger to protecting affected cells from dying! It is found in all dangerous cancers from Melanoma to hepatoma. Aside from Anti-MET, only IL-2, and Interferon can reach these. Although anti-P85 could play a role! It involves the NOTCH and the Wnt as well as the CRKL (reelin) through GAB1 the binder to Grb2! It involves the HIF1 and VHL, and everything else dangerous !
its laws that we need to harvest and follow to win the cure, yes you need to follow the cellular pathways and select a point of intervention to stop or amplify in order to kill bad cells. We also have to know the nature of the environment of pathways which contain facilitators (enzymes),substrates(Homeobox) and Breakers (Rb1), repair mechanisms (BRCA), CBF(leukemias) or point of traffic signal orienting the reactions(Homeobox/CBF), and amplifiers (c-MYC, growth factor).
Bad cancers are those that:
1-Recruit genes that leads to malformations (DDR2) (FAK) (VEGF)
2-Recruit genes that restore embryonic potentials (c-MET) (STEM CELLS)
3-Recruit genes Regulating reactions or Homeobox (CBF)
4-Recruit the NOTCH, AND THE Wnt
5-KNOCKS OUT Breakers, repair and regulators, induce transcription factors or affect the miRNA or the polymerases.
6-Recruit and command Ubiquitilation machinery or the Helicases.
7-Recruit the Bcl (s)
8-recruit omnipresent co-factors ("wild gene") such as Gerb2. GAB1
It is quite apparent that genes that are associated with a growth factor will be imitating a chronic stimulation (exposure), or a driver situation. The c-MET is a gene that encodes a growth factor, and not just any growth factor,
"c-Met (MET or MNNG HOS Transforming gene) is a proto-oncogene that encodes a protein known as hepatocyte growth factor receptor (HGFR).[1][2] The hepatocyte growth factor receptor protein possesses tyrosine-kinase activity.[3] The primary single chain precursor protein is post-translationally cleaved to produce the alpha and beta subunits, which are disulfide linked to form the mature receptor."
This GROWTH FACTOR will affect all major "wild gene" and amplify them like the "CAPS LOCK" button of your computers!
The like of FGF2, HGFR is another dangerous trigger to protecting affected cells from dying! It is found in all dangerous cancers from Melanoma to hepatoma. Aside from Anti-MET, only IL-2, and Interferon can reach these. Although anti-P85 could play a role! It involves the NOTCH and the Wnt as well as the CRKL (reelin) through GAB1 the binder to Grb2! It involves the HIF1 and VHL, and everything else dangerous !
Saturday, September 14, 2013
Some of the interesting Basic questions in Oncology
1.Understanding side effects better in order to design a response or treatment strategy!
--------------------------------------------------------------------------------------
There nothing annoying more the Oncologist and of course the cancer patient who is victimized than chemotherapy side effects. To me this is a experienced as a "let down" from sometimes a good drug. Here we are having a good response or even a stable disease, but the side effect pushes the treatment to a halt.
And quite frankly, current literature aside from listing the side effect, does not provide much in terms of why the side effect happened in the first place. And I understand it is difficult to say, but let it ride is not always the best option. It leaves in the mind of the Oncologist an unexplained "caveat". One of the thing driving medication prescription patterns is not only response to therapy based on phase II or III randomized studies, but rates of response to treatment and panoply and intensity of side effects of the drug. These factors determine the level of "comfort" with the drug. And with that level of comfort comes the "selling" of the drug to our patients who are the ultimate consumer.
The point is that deciphering the mechanisms underlying a side effect is not clear.
1-Is the side effect a direct effect from the drug
2.Is the side effect due to subsequently released cytokines
3.does patient have to have a deficiency in their genes (gene Heterozygosity ) to experience it
4.Is the side effect a bystander effect
etc...
At CRBCM, we are interested in deciphering the mechanism(s) of RASHES during the use Anti-EGFR and various Kinases. It is said that the worse the RASH the higher the response to Cetuximab and Tareceva for that matter. BUT THE WHY HAS BEEN LEFT FOR US TO GUESS!
