At molecular level, nature uses a simple language sometime to achieve big things. Attraction of electron by proton, the unstable nature of a celibate electron looking to couple with another electron, allosteric change of shape of molecules that match an active site of another molecule or chemical based post-translational shape modification to expose active sites of molecules. All these to phosphorylate, methylate or otherwise tamper with shapes of molecules to allow pathways to unfold!
The surprising success of ATRA in Promyelocytic Leukemia is an outstanding example of the success of this approach in therapeutic medicine.The activity at retinoic acid Receptor, and various shape that could potentially fit into the Active sites at AP-1, occupying sites at NFAT, or Leucine Zipper or even just c-JUn and c-fos all could have potentially profound therapeutic effects in those disease processes that hinges on the NFAT-AP1 interaction. Particularly the leukemia, and cancer such as Melanoma where the CDK4 gene is important. Yes you can create an Antibody, but remember a simple matching form can do the trick by a simple lovely lodging of molecule into an activity site, paralyzing it for use!
We need more of this type of intervention...
Wednesday, December 4, 2013
Tuesday, December 3, 2013
Presenting our TBI project !
14th Annual Rio Grande Trauma Conference & Pediatric Update- Abstract Presentati
|  11:20 AM (8 hours ago) | | ||
Importance of Hypoxia in cancer Biology
Hypoxia is not unexpected in normal cellular biology and mechanism to deal with are well set even at gene level. The existence of Hypoxia induced Factor gene is a proof of the such a process. Its interaction with the Von Hippel Lindau gene well described as it induce the clear cell kidney cancer. hypoxia result in increased free Radicals and various acids (hypochloric, acetic acids, superoxide, and Hydrogen peroxide).
local conditions may worsen the toxic conditions of these highly "Reactive Oxygen Species" (ROS). In certain tissues or condition where there is highly "catalytic Iron or Cupper" (liver or substancia Nigra) the hypoxia (or Alcohol) will yield highly toxic molecules that will "burn" local tissues. In a attempt to remedy the situation, the body will engage angiogenic genes to bring about new blood vessel to improve the local Oxygen levels. (VEGF, and subsequently the EGFR will be highly engaged). In the lungs, there is a typical cancer that happens in non smokers that has high expression of mutations of the EGFR, and respond highly to Gefitinib and Tarceva. Checking for EGFR Mutation is now standard of care in lung cancer, meaning failure to evaluate EGFR is careless care since there is a unique response of these cancers that should be used prior to considering other therapies!
The Anoxic process happens in the Cytoplasm and the peri-nuclear region popularly knwon these day as epigenetic Zone. It also involve where the cell breath or the Mitochondria. With the involvement of the Mitochondria comes the MTOR. Because the MTOR are here downstream from the EGFR, combination of Anti-EGFR with the MTOR inhibitor failed to show addititive effects in some cancers. It is now suggested that the MTOR inhibitors follow the anti-EGFR as if the early use of anti-EGFRs prepare the way to the effect (somewhat sensitize) of the MTOR inhibitors. Further proof of concept is needed although suggestions have been put forth.
The body has mechanisms to dampen the effects of the above toxic agents of which production has been boosted by the wide inconsiderate use of Anti-Oxidants (ignorance of potential presence of highly catalytic iron and Cupper, or Zinc for that matter). We know what ionized Aluminum does for Parkinson disease...
Glutathion, Nicotinamid Adenine Dinucleotide (NAD), Nerf2, and other dismutase and various Sirtuins are our mechanisms of control.
The report suggesting the almighty Bcl-2 uses depletion of Gluthatione to block Apoptosis from ensuing point to the importance of Gluthatione in biologic events!
(TO BE CONTINUED)
local conditions may worsen the toxic conditions of these highly "Reactive Oxygen Species" (ROS). In certain tissues or condition where there is highly "catalytic Iron or Cupper" (liver or substancia Nigra) the hypoxia (or Alcohol) will yield highly toxic molecules that will "burn" local tissues. In a attempt to remedy the situation, the body will engage angiogenic genes to bring about new blood vessel to improve the local Oxygen levels. (VEGF, and subsequently the EGFR will be highly engaged). In the lungs, there is a typical cancer that happens in non smokers that has high expression of mutations of the EGFR, and respond highly to Gefitinib and Tarceva. Checking for EGFR Mutation is now standard of care in lung cancer, meaning failure to evaluate EGFR is careless care since there is a unique response of these cancers that should be used prior to considering other therapies!
The Anoxic process happens in the Cytoplasm and the peri-nuclear region popularly knwon these day as epigenetic Zone. It also involve where the cell breath or the Mitochondria. With the involvement of the Mitochondria comes the MTOR. Because the MTOR are here downstream from the EGFR, combination of Anti-EGFR with the MTOR inhibitor failed to show addititive effects in some cancers. It is now suggested that the MTOR inhibitors follow the anti-EGFR as if the early use of anti-EGFRs prepare the way to the effect (somewhat sensitize) of the MTOR inhibitors. Further proof of concept is needed although suggestions have been put forth.
The body has mechanisms to dampen the effects of the above toxic agents of which production has been boosted by the wide inconsiderate use of Anti-Oxidants (ignorance of potential presence of highly catalytic iron and Cupper, or Zinc for that matter). We know what ionized Aluminum does for Parkinson disease...
Glutathion, Nicotinamid Adenine Dinucleotide (NAD), Nerf2, and other dismutase and various Sirtuins are our mechanisms of control.
The report suggesting the almighty Bcl-2 uses depletion of Gluthatione to block Apoptosis from ensuing point to the importance of Gluthatione in biologic events!
(TO BE CONTINUED)
Monday, December 2, 2013
For your better reading about TBI gene based pathophysiology
Once the TBI's injury occurs, data have shown that the size of the
lesion is dependent not only on the extent and force of the trauma, but
also on amount of subsequent reactive inflammatory and anoxic event
that follow the trauma. Also the baseline level Activity of the Notch
prior to the event is critical in minimizing the incoming effects of the
trauma. As upregulation of the Notch sometime pre-exists in some Nerve
cells such as the one in the Retinal cells. Here such upregulation
seems to contribute to allowing de-differentiation proning cell to
proliferation. Whether MEK is involved is beside the point, This
influence of the Notch seems overall Neuroprotective when it comes to
resisting inflammatory reactions.
The force of the Trauma cannot be neglected as it can cause a commotion stretching or changing the axial diameter of the cell sufficiently to induce stress and the c-JUN pathways, but it can also be sectional, directly killing the pre-synaptic Neuron. Such a section will disturb profoundly events occurring at the presynaptic membrane with pertubation and release of multiple preexcitatory Glutamate and the like, potentially inducing seizures in the TBI victims. Evidences suggest, TBI inducing such a trauma induced section of the presynaptic neuron, will impact post synaptic events not only by lack of normal stimulation, a preliminary event to Anoikis of the post synaptic Neuron, but also use free NMDA receptors to potentiate Anoxic events into production of powerful toxic free radical and Oxidant beyond Nitric Oxide. Without an sufficient upregulation of both the Nrf2 and the Nicotinamid (NAD) systems, the targeted Neuron is at risk of dying more likey through the Caspase 1 pathway. Anoikis kills more likely through the Caspase 3 apoptotic pathway!
The Anoxia described above is evidently more severe if vascular section resulted from the trauma directly, however vascular compression coming from swelling of the brain tissue may achieve the same Anoxia. Stimulation of the VRAC by various liberated toxic Peptides may affects ions (including Calcium) channels, leading to significant edema. It is proposed that Tamoxifen may dampen this reaction and could be of use. The purported effect of Tamoxifen could be Estrogen Receptor driven since there will more likely be upregulated under the effect of TNF and Interferon (cytokines) coming from inflammatory white cells called into the theater of the TBI.
Indeed, after a trauma that could potention section a blood vessel, or cause erosion of the endothelial surface, extracellular material such as Collagen will trigger Platelet derived events (PDGFR and PDGF) which will also, through CXCL/CCR3 or 4 trigger Macrophage attraction. The macrophages in turn will expand the reaction by calling T-cells (and this recruitment is worsen by IL1 through its integrin action at Endothelial level) but also secrete several cytokine including TGF alpha which could activate both the p38-MAPK pathways (that upregulate NOTCH dampens) or the PI3K/AKT pathways
leading to downstream Oxidative events that may expand into the pCREB/MTOR paricularly if stress-c-JUN-NF-kB are in play. This cycle will lead to NADH, Free radicals That could only be Dampened by the involvement of the Nerf (s) and the Sirtuins and their activators (the Buteins).
And there you have it Buteins are Neuroprotective. The MTOR inhibitors will be protective through the activation of c-AMP of course!
The force of the Trauma cannot be neglected as it can cause a commotion stretching or changing the axial diameter of the cell sufficiently to induce stress and the c-JUN pathways, but it can also be sectional, directly killing the pre-synaptic Neuron. Such a section will disturb profoundly events occurring at the presynaptic membrane with pertubation and release of multiple preexcitatory Glutamate and the like, potentially inducing seizures in the TBI victims. Evidences suggest, TBI inducing such a trauma induced section of the presynaptic neuron, will impact post synaptic events not only by lack of normal stimulation, a preliminary event to Anoikis of the post synaptic Neuron, but also use free NMDA receptors to potentiate Anoxic events into production of powerful toxic free radical and Oxidant beyond Nitric Oxide. Without an sufficient upregulation of both the Nrf2 and the Nicotinamid (NAD) systems, the targeted Neuron is at risk of dying more likey through the Caspase 1 pathway. Anoikis kills more likely through the Caspase 3 apoptotic pathway!
The Anoxia described above is evidently more severe if vascular section resulted from the trauma directly, however vascular compression coming from swelling of the brain tissue may achieve the same Anoxia. Stimulation of the VRAC by various liberated toxic Peptides may affects ions (including Calcium) channels, leading to significant edema. It is proposed that Tamoxifen may dampen this reaction and could be of use. The purported effect of Tamoxifen could be Estrogen Receptor driven since there will more likely be upregulated under the effect of TNF and Interferon (cytokines) coming from inflammatory white cells called into the theater of the TBI.
Indeed, after a trauma that could potention section a blood vessel, or cause erosion of the endothelial surface, extracellular material such as Collagen will trigger Platelet derived events (PDGFR and PDGF) which will also, through CXCL/CCR3 or 4 trigger Macrophage attraction. The macrophages in turn will expand the reaction by calling T-cells (and this recruitment is worsen by IL1 through its integrin action at Endothelial level) but also secrete several cytokine including TGF alpha which could activate both the p38-MAPK pathways (that upregulate NOTCH dampens) or the PI3K/AKT pathways
leading to downstream Oxidative events that may expand into the pCREB/MTOR paricularly if stress-c-JUN-NF-kB are in play. This cycle will lead to NADH, Free radicals That could only be Dampened by the involvement of the Nerf (s) and the Sirtuins and their activators (the Buteins).
And there you have it Buteins are Neuroprotective. The MTOR inhibitors will be protective through the activation of c-AMP of course!
Genes in TBI /Cytokines/pathophysiology of TBI at gene level!
NOTCH1
Hes1
FGF2
NMDA
ERK 1&2
NF-kB
P38
Nerf-1,2
CXCL4
CCR3,4
NADP
VRAC
Brd-U
PSA-NCAM
SOX9
DAPT
MAPK
TNF
TGF-alpha
RANTES
CRE
Wnt1
Once the TBI's injury occurs, data has shown that the size of the lesion is dependent not only on the extent and force of the trauma, but also on amount of subsequent reactive inflammatory and anoxic event that follow the trauma. Also the baseline level Activity of the Notch prior to the event is critical in minimizing the incoming effects of the trauma. As upregulation of the Notch sometime pre-exists in some Nerve cells such as the one in the Retinal cells. Here such upregulation seems to contribute to allowing de-differentiation proning cell to proliferation. Whether MEK is involved is beside the point, This influence of the Notch seems overall Neuroprotective when it comes to resisting inflammatory reactions.
The force of the Trauma cannot be neglected as it can cause a commotion stretching or changing the axial diameter of the cell sufficiently to induce stress and the c-JUN pathways, but it can also be sectional, directly killing the pre-synaptic Neuron. Such a section will disturb profoundly events occurring at the presynaptic membrane with pertubation and release of multiple preexcitatory Glutamate and the like, potentially inducing seizures in the TBI victims. Evidences suggest, TBI inducing such a trauma induced section of the presynaptic neuron, will impact post synaptic events not only by lack of normal stimulation, a preliminary event to Anoikis of the post synaptic Neuron, but also use free NMDA receptors to potentiate Anoxic events into production of powerful toxic free radical and Oxidant beyond Nitric Oxide. Without an sufficient upregulation of both the Nrf2 and the Nicotinamid (NAD) systems, the targeted Neuron is at risk of dying more likey through the Caspase 1 pathway. Anoikis kills more likely through the Caspase 3 apoptotic pathway!
The Anoxia described above is evidently more severe if vascular section resulted from the trauma directly, however vascular compression coming from swelling of the brain tissue may achieve the same Anoxia. Stimulation of the VRAC by various liberated toxic Peptides may affects ions (including Calcium) channels, leading to significant edema. It is proposed that Tamoxifen may dampen this reaction and could be of use. The purported effect of Tamoxifen could be Estrogen Receptor driven since there will more likely be upregulated under the effect of TNF and Interferon (cytokines) coming from inflammatory white cells called into the theater of the TBI.
Indeed, after a trauma that could potention section a blood vessel, or cause erosion of the endothelial surface, extracellular material such as Collagen will trigger Platelet derived events (PDGFR and PDGF) which will also, through CXCL/CCR3 or 4 trigger Macrophage attraction. The macrophages in turn will expand the reaction by calling T-cells (and this recruitment is worsen by IL1 through its integrin action at Endothelial level) but also secrete several cytokine including TGF alpha which could activate both the MAPK pathways (that upregulate NOTCH dampens) or the PI3K/AKT pathways
leading to downstream Oxidative events that may expand into the CRE/MTOR paricularly if stress-c-JUN-NF-kB are in play. This cycle will lead to NADH, Free radicals That could only be Dampened by the involvement of the Nerf (s) and the Sirtuins and their activators (the Buteins).
And there you have it Buteins are Neuroprotective. The MTOR inhibitors will be protective through the ctivation of c-AMP of course!
Hes1
FGF2
NMDA
ERK 1&2
NF-kB
P38
Nerf-1,2
CXCL4
CCR3,4
NADP
VRAC
Brd-U
PSA-NCAM
SOX9
DAPT
MAPK
TNF
TGF-alpha
RANTES
CRE
Wnt1
Once the TBI's injury occurs, data has shown that the size of the lesion is dependent not only on the extent and force of the trauma, but also on amount of subsequent reactive inflammatory and anoxic event that follow the trauma. Also the baseline level Activity of the Notch prior to the event is critical in minimizing the incoming effects of the trauma. As upregulation of the Notch sometime pre-exists in some Nerve cells such as the one in the Retinal cells. Here such upregulation seems to contribute to allowing de-differentiation proning cell to proliferation. Whether MEK is involved is beside the point, This influence of the Notch seems overall Neuroprotective when it comes to resisting inflammatory reactions.
The force of the Trauma cannot be neglected as it can cause a commotion stretching or changing the axial diameter of the cell sufficiently to induce stress and the c-JUN pathways, but it can also be sectional, directly killing the pre-synaptic Neuron. Such a section will disturb profoundly events occurring at the presynaptic membrane with pertubation and release of multiple preexcitatory Glutamate and the like, potentially inducing seizures in the TBI victims. Evidences suggest, TBI inducing such a trauma induced section of the presynaptic neuron, will impact post synaptic events not only by lack of normal stimulation, a preliminary event to Anoikis of the post synaptic Neuron, but also use free NMDA receptors to potentiate Anoxic events into production of powerful toxic free radical and Oxidant beyond Nitric Oxide. Without an sufficient upregulation of both the Nrf2 and the Nicotinamid (NAD) systems, the targeted Neuron is at risk of dying more likey through the Caspase 1 pathway. Anoikis kills more likely through the Caspase 3 apoptotic pathway!
The Anoxia described above is evidently more severe if vascular section resulted from the trauma directly, however vascular compression coming from swelling of the brain tissue may achieve the same Anoxia. Stimulation of the VRAC by various liberated toxic Peptides may affects ions (including Calcium) channels, leading to significant edema. It is proposed that Tamoxifen may dampen this reaction and could be of use. The purported effect of Tamoxifen could be Estrogen Receptor driven since there will more likely be upregulated under the effect of TNF and Interferon (cytokines) coming from inflammatory white cells called into the theater of the TBI.
Indeed, after a trauma that could potention section a blood vessel, or cause erosion of the endothelial surface, extracellular material such as Collagen will trigger Platelet derived events (PDGFR and PDGF) which will also, through CXCL/CCR3 or 4 trigger Macrophage attraction. The macrophages in turn will expand the reaction by calling T-cells (and this recruitment is worsen by IL1 through its integrin action at Endothelial level) but also secrete several cytokine including TGF alpha which could activate both the MAPK pathways (that upregulate NOTCH dampens) or the PI3K/AKT pathways
leading to downstream Oxidative events that may expand into the CRE/MTOR paricularly if stress-c-JUN-NF-kB are in play. This cycle will lead to NADH, Free radicals That could only be Dampened by the involvement of the Nerf (s) and the Sirtuins and their activators (the Buteins).
And there you have it Buteins are Neuroprotective. The MTOR inhibitors will be protective through the ctivation of c-AMP of course!
Saturday, November 30, 2013
RANDOM NEWS (from various journals)
1. In Bladder cancer, papillary type, STAG2 Mutation claimed to announce a low risk disease (low rates of node involvement)
Cohesin subunit SA-2. STAG2.
2 Zometa preferred in Myeloma
3.Lenalidomide proves effective in Mantle cell, a study suggests!
4. don't forget to test patient with Metastatic Melanoma for BRAF Mutation, and recommend Dabrafenib!
5. Interesting that study by Julian Prell where D Dimer level of greater than 2mg/L predicted higher risk of DVT post surgeries (craniotomies).
6.Intereting that proposed case of Cancer Related Retinopathy treated with Rituximab!
7.How many genes should be looked at in each disease to plan individulized therapeutic intervention?
8.T-DM1 maintains its reputation in Her-2 positive Breast cancer!
9.Cediranib, and Trebananib being tested in Ovarian cancers!
10. Still rising interest on Ramucirumab in advanced Gastric cancers, FDA still to render its judgement!
11.Alectinib, in refractory Alk positive NSCLC post Crizotinib (ASCO), interesting report!
12 Agree ! who really uses FEC in the Neoadjuvant setting in the US? why is it that these studies are done knowing well they deviate from community practices?
13. People continue to use widely Finasteride in Prostate cancer prevention, where is the panel concern that those who were treated with these drugs, develop bad diseases if the prevention fails!
Cohesin subunit SA-2. STAG2.
2 Zometa preferred in Myeloma
3.Lenalidomide proves effective in Mantle cell, a study suggests!
4. don't forget to test patient with Metastatic Melanoma for BRAF Mutation, and recommend Dabrafenib!
5. Interesting that study by Julian Prell where D Dimer level of greater than 2mg/L predicted higher risk of DVT post surgeries (craniotomies).
6.Intereting that proposed case of Cancer Related Retinopathy treated with Rituximab!
7.How many genes should be looked at in each disease to plan individulized therapeutic intervention?
8.T-DM1 maintains its reputation in Her-2 positive Breast cancer!
9.Cediranib, and Trebananib being tested in Ovarian cancers!
10. Still rising interest on Ramucirumab in advanced Gastric cancers, FDA still to render its judgement!
11.Alectinib, in refractory Alk positive NSCLC post Crizotinib (ASCO), interesting report!
12 Agree ! who really uses FEC in the Neoadjuvant setting in the US? why is it that these studies are done knowing well they deviate from community practices?
13. People continue to use widely Finasteride in Prostate cancer prevention, where is the panel concern that those who were treated with these drugs, develop bad diseases if the prevention fails!
Call for a National Cytokine Bank!
If anything has be to learned from the Traumatic Brain Injury experience, it is that the area of destruction initiated by a trauma event continue to expand over time because of secondary biological events happening after the injury has been incurred. The events post trauma have such an importance that they actually trumpet the initial event because they are not only local (secondary brain edema can lead to seizures) but also distant ( cytokines and chemokines released will affect distant receptor in the hippocampus, globus pallidus, substantia Nigra. purkinje cells etc..) leading to what we know as part of POST Traumatic Stress disorders (PTSD).
In Melanoma, this dangerous disease, the MCP-1 has been characterized and the importance of Interferon as therapeutic intervention has been clearly demonstrated, yet our interest in cytokines remains fragmentary at best!
We have tissue Banks mostly prompted by interest in racial disparities, but to this day cytokine disparities has not been fully exploited in therapeutic interventions. We have plasma centers but no Cytokine centers!
The advent of treatment at target level calls for a National Cytokine Center
DR Kankonde
Director El Paso II Plasma center!
In Melanoma, this dangerous disease, the MCP-1 has been characterized and the importance of Interferon as therapeutic intervention has been clearly demonstrated, yet our interest in cytokines remains fragmentary at best!
We have tissue Banks mostly prompted by interest in racial disparities, but to this day cytokine disparities has not been fully exploited in therapeutic interventions. We have plasma centers but no Cytokine centers!
The advent of treatment at target level calls for a National Cytokine Center
DR Kankonde
Director El Paso II Plasma center!
Thursday, November 28, 2013
PART II: UNTIL WE STOP THE BICKERING!
There is no one Cure. There are many cures. Indeed there is no one Breast cancer but many breast Cancers since there many underlying mechanisms leading to a syndrome that we can call Breast cancer. And with each underlying pathology comes a different cure! With 25,000 genes interacting with one another, the probabilities are endless. There are mechanisms that are more frequent and every scientist is working hard to find one overwhelming solutions but do not be discourage, pick one lead and you are bound to be nominated for something, so don't be distracted by big wasteful institutions. Just work hard in your corner and achieve a cure of your own! And there are plenty opportunities!
Take the c-Myc, a master in genetic proliferation, soon you find out he needs Max to work. Talk, interfere, and hinder Max and see what happen in those diseases where c-Myc is a driver mutation. Blocking obligatory chaperon, blocking pathways, knocking promoter genes or their activators, silencing supporting genes, are just a few example to reach the various cures! Increasing cellular differentiation, or activating senescence seems to dampen neoplastic transformation leading to some "cure" state. In short opportunities abound when it come to discovering a cure. This is why the Bickering is purposeless for those engaged in the real search! Be a big MAN AND LEAVE CRBCM ALONE ABOVE ALL! GO FIND A CURE TO PROPOSE INSTEAD!
Take the c-Myc, a master in genetic proliferation, soon you find out he needs Max to work. Talk, interfere, and hinder Max and see what happen in those diseases where c-Myc is a driver mutation. Blocking obligatory chaperon, blocking pathways, knocking promoter genes or their activators, silencing supporting genes, are just a few example to reach the various cures! Increasing cellular differentiation, or activating senescence seems to dampen neoplastic transformation leading to some "cure" state. In short opportunities abound when it come to discovering a cure. This is why the Bickering is purposeless for those engaged in the real search! Be a big MAN AND LEAVE CRBCM ALONE ABOVE ALL! GO FIND A CURE TO PROPOSE INSTEAD!
Until we stop the bickering!
It is increasingly evident to us that the main obstacle to cancer cure is MAN. The need for competitiveness, playing politics, pulling each other and egoism all affects where funds should go as we look at an evolving biologic phenomenon that is the living cell. The attack and call for closure of our blog is just an example of such negative force that help the cure escape our grip. Yes someone ill motivated has bombarded our blog with computer based viral attacks, electronically unsubscribed us from donor journal and memos, bug our applications to NIH, and spread venomous words about CRBCM to hinder our progress. We are a "Coalition" meaning a corp of people ready to fight! We will fight back with precision, deliberate fugue and determination because we believe that our cause is just and the right thing to be doing in this time of our lives. The thing is people are still dying with cancers whether you like CRBCM or not. And we believe in the cure!
The cure itself has undergone significant progress over time. It was once believed that to be cured of cancer is to be totally free of cancerous cells. But evidence has suggested that turning cancer into a "chronic" disease reduces mortality of the cancer to that level of mortality equivalent to or matching that of the normal population. That is people with cancer may die from another conditions like anybody else! That is equivalent to cure from cancer. Cancer is bad because it causes Certain death within a short period of time. Removing this notion is critical in our search for the cure! In solid tumor, evidences have suggested that if you live more than 5 years, your chances of dying is close to a cure! Bringing another new dimension to the notion of cure after cancer. This 5 year survival notion does not apply to breast cancers, bringing to us another challenge to CRBCM. Why is it that Breast cancer cannot go away after 5 years. Our suspicion is that a wrong "consensus" has slipped into the mind of cancer cells. They missed the message that they should go away and gene pathways such as the NOTCH may be involved! Consensus pathways are not just limited to the NOTCH and all need to be explored!
The failure of Chemotherapy to achieve more that 20% of cures has awaken us to the fact that an indiscriminate killing of cells is not the way to go. We should have known this since even the history of the world has taught us this. New epidemic diseases never wiped the human race although they can cause significant mortality. Man work hard to limit the casualties. At cellular level, new challenges to the cancer cells are dealt with the same. The cells are informed by dying cells about what is happening, they call their CDC organization and their CDC studies this new attack and prepare their answers, and there are already prepared old answers, but new answers are made up using the NF-kBs. Those new answers are ultimately imprinted in the epigenetic zones of the cell. Answers that have proven effective more than once are eventually imprinted in the DNA and are transmitted to daughter cells leading to the growth or adaptation of both layers of human immunity.
The advent of genetic based target therapy has proven to be a significant progression in our success in our fight for the cure. Lessons learned from fighting inborn errors of metabolism has provided significant experience in the fight for the cure. Gene interference techniques , replacement of missing molecules and adding down stream missing particles or enzymes have been successfully used to correct deficient pathways, leading to impressive response rates even in cancers that were notorious for killing their victims in a short times. Metastatic Melanoma and pancreatic cancers are such venomous examples!
Today, in Melanoma expressing the Mutated BRAF overexpression, Vemurafenib and similar new agents have proven that inhibiting BRAFV600E leading to a change in the clinical evolution of these disease. If anything has to be learned from the limited experience with these drugs, their effects appear ephemeral because we seem to ignore the importance of the "consensus message" that is inbred in the neoplastic transformation.
The cure itself has undergone significant progress over time. It was once believed that to be cured of cancer is to be totally free of cancerous cells. But evidence has suggested that turning cancer into a "chronic" disease reduces mortality of the cancer to that level of mortality equivalent to or matching that of the normal population. That is people with cancer may die from another conditions like anybody else! That is equivalent to cure from cancer. Cancer is bad because it causes Certain death within a short period of time. Removing this notion is critical in our search for the cure! In solid tumor, evidences have suggested that if you live more than 5 years, your chances of dying is close to a cure! Bringing another new dimension to the notion of cure after cancer. This 5 year survival notion does not apply to breast cancers, bringing to us another challenge to CRBCM. Why is it that Breast cancer cannot go away after 5 years. Our suspicion is that a wrong "consensus" has slipped into the mind of cancer cells. They missed the message that they should go away and gene pathways such as the NOTCH may be involved! Consensus pathways are not just limited to the NOTCH and all need to be explored!
The failure of Chemotherapy to achieve more that 20% of cures has awaken us to the fact that an indiscriminate killing of cells is not the way to go. We should have known this since even the history of the world has taught us this. New epidemic diseases never wiped the human race although they can cause significant mortality. Man work hard to limit the casualties. At cellular level, new challenges to the cancer cells are dealt with the same. The cells are informed by dying cells about what is happening, they call their CDC organization and their CDC studies this new attack and prepare their answers, and there are already prepared old answers, but new answers are made up using the NF-kBs. Those new answers are ultimately imprinted in the epigenetic zones of the cell. Answers that have proven effective more than once are eventually imprinted in the DNA and are transmitted to daughter cells leading to the growth or adaptation of both layers of human immunity.
The advent of genetic based target therapy has proven to be a significant progression in our success in our fight for the cure. Lessons learned from fighting inborn errors of metabolism has provided significant experience in the fight for the cure. Gene interference techniques , replacement of missing molecules and adding down stream missing particles or enzymes have been successfully used to correct deficient pathways, leading to impressive response rates even in cancers that were notorious for killing their victims in a short times. Metastatic Melanoma and pancreatic cancers are such venomous examples!
Today, in Melanoma expressing the Mutated BRAF overexpression, Vemurafenib and similar new agents have proven that inhibiting BRAFV600E leading to a change in the clinical evolution of these disease. If anything has to be learned from the limited experience with these drugs, their effects appear ephemeral because we seem to ignore the importance of the "consensus message" that is inbred in the neoplastic transformation.
Tuesday, November 26, 2013
Reflexions at CRBCM
I like the time I am living in today when it comes to progress in Medicine. We have more answers to what seemed mysterious, "only God knows" kind of time!
I remember helping during or later on performing surgery in Africa as a young doctor in the early 1980s. Just to lose the patient from "undetermined " complications. The high Mortality of peritonitis, sepsis and other systemic diseases continue to mark our experience in Medicine because so much of what is happening during the pathophysiology of these conditions, remains unknown, or I say today, unspecified.
The realization today that most of these events are genetically based brings comfort in a way. Because it brings the challenge to a more human dimension. It is no longer "only God Knows" but rather "are we looking at the right gene or cytokine?" What receptor is at play? where can we interfere to change the course of the process? New biomarkers should now be defined in these diseases, and I mean genetic biomarkers!
Diseases like "Crohn's and ulcerative Colitis " were just mysterious when first discovered in the late 1970s. Today all makes sense, failure at an abnormal NOD2 gene, abnormality of the NLRC4 gene and subsequent failure of recruitment and initiatation of the Caspase cascade makes perfect sense to me now! I can now see it and play with the scenarios. I can see how MAVS/IRF3/IKK and there TICAM-1 comes to play in this disease. VISA, RIG-1/IPS-1 and other genes. Hell, I understand the roles of the Retinoic Acid Receptor and induced genes.This is good for unraveling the mystery.
I see the role of OCTN-1 in the absorption at the Intestinal Epithelium and its interaction with PDZK-1, and potential alteration of ion channels and its relation to Uric Acid stone in this disease. I can also understand why affected individuals can lose their hair (check out FARP2). The role of Estrogen and its receptor now influenced by Interferon and other cytokines (TNF,TGF etc..) brings down the extra thrombotic risk. Natalizumab brings in the power of endothelial recruitment of Lymphocytes by stressing the role of Integrins.
It really reminds me of cooling effects given to TBI patients. Here cooling was effective in TBI through decreasing IL-1. In all this review I was struck by MAVS, is it a new biomarker of viral involvement or Mitochondrial implication in the immune reaction?
I AM GLAD FOR OUR TIME, A TRANSITION TIME FOR WHAT WILL BE THE MEDICINE OF THE NEXT 50 YEARS. AFTER THAT, HUMANS WILL GO INTO "NANO" IN MEDICINE, I HOPE!
I remember helping during or later on performing surgery in Africa as a young doctor in the early 1980s. Just to lose the patient from "undetermined " complications. The high Mortality of peritonitis, sepsis and other systemic diseases continue to mark our experience in Medicine because so much of what is happening during the pathophysiology of these conditions, remains unknown, or I say today, unspecified.
The realization today that most of these events are genetically based brings comfort in a way. Because it brings the challenge to a more human dimension. It is no longer "only God Knows" but rather "are we looking at the right gene or cytokine?" What receptor is at play? where can we interfere to change the course of the process? New biomarkers should now be defined in these diseases, and I mean genetic biomarkers!
Diseases like "Crohn's and ulcerative Colitis " were just mysterious when first discovered in the late 1970s. Today all makes sense, failure at an abnormal NOD2 gene, abnormality of the NLRC4 gene and subsequent failure of recruitment and initiatation of the Caspase cascade makes perfect sense to me now! I can now see it and play with the scenarios. I can see how MAVS/IRF3/IKK and there TICAM-1 comes to play in this disease. VISA, RIG-1/IPS-1 and other genes. Hell, I understand the roles of the Retinoic Acid Receptor and induced genes.This is good for unraveling the mystery.
I see the role of OCTN-1 in the absorption at the Intestinal Epithelium and its interaction with PDZK-1, and potential alteration of ion channels and its relation to Uric Acid stone in this disease. I can also understand why affected individuals can lose their hair (check out FARP2). The role of Estrogen and its receptor now influenced by Interferon and other cytokines (TNF,TGF etc..) brings down the extra thrombotic risk. Natalizumab brings in the power of endothelial recruitment of Lymphocytes by stressing the role of Integrins.
It really reminds me of cooling effects given to TBI patients. Here cooling was effective in TBI through decreasing IL-1. In all this review I was struck by MAVS, is it a new biomarker of viral involvement or Mitochondrial implication in the immune reaction?
I AM GLAD FOR OUR TIME, A TRANSITION TIME FOR WHAT WILL BE THE MEDICINE OF THE NEXT 50 YEARS. AFTER THAT, HUMANS WILL GO INTO "NANO" IN MEDICINE, I HOPE!
crbcm is coming to age
I tell my children that one of the things that make us adult is the confrontation by legal challenges.
It is a sign of a successful maturity to be blindsided by eager vandals who envy your performances and will trigger calls for lawsuits. The CRBCM has used references, published facts that exist and come to us by e-mails and other venues. All we have done is bring to our reviewers material that exists, some time unedited to show we are not in the business of making up these reported facts. In some malevolent brains, it is time to complain. We will modify our reports to be more of a commentary now to curtail these vicious attacks. One thing for sure, we are on the right path, and our fight is just, and threatening to bandits! Whatever result from these attacks will not stop progress at CBCM!
It is a sign of a successful maturity to be blindsided by eager vandals who envy your performances and will trigger calls for lawsuits. The CRBCM has used references, published facts that exist and come to us by e-mails and other venues. All we have done is bring to our reviewers material that exists, some time unedited to show we are not in the business of making up these reported facts. In some malevolent brains, it is time to complain. We will modify our reports to be more of a commentary now to curtail these vicious attacks. One thing for sure, we are on the right path, and our fight is just, and threatening to bandits! Whatever result from these attacks will not stop progress at CBCM!
Sunday, November 24, 2013
IBRUTINIB APPROVED FOR MANTLE CELL LYMPHOMA
Ibrutininb, a Bruton's Tyrokinase Inhibitor, was approved as a second line agent in recurrent Mantle cell lymphoma. The approval was based on prolongation of disease free survival only in this setting. Ibrutinib 560 mg was given in the study that led to approval.
65.8 % in Overall response rate, of which 17% were complete Response.
Warning though:
5% had bleeding (subdural Hematoma, GI bleed, or Hematuria)
Infection, myelosuppression renal toxicity abdominal pains were also part of the side effects
Change dosage (reduce) if using concomitantly a CYP3A inhibitor. Or avoid it if you can!
65.8 % in Overall response rate, of which 17% were complete Response.
Warning though:
5% had bleeding (subdural Hematoma, GI bleed, or Hematuria)
Infection, myelosuppression renal toxicity abdominal pains were also part of the side effects
Change dosage (reduce) if using concomitantly a CYP3A inhibitor. Or avoid it if you can!
CRBCM was proud to participate!
|
A Message from Medical Center of the Americas:
On
behalf of RedSky and the Medical Center of the Americas Foundation, I
would like to thank you for attending the region’s first-ever biomedical
research symposium BIOMED 2013. Over 350 researchers,
clinicians and nurses, high school and college students, and other
healthcare professionals attended. It was an invigorating day that
enabled the open exchange of information, with remarkable speakers,
moderators, presenters, and exhibitors from across the region and the
country.
For participating in BIOMED 2013, you will receive Synapse,
the region’s first and only life sciences news digest. It was created
in 2010 in response to the life sciences boom taking place in El Paso
and the region. Target audience includes civic, corporate, political,
higher education, medical and scientific leaders. Synapse is primarily an online publication – www.mcaSynapse.org. Its main sections are:
You will receive Synapse
once a month into your email inbox. To unsubscribe from the
distribution list, click on “unsubscribe” in the email footer or send an
email at anytime to the editor at Noemi@MCAmericas.org.
Here are a few things to know to get you started as a Synapse reader:
Save The Date - BIOMED 2014
BIOMED 2014, scheduled for November 14 and 15, 2014,
will be at the Convention Center located at 1 Civic Center Plaza, in
Downtown El Paso. We hope to see you there and will be in touch soon
with more updates. In the meantime, our kindest wishes to you and your
family for the holidays.
Warm Regards,
Neyha Sehgal | Assistant Director of Market Analysis
RedSky | 201 East Main Street, Suite 401 | El Paso, Texas 79901
(P): (915) 773-5804 | (F): (915) 231-1949
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Saturday, November 23, 2013
MICROGLIAL SENSOME/ SHARING WITH OUR READERS AS ORDERED!
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Contact: Sue McGreevey
smcgreevey@partners.org
617-724-2764
Massachusetts General Hospital
Mass. General study identifies genes uniquely expressed by the brain's immune cells
Identifying 'sensome' of microglia could improve understanding, treatments for neurodegenerative disorders
Massachusetts General Hospital (MGH) investigators have used a new sequencing method to identify a group of genes used by the brain's immune cells – called microglia – to sense pathogenic organisms, toxins or damaged cells that require their response. Identifying these genes should lead to better understanding of the role of microglia both in normal brains and in neurodegenerative disorders and may lead to new ways to protect against the damage caused by conditions like Alzheimer's and Parkinson's diseases. The study, which has been published online in Nature Neuroscience, also finds that the activity of microglia appears to become more protective with aging, as opposed to increasingly toxic, which some previous studies had suggested."We've been able to define, for the first time, a set of genes microglia use to sense their environment, which we are calling the microglial sensome," says Joseph El Khoury, MD, of the MGH Center for Immunology and Inflammatory Diseases and Division of Infectious Diseases, senior author of the study. "Identifying these genes will allow us to specifically target them in diseases of the central nervous system by developing ways to upregulate or downregulate their expression."
A type of macrophage, microglia are known to constantly survey their environment in order to sense the presence of infection, inflammation, and injured or dying cells. Depending on the situation they encounter, microglia may react in a protective manner – engulfing pathogenic organisms, toxins or damaged cells – or release toxic substances that directly destroy microbes or infected brain cells. Since this neurotoxic response can also damage healthy cells, keeping it under control is essential, and excess neurotoxicity is known to contribute to the damage caused by several neurodegenerative disorders.
El Khoury's team set out to define the transcriptome – the complete set of RNA molecules transcribed by a cell – of the microglia of healthy, adult mice and compared that expression profile to those of macrophages from peripheral tissues of the same animals and of whole brain tissue. Using a technique called direct RNA sequencing, which is more accurate than previous methods, they identified a set of genes uniquely expressed in the microglia and measured their expression levels, the first time such a gene expression 'snapshot' has been produced for any mammalian brain cell, the authors note.
Since aging is known to alter gene expression throughout the brain, the researchers then compared the sensome of young adult mice to that of aged mice. They found that – contrary to what previous studies had suggested – the expression of genes involved in potentially neurotoxic actions, such as destroying neurons, was downregulated as animals aged, while the expression of neuroprotective genes involved in sensing and removing pathogens was increased. El Khoury notes that the earlier studies suggesting increased neurotoxicity with aging did not look at the cells' full expression profile and often were done in cultured cells, not in living animals.
"Establishing the sensome of microglia allows us to clearly understand how they interact with and respond to their environment under normal conditions," he explains. "The next step is to see what happens under pathologic conditions. We know that microglia become more neurotoxic as Alzheimer's disease and other neurodegenerative disorders progress, and recent studies have identified two of the microglial sensome genes as contributing to Alzheimer's risk. Our next steps should be defining the sensome of microglia and other brain cells in humans, identifying how the sensome changes in central nervous system disorders, and eventually finding ways to safely manipulate the sensome pharmacologically."
###
El Khoury is an associate professor of Medicine at Harvard Medical School. Suzanne Hickman of the MGH Center for Immunology and Inflammatory Diseases (CIID), is lead and co-corresponding author of the Nature Neuroscience report. Additional co-authors are Nathan Kingery and Terry Means, PhD, MGH CIID; Toshiro Ohsumi and Mark L Borowsky, PhD, MGH Molecular Biology, and Li-chong Wang, MD, PhD, Advanced Cell Diagnostics, Hayward, Calif. The study was supported by National Institute of Neurological Disorders and Stroke grant NS059005 and National Institute of Aging grant AG032349.
Massachusetts General Hospital, founded in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH conducts the largest hospital-based research program in the United States, with an annual research budget of more than $775 million and major research centers in AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, human genetics, medical imaging, neurodegenerative disorders, regenerative medicine, reproductive biology, systems biology, transplantation biology and photomedicine.
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Friday, November 22, 2013
The CRBCM, over 30,000 pageviews in a year!
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| A slew of Other countrie with less than 93, they just stop counting! |
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| Entry | Pageviews |
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United States
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19174
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Russia
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2130
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Germany
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1313
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France
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671
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United Kingdom
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461
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Ukraine
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440
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Malaysia
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375
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Poland
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347
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China
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267
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South Korea
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93
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Cooperative research at CRBCM
From: Zhang, Jianying <jzhang@utep.edu<mailto:jzhang
Date: Tue, Nov 19, 2013 at 11:06 AM
Subject: FW: Lung cancer project preliminary data
To: Mutombo Kankonde <drkcancerclinic@gmail.com<
Cc: chaiyurong <yrchai@live.cn<mailto:yrchai@
Dear Dr. Kankonde,
Please see the attached PCR data on lung tissues. Dr. Chai has completed the RT-PCR and Q-PCR on five lung tissues with three genes. If you have any question, please let us know.
Could you please ask the tissue bank to provide more samples?
Best regards,
Jianying Zhang, M.D., Ph.D.
Professor
Department of Biological Sciences
The University of Texas at El Paso
500 West University Avenue
El Paso, Texas 79968
Tel: 915-747-6995<tel:915-747-6995>
Date: Tue, Nov 19, 2013 at 11:06 AM
Subject: FW: Lung cancer project preliminary data
To: Mutombo Kankonde <drkcancerclinic@gmail.com<
Cc: chaiyurong <yrchai@live.cn<mailto:yrchai@
Dear Dr. Kankonde,
Please see the attached PCR data on lung tissues. Dr. Chai has completed the RT-PCR and Q-PCR on five lung tissues with three genes. If you have any question, please let us know.
Could you please ask the tissue bank to provide more samples?
Best regards,
Jianying Zhang, M.D., Ph.D.
Professor
Department of Biological Sciences
The University of Texas at El Paso
500 West University Avenue
El Paso, Texas 79968
<tel:915-747-6995<tel:915-747- 6995>> (office); 915-747-5343<tel:915-747-5343> <tel:915-747-5343<tel:915-747- 5343>>/5183 (lab)
Fax: 915-747-5808<tel:915-747-5808><tel:915-747-5808<tel:915-747- 5808>>
The Hedgehog, Ptch1, AND the Gli zinc-finger transcription factors
If there is an example where GENE INTERFERENCE could have a meaningful impact, it is in this pathway like a deluge of gene activations. The impact could extend from Basal cell to bladder cancers to Gliomas!
"PTCH1 is a member of the patched gene family and is the receptor for sonic hedgehog, a secreted molecule implicated in the formation of embryonic structures and in tumorigenesis. This gene functions as a tumor suppressor. The PTCH1 gene product, is a transmembrane protein that suppresses the release of another protein called smoothened, and when sonic hedgheog binds PTCH1, smoothened is released and signals cell proliferation." wikipedia.
POLIZIO ET AL
The vertebrate Hedgehog (Hh) pathway has essential functions during development and tissue homeostasis in normal physiology, and its dysregulation is a common theme in cancer. The Hh ligands (Sonic Hh, Indian Hh, and Desert Hh) bind to the receptors Patched1 and Patched2, resulting in inhibition of their repressive effect on Smoothened (Smo). Smo is a seven-transmembrane protein, which was only recently shown to function as a G protein–coupled receptor (GPCR) with specificity toward the heterotrimeric guanine nucleotide-binding protein Gi. In addition to activating Gi, Smo signals through its C-terminal tail to inhibit Suppressor of Fused, resulting in stabilization and activation of the Gli family of transcription factors, which execute a transcriptional response to so-called "canonical Hh signaling."
WHEN YOU TALK ABOUT ZINC-FINGER YOU KNOW YOU ARE TALKING ABOUT HISTONE MODULATION AND DIRECT DNA INTERACTION, ALL OCCURING MOSTLY THE EPIGENETIC ZONE MOSTLY! THEREFORE THIS COULD EFFECT EVEN THE LEUKEMIAS!
THE CRBCM IS TAKING A CLOSER LOOK!
"PTCH1 is a member of the patched gene family and is the receptor for sonic hedgehog, a secreted molecule implicated in the formation of embryonic structures and in tumorigenesis. This gene functions as a tumor suppressor. The PTCH1 gene product, is a transmembrane protein that suppresses the release of another protein called smoothened, and when sonic hedgheog binds PTCH1, smoothened is released and signals cell proliferation." wikipedia.
POLIZIO ET AL
The vertebrate Hedgehog (Hh) pathway has essential functions during development and tissue homeostasis in normal physiology, and its dysregulation is a common theme in cancer. The Hh ligands (Sonic Hh, Indian Hh, and Desert Hh) bind to the receptors Patched1 and Patched2, resulting in inhibition of their repressive effect on Smoothened (Smo). Smo is a seven-transmembrane protein, which was only recently shown to function as a G protein–coupled receptor (GPCR) with specificity toward the heterotrimeric guanine nucleotide-binding protein Gi. In addition to activating Gi, Smo signals through its C-terminal tail to inhibit Suppressor of Fused, resulting in stabilization and activation of the Gli family of transcription factors, which execute a transcriptional response to so-called "canonical Hh signaling."
WHEN YOU TALK ABOUT ZINC-FINGER YOU KNOW YOU ARE TALKING ABOUT HISTONE MODULATION AND DIRECT DNA INTERACTION, ALL OCCURING MOSTLY THE EPIGENETIC ZONE MOSTLY! THEREFORE THIS COULD EFFECT EVEN THE LEUKEMIAS!
THE CRBCM IS TAKING A CLOSER LOOK!
"Gli regulation by the opposing activities of Fused and Suppressor of Fused
Hedgehog (Hh) proteins are secreted factors that control cell proliferation
and cell-fate specification1. Hh signalling is mediated in vertebrates
by the Gli zinc-finger transcription factors (Gli1, Gli2 and Gli3) and in
Drosophila by the Gli homologue Cubitus interruptus"
OTHER GENES IMPLICATED!
OTHER GENES IMPLICATED!
PTCH1 gene
WNT3A
IRF6
GLI
TGF-beta
TrkC: Neurotropin -Receptor
AND THE DANCE OF GENES CONTINUE!
AND THE DANCE OF GENES CONTINUE!
IN OTHER CPRIT NEWS: LAST MEMBER TO THE COMMITTEE
We learned that the last member to the Oversight Committee has been appointed. A lawyer with strong background with cancer research through his father. Reportedly, his own brother and father died of cancer. We wish him well and will look forward to his contribution to an unbiased fight for the cure.
CPRIT was created for all Texans but university and political folks in Houston, Austin and the third university city/DALLAS... (EL Paso was passed over and deliberately ignored!)
had successfully highjacked the process. Greed did not stop, in fighting resulted leading to revelation of misconducts which till today remain unpunished. Heads did roll because that was inevitable. New heads are in but the game remains intact, at least we believe. The escamotage of the original purpose of this organization which was to find the cure to cancers, by the game to take public funds by influential institutions has been deplored! But we fear that the new CPRIT will struggle to look fair but achieve the same.
There is no bad deed that remain unpunished until someone, somewhere feel the need to lead toward a sane CPRIT!
We can only pray to God now that this will be the case, or save us for another crisis! The boys are out lining their games because there is money to be gained !
CPRIT was created for all Texans but university and political folks in Houston, Austin and the third university city/DALLAS... (EL Paso was passed over and deliberately ignored!)
had successfully highjacked the process. Greed did not stop, in fighting resulted leading to revelation of misconducts which till today remain unpunished. Heads did roll because that was inevitable. New heads are in but the game remains intact, at least we believe. The escamotage of the original purpose of this organization which was to find the cure to cancers, by the game to take public funds by influential institutions has been deplored! But we fear that the new CPRIT will struggle to look fair but achieve the same.
There is no bad deed that remain unpunished until someone, somewhere feel the need to lead toward a sane CPRIT!
We can only pray to God now that this will be the case, or save us for another crisis! The boys are out lining their games because there is money to be gained !
AT CPRIT: many attempts to get rid of us!
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THE NEW CPRIT IS TRYING TO GET RID OF OLD APPLICANTS!
THIS E MAIL KEEPS COMING BACK DESPITE OUR MANY ATTEMPTS TO SUBCRIBE
THIS JUST A VAIN WAY TO GET RID ON NON UNIVERSITY APPLICANTS!
THE GAME SEEMS TO BE BACK IN FULL FORCE.
AND YOU WOULD THINK THEY ARE GENUINE WITH THEIR EFFORTS TO COME CLEAN.
IF THIS IS A MISTAKE, THEY SHOULD CORRECT IT!
Wednesday, November 20, 2013
Tuesday, November 19, 2013
slide IV; THE ARRIVAL OF THE MACROPHAGES AT THE TBI SITE!
Aside from the stress and Hypoxia, There no event more significant after TBI then the arrival of the macrophage at the scene, in terms of long term prognosis.
this set the stage for massive Cytokine release and attraction of other inflammatory cells and shock to the genetic make-up of the Neuron and its sheath.
To be continued!
this set the stage for massive Cytokine release and attraction of other inflammatory cells and shock to the genetic make-up of the Neuron and its sheath.
To be continued!
slide III. WHERE ARE WE IN RESEARCH ON THE THE TBI TOPIC; HOW TO STOP THE CYTOKINES?
HOW TO PRESERVE POST SYNAPTIC NEURON DESTRUCTION
HOW TO STOP THE CYTOKINES INDUCED BY STRESS AND THE INFLAMMATORY RESPONSE?
1.HYPOTHERMIA TO COOL PRODUCTION OF STRESS AND INFLAMMATORY RESPONSES!
-ie Reducing production of IL-1 beta to decrease frequency of cellular attachment to endothelial /blood vessel to reduce tissue destruction. (Integrin Alpha-v-beta-5-target of therapy).
2. MASS EFFECT AND INTERRUPTION OF BLOOD VESSEL LEAD TO ANOXIA
-ie Activity at NMDA receptors---interaction with NOX2 leads to Super-Oxide production.
-ie NMDA needed in the production of Peroxy-nitrite (beyond the Nitric Oxyde).
-ie NADPH Oxidase derived Reactive Oxygen Species (ROS)
-HIF-1- Angiogenesis - VEGF- (EGFR cross-talking)
3.PKC inhibition reduces STRESS RESPONSE
4.AT HIPPOCAMPUS : Prodymorphin and its derivative peptides could modulate neurotransmitters by interacting with the activation of presynatic k opioid receptors.
-also Hyperactivation of NMDAR increases Calcium influx, through the CRMP2, resulting in decrease of Hyppocampal Neuronal death by reducing surface expression of Dendritic NR2B receptors.
5.EXCITATORY RESPONSES
-ie. Decrease of GABA release in inhibitory Interneuron synapses increase risk of Seizure activity. This associated potentially with increase activity at excitatatory synapses resulting from AMPA Receptor conductance.
-ie Glutamate removal (from synapses) critical in controlling excitatory stimulation
6.NOW the focus in on CAP'N COLLARS!
these factor's transcription leads to Nrf 1,2,3 (Nrf (s) activity at Blood Barrier)
ie Protein Tyrosine Phosphase inhibits the Nrf.
==========================================
Gobally, the research is haphazard.
but there is increased focus on delayed effect
and recognition of the role of post synaptic Neuron in the long term outcome and chances of Rehabilitation
and its vulnerability to inflammatory attacks. NOTE THE INCREASE MENTION OF GENES!
PLEASE NOTE THE MENTIONED GENES AS THEY WILL COME-UP AS WE DISCUSS THE SIRTUINS!
HOW TO STOP THE CYTOKINES INDUCED BY STRESS AND THE INFLAMMATORY RESPONSE?
1.HYPOTHERMIA TO COOL PRODUCTION OF STRESS AND INFLAMMATORY RESPONSES!
-ie Reducing production of IL-1 beta to decrease frequency of cellular attachment to endothelial /blood vessel to reduce tissue destruction. (Integrin Alpha-v-beta-5-target of therapy).
2. MASS EFFECT AND INTERRUPTION OF BLOOD VESSEL LEAD TO ANOXIA
-ie Activity at NMDA receptors---interaction with NOX2 leads to Super-Oxide production.
-ie NMDA needed in the production of Peroxy-nitrite (beyond the Nitric Oxyde).
-ie NADPH Oxidase derived Reactive Oxygen Species (ROS)
-HIF-1- Angiogenesis - VEGF- (EGFR cross-talking)
3.PKC inhibition reduces STRESS RESPONSE
4.AT HIPPOCAMPUS : Prodymorphin and its derivative peptides could modulate neurotransmitters by interacting with the activation of presynatic k opioid receptors.
-also Hyperactivation of NMDAR increases Calcium influx, through the CRMP2, resulting in decrease of Hyppocampal Neuronal death by reducing surface expression of Dendritic NR2B receptors.
5.EXCITATORY RESPONSES
-ie. Decrease of GABA release in inhibitory Interneuron synapses increase risk of Seizure activity. This associated potentially with increase activity at excitatatory synapses resulting from AMPA Receptor conductance.
-ie Glutamate removal (from synapses) critical in controlling excitatory stimulation
6.NOW the focus in on CAP'N COLLARS!
these factor's transcription leads to Nrf 1,2,3 (Nrf (s) activity at Blood Barrier)
ie Protein Tyrosine Phosphase inhibits the Nrf.
==========================================
Gobally, the research is haphazard.
but there is increased focus on delayed effect
and recognition of the role of post synaptic Neuron in the long term outcome and chances of Rehabilitation
and its vulnerability to inflammatory attacks. NOTE THE INCREASE MENTION OF GENES!
PLEASE NOTE THE MENTIONED GENES AS THEY WILL COME-UP AS WE DISCUSS THE SIRTUINS!
slide II. RECOGNITION OF FUNDAMENTAL PHYSIOLOGIC / GENETIC BASIS OF TBI
1.ALL CELLULAR EVENTS AND DISEASES ARE GENETICALLY BASED
2.RECOGNITION THAT EFFECT OF TBI ARE IMMEDIATE AND DELAYED
a. IMMEDIATE :-COUP AND CONTRECOUP! (Bi-axial deformation of Neurons)
- CONCUSSION,
- COMPRESSION
b. DELAYED
-ANOXIA
-STRESS INDUCED
-INFLAMMATORY : ACTIVATION OF FACTOR TRANSCRIPTION AND CYTOKINE RELEASE!
3.TISSUE AFFECTED (primarily and/or secondarily)
==LONG PROJECTING AXONE
==MYELIN
==BLOOD VESSEL
==SUSCEPTIBILITY TO CYTOKINES BY VARIOUS BRAIN AREAS
==ACTIVITY AT VARIOUS BRAIN RECEPTORS
2.RECOGNITION THAT EFFECT OF TBI ARE IMMEDIATE AND DELAYED
a. IMMEDIATE :-COUP AND CONTRECOUP! (Bi-axial deformation of Neurons)
- CONCUSSION,
- COMPRESSION
b. DELAYED
-ANOXIA
-STRESS INDUCED
-INFLAMMATORY : ACTIVATION OF FACTOR TRANSCRIPTION AND CYTOKINE RELEASE!
3.TISSUE AFFECTED (primarily and/or secondarily)
==LONG PROJECTING AXONE
==MYELIN
==BLOOD VESSEL
==SUSCEPTIBILITY TO CYTOKINES BY VARIOUS BRAIN AREAS
==ACTIVITY AT VARIOUS BRAIN RECEPTORS
slide I INTRODUCTORY REMARKS ON TBI
Definition
"Traumatic brain injury (TBI) is a nondegenerative, noncongenital insult to the brain from an external mechanical force, possibly leading to permanent or temporary impairment of cognitive, physical, and psychosocial functions, with an associated diminished or altered state of consciousness. "MEASUREMENTS OF TBI EFFECTS
1.Glasgow Coma Scale
2.Ranchos Los Amigos Scale of Cognitive Functioning
3TBI defined by the Head Injury Interdisciplinary Special Interest Group of the American Congress of Rehabilitation Medicine
Dawodu et al.
- Any period of loss of consciousness (LOC),
- Any loss of memory for events immediately before or after the accident,
- Any alteration in mental state at the time of the accident,
- Focal neurologic deficits, which may or may not be transient."1.74 million persons sustain mild TBI requiring an office visit or temporary disability for at least 1 day. 2.5-6.5 million Americans live with TBI-related disabilities.Costing 4-10 billions a year to the american Economy based of various estimates!Approximately 52,000 US deaths per year result from TBI.
Glasgow Coma Scale
The Glasgow Coma Scale (GCS) defines the severity of a TBI within 48 hours of injury.Eye opening
- Spontaneous = 4
- To speech = 3
- To painful stimulation = 2
- No response = 1
Motor response
- Follows commands = 6
- Makes localizing movements to pain = 5
- Makes withdrawal movements to pain = 4
- Flexor (decorticate) posturing to pain = 3
- Extensor (decerebrate) posturing to pain = 2
- No response = 1
Verbal response
- Oriented to person, place, and date = 5
- Converses but is disoriented = 4
- Says inappropriate words = 3
- Says incomprehensible sounds = 2
- No response = 1
- Severe TBI = 3-8
- Moderate TBI = 9-12
- Mild TBI = 13-15
Monday, November 18, 2013
Looking into buying a practice to expand Greater East Cancer Center!
Some of the considerations found on the internet!
==========================================
Practice Cashflow valuation
1>Operating Cost of physician
-staff
-non physician staff provider salaries
-rent
-leases
-loans
-cost of new equipment/Amortizing
-supplies
-Building Insurance
-Malpractice Insurance
-taxes
-social securities
-fair market payment to physicians
-transportation and various fees
Total/gross revenue
Total Operating costs
-------------------------------------------------
Total benefits/profits
Number of Investors
-------------------------------------------------
Practice location
==========================================
Practice Cashflow valuation
1>Operating Cost of physician
-staff
-non physician staff provider salaries
-rent
-leases
-loans
-cost of new equipment/Amortizing
-supplies
-Building Insurance
-Malpractice Insurance
-taxes
-social securities
-fair market payment to physicians
-transportation and various fees
Total/gross revenue
Total Operating costs
-------------------------------------------------
Total benefits/profits
Number of Investors
-------------------------------------------------
Practice location
Saturday, November 16, 2013
Role of Avastin-Anti-JAK2 and Anti-c-MET in Metastatic triple negative and possibly inflammatory Breast Cancer PART II
Role of Avastin-Anti-JAK2 and Anti-c-MET in Metastatic triple negative and possibly inflammatory Breast Cancer
============================================================
OF NOTE, for you to continue following:
" CTGF, also known as CCN2 or connective tissue growth factor,[1][2] is a matricellular protein of the CCN family of extracellular matrix-associated heparin-binding proteins (see also CCN intercellular signaling protein).[3][4][5] CTGF has important roles in many biological processes, including cell adhesion, migration, proliferation, angiogenesis, skeletal development, and tissue wound repair, and is critically involved in fibrotic disease and several forms of cancers.[1][2][6wikipedia.
Members of the CCN protein family, including CTGF, are structurally characterized by having four conserved, cysteine residue-rich domains, and these domains are, from N- to C-termini, the insulin-like growth factor binding protein (IGFBP) domain, von Willebrand type C repeats (vWC) domain, the thrombospondin type 1 repeat (TSR) domain, and a C-terminal domain (CT) with a cysteine knot motif. CTGF mediates its functions through binding to various cell surface receptors in a context-dependent manner, including integrin receptors,[7][8][9] cell surface heparan sulfate proteoglycans (HSPGs),[10] LRPs,[11] and TrkA.[12] In addition, CTGF also binds growth factors and extracellular matrix proteins. The N-terminal half of CTGF interacts with aggrecan,[13] the TSR domain interacts with VEGF,[14] and the CT domain interacts with members of the TGF-β superfamily, fibronectin, perlecan, fibulin-1, slit, and mucins.["wikipedia
=======================================================================
TNF, INTERFERON alpha, JAK-2,CNN2.
==============================
According to Schultz,
TNF alpha potentiates the negative influence of Intereferon-alpha on CCN proteins. "the CCN proteins are known to be involved in the development, homeostasis, and repair of mesenchymal cells", to which breast cancer cells belong. WISP3/CCN6, incriminated in the Inflammatory Breast Cancer, member of the Wnt1.
In fact WISP3 has "growth and angiogenesis inhibitory functions" (ASCO).
Should interferon alpha knocks down the WISP3, "overexpression of the epithelial adhesion molecule protein E-Cadherin, overexpression of RhoC oncogene, and high frequency of p53 gene Mutations could result as seen in inflammatory Breast cancers!
now the statement that follows has deep meaning (careful now!)
"The inhibitory effect of Interferon-gamma on CTGF could almost be completely compensated by JAK-2 inhibitor AG-409". This implies that the "CTGF expression is negatively regulated by the JAK/STAT signaling pathway in a independant manner". This suggests that a JAK-2 Inhibitor could stop part on the neoplastic transformation, and play a therapeutic role!
ROLE OF AVASTIN
===============
another CCN1/CYR61 has angiogenic function which it assumes by binding to an Integrin (Alpha-v-Beta1) of endothelial cells. CYR6 promotes proliferation, migration and adhesion and survival. It also enhances Cytotoxicity of TNF alpha on fibroblasts. CYR61 gene expression is induced by the WNT3A. Bringing further the Wnt pathway into the mix.
(Leap to Autoimmune disease)
The overexpression of the WISP3 inhibit BMP and the Wnt signaling. It has been found Upregulated in Rheumatoid arthritis. It could indeed serve as a bio-marker !
Wisp3/CCN6 controls Homeostasis as stated above. It has been reported that the overexpression of WISP3 increase the activities of the SuperOxide Dismutase, a cell anti-Oxidant that palys a protective role. And therefore decrease of WISP3, may heavily play into the the neoplastic process!
Furthermore, Mutation or suppression of WISP3 increases VEGF, affects cell growth, and impact neoplastic angiogenesis and cancerous invasion of tissues! Wisp3 cell metastasis is driven through its attachment to Integrin AvB5. "a potential target for therapy! (there you have it thanks to all researchers who got there before us!)
THE CRBCM IS WORKING HARD TOWARD THE CURE...AND WILL NOT BE DISTRACTED BY POLITICS THAT " FLORISH" IN FUNDING INSTITUTIONS IN TEXAS, NIH AND ELSEWHERE...HELL WE ARE CURRENTLY FUNDING OUR OWN RESEARCH WITH THE HELP OF GREATER EAST CANCER CENTER! WE WILL GET THERE FOLLOWING OUR OWN SNIFF!
OF NOTE
When somebody shows unnecessary signs of rudeness, grumpiness or stubbornness. Over competitiveness is also a symptom of florish behavior and they .....
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DetailsI.Role of Avastin-Anti-JAK2 and Anti-c-MET in Metastatic triple negative and possibly inflammatory Breast Cancer
PART I (speculative thoughts)
1.It is increasingly recognized that the development of the triple negative breast cancer is linked to abnormalities of gene expression at the Wnt (& NOTCH) pathways, abnormal levels of Cytokines/growth factors and perturbances or predisposition to autoimmune diseases (AS SUGGESTED BY THE bASAL LIKE CELL MORPHOLOGY which comes from autoimmune component involvement)!
The various genetic pathways involved provide tremendous opportunities for target therapy interventions. Testing through clinical trials and laboratory studies appear to be the main ways to ascertain the effectiveness of proposed interventions.
Here we submit the Hypothesis that a known Anti-JAK-2 in combination with both an Anti-c-MET and an Anti-VEGF could slow down the metastatic progression of triple negative breast cancer and secondarily have a role in inflammatory breast cancers.
We are also going to identify through this study other opportunities of therapeutic interventions as we discuss the flow of causal events leading to the malignant transformation of Breast cells.
2.Potential Pathophysiology in these Breast Cancers.
---------------------------------------------------
2.1 As women enter the reproductive age, with the advent of Menarche, starts a period of their lives with increased Estrogen production. It has been reported (K-S et al) that" Estrogens have been shown to markedly modulate the immune system...mostly by regulating " namely IL-2 and Interferon-gamma. The increase of these cytokines was driven through the modulation of their promoter activities.
It is worth mentioning here that IL-4 production was not increased by this Estrogen surge.
N. et al suggested that under Estrogen stimulation "the production of interferon-gamma was enhanced by E2 stimulation. And that E2 increases not only the number of cells expressing IFN-gamma but also the IFN-gamma levels in each cells". These authors did emphasize that the enhancement of interferon was through the Estrogen Receptor (ER) ie ER alpha, beta and mERs.
The positive regulatory feedback loop between Interferons and Estrogen Receptor-alpha was also the focus of work reported by R. et al. Indeed "patients with Systemic Lupus Erythematosis, an Autoimmune disease, AFFECTING WOMEN OF CHILD BEARING AGE, were found to have an even more of an increase in Interferon-gamma which increases levels of Receptors for Estrogen. This Estrogen Receptor response was driven through "activation of signal transducers and activation of Transcription 1 (STAT1) by Interferon".
(This provide the link to autoimmune diseases, It also means that all of the sudden you have a period of life with high Estrogen with too many receptors, you know they will be a "violent" desensitization of these receptors which in fact you will not find in Triple negative Breast Cancers which happen in women of "child bearing age").(And here comes the intervention of the STATS! with STAT5a the more specific one!)
2.2Overexpression of TNF is also induced by Estrogen
----------------------------------------------------------
Kod... et al:
"Certain autoimmune diseases are also associated with excess levels of Tumor Necrosis Factor-TNF alpha, and Anti-TNF drugs are known to be useful". The elevation of TNF alpha is known to activate the NF-kB pathways. (HERE COMES CYTOKINES' EXPANSION). And through the MAPK, the same activation will reach the JNK which leads to transcription of C-jun and ATF2, opening the door to cell proliferation.
Wikipedia suggests that TNF also can lead to"induction of death signaling and therefore could be pro-Apoptotic" but remember this is the thing taken care of by SMAD4-E3 which help escape proliferative control! The path to Neoplastic proliferation is set!
Through the Ubiquitins comes also the involvement of the NOTCH!
(see for yourself NOTCH-MAML1-EP300..........ubiquitins 8---E3 (RNF 41)
and with the NOTCH comes in the Wnt, loss of cellular boundaries and shape, and "consensus" to survive!
Continuing here!
Estrogen is known to "upregulate TNF production by increasing the number of TNF producing cells"
AND IN BREAST CANCER BIOLOGY, THE ELEVATION OF TNF SYNERGIZES THE ELEVATION OF INTERFERON gamma EFFECT ON CTGF/CCN2 (SCH...et al!)
this is the same CCN that drive by chemotaxis bone metastatic invasion 9 and metastasis is driven! wonder why the bone marrow is an early relatively "irrelevant" metastasis ! (keep you knives where they are, I see you ready to brandish them!). Science is talking for now!
TO BE CONTINUED ....BY
2.3. TNF, INTERFERON-gamma, JAK-2, AND CCN2.
===========================================
1.It is increasingly recognized that the development of the triple negative breast cancer is linked to abnormalities of gene expression at the Wnt (& NOTCH) pathways, abnormal levels of Cytokines/growth factors and perturbances or predisposition to autoimmune diseases (AS SUGGESTED BY THE bASAL LIKE CELL MORPHOLOGY which comes from autoimmune component involvement)!
The various genetic pathways involved provide tremendous opportunities for target therapy interventions. Testing through clinical trials and laboratory studies appear to be the main ways to ascertain the effectiveness of proposed interventions.
Here we submit the Hypothesis that a known Anti-JAK-2 in combination with both an Anti-c-MET and an Anti-VEGF could slow down the metastatic progression of triple negative breast cancer and secondarily have a role in inflammatory breast cancers.
We are also going to identify through this study other opportunities of therapeutic interventions as we discuss the flow of causal events leading to the malignant transformation of Breast cells.
2.Potential Pathophysiology in these Breast Cancers.
---------------------------------------------------
2.1 As women enter the reproductive age, with the advent of Menarche, starts a period of their lives with increased Estrogen production. It has been reported (K-S et al) that" Estrogens have been shown to markedly modulate the immune system...mostly by regulating " namely IL-2 and Interferon-gamma. The increase of these cytokines was driven through the modulation of their promoter activities.
It is worth mentioning here that IL-4 production was not increased by this Estrogen surge.
N. et al suggested that under Estrogen stimulation "the production of interferon-gamma was enhanced by E2 stimulation. And that E2 increases not only the number of cells expressing IFN-gamma but also the IFN-gamma levels in each cells". These authors did emphasize that the enhancement of interferon was through the Estrogen Receptor (ER) ie ER alpha, beta and mERs.
The positive regulatory feedback loop between Interferons and Estrogen Receptor-alpha was also the focus of work reported by R. et al. Indeed "patients with Systemic Lupus Erythematosis, an Autoimmune disease, AFFECTING WOMEN OF CHILD BEARING AGE, were found to have an even more of an increase in Interferon-gamma which increases levels of Receptors for Estrogen. This Estrogen Receptor response was driven through "activation of signal transducers and activation of Transcription 1 (STAT1) by Interferon".
(This provide the link to autoimmune diseases, It also means that all of the sudden you have a period of life with high Estrogen with too many receptors, you know they will be a "violent" desensitization of these receptors which in fact you will not find in Triple negative Breast Cancers which happen in women of "child bearing age").(And here comes the intervention of the STATS! with STAT5a the more specific one!)
2.2Overexpression of TNF is also induced by Estrogen
----------------------------------------------------------
Kod... et al:
"Certain autoimmune diseases are also associated with excess levels of Tumor Necrosis Factor-TNF alpha, and Anti-TNF drugs are known to be useful". The elevation of TNF alpha is known to activate the NF-kB pathways. (HERE COMES CYTOKINES' EXPANSION). And through the MAPK, the same activation will reach the JNK which leads to transcription of C-jun and ATF2, opening the door to cell proliferation.
Wikipedia suggests that TNF also can lead to"induction of death signaling and therefore could be pro-Apoptotic" but remember this is the thing taken care of by SMAD4-E3 which help escape proliferative control! The path to Neoplastic proliferation is set!
Through the Ubiquitins comes also the involvement of the NOTCH!
(see for yourself NOTCH-MAML1-EP300..........ubiquitins 8---E3 (RNF 41)
and with the NOTCH comes in the Wnt, loss of cellular boundaries and shape, and "consensus" to survive!
Continuing here!
Estrogen is known to "upregulate TNF production by increasing the number of TNF producing cells"
AND IN BREAST CANCER BIOLOGY, THE ELEVATION OF TNF SYNERGIZES THE ELEVATION OF INTERFERON gamma EFFECT ON CTGF/CCN2 (SCH...et al!)
this is the same CCN that drive by chemotaxis bone metastatic invasion 9 and metastasis is driven! wonder why the bone marrow is an early relatively "irrelevant" metastasis ! (keep you knives where they are, I see you ready to brandish them!). Science is talking for now!
TO BE CONTINUED ....BY
2.3. TNF, INTERFERON-gamma, JAK-2, AND CCN2.
===========================================
Thursday, November 14, 2013
NEW GENES ARE BEING INCLUDED IN THE CLINICAL THERAPY OF LUNG CANCERS!
ASIDE FROM THOSE INCORPORATED IN THE GUIDELINES OF ONCOLOGY PRACTICE
1.EGFR
2.ALK
Now we are hearing about the following
1.ROS-1
2.MEK-1
3.RET
4.BRAF
5.HER-2
6.PI3KCA
7.KRAS
8.PD-1,2
9.ERCC1
10.BRCA-1 mRNA
11 P53
What about the therapeutic roles of :
GSTM-1 and GSTT1,FAK, Wnt, Notch, p16,
HIF and VGEF and the CYP1A1,P ?
1.EGFR
2.ALK
Now we are hearing about the following
1.ROS-1
2.MEK-1
3.RET
4.BRAF
5.HER-2
6.PI3KCA
7.KRAS
8.PD-1,2
9.ERCC1
10.BRCA-1 mRNA
11 P53
What about the therapeutic roles of :
GSTM-1 and GSTT1,FAK, Wnt, Notch, p16,
HIF and VGEF and the CYP1A1,P ?
WE WELCOME AND ACKNOWLEDGE OUR NEW READERS FROM MALAYSIA
WE WELCOME AND ACKNOWLEDGE YOU, OUR NEW READERS FROM MALAYSIA, AND THANK YOU FOR YOUR UPCOMING COMMENTS!
WE ARE PROUD TO ANNOUNCE THAT WE HAVE BEEN INVITED TO PRESENT AND DEFEND OUR POSTER RELATED TO TRAUMATIC BRAIