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!
Saturday, September 14, 2013
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.
Thursday, September 12, 2013
Melanoma: the chiken and egg story once more!
If you read about Melanoma pathophysiology, the emphasis is clearly on p16/CDK2A and on p14ARF. Other will emphasize the BRAF and PTENand BRCA2. But when you think about this, These are important modulator of cell division processes which in this disease are gone awry.
-------------------------------------------------------
wikipedia:
"The protein (p16) is a cyclin-dependent kinase (CDK) inhibitor that slows down the progression of the cell cycle by inactivating the Cyclin dependent kinase that phosphorylates the retinoblastoma protein (pRb). Both p16 and retinoblastoma (pRb) are important tumor suppressors that regulate the cell cycle. In addition to protein p16, pRB there are many other important tumor suppressors that regulate the cell cycle and one of them is protein p53. Cyclin D1 promotes the progression of the cell cycle to the S phase by cyclin D-dependent kinases (CDK4/CDK6). However, the activities of CDK4/CDK6 are restricted by protein p16 since protein p16 is a potent inhibitor of CDKs. Protein Rb, p16 and cyclin D1 are major restriction factors of the cell cycle restriction check points. The progression of cells from G1 phase to S phase is blocked by protein p16, which is a potential tumor suppressor that acts to disrupt the complex cyclin D1 and CDK 4 or 6. The most critical point in cell cycle regulation is the G1 checkpoint and it is at this checkpoint, that the complex cyclin D1 interactions take place to determine whether the cell cycle goes back into a quiescent state (G0) phase or enter into the S phase, where cells are destined to divide. when cells enter into the S phase the cells divide uncontrollably and that leads to cancer. It is important to note that Cyclin D1 is not a kinase but it activates kinases and it also appears to be most strongly implicated in human carcinogenesis."
=======================================
The point is that by the time these regulators of cell cycle enter the game, and their role magnified, TUMOR GROWTH factor amplification is already in effect driving this madness neoplastic process. and the lack of breaks due to mutations in these named genes become a critical failure to stop cell division. One should therefore ask what started the the growth factor in the first place.
Growth cycle amplification result from high activity of Epigenetic phenomena. UV light perturbs not the necessarily the p16 molecules, but membrane structures including WNT and NOTCH and various Receptors. At the receptors, stress will induce response including HSP-90, NK-kB, c-JUN which will start epigenetic phenomena including TGF and c-MYC (remember c-MYC is a "critical mediator of the NOTCH").
Interferon at high dose is the only therapeutic intervention in adjuvant setting because it affect cytokines and the TGF of the cellular world.
Failure to repair cellular damage will exacerbate the FAK, NOTCH and the WNT. Cellular loss of polarization,and deformation leading to warts and Nevi clearly involve membranous phenomena.
========================= The involvement of the GNAQ gene in Uveal Melanoma further re-enforces the notion that the initial insult is at the membrane.
you tell me what comes first, the chicken or the egg or p16 or the TGF and epigenetic disturbances?
-----------------------------------------------------------------------------------------
"Guanine nucleotide-binding protein G(q) subunit alpha is a protein that in humans is encoded by the GNAQ gene.[1]
Guanine nucleotide-binding proteins are a family of heterotrimeric proteins that couple cell surface, 7-transmembrane domain receptors to intracellular signaling pathways".(wikipedia)
Transforming growth factor beta stabilizes p15INK4B protein, increases p15INK4B-cdk4 complexes, and inhibits cyclin D1-cdk4 association in human mammary epithelial cells.
C Sandhu, J Garbe,-------------------------------------------------------
wikipedia:
"The protein (p16) is a cyclin-dependent kinase (CDK) inhibitor that slows down the progression of the cell cycle by inactivating the Cyclin dependent kinase that phosphorylates the retinoblastoma protein (pRb). Both p16 and retinoblastoma (pRb) are important tumor suppressors that regulate the cell cycle. In addition to protein p16, pRB there are many other important tumor suppressors that regulate the cell cycle and one of them is protein p53. Cyclin D1 promotes the progression of the cell cycle to the S phase by cyclin D-dependent kinases (CDK4/CDK6). However, the activities of CDK4/CDK6 are restricted by protein p16 since protein p16 is a potent inhibitor of CDKs. Protein Rb, p16 and cyclin D1 are major restriction factors of the cell cycle restriction check points. The progression of cells from G1 phase to S phase is blocked by protein p16, which is a potential tumor suppressor that acts to disrupt the complex cyclin D1 and CDK 4 or 6. The most critical point in cell cycle regulation is the G1 checkpoint and it is at this checkpoint, that the complex cyclin D1 interactions take place to determine whether the cell cycle goes back into a quiescent state (G0) phase or enter into the S phase, where cells are destined to divide. when cells enter into the S phase the cells divide uncontrollably and that leads to cancer. It is important to note that Cyclin D1 is not a kinase but it activates kinases and it also appears to be most strongly implicated in human carcinogenesis."
=======================================
The point is that by the time these regulators of cell cycle enter the game, and their role magnified, TUMOR GROWTH factor amplification is already in effect driving this madness neoplastic process. and the lack of breaks due to mutations in these named genes become a critical failure to stop cell division. One should therefore ask what started the the growth factor in the first place.
Growth cycle amplification result from high activity of Epigenetic phenomena. UV light perturbs not the necessarily the p16 molecules, but membrane structures including WNT and NOTCH and various Receptors. At the receptors, stress will induce response including HSP-90, NK-kB, c-JUN which will start epigenetic phenomena including TGF and c-MYC (remember c-MYC is a "critical mediator of the NOTCH").
Interferon at high dose is the only therapeutic intervention in adjuvant setting because it affect cytokines and the TGF of the cellular world.
Failure to repair cellular damage will exacerbate the FAK, NOTCH and the WNT. Cellular loss of polarization,and deformation leading to warts and Nevi clearly involve membranous phenomena.
========================= The involvement of the GNAQ gene in Uveal Melanoma further re-enforces the notion that the initial insult is at the membrane.
you tell me what comes first, the chicken or the egg or p16 or the TGF and epigenetic disturbances?
-----------------------------------------------------------------------------------------
"Guanine nucleotide-binding protein G(q) subunit alpha is a protein that in humans is encoded by the GNAQ gene.[1]
Guanine nucleotide-binding proteins are a family of heterotrimeric proteins that couple cell surface, 7-transmembrane domain receptors to intracellular signaling pathways".(wikipedia)
And, I am still heard!
 |
Contact us at
support@radioairplay.com (800) 399-9318 |
|
Hello Clement Albert,
|
||
|
||
|
We think you'll agree that Radio Airplay is a better promotional tool than ever. More than 50,000 artists rely on Airplay to get their music out there, and here's why:
|
||
If you are diabetic, water is your friend!
It is really true that we keep we keep emphasizing that in Diabetes Mellitus sugar cannot be allowed in the cell, and that without the sugar in the cell the intra-cellular milieu will use fat (which is Acid) to make energy molecules. There is in the diabetic body cells a build up of Acid within the cell that why we nee the Insulin to open the door to sugar into the cell to decrease the Use of Fatty Acid for energy production.
As sugar we ingest reaches the blood, It becomes unable to go into the cells where it is needed for Energy (ATP) production because Insulin is missing to open cellular doors. The sugar quickly build-up in our. at the And you know something has got to give. Well at the kidney level, the kidney can only keep so much sugar inside us, at one point the flood gates open, and our kidney let go the sugar though its gates because the sugar rise to intolerable levels. And with the sugar goes WATER...WATER.
Diabetes (going through) was not about sugar, it was about Water going through! And we keep loosing that part of the story! Water-Water Water is really really important. With less water we lose the tone of of the blood vessel and with less tone in our blood vessel, small blood vessels close and the Organ where this happens suffer dearly. In your eyes, injury occur you can go blind! In your nerves, loss of tone of blood vessel feeding the nerve itself, leads to Neuropathy. Yes drinking plenty as a diabetic will lead to increased Urination, an inconvenience, but remember life of your Organs depend on it as long as you keep sugar under control (with Medications if need be!)
Water, Water, AND WATER FOR THE PROTECTION OF THE TONE IN BLOOD VESSELS!
Remember what protect the kidney is a well known medication called Lisinopril (ACE Inhibitor) which by reducing the TONE in the Kidney blood vessel, let Water come through to flush them! Water good for you all around!
It is sad that we do not monitor this as closely (tight) as we should in modern medical practice!
As sugar we ingest reaches the blood, It becomes unable to go into the cells where it is needed for Energy (ATP) production because Insulin is missing to open cellular doors. The sugar quickly build-up in our. at the And you know something has got to give. Well at the kidney level, the kidney can only keep so much sugar inside us, at one point the flood gates open, and our kidney let go the sugar though its gates because the sugar rise to intolerable levels. And with the sugar goes WATER...WATER.
Diabetes (going through) was not about sugar, it was about Water going through! And we keep loosing that part of the story! Water-Water Water is really really important. With less water we lose the tone of of the blood vessel and with less tone in our blood vessel, small blood vessels close and the Organ where this happens suffer dearly. In your eyes, injury occur you can go blind! In your nerves, loss of tone of blood vessel feeding the nerve itself, leads to Neuropathy. Yes drinking plenty as a diabetic will lead to increased Urination, an inconvenience, but remember life of your Organs depend on it as long as you keep sugar under control (with Medications if need be!)
Water, Water, AND WATER FOR THE PROTECTION OF THE TONE IN BLOOD VESSELS!
Remember what protect the kidney is a well known medication called Lisinopril (ACE Inhibitor) which by reducing the TONE in the Kidney blood vessel, let Water come through to flush them! Water good for you all around!
It is sad that we do not monitor this as closely (tight) as we should in modern medical practice!
Wednesday, September 11, 2013
WHAT'S IN THE NEWS!
*reportedly dose dense Taxol carbo
with Taxol given weekly at 80mg/m2 day 1,8,15
and Carbo full dose AUC -6 given every 3 weeks
for 6 Cycles showing better results in Ovarian cancer
benefit 10 months difference Vs conventional chemoth. Q3weeks.
631 pts registered
stage II-IV
Dose dense in Ovarian Cancer!!!
*Once again no risk difference of treatment of breast cancer in pregnancy confirmed.
*Now old story
Metastatic Lung cancer
1st line if squamous---Gemzar cisplatin
1st line if non squamous -Premetrex-Cisplatin (AVASTIN)
BUT REMEMBER TARGET THERAPY SCREEN FOR EGFR, ROS,ALK
ADD CETUXIMAB (TO VINORELBINE CISPLATIN PER FLEX)
CRIZOTINIB
NOW BEING CONDISERED LIGAND OF PDL-1.
*WHAT IS DOT1L ?
*GANETESPIB, AN ANTI HEAT SHOCK PROTEIN INHIBITOR, THIS DRUG MUST BE MORE IMPORTANT IN LUNG CANCER PREVENTION!?
with Taxol given weekly at 80mg/m2 day 1,8,15
and Carbo full dose AUC -6 given every 3 weeks
for 6 Cycles showing better results in Ovarian cancer
benefit 10 months difference Vs conventional chemoth. Q3weeks.
631 pts registered
stage II-IV
Dose dense in Ovarian Cancer!!!
*Once again no risk difference of treatment of breast cancer in pregnancy confirmed.
*Now old story
Metastatic Lung cancer
1st line if squamous---Gemzar cisplatin
1st line if non squamous -Premetrex-Cisplatin (AVASTIN)
BUT REMEMBER TARGET THERAPY SCREEN FOR EGFR, ROS,ALK
ADD CETUXIMAB (TO VINORELBINE CISPLATIN PER FLEX)
CRIZOTINIB
NOW BEING CONDISERED LIGAND OF PDL-1.
*WHAT IS DOT1L ?
*GANETESPIB, AN ANTI HEAT SHOCK PROTEIN INHIBITOR, THIS DRUG MUST BE MORE IMPORTANT IN LUNG CANCER PREVENTION!?
Tuesday, September 10, 2013
Clinical genetic questions in Hepatitis
As we discuss deeper about the NOTCH and its activity, one of the disease syndrome that comes to mind is the pathobiology of conditions such as Hepatitis. we know the NOTCH is involved in both cellular membrane events as well epigenetic phenomena in the cell. By epigenetic phenomena, we would consider cytokines/growth factors production as a result of gene activity in this are of the cell. The NOTCH delve into these activities heavily. Cell to cell contacts and adhesion, loss of tissue boundaries and eventual transformation in recalcitrant Neoplasms are all potential activities of the NOTCH at liver lesion.
In Hepatitis, "liver injury is thought to be mediated by a strong cytotoxic T cell mediated reaction against infected hepatocytes that express viral Antigens at their surface". (Wedemer et al). Well T cell differentiation is ensured by The NOTCH.
Viral entrance in the cell occurs at the menbrane, the cell membrane where the NOTCH is ultimately located, the cell membrane where all receptors, Metalloproteases and ADAMS12 have been discussed to be active. The NOTCH is very much present.
Other aspects of interest in this disease are the chronicity of certain viral hepatitis and their leading to Cirrhosis which include an unfortunate commitment to disorderly nodular regeneration as if pushed by the NOTCH. The fact that it does not occur in Hepatitis A is an exciting observation. Is there links to the single RNA nature of the Virus instead of a larger Double stranded gene material of the Hepatitis B. Is this linked to certain the silencing of certain Histocompatibility Antigens. We know that Fulminant disease expression might be linked to HLA expression as well as patterns of gene silencing by epigenetic events. Attack of cytokines of self tolerance mechanisms of defense have been insufficiently studied, basically until we re-examine this disease at molecular level, progress in this are will be profoundly limited. We tend to stop our interest as soon as a vaccine has been developed (such as in in Hepatitis A ).
NOTCH activity in this disease is a legitimate target of studies...At CRBCM, we keep this in mind while fighting BAYLOR University Tissue bank which until now is trying to stop our research progress, using CPRIT funds (Texans'money). In life never dismiss the weak!
A coalition will fight until the end for its cause...let it be known!
In Hepatitis, "liver injury is thought to be mediated by a strong cytotoxic T cell mediated reaction against infected hepatocytes that express viral Antigens at their surface". (Wedemer et al). Well T cell differentiation is ensured by The NOTCH.
Viral entrance in the cell occurs at the menbrane, the cell membrane where the NOTCH is ultimately located, the cell membrane where all receptors, Metalloproteases and ADAMS12 have been discussed to be active. The NOTCH is very much present.
Other aspects of interest in this disease are the chronicity of certain viral hepatitis and their leading to Cirrhosis which include an unfortunate commitment to disorderly nodular regeneration as if pushed by the NOTCH. The fact that it does not occur in Hepatitis A is an exciting observation. Is there links to the single RNA nature of the Virus instead of a larger Double stranded gene material of the Hepatitis B. Is this linked to certain the silencing of certain Histocompatibility Antigens. We know that Fulminant disease expression might be linked to HLA expression as well as patterns of gene silencing by epigenetic events. Attack of cytokines of self tolerance mechanisms of defense have been insufficiently studied, basically until we re-examine this disease at molecular level, progress in this are will be profoundly limited. We tend to stop our interest as soon as a vaccine has been developed (such as in in Hepatitis A ).
NOTCH activity in this disease is a legitimate target of studies...At CRBCM, we keep this in mind while fighting BAYLOR University Tissue bank which until now is trying to stop our research progress, using CPRIT funds (Texans'money). In life never dismiss the weak!
A coalition will fight until the end for its cause...let it be known!
UPDATE AFTER 1 YEAR OF CRBCM EXISTENCE!
UPDATE OF FOLLOWERS/REVIEWS IN 1 YEAR OF CRBCM EXISTENCE ,
United States
|
16092
|
Russia
|
2060
|
Germany
|
1223
|
France
|
478
|
United Kingdom
|
429
|
Poland
|
337
|
Ukraine
|
318
|
China
|
204
|
Sweden
|
90
|
Taiwan
|
78
|
OVER 20 OTHER COUNTRIES FOLLOWING WITH LESS FREQUENCY
|
PEOPLE WILL STOP SCIENCE FROM HAPPENING!
The biggest stop to science progress is still HUMAN. Full of politics and a little greed and above all full of competitive spirit. You ask for help to complete a project, the value of the project does not come first. Money, who are you, who do you know. What you may achieve without us? all irrelevent questions will stop progress on research of public health important. For the Universties, the spirit of competition comes first.
Below is the perfect example:
"
Below is the perfect example:
"
Thank you very much for
your recent tissue request. After review, I would like to seek the
following information before presenting your request to the committee.