DIARRHEA WITH CPT-11 OR THE ANTI-EGFR AND THE SUNITINIB (TKIs)
THE NEUROPATHY
----------------------.Now Neuropathy is an interesting one.!!
ie. post synaptic Neuron death during post Brain or nerve injury has been partly attributed to inflammatory Cytokines liberated in supportive glial cells. But we know that in Diabetics that obliteration of vasa vasorum or more clearly in (the nerve) small vessel feeding the nerve (vasa nervosa I am suggesting1) may play a role. There is no question in my mind that drugs such as the Taxanes will induce epigenetic consequences liberating some nocive Interleukins...
Bleeding from Avastin is an intriging one, somewhere I remember that an cofactor gene or anchor to the VEGF is affected. will sharpen my understanding again before delving further into this discussion.
Gene wise this is an interesting area since most of the target therapy since to share these side effect.
ONE OF THE INTRIGUING SET OF SIDE EFFECTS RESEARCH, IS THE DIFFERENCE OF IN THE PANOPLY OF SIDE EFFECTS BETWEEN AN ANTI-BRAF AGENT AND AN ANTI-MEK.
THE SLEW OF SIDE EFFECTS IS SIMILAR HOWEVER, THE ANTI-BRAF GIVES YOU A SURPRISING SIDE EFFECT. NOT ONLY IT GIVES YOU A DERMATITIS/RASH BUT IT PUSHES THE ENVELOP FURTHER TO GIVE YOU A SQUAMOUS CELL CANCER OF THE SKIN! AS IF NOW THE NF-kB IS INVOLVED? AS IF THE HSP 90 (OR IS-IT HSP 60 ) AND OF COURSE THE Wnt AND NOTCH? OR MAY BE REPAIR MECHANISMS OF SKIN DAMAGE CAN'T HANDLE THE CYTOKINES AFFECTING THE EPIDERMAL RECEPTORS? DAMAGE TO RECEPTORS? REALLY A TEASER WHEN IT COMES TO EXCITED RESEARCHERS!
2.WHICH ONE DOES WHAT?
=======================
FDA approved anti JAK
-Tofacinib (anti JAK 1 and 3)
-Ruxolitinib (Anti JAK 1 and 2)
One of the reality in the cell, is the issue of Heterozygosity of genes which affect how we respond to drugs and stimuli, a fact clearly affecting our prognosis. But surprisingly, some form of genes give squarely the opposing effect! Basically we could be death or alive because the same gene has a minimal molecular change. (the story of Sickle cell comes running in my mind). Another interesting set of fact is that some cellular molecule belong to a "same family" but could play opposing role Interleukin 4 vs Interleukin-1 for example. And now the JAK, the Metalloproteases, the TGFs,the Interferons, the MUC gene,THE SRC, the STATs and it goes on and on. We need mapping of these things to design a strategy of Use.AND AS I USUALLY SAY, COMPUTER CAN HELP. LET'S FACE IT ONE MIND CANNOT DO WHAT A PC CAN!
--------------------------------------------------------------------------------------
There nothing annoying more the Oncologist and of course the cancer patient who is victimized than chemotherapy side effects. To me this is a experienced as a "let down" from sometimes a good drug. Here we are having a good response or even a stable disease, but the side effect pushes the treatment to a halt.
And quite frankly, current literature aside from listing the side effect, does not provide much in terms of why the side effect happened in the first place. And I understand it is difficult to say, but let it ride is not always the best option. It leaves in the mind of the Oncologist an unexplained "caveat". One of the thing driving medication prescription patterns is not only response to therapy based on phase II or III randomized studies, but rates of response to treatment and panoply and intensity of side effects of the drug. These factors determine the level of "comfort" with the drug. And with that level of comfort comes the "selling" of the drug to our patients who are the ultimate consumer.
The point is that deciphering the mechanisms underlying a side effect is not clear.
1-Is the side effect a direct effect from the drug
2.Is the side effect due to subsequently released cytokines
3.does patient have to have a deficiency in their genes (gene Heterozygosity ) to experience it
4.Is the side effect a bystander effect
etc...
At CRBCM, we are interested in deciphering the mechanism(s) of RASHES during the use Anti-EGFR and various Kinases. It is said that the worse the RASH the higher the response to Cetuximab and Tareceva for that matter. BUT THE WHY HAS BEEN LEFT FOR US TO GUESS!
DIARRHEA WITH CPT-11 OR THE ANTI-EGFR AND THE SUNITINIB (TKIs)
THE NEUROPATHY
----------------------.Now Neuropathy is an interesting one.!!
ie. post synaptic Neuron death during post Brain or nerve injury has been partly attributed to inflammatory Cytokines liberated in supportive glial cells. But we know that in Diabetics that obliteration of vasa vasorum or more clearly in (the nerve) small vessel feeding the nerve (vasa nervosa I am suggesting1) may play a role. There is no question in my mind that drugs such as the Taxanes will induce epigenetic consequences liberating some nocive Interleukins...
Bleeding from Avastin is an intriging one, somewhere I remember that an cofactor gene or anchor to the VEGF is affected. will sharpen my understanding again before delving further into this discussion.
Gene wise this is an interesting area since most of the target therapy since to share these side effect.
ONE OF THE INTRIGUING SET OF SIDE EFFECTS RESEARCH, IS THE DIFFERENCE OF IN THE PANOPLY OF SIDE EFFECTS BETWEEN AN ANTI-BRAF AGENT AND AN ANTI-MEK.
THE SLEW OF SIDE EFFECTS IS SIMILAR HOWEVER, THE ANTI-BRAF GIVES YOU A SURPRISING SIDE EFFECT. NOT ONLY IT GIVES YOU A DERMATITIS/RASH BUT IT PUSHES THE ENVELOP FURTHER TO GIVE YOU A SQUAMOUS CELL CANCER OF THE SKIN! AS IF NOW THE NF-kB IS INVOLVED? AS IF THE HSP 90 (OR IS-IT HSP 60 ) AND OF COURSE THE Wnt AND NOTCH? OR MAY BE REPAIR MECHANISMS OF SKIN DAMAGE CAN'T HANDLE THE CYTOKINES AFFECTING THE EPIDERMAL RECEPTORS? DAMAGE TO RECEPTORS? REALLY A TEASER WHEN IT COMES TO EXCITED RESEARCHERS!
2.WHICH ONE DOES WHAT?
=======================
FDA approved anti JAK
-Tofacinib (anti JAK 1 and 3)
-Ruxolitinib (Anti JAK 1 and 2)
One of the reality in the cell, is the issue of Heterozygosity of genes which affect how we respond to drugs and stimuli, a fact clearly affecting our prognosis. But surprisingly, some form of genes give squarely the opposing effect! Basically we could be death or alive because the same gene has a minimal molecular change. (the story of Sickle cell comes running in my mind). Another interesting set of fact is that some cellular molecule belong to a "same family" but could play opposing role Interleukin 4 vs Interleukin-1 for example. And now the JAK, the Metalloproteases, the TGFs,the Interferons, the MUC gene,THE SRC, the STATs and it goes on and on. We need mapping of these things to design a strategy of Use.AND AS I USUALLY SAY, COMPUTER CAN HELP. LET'S FACE IT ONE MIND CANNOT DO WHAT A PC CAN!
A formidable opponent in the fight for the cure!
The only purpose of the cell is to survive, and to do so it has ability to not only live without resources or Oxygen for that matter for a while at least, through autophagia, the cell can live for a period of time without outside influx of nutrients. The cell can escape its environment to friendly shores, it can proliferate to increase the odds that at least one of the daughter cells can survive, through the years, the cell has learned to keep record of what mechanisms that helped it survive "bad weathers". It has build in Homeobox or Core binding Factors made of specific catalysts for only certain reactions and their determined sequence to orient the way metabolism should go. It has a wide variety of repair genes and regulators to temper rates of reactions and correct mistakes, It has a number of Paracrine or Autocrine secretions to maintain its growth (and this despite an incredible variety of Receptors and various exposures to a gamut of stimuli...One such paracrine and autocrine Molecule is: FGF2 which belong to the family of:
"Fibroblast growth factors, or FGFs, are a family of growth factors, with members involved in angiogenesis, wound healing, embryonic development and various endocrine signaling pathways. The FGFs are heparin-binding proteins and interactions with cell-surface-associated heparan sulfate proteoglycans have been shown to be essential for FGF signal transduction. FGFs are key players in the processes of proliferation and differentiation of wide variety of cells and tissues." wikipedia
FGF2 is a powerful defense against cellular death. It has been also accused of conferring resistance to chemotherapy. Through its link with JAK 2 which promotes it, FGF2 has risen to become one of the most formidable challenge to treating hematologic malignancies. It is reminiscent to IL-1, and its wound healing activities put it squarely at the FAK, its Heparan sulfate covered receptor is reminiscent of failing receptors of the triple negative Breast cancer. It confers Chemotherapy resistance such the one seen in Sarcoma,. Its angiogenesis activity put it in the metastatic cellular potentials. Its membrane localization put it closer to the Notch and Wnt. And has a growth factor and through the JAK-STAT, it has ample epigenetic consequences. FGF2, a Biomarker to deal with absolutely in the fight for the cure!
"Fibroblast growth factors, or FGFs, are a family of growth factors, with members involved in angiogenesis, wound healing, embryonic development and various endocrine signaling pathways. The FGFs are heparin-binding proteins and interactions with cell-surface-associated heparan sulfate proteoglycans have been shown to be essential for FGF signal transduction. FGFs are key players in the processes of proliferation and differentiation of wide variety of cells and tissues." wikipedia
FGF2 is a powerful defense against cellular death. It has been also accused of conferring resistance to chemotherapy. Through its link with JAK 2 which promotes it, FGF2 has risen to become one of the most formidable challenge to treating hematologic malignancies. It is reminiscent to IL-1, and its wound healing activities put it squarely at the FAK, its Heparan sulfate covered receptor is reminiscent of failing receptors of the triple negative Breast cancer. It confers Chemotherapy resistance such the one seen in Sarcoma,. Its angiogenesis activity put it in the metastatic cellular potentials. Its membrane localization put it closer to the Notch and Wnt. And has a growth factor and through the JAK-STAT, it has ample epigenetic consequences. FGF2, a Biomarker to deal with absolutely in the fight for the cure!
Friday, September 13, 2013
fighting secondary malignancy post BRAF therapy
To avoid secondary malignancy BRAF inhibitor should be associated
to anti HSP90 (reduce stress associated side effects)
or the MTOR Inhibitors
or drugs that may affect the VHL/HIF-1 .
Is MEK inhibition a marker of RASK, it is the site of endothelial - epithelial interchange?
to anti HSP90 (reduce stress associated side effects)
or the MTOR Inhibitors
or drugs that may affect the VHL/HIF-1 .
Is MEK inhibition a marker of RASK, it is the site of endothelial - epithelial interchange?
Next fight in the gene battle/computer models needed!
Yes we have decipher the human genome
But the epigenetic Zone is where things are happening
what are the patterns of Methylated genes, what is the miRNA patterns and quantity,
what are the active Regulators, Genetic repair genes, what is mutated, what is secondarily amplified, what is primarily amplified, what Receptors is altered, what ion-channels, is there cheloid factor activity involving the FAK, the NOTCH the Wnt, what pathways is activated, these are the questions that really matter, what CBF or Homebox are expressed, is there new translocations?
Each Neoplastic cell need this level of report!
Computer models needed!
But the epigenetic Zone is where things are happening
what are the patterns of Methylated genes, what is the miRNA patterns and quantity,
what are the active Regulators, Genetic repair genes, what is mutated, what is secondarily amplified, what is primarily amplified, what Receptors is altered, what ion-channels, is there cheloid factor activity involving the FAK, the NOTCH the Wnt, what pathways is activated, these are the questions that really matter, what CBF or Homebox are expressed, is there new translocations?
Each Neoplastic cell need this level of report!
Computer models needed!
fighting the Cytokines!
As we advance in our knowledge, it will be increasingly apparent that new biomarkers of disease will be defined for a variety of diseases. The increasing role of Cytokine and growth factors will be recognised. Indeed the inclusion of Obesity as a disease state can only be ascertain only because it is accompnied by abnornal level of Cytokins, growth factor and a number of Metabolic protein capable of inducing a disease state.
We also know that not all Cytokines are equal. Inhibition at the receptor of these specific receptor will be increasingly a way to address specific increase of these Cytokine. This fight had already started in Asthma where Interleukins 4, and 13
"Pitrakinra (Aerovant) is a human recombinant protein. It is an IL-4 and IL-13 antagonist in phase IIa studies for asthma. Its mechanism of action is by interruption of the Th2 lymphocyte immune response that underlies the inflammatory hyperresponsiveness in the airway epithelium of asthmatics.
Asthma results from a dysregulated, hyperresponsive immune response in the airways. Some immune cells in allergic asthmatics respond aggressively to foreign allergens with the release of IL-4 and -13, two key mediators that initiate a cycle of inflammation in the lung. Aerovant is an IL4Ra receptor antagonist that blocks the inflammatory effects of interleukins-4 and -13 (IL-4 and IL-13), thereby promoting a more balanced immune response." wikipedia
A cautious note though, IL 4 has been noted by some to be a good guy! IL-4 may be protective, so go easy. If you decrease it much, the ratio may break the balance (we are still looking into this!).
Aging is full of deleterious Cytokines, we believe a balance should be carefully maintain....Caution, just because it is increased does not means it is bad, homeostasis sometime require elevated protection or "protective Cytokines". Let's be discriminatory when it comes to Cytokines...the interferon story support our cautionary tale!
We also know that not all Cytokines are equal. Inhibition at the receptor of these specific receptor will be increasingly a way to address specific increase of these Cytokine. This fight had already started in Asthma where Interleukins 4, and 13
"Pitrakinra (Aerovant) is a human recombinant protein. It is an IL-4 and IL-13 antagonist in phase IIa studies for asthma. Its mechanism of action is by interruption of the Th2 lymphocyte immune response that underlies the inflammatory hyperresponsiveness in the airway epithelium of asthmatics.
Asthma results from a dysregulated, hyperresponsive immune response in the airways. Some immune cells in allergic asthmatics respond aggressively to foreign allergens with the release of IL-4 and -13, two key mediators that initiate a cycle of inflammation in the lung. Aerovant is an IL4Ra receptor antagonist that blocks the inflammatory effects of interleukins-4 and -13 (IL-4 and IL-13), thereby promoting a more balanced immune response." wikipedia
A cautious note though, IL 4 has been noted by some to be a good guy! IL-4 may be protective, so go easy. If you decrease it much, the ratio may break the balance (we are still looking into this!).
Aging is full of deleterious Cytokines, we believe a balance should be carefully maintain....Caution, just because it is increased does not means it is bad, homeostasis sometime require elevated protection or "protective Cytokines". Let's be discriminatory when it comes to Cytokines...the interferon story support our cautionary tale!
Recognition at CRBCM
Dear Dr. Mutombo Kankonde,
You are one of the many valued members within our community celebrating a birthday this month. At the Physicians Consulting Network, we would like to take this opportunity to wish you a very Happy Birthday. In addition, we would like to take this opportunity to celebrate you for the contributions you have made to our research and hopefully will continue to make over the coming year.
Please click on the following link so we can further extend our best wishes to you.
http://marketing.gfkamerica.com/121112-1342/index_bd.html
You are one of the many valued members within our community celebrating a birthday this month. At the Physicians Consulting Network, we would like to take this opportunity to wish you a very Happy Birthday. In addition, we would like to take this opportunity to celebrate you for the contributions you have made to our research and hopefully will continue to make over the coming year.
Please click on the following link so we can further extend our best wishes to you.
http://marketing.gfkamerica.com/121112-1342/index_bd.html
Important Reminders About Our December 2012 Integration
-------------------------------------------------------------------------------------------------
and thank you!
we continue our work through the years to come
Dr kankonde.
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