I see that you have now marked the IRB Status as “Exempt.” Can you
explain how this research is exempt? You explain in the description that
protocols have been approved for both Dr. Kankonde’s and your labs, but
do those apply to this specific research
protocol/proposal?
Also, are you a named PI on this grant?
Do you have a title at your institution, such as Assistant
Professor, Director, Researcher, etc? This should be put in the “Title”
section, not “Dr.”
Can you please spell out UTEP and CRBCM? Also, are these the
institutions where the research will be performed? I see you are using a
gmail address, so am just seeking if this will be done through Dr. K
Cancer Clinic instead of at University of Texas El
Paso.
Your research plan states that Dr. Kankonde has approval to supply
the 50 fresh lung cancer tissue samples. If so, why are you seeking 50
samples from the bank? Please clarify here, just so the committee is not
confused!
Lastly, do you have any preliminary data or significant articles to
show those 3 cancer genes are important in establishing early detection
of lung cancer?
Thanks,"
---------------------------------------------------------------------------------------------
This is what the CRBCM has to deal with daily to block advances!
"Can you spell out UTEP....instead of at the University of Texas " This question tell you many things and raises question on INTENTIONS? How can one request what they know?
Monday, September 9, 2013
NOTCH NOTCH, who's there!?
NOTCH NOTCH NOTCH every single where!
Research at NIH reported that metastasis occur when the cancer cell has created an invasive extension called INVADOPODIA. To form these invadopodia the cell has to modify its membranous boundaries.
Cancer cells live in a relatively hypoxic milieu which activates HIF-1 the Hypoxia Induced Factor, which of course will go on to induce formation of transcription factors to deal with the hypoxic milieu. But one of the target pathways turned on by HIF1 is "THE NOTCH SIGNALING PATHWAY, which an important means of cell to cell communication" (Begona Diaz et al.). And you just know that the NOTCH is going to do its things in the epigenetic area which include activating c-MYC, inducing Cytokine formation, inducing growth factors including those involving epidermal growth factor. Indeed at appropriate Integrins, the NOTCH resulting effect is to FLIP-IN HB-EGF (heparin-binding Epidermal Growth Factor) and FLOP-OUT Metallopreotease. One of the Integrins involved is ADAMS-12 which is further involved under the metalloproteases effect, amplifying extracellular events and on the membrane, prompting the INVADOPODIA. According to these authors "ADAMS-12 is an important effector of INVADOPODIA" and ensures the Cross talk NOTCH versus EGFR. And with the cross talk EGFR versus VEGF. path to Metastatasis enabling is crossed!
The NOTCH, so omnipresent, it is sometimes ignored by distracted scientists!
HOW MANY TARGETS are listed here!?
Research at NIH reported that metastasis occur when the cancer cell has created an invasive extension called INVADOPODIA. To form these invadopodia the cell has to modify its membranous boundaries.
Cancer cells live in a relatively hypoxic milieu which activates HIF-1 the Hypoxia Induced Factor, which of course will go on to induce formation of transcription factors to deal with the hypoxic milieu. But one of the target pathways turned on by HIF1 is "THE NOTCH SIGNALING PATHWAY, which an important means of cell to cell communication" (Begona Diaz et al.). And you just know that the NOTCH is going to do its things in the epigenetic area which include activating c-MYC, inducing Cytokine formation, inducing growth factors including those involving epidermal growth factor. Indeed at appropriate Integrins, the NOTCH resulting effect is to FLIP-IN HB-EGF (heparin-binding Epidermal Growth Factor) and FLOP-OUT Metallopreotease. One of the Integrins involved is ADAMS-12 which is further involved under the metalloproteases effect, amplifying extracellular events and on the membrane, prompting the INVADOPODIA. According to these authors "ADAMS-12 is an important effector of INVADOPODIA" and ensures the Cross talk NOTCH versus EGFR. And with the cross talk EGFR versus VEGF. path to Metastatasis enabling is crossed!
The NOTCH, so omnipresent, it is sometimes ignored by distracted scientists!
HOW MANY TARGETS are listed here!?
ADAM12, an effector of invadopodia signaling
ADAM12 functions in the cell by cutting other proteins. Hypoxia and notch signaling increased the amount of ADAM12 in the cell. Media obtained from hypoxic cells but not cells that lacked ADAM12-induced invadopodia formation in cells growing under normal oxygen levels. Diaz concluded that ADAM12 activity released an invadopodia-promoting factor. One of the potential candidates was heparin-binding epidermal growth factor (HB-EGF).
Crosstalk between notch and EGFR signaling linked by ADAM12
HB-EGF, which can be released from the cell by ADAM12’s activity, activates the epidermal growth factor receptor (EGFR). Adding HB-EGF to normoxic cells promoted invadopodia formation, while inhibiting HB-EGF decreased invadopodia in hypoxic cells. Inhibiting any component of the upstream pathway, Notch or ADAM12, prevented cells from releasing HB-EGF in response to hypoxia.
- See more at: http://beaker.sanfordburnham.org/2013/08/kicking-invasion-up-a-notch/#sthash.xhKP53nR.dpuf
ADAM12 functions in the cell by cutting other proteins. Hypoxia and notch signaling increased the amount of ADAM12 in the cell. Media obtained from hypoxic cells but not cells that lacked ADAM12-induced invadopodia formation in cells growing under normal oxygen levels. Diaz concluded that ADAM12 activity released an invadopodia-promoting factor. One of the potential candidates was heparin-binding epidermal growth factor (HB-EGF).
Crosstalk between notch and EGFR signaling linked by ADAM12
HB-EGF, which can be released from the cell by ADAM12’s activity, activates the epidermal growth factor receptor (EGFR). Adding HB-EGF to normoxic cells promoted invadopodia formation, while inhibiting HB-EGF decreased invadopodia in hypoxic cells. Inhibiting any component of the upstream pathway, Notch or ADAM12, prevented cells from releasing HB-EGF in response to hypoxia.
- See more at: http://beaker.sanfordburnham.org/2013/08/kicking-invasion-up-a-notch/#sthash.xhKP53nR.dpuf
ADAM12, an effector of invadopodia signaling
ADAM12 functions in the cell by cutting other proteins. Hypoxia and notch signaling increased the amount of ADAM12 in the cell. Media obtained from hypoxic cells but not cells that lacked ADAM12-induced invadopodia formation in cells growing under normal oxygen levels. Diaz concluded that ADAM12 activity released an invadopodia-promoting factor. One of the potential candidates was heparin-binding epidermal growth factor (HB-EGF).
Crosstalk between notch and EGFR signaling linked by ADAM12
HB-EGF, which can be released from the cell by ADAM12’s activity, activates the epidermal growth factor receptor (EGFR). Adding HB-EGF to normoxic cells promoted invadopodia formation, while inhibiting HB-EGF decreased invadopodia in hypoxic cells. Inhibiting any component of the upstream pathway, Notch or ADAM12, prevented cells from releasing HB-EGF in response to hypoxia.
- See more at: http://beaker.sanfordburnham.org/2013/08/kicking-invasion-up-a-notch/#sthash.xhKP53nR.dpuf
ADAM12 functions in the cell by cutting other proteins. Hypoxia and notch signaling increased the amount of ADAM12 in the cell. Media obtained from hypoxic cells but not cells that lacked ADAM12-induced invadopodia formation in cells growing under normal oxygen levels. Diaz concluded that ADAM12 activity released an invadopodia-promoting factor. One of the potential candidates was heparin-binding epidermal growth factor (HB-EGF).
Crosstalk between notch and EGFR signaling linked by ADAM12
HB-EGF, which can be released from the cell by ADAM12’s activity, activates the epidermal growth factor receptor (EGFR). Adding HB-EGF to normoxic cells promoted invadopodia formation, while inhibiting HB-EGF decreased invadopodia in hypoxic cells. Inhibiting any component of the upstream pathway, Notch or ADAM12, prevented cells from releasing HB-EGF in response to hypoxia.
- See more at: http://beaker.sanfordburnham.org/2013/08/kicking-invasion-up-a-notch/#sthash.xhKP53nR.dpuf
ADAM12, an effector of invadopodia signaling
ADAM12 functions in the cell by cutting other proteins. Hypoxia and notch signaling increased the amount of ADAM12 in the cell. Media obtained from hypoxic cells but not cells that lacked ADAM12-induced invadopodia formation in cells growing under normal oxygen levels. Diaz concluded that ADAM12 activity released an invadopodia-promoting factor. One of the potential candidates was heparin-binding epidermal growth factor (HB-EGF).
Crosstalk between notch and EGFR signaling linked by ADAM12
HB-EGF, which can be released from the cell by ADAM12’s activity, activates the epidermal growth factor receptor (EGFR). Adding HB-EGF to normoxic cells promoted invadopodia formation, while inhibiting HB-EGF decreased invadopodia in hypoxic cells. Inhibiting any component of the upstream pathway, Notch or ADAM12, prevented cells from releasing HB-EGF in response to hypoxia.
- See more at: http://beaker.sanfordburnham.org/2013/08/kicking-invasion-up-a-notch/#sthash.xhKP53nR.dpuf
ADAM12 functions in the cell by cutting other proteins. Hypoxia and notch signaling increased the amount of ADAM12 in the cell. Media obtained from hypoxic cells but not cells that lacked ADAM12-induced invadopodia formation in cells growing under normal oxygen levels. Diaz concluded that ADAM12 activity released an invadopodia-promoting factor. One of the potential candidates was heparin-binding epidermal growth factor (HB-EGF).
Crosstalk between notch and EGFR signaling linked by ADAM12
HB-EGF, which can be released from the cell by ADAM12’s activity, activates the epidermal growth factor receptor (EGFR). Adding HB-EGF to normoxic cells promoted invadopodia formation, while inhibiting HB-EGF decreased invadopodia in hypoxic cells. Inhibiting any component of the upstream pathway, Notch or ADAM12, prevented cells from releasing HB-EGF in response to hypoxia.
- See more at: http://beaker.sanfordburnham.org/2013/08/kicking-invasion-up-a-notch/#sthash.xhKP53nR.dpuf
Sunday, September 8, 2013
OUR FASCINATION WITH THE NOTCH IS JUSTIFIED!
If you read carefully with open mind everything we have written about the NOTCH
you may have detected that Mutations at the NOTCH appears to be associated with diseases that not only
are refractory and bent to resist, but also has a "consensus" to progress no matter what!
This is seen with Leukemia, brain tumors,pancreatic cancers, melanoma.
we strongly believe that disturbance at the NOTCH are the reason for the "foolish" mission of cancers to resist no matter what, and to succeed this mission, the NOTCH has to skirt Apoptotic measures! Mutations at the NOTCH have to involve or block all Apoptosis procedures in order to induce an acute leukemia, and for a "consensus", it has to imprint the message through epigenetic events.
When the NOTCH fails to block all apoptotic phenomena, a Myelodysplasia Occurs.
Remember Myelodysplasia most of the time involve Deletion of Chromosome 7 (where the NOTCH was discovered"NOTCH1 was first described as an oncogene by virtue of its involvement in the t(7;9)translocation found in the subset of patients with T cell Acute Lymphoblastic Leukemia" (Clurman). In Acute Leukemia...the where the NOTCH1 was noted there is "impaired differentiation and ENHANCED SELF RENEWAL" the author adds. The enhanced self renew is not only prolong survival but a successful shut down of Apoptosis venues. If the cancerous cell does not shut down successfully the Apoptotic trap, what you get is a Myelodysplasia. "Accelerated apoptosis is the hallmark of early MDS, which explain the paradoxical finding of Normal or Hypercellular marrow in most patients. The malignant clone has an inherent susceptibility to apoptotic cell death" (Alan List et al) But as the epigenetic NOTCH activity continues, the resulting disturbances associated with high level of Cytokines and growth factor results in cellular "autodestructions" of receptors ( a desensitization mechanisms). At the NOTCH which is involved in T cell differentiation, "direct T cell suppression akin to Aplastic Anemia" (List).
This also explain why epigenetic events point to susceptibility to
you may have detected that Mutations at the NOTCH appears to be associated with diseases that not only
are refractory and bent to resist, but also has a "consensus" to progress no matter what!
This is seen with Leukemia, brain tumors,pancreatic cancers, melanoma.
we strongly believe that disturbance at the NOTCH are the reason for the "foolish" mission of cancers to resist no matter what, and to succeed this mission, the NOTCH has to skirt Apoptotic measures! Mutations at the NOTCH have to involve or block all Apoptosis procedures in order to induce an acute leukemia, and for a "consensus", it has to imprint the message through epigenetic events.
When the NOTCH fails to block all apoptotic phenomena, a Myelodysplasia Occurs.
Remember Myelodysplasia most of the time involve Deletion of Chromosome 7 (where the NOTCH was discovered"NOTCH1 was first described as an oncogene by virtue of its involvement in the t(7;9)translocation found in the subset of patients with T cell Acute Lymphoblastic Leukemia" (Clurman). In Acute Leukemia...the where the NOTCH1 was noted there is "impaired differentiation and ENHANCED SELF RENEWAL" the author adds. The enhanced self renew is not only prolong survival but a successful shut down of Apoptosis venues. If the cancerous cell does not shut down successfully the Apoptotic trap, what you get is a Myelodysplasia. "Accelerated apoptosis is the hallmark of early MDS, which explain the paradoxical finding of Normal or Hypercellular marrow in most patients. The malignant clone has an inherent susceptibility to apoptotic cell death" (Alan List et al) But as the epigenetic NOTCH activity continues, the resulting disturbances associated with high level of Cytokines and growth factor results in cellular "autodestructions" of receptors ( a desensitization mechanisms). At the NOTCH which is involved in T cell differentiation, "direct T cell suppression akin to Aplastic Anemia" (List).
This also explain why epigenetic events point to susceptibility to
Anti-thymocyte globulin in MDS.
When the NOTCH is involved successfully, the result is an acute leukemia nothing less...and Myelofibrosis results from consequent epigenetic activities here leading to cytokine (interleukins) production and disturbances.
Saturday, September 7, 2013
A SLEW OF INTERVENTIONS CAN AFFECT THE NOTCH
Rather than sitting in awe before this dangerous phenomena that is the NOTCH, It is time to take a closer look at a comprehensive corrective measures to face it. Mutations at the NOTCH involve many killer cancers. Our patients are dying when we "navigate" cautiously with timid treatments!
We know the NOTCH has a Membrane base but "lightning fast" involves epigenetic and nuclear events. It is time to take a stand and face this monstrous challenge in a more systematic way. Again c-MYC is a critical Mediator of the Notch activity, it is therefore a potential good Biomarker of its activity. This NOTCH first described in Hematologic disease (it is involved with t(7,9) translocation) gives a powerful message of "apoptosis consensus to leukemic cell" most likely by its relations with the AKT/MTOR implications.
It is a Membrane based and act
1.as a Receptors and theirs various Co-factors (affected by CYTOKINES (IL21,granzyme), GROWTH FACTORS (TGF beta), and NEUROFACTORS), Endophilin,MAML1,
2.As a Endocytototic apparatus, indeed the internal portion of these proteins enter the cell after Detachment (FAK involved)
3.It is affected by important molecules at the membranes (Cyclic AMP, secretases, an the Hedghog pathway, ions channels, Rho-GTPase)
It goes on in the Cytosol where transporters must be involved
and affects main pathways through some anchors and related co-activators/adaptators (Grb2) and interact with wild genes FYN, SMRTR, Six1,dHBP1,TRAF6, HSP60-90,Ctip-2
some of its related proteins will undergo Ubiquilation E6
It goes on to the Nucleus to affect epigenetic events miR524, c-MYC, SMAD7, HES promoter,
Here is summarized work of many researchers, we thank them for their ccontibutions, but it is time to stop admiring Mutations at NOTCH, and take a stand!
We know the NOTCH has a Membrane base but "lightning fast" involves epigenetic and nuclear events. It is time to take a stand and face this monstrous challenge in a more systematic way. Again c-MYC is a critical Mediator of the Notch activity, it is therefore a potential good Biomarker of its activity. This NOTCH first described in Hematologic disease (it is involved with t(7,9) translocation) gives a powerful message of "apoptosis consensus to leukemic cell" most likely by its relations with the AKT/MTOR implications.
It is a Membrane based and act
1.as a Receptors and theirs various Co-factors (affected by CYTOKINES (IL21,granzyme), GROWTH FACTORS (TGF beta), and NEUROFACTORS), Endophilin,MAML1,
2.As a Endocytototic apparatus, indeed the internal portion of these proteins enter the cell after Detachment (FAK involved)
3.It is affected by important molecules at the membranes (Cyclic AMP, secretases, an the Hedghog pathway, ions channels, Rho-GTPase)
It goes on in the Cytosol where transporters must be involved
and affects main pathways through some anchors and related co-activators/adaptators (Grb2) and interact with wild genes FYN, SMRTR, Six1,dHBP1,TRAF6, HSP60-90,Ctip-2
some of its related proteins will undergo Ubiquilation E6
It goes on to the Nucleus to affect epigenetic events miR524, c-MYC, SMAD7, HES promoter,
Here is summarized work of many researchers, we thank them for their ccontibutions, but it is time to stop admiring Mutations at NOTCH, and take a stand!
*FBW7/hCDC4, an ubiquitin ligase, a substrate of E3,
It targets c-Myc, c-JUN and Notch for degradation through Ubiquitlation and proteasome degradation.
This is Mutated in grave cancer including Colon cancer and Acute lymphoblastic leukemia.
and of interest c-Myc is a critical Mediator of NOTCH activity. Putting notch in epigenetic phenomena rather than at the membrane where it is said to drive cellular consensus ! Bad disease are determined to be bad here!
Notch1 involvement (and potentially the Wnt) determine the consensus to be bad in T-cell leukemia despite therapy. It is "a member of the Notch family. Members of this Type 1 transmembrane protein family share structural characteristics including an extracellular domain consisting of multiple epidermal growth factor-like (EGF) repeats, and an intracellular domain consisting of multiple, different domain types. Notch family members play a role in a variety of developmental processes by controlling cell fate decisions."(wikipedia)
Notch power is demonstrated by the fact that it induced Malformation (ie Bicuspid Aortic valve and Aortic Aneurysm). It is the Anti-apoptotic somewhat irreversible power of the Notch which makes this gene a dangerous contender for chemotherapeutic drugs (we suspect). Researchers are now suggesting that p561ck could be the target to knock down in T-cell to affect the fate of these leukemic cells.
Notch Cooperates with the Reelin pathway mainly in the brain
Notch has various co-factors (MAML1)
and acts on several promoters (HES) of genes (see Ankyrin)
Cross talk with Tumor Growth factors and Neurofactors
The NOTCH family of genes are "wild genes":
In a recent publication,
" However it was recently shown that increased Notch signaling in transgenic mice mimics the symptoms of the disease [6]. Various substrates have been described for Itch in mammals: CXCR4 [7], p73, p63 [8], [9] smad 7 [10], Jun [11], Deltex (DTX, [12]) and Endophilin [13]. In general Itch targets its substrates to degradation, with some exceptions: AIP4 regulates the cell surface expression of select TRP channels by enhancing their ubiquitination and endocytosis but without facilitating their degradation [14]. Itch activity on junB is enhanced by Ser/Thr phosphorylation by MEKK1-JNK1 kinases [11], and reduced by Tyr phosphorylation in a fyn-dependent manner [15]. Thus it is difficult to attribute general characteristics to Itch, except that it is located in the endosomal system [7], [13], [16] and that it is autoubiquitinated [12], [17]. Furthermore the type of chains formed on its substrates is not often identified (except for K29-linked polyubiquitin chains on DTX and itself, [12]). Even less is known in Drosophila about the mechanisms controlled by Su(dx), Notch being its unique described target in this organism. Sakata et al. [18] have shown that ubiquitination of Drosophila Notch depends on Nedd4 (an E3 ubiquitin ligase belonging to the same family as Su(dx)) and on the presence of a PPSY motif in the intracellular region of Notch. Nedd4 is involved in the constitutive endocytosis of Notch and regulates its stability. Wilkin et al. [19] have demonstrated that Su(dx) and/or Nedd4 regulate sorting of Notch full-length within the early endosome. However these authors did not determine whether ubiquitination of Notch targets it for degradation, recycling or some other fate."
making the case for a "itch " to the NOTCH and to the variety of interactions that will take days to write about!
"IL-21-stimulated human plasmacytoid dendritic cells secrete granzyme B, which impairs their capacity to induce T-cell proliferation" a new approach to treating ALL!
It targets c-Myc, c-JUN and Notch for degradation through Ubiquitlation and proteasome degradation.
This is Mutated in grave cancer including Colon cancer and Acute lymphoblastic leukemia.
and of interest c-Myc is a critical Mediator of NOTCH activity. Putting notch in epigenetic phenomena rather than at the membrane where it is said to drive cellular consensus ! Bad disease are determined to be bad here!
Notch1 involvement (and potentially the Wnt) determine the consensus to be bad in T-cell leukemia despite therapy. It is "a member of the Notch family. Members of this Type 1 transmembrane protein family share structural characteristics including an extracellular domain consisting of multiple epidermal growth factor-like (EGF) repeats, and an intracellular domain consisting of multiple, different domain types. Notch family members play a role in a variety of developmental processes by controlling cell fate decisions."(wikipedia)
Notch power is demonstrated by the fact that it induced Malformation (ie Bicuspid Aortic valve and Aortic Aneurysm). It is the Anti-apoptotic somewhat irreversible power of the Notch which makes this gene a dangerous contender for chemotherapeutic drugs (we suspect). Researchers are now suggesting that p561ck could be the target to knock down in T-cell to affect the fate of these leukemic cells.
Notch Cooperates with the Reelin pathway mainly in the brain
Notch has various co-factors (MAML1)
and acts on several promoters (HES) of genes (see Ankyrin)
Cross talk with Tumor Growth factors and Neurofactors
The NOTCH family of genes are "wild genes":
In a recent publication,
AIP4/Itch Regulates Notch Receptor Degradation in the Absence of Ligand
" However it was recently shown that increased Notch signaling in transgenic mice mimics the symptoms of the disease [6]. Various substrates have been described for Itch in mammals: CXCR4 [7], p73, p63 [8], [9] smad 7 [10], Jun [11], Deltex (DTX, [12]) and Endophilin [13]. In general Itch targets its substrates to degradation, with some exceptions: AIP4 regulates the cell surface expression of select TRP channels by enhancing their ubiquitination and endocytosis but without facilitating their degradation [14]. Itch activity on junB is enhanced by Ser/Thr phosphorylation by MEKK1-JNK1 kinases [11], and reduced by Tyr phosphorylation in a fyn-dependent manner [15]. Thus it is difficult to attribute general characteristics to Itch, except that it is located in the endosomal system [7], [13], [16] and that it is autoubiquitinated [12], [17]. Furthermore the type of chains formed on its substrates is not often identified (except for K29-linked polyubiquitin chains on DTX and itself, [12]). Even less is known in Drosophila about the mechanisms controlled by Su(dx), Notch being its unique described target in this organism. Sakata et al. [18] have shown that ubiquitination of Drosophila Notch depends on Nedd4 (an E3 ubiquitin ligase belonging to the same family as Su(dx)) and on the presence of a PPSY motif in the intracellular region of Notch. Nedd4 is involved in the constitutive endocytosis of Notch and regulates its stability. Wilkin et al. [19] have demonstrated that Su(dx) and/or Nedd4 regulate sorting of Notch full-length within the early endosome. However these authors did not determine whether ubiquitination of Notch targets it for degradation, recycling or some other fate."
making the case for a "itch " to the NOTCH and to the variety of interactions that will take days to write about!
"IL-21-stimulated human plasmacytoid dendritic cells secrete granzyme B, which impairs their capacity to induce T-cell proliferation" a new approach to treating ALL!
Friday, September 6, 2013
Speculations on DPC4 gene!
"The K-ras oncogene is activated in approximately 90% of pancreatic
adenocarcinomas, and the DPC4 (MADH4/SMAD4) tumor suppressor gene is
inactivated in approximately 55% of pancreatic adenocarcinomas." McCarthy et al.
===================================================================
Another functional Misnomer the DPC4 gene
It is a growth factor that stops proliferation (GROWTH FACTOR THAT INHIBITS IT!)
It is one of these things that nature has created to balance its growth. And when the breaks are absent, proliferation of cells will go wild. I suspect it is one of the genes that comes into effect early at the end of embryogenesis when tissue differentiation has to end. It got to have links to the NOTCH to be so powerful a gene! With the NOTCH, this will explain how so determined cancer induced by this deletion will stubbornly progress thinking it is doing the right thing! NOTCH is the guy that convince cells to agree to the mission! Coupling the determination of the NOTCH with removing break to proliferation makes for one deadly disease! The cells don't know the mission is destructive! The KRAS amplification is also a result of removal of breaks! Indeed reports of repression of EVI1, Mir-96, and even GLUT1 seem to abound in Pancreatic cancer. What is of fascination is that GLUT 1 that we reported to be linked to HIF-1 and VHL and antioxidants, is said to be "downstream from c-MYC" the gene amplifier! (proliferative by excellence) DPC4 must act on c-MYC through this conduit! The VHL will impact EGFR and sure enough angiogenesis could be "depressed" impairing delivery (and effectiveness) of Chemotherapy in these disease. Only Microtubule effect will come to concur this of course!(affecting the NOTCH!)
It is now evident that to slow down Pancreatic cancer
we should focus on
Disturbing ions channel, watch the FAK, impacting on Actin metabolism, expanding GLUT1, block c-MYC
and let's go to work!
ONE Thing THOUGH, the Devil Wnt is not far (when NOTCH is awaken)!
1.KRAS, " normal tissue signaling, and the mutation of a KRAS gene is an essential step in the development of many cancers.[3] Like other members of the Ras family, the KRAS protein is a GTPase and is an early player in many signal transduction pathways. KRAS is usually tethered to cell membranes because of the presence of an isoprenyl group on its C-terminus." wikipedia
It is interesting to know that with KRAS activation follow the activation of RALGDS which through the Arrestins wake up the DVL (devil) preparing the cell to early proliferation and metastasis through the Wnt.
(wikipedia)
===================================================================
Another functional Misnomer the DPC4 gene
It is a growth factor that stops proliferation (GROWTH FACTOR THAT INHIBITS IT!)
It is one of these things that nature has created to balance its growth. And when the breaks are absent, proliferation of cells will go wild. I suspect it is one of the genes that comes into effect early at the end of embryogenesis when tissue differentiation has to end. It got to have links to the NOTCH to be so powerful a gene! With the NOTCH, this will explain how so determined cancer induced by this deletion will stubbornly progress thinking it is doing the right thing! NOTCH is the guy that convince cells to agree to the mission! Coupling the determination of the NOTCH with removing break to proliferation makes for one deadly disease! The cells don't know the mission is destructive! The KRAS amplification is also a result of removal of breaks! Indeed reports of repression of EVI1, Mir-96, and even GLUT1 seem to abound in Pancreatic cancer. What is of fascination is that GLUT 1 that we reported to be linked to HIF-1 and VHL and antioxidants, is said to be "downstream from c-MYC" the gene amplifier! (proliferative by excellence) DPC4 must act on c-MYC through this conduit! The VHL will impact EGFR and sure enough angiogenesis could be "depressed" impairing delivery (and effectiveness) of Chemotherapy in these disease. Only Microtubule effect will come to concur this of course!(affecting the NOTCH!)
It is now evident that to slow down Pancreatic cancer
we should focus on
Disturbing ions channel, watch the FAK, impacting on Actin metabolism, expanding GLUT1, block c-MYC
and let's go to work!
ONE Thing THOUGH, the Devil Wnt is not far (when NOTCH is awaken)!
1.KRAS, " normal tissue signaling, and the mutation of a KRAS gene is an essential step in the development of many cancers.[3] Like other members of the Ras family, the KRAS protein is a GTPase and is an early player in many signal transduction pathways. KRAS is usually tethered to cell membranes because of the presence of an isoprenyl group on its C-terminus." wikipedia
It is interesting to know that with KRAS activation follow the activation of RALGDS which through the Arrestins wake up the DVL (devil) preparing the cell to early proliferation and metastasis through the Wnt.
(wikipedia)
Activities at CRBCM
*The CRBCM has moved to 11601 Pellicano Drive, suite A2 in EL PASO, same Zip code. newer building
Here we finally have direct frontage to the street, our lights will shine among other organizations in the fight for survival and expansion. The location is cheaper, and the management more dynamic and responsive! This is the right place to be right now ! We have made our debut, now time to be more in the public face!
*Still exploring more expansion, we have now met September 5th Developers and will be part of the plan of new Medical Building. We thank Developers for inviting us to the table. El Paso is growing with us!
* Dr Kankonde is now Medical Director at the Grifols/Talecris Plasma laboratory known as EL PASO II. Training as Medical lab director is in full swing and progressing on target! We are where it is happening. Over 16000 donors a year at this location...our team is working well. We can accommodate more donors, the need is here now!
*CRBCM has submitted few research proposals, we are waiting to hear...
We are hard at work planning for Breast cancer Month activity...October 2013!
* Contract with UTEP on work on PCR work on lung cancer progressing well, and should be finalized this week. The tissue Bank (University of Virginia) is ready to send samples! And fund from MDHonors have been received (thank you!). We are ready to embark in our project thanks to Professor Jianying Zhang!
Here we finally have direct frontage to the street, our lights will shine among other organizations in the fight for survival and expansion. The location is cheaper, and the management more dynamic and responsive! This is the right place to be right now ! We have made our debut, now time to be more in the public face!
*Still exploring more expansion, we have now met September 5th Developers and will be part of the plan of new Medical Building. We thank Developers for inviting us to the table. El Paso is growing with us!
* Dr Kankonde is now Medical Director at the Grifols/Talecris Plasma laboratory known as EL PASO II. Training as Medical lab director is in full swing and progressing on target! We are where it is happening. Over 16000 donors a year at this location...our team is working well. We can accommodate more donors, the need is here now!
*CRBCM has submitted few research proposals, we are waiting to hear...
We are hard at work planning for Breast cancer Month activity...October 2013!
* Contract with UTEP on work on PCR work on lung cancer progressing well, and should be finalized this week. The tissue Bank (University of Virginia) is ready to send samples! And fund from MDHonors have been received (thank you!). We are ready to embark in our project thanks to Professor Jianying Zhang!
| Zhang, Jianying | WE ARE STILL WAITING TO SEE WHAT HAPPENS WITH CPRIT, WATCHING ACTIVITIES THERE! HOPEFULLY AT LEAST ONE OF OUR PROJECTS WILL BE TO THEIR LIKING! LAST WE HEARD WAS A FOX NEWS REPORT PUBLISHED 8/5/13, GO TO ARTICLE! |
Thursday, September 5, 2013
In Cancer target therapy, BIG IS NOT NECESSARILY BETTER.
Scientists have long understood that our fascination with major pathways in the cell should be modulated
and attention to smaller and intermediary molecules should be heightened. It is true that driver molecules could be sitting in the main high way of the pathways. But increasingly, it has become evident that supportive genes that maintain the Pathway flow, those that regulate, modulate, start or maintain the pathways or redirect differentiation are just as important and may be at time larger in importance for therapeutic intervention.
The discovery that some major chemotherapy drugs keep some special places in our armamentarium of therapeutic interventions not because of their recognized main effects on genes but rather from their Epigenetic effects, how they affect de-acethylation or methylation, miRNA or other related events, have shown the importance of "secondary" changes they impose!
In Pancreatic cancers, the most recognized Mutation is that involving KRAS ( and secondarily the EGFR). However attacks or inhibition of KRAS has not assured remarkable successes. Anti-EGFR have not convincingly improved survival although with some effect. Today Researcher are starting to look at supportive genes: the switch genes, those that keep autophosphorylation on, The Cbl, the Shc, PYK2,
FAK (cheloid effect), PKB and Lyn, the Grb2, The COT when it comes to MEK.
We have neglected the role of TGF alpha as a stressor in this disease although it is the inducer of EGFR.
We have chosen to ignore AP-1 when it is the major inducer of IL-1 (IL-8) and contributor somehow of exacerbation or a consequence of NF-kB intervention in this disease.
Other aspect is the role of maintenance therapy in metastatic Pancreatic cancers, Indeed we know that Activity at KRAS are somewhat obligatory to the driving of this disease, yet we have not checked the status of the KRAS after completion of primary therapy, and attempted to suppress this this in maintenance setting.
The CRBCM is looking into this also!
(Of note major Mutations still involve P16ink4A, EGFR, DPC4/SMAD4,BRCA2,MHL1,MSH2,KRAS,CDKN2A,PMS1, and TGF(s)) in pancreatic cancers!
and attention to smaller and intermediary molecules should be heightened. It is true that driver molecules could be sitting in the main high way of the pathways. But increasingly, it has become evident that supportive genes that maintain the Pathway flow, those that regulate, modulate, start or maintain the pathways or redirect differentiation are just as important and may be at time larger in importance for therapeutic intervention.
The discovery that some major chemotherapy drugs keep some special places in our armamentarium of therapeutic interventions not because of their recognized main effects on genes but rather from their Epigenetic effects, how they affect de-acethylation or methylation, miRNA or other related events, have shown the importance of "secondary" changes they impose!
In Pancreatic cancers, the most recognized Mutation is that involving KRAS ( and secondarily the EGFR). However attacks or inhibition of KRAS has not assured remarkable successes. Anti-EGFR have not convincingly improved survival although with some effect. Today Researcher are starting to look at supportive genes: the switch genes, those that keep autophosphorylation on, The Cbl, the Shc, PYK2,
FAK (cheloid effect), PKB and Lyn, the Grb2, The COT when it comes to MEK.
We have neglected the role of TGF alpha as a stressor in this disease although it is the inducer of EGFR.
We have chosen to ignore AP-1 when it is the major inducer of IL-1 (IL-8) and contributor somehow of exacerbation or a consequence of NF-kB intervention in this disease.
Other aspect is the role of maintenance therapy in metastatic Pancreatic cancers, Indeed we know that Activity at KRAS are somewhat obligatory to the driving of this disease, yet we have not checked the status of the KRAS after completion of primary therapy, and attempted to suppress this this in maintenance setting.
The CRBCM is looking into this also!
(Of note major Mutations still involve P16ink4A, EGFR, DPC4/SMAD4,BRCA2,MHL1,MSH2,KRAS,CDKN2A,PMS1, and TGF(s)) in pancreatic cancers!
Wednesday, September 4, 2013
It is time to take it or leave it! SEASONAL FLU VACCINE!
DATE: September 4, 2013
SUBJECT: 2013-14 Seasonal Influenza Vaccination Program
It's that time again! Flu season is approaching and all Medical Staff members, employees and volunteers will be required to provide documentation of a current influenza vaccination. As always, THE Hospital will provide free flu shots to our medical staff in the Employee Health Office at the hospital starting Monday, September 16. The schedule for ongoing immunization clinics at the hospital is listed in the table below. If you choose to be vaccinated elsewhere, you must provide proof of that vaccination in writing to the Medical Staff Office.
Any Medical Staff member requiring a medical or religious exemption from vaccination must submit a request for exemption in writing to the Medical Staff Office from their personal physician stating the reason for exemption.
Documentation of vaccination or exemption must be received by the Medical Staff Office by October 15 or the Medical Staff member's privileges will be suspended for the entire influenza season.
Thanks as always for helping keep our patients and our coworkers healthier during the influenza season.
FROM HYPOXIA TO CANCER/ HTLV1 (RAPID COMPLICATION OF CELLULAR EVENTS)
What is really going on in the tissue is that there is a relative Hypoxia in the tissue. These Hypoxic conditions are exacerbated in Obese individual because of coexisting sleep apnea. During sleep Apnea, the body goes into an hypoxic mode because of the frequent Apnea. At cellular level Hypoxia has to be dealt with rapidly because the cell use insufficiently Glucose for the generation of ATP the molecular energy. So Glucose influs is needed to maintain cell life without building up Acids. There is cellular response to hypoxia which 2 folds
1. Rapid transcription factor response which leads to increase of GLUT1 the amount of receptors for Glucose. The cell needs sugar more because it can only produce 3-4 ATP instead of all it can using the Mitochondrial Kreb cycle. Receptors to Glucose increase sharply, weakening in fact the cell because we now know that Viruses (HTLV1) use the same Receptors to penetrate the cell! Making GLUT1 a legitimate target during HTLV1 infection. (watch for Hypertrophy here as cell lose polarity) (WATCH WHAT TGF IS DOING BY NOW WITH THIS RECEPTOR! STRESS WILL START HSP90)
2. Exacerbation of Activity the Hypoxic Intrinsic Factor (HIF1). With a name like this, when else can it acts. Of course in Hpoxic condition. There is a global perception that Oxygen is needed pronto so this HIF has to do some thing to that effect. Oxygen has to come from blood, so it figure we have to do something to the blood vessel. HIF goes to the promoter of VEGF and activates it leading to smooth muscle of blood vessel effect (contributing to Diabetic Retinopathy treated by Avastin)).
Watching all these activities is a big monster in the room called VHL which is linked to VEGF through its interaction with AUF1, and Ubiquitilation of HIF1 is not far away. (If you speak VHL, Renal cancer is ready to start! and the worse kind called "clear cell")
In the global Acidic conditions imposed by Hypoxia followed by ineffective Glycolysis, free radical ensues ready to cause potentially cancer...taking Anti-Oxidants is good to dampen the free Radicals and danger of DNA Adducts production. But remember Anti-Oxidants activities must occur in safe presence of Iron. Women with Iron deficiency because of menses could go "viral" here we surmise and develop a weird lung cancer EGFR positive because of the EGFR and VEGF "cross talk".
Again at cellular level, what start with lack of Oxygen can go "viral" and "neoplastic" on you lightening fast...particularly if it (hypoxia that is) comes to be every time you sleep or dose off!
1. Rapid transcription factor response which leads to increase of GLUT1 the amount of receptors for Glucose. The cell needs sugar more because it can only produce 3-4 ATP instead of all it can using the Mitochondrial Kreb cycle. Receptors to Glucose increase sharply, weakening in fact the cell because we now know that Viruses (HTLV1) use the same Receptors to penetrate the cell! Making GLUT1 a legitimate target during HTLV1 infection. (watch for Hypertrophy here as cell lose polarity) (WATCH WHAT TGF IS DOING BY NOW WITH THIS RECEPTOR! STRESS WILL START HSP90)
2. Exacerbation of Activity the Hypoxic Intrinsic Factor (HIF1). With a name like this, when else can it acts. Of course in Hpoxic condition. There is a global perception that Oxygen is needed pronto so this HIF has to do some thing to that effect. Oxygen has to come from blood, so it figure we have to do something to the blood vessel. HIF goes to the promoter of VEGF and activates it leading to smooth muscle of blood vessel effect (contributing to Diabetic Retinopathy treated by Avastin)).
Watching all these activities is a big monster in the room called VHL which is linked to VEGF through its interaction with AUF1, and Ubiquitilation of HIF1 is not far away. (If you speak VHL, Renal cancer is ready to start! and the worse kind called "clear cell")
In the global Acidic conditions imposed by Hypoxia followed by ineffective Glycolysis, free radical ensues ready to cause potentially cancer...taking Anti-Oxidants is good to dampen the free Radicals and danger of DNA Adducts production. But remember Anti-Oxidants activities must occur in safe presence of Iron. Women with Iron deficiency because of menses could go "viral" here we surmise and develop a weird lung cancer EGFR positive because of the EGFR and VEGF "cross talk".
Again at cellular level, what start with lack of Oxygen can go "viral" and "neoplastic" on you lightening fast...particularly if it (hypoxia that is) comes to be every time you sleep or dose off!
MORE SUPPUTATIONS IN GENETIC TARGETING THERAPY
My deep investigation into Hypoxia has led to an interesting set of clinical questions
What is again the role of Mitotane in the treatment of Pancreatic cancer?
can Mitotane add to Anti-VEGF in the treatment of Pancreatic or Renal cancers
Is there a role of AUF1 in monitoring Anti-VEGF therapeutic effect
in other words can AUF1 elevation predicts Diabetic retinopathy.
Role of Geldanamycine in pancreatic and esophageal cancers!
Hummm...need to look into these!
What is again the role of Mitotane in the treatment of Pancreatic cancer?
can Mitotane add to Anti-VEGF in the treatment of Pancreatic or Renal cancers
Is there a role of AUF1 in monitoring Anti-VEGF therapeutic effect
in other words can AUF1 elevation predicts Diabetic retinopathy.
Role of Geldanamycine in pancreatic and esophageal cancers!
Hummm...need to look into these!
Monday, September 2, 2013
The trenches of stress
Whether the stimuli to stress be physical (heat, radiation, cold etc) or autoimmune or infectious(Interleukins, TNF,other cytokines and cyclins, etc.).deep into the "bowel" of the cell these events have a chemical effect involving genes that are also involved in proliferation, amplification, cellular differentiation, division etc. Cellular stress potentially could lead to Apoptosis. Therefore anti-apoptotic genes are also stimulated to stop the cell from dying from a "benign and non overwhelming " stress. Anti-Apoptotic genes include those that directly stops Apoptosis from Happening (GADD45, MyD118, Ing1p33inca etc) but also those involved in DNA repair XRCC1, PARP1,2,APEX1,PCNA.
of note, this section identify PCNA, a series of polymerase cofactor enzymes/proteins, as an important target for intervention!and Ing1 protects against UV induced Apoptosis per researchers!
- APEX1,[4]
- APTX,[5][6]
- OGG1,[7]
- PARP2,[8]
- PCNA,[9]
- PNKP,[10][11]
- POLB,[12][9][13][14] and
- PARP1.[6][15]wikipedia
- PCNA has been shown to interact with Ku70,[13][14] MSH3,[13][15][16] Werner syndrome ATP-dependent helicase,[17][18] RFC2,[13][19][20] RFC3,[13][21] RFC1,[13][22][23][24][25] RFC4,[13][19] RFC5,[13][19][24] GADD45G,[26][27] CDC25C,[28] MUTYH,[29] Flap structure-specific endonuclease 1,[30][31][32][33][34][35][36] Cyclin O,[13][37] CHTF18,[13] Y box binding protein 1,[38] Cyclin D1,[39][40] Annexin A2,[13] MSH6,[13][15][16] DNMT1,[41][42][43] HDAC1,[44] KCTD13,[45] XRCC1,[46] Cyclin-dependent kinase 4,[40][47] Ku80,[13][14][48] HUS1,[49] GADD45A,[50][51][52][53][54] POLD2,[55] ING1,[56] POLH,[57] KIAA0101,[36] POLDIP2,[58] EP300,[59] MCL1,[60] POLD3,[13][61] Cyclin-dependent kinase inhibitor 1C,[62] POLL,[63][64][65] Ubiquitin C[66][67][68] and P21.[23][32][36][62][69][70][71][72]wikipedia
- DNA damage repair and those involved in containment of Oxidative attacks are very much part of genetic coping mechanisms against stress induced damages to the cell. Suffice is to say that these events are epigenetic and will also involve the MeCTR and DNMT1 as mentioned above.
of note, this section identify PCNA, a series of polymerase cofactor enzymes/proteins, as an important target for intervention!and Ing1 protects against UV induced Apoptosis per researchers!
Sunday, September 1, 2013
Genes involved in stressful events
PATTERNS OF STRESS
It is by now evident that there is multiple types of stress
all of which have different genetic basis
The variety of stresses seems mostly determined by stimuli inducing them.
Indeed stress induced by an a new infection is different than that induced by a stressful job interview. Stress leading to a constant level of subluminal anxiety seems to be the most life threatening as it stimulate a set of of genes that are either directly linked to survival or secondary linked to its pathway.
globally, No stress is the same.
Various stresses:
1.stress due to an interview
2.stress due to pressure of a deadline
3. stress due to an undefined fear
4.stress due to an infection
5.stress imposed by immunization to our systems
6.the Somogyi effect
7. fear and flight reaction
8.stress imposed by hard jobs, "needed but not liked" jobs, tasks, or bosses (and some times spouses).
9.Stress imposed by inflammatory bowel diseases or autoimmune syndromes!stress of chronic diseases (Obesity, Hypertension, etc.) and other non curable diseases
etc.
our abilities to cope
the sudden or length nature and duration of the stimuli,
acknowledging the stress
our response to the stress and whether or ot we achieve complete or partial remission to the stress
all these factors impact both short and long term consequences of stress in our systems.
MOST IMPORTANTLY AS FAR AS OUR SURVIVAL IS CONCERNED, THE GENES SOLICITED DURING AND AFTER THE EVENT/STIMULI ARE CLEAR DETERMINANTS AND MOST IMPORTANT FOR LONG TERM OUTCOME.
GENES INVOLVED IN STRESSES
=========================
Depending on the sudden-acuteness or chronicity of the stimuli, we use various genes. There are genes involved in immediate reaction to the stimuli, genes due to receptor-stimuli interactions, pathways elicited whether necessary or not, downstream consequences of elicited pathways, and of course cycline effects as a result. Hormonal involvement is often part or the initial stimulation, but other hormone disturbances are a result of persistent cyclins'effects. Mechanisms of coping include not only genes meant to provide us potential to process and adjust to the stimuli, but also pre-printed patterns in the epigenetic zone, and ratios of hormones which prone us to coping evenly and sanely to the stimuli.
The importance of the nature of stimulation cannot be "stressed" enough.
ie. when the stress is an autoimmune disease, the role of TNF, and TGF cannot be over-emphasized,
ie. when it is an infection, although TNF and TGFs play an important role, Cyclins (IL-1, IL-6, 10,12,13 and even 23) comes into play. (remember the protective IL-4)
ie. sudden inducing fear events stimulate the fear and flight reaction (Adrenaline, noradrenaline,steroids(including the Androgen receptor gene) and even somatostatins and other GI "Enterokines" etc).
In the Brain, Oxycytosin, serotonin, and other neuro-factors (BDNF).
It cannot be a surprise that Hypertension will involve vasopressin, neurotensin
and some stimuli will involve IGF-1, PON-1,PR4 like genes and ATF4, to list just a few genes!
It is interesting that genes involved in stress management not only include the NF-kB but genes known to immunize or protect good cells from chemotherapeutic drugs!
The critical involvement of Actin-dependent pathways is worth being noted!
Mitochondrial glycolytic and Oxidative participation is very much related to the nature of the stimuli...and so is the MTOR participation which way heavily on survival impact!
full list of genes to follow!
It is by now evident that there is multiple types of stress
all of which have different genetic basis
The variety of stresses seems mostly determined by stimuli inducing them.
Indeed stress induced by an a new infection is different than that induced by a stressful job interview. Stress leading to a constant level of subluminal anxiety seems to be the most life threatening as it stimulate a set of of genes that are either directly linked to survival or secondary linked to its pathway.
globally, No stress is the same.
Various stresses:
1.stress due to an interview
2.stress due to pressure of a deadline
3. stress due to an undefined fear
4.stress due to an infection
5.stress imposed by immunization to our systems
6.the Somogyi effect
7. fear and flight reaction
8.stress imposed by hard jobs, "needed but not liked" jobs, tasks, or bosses (and some times spouses).
9.Stress imposed by inflammatory bowel diseases or autoimmune syndromes!stress of chronic diseases (Obesity, Hypertension, etc.) and other non curable diseases
etc.
our abilities to cope
the sudden or length nature and duration of the stimuli,
acknowledging the stress
our response to the stress and whether or ot we achieve complete or partial remission to the stress
all these factors impact both short and long term consequences of stress in our systems.
MOST IMPORTANTLY AS FAR AS OUR SURVIVAL IS CONCERNED, THE GENES SOLICITED DURING AND AFTER THE EVENT/STIMULI ARE CLEAR DETERMINANTS AND MOST IMPORTANT FOR LONG TERM OUTCOME.
GENES INVOLVED IN STRESSES
=========================
Depending on the sudden-acuteness or chronicity of the stimuli, we use various genes. There are genes involved in immediate reaction to the stimuli, genes due to receptor-stimuli interactions, pathways elicited whether necessary or not, downstream consequences of elicited pathways, and of course cycline effects as a result. Hormonal involvement is often part or the initial stimulation, but other hormone disturbances are a result of persistent cyclins'effects. Mechanisms of coping include not only genes meant to provide us potential to process and adjust to the stimuli, but also pre-printed patterns in the epigenetic zone, and ratios of hormones which prone us to coping evenly and sanely to the stimuli.
The importance of the nature of stimulation cannot be "stressed" enough.
ie. when the stress is an autoimmune disease, the role of TNF, and TGF cannot be over-emphasized,
ie. when it is an infection, although TNF and TGFs play an important role, Cyclins (IL-1, IL-6, 10,12,13 and even 23) comes into play. (remember the protective IL-4)
ie. sudden inducing fear events stimulate the fear and flight reaction (Adrenaline, noradrenaline,steroids(including the Androgen receptor gene) and even somatostatins and other GI "Enterokines" etc).
In the Brain, Oxycytosin, serotonin, and other neuro-factors (BDNF).
It cannot be a surprise that Hypertension will involve vasopressin, neurotensin
and some stimuli will involve IGF-1, PON-1,PR4 like genes and ATF4, to list just a few genes!
It is interesting that genes involved in stress management not only include the NF-kB but genes known to immunize or protect good cells from chemotherapeutic drugs!
The critical involvement of Actin-dependent pathways is worth being noted!
Mitochondrial glycolytic and Oxidative participation is very much related to the nature of the stimuli...and so is the MTOR participation which way heavily on survival impact!
full list of genes to follow!
Subscribe to:
Posts (Atom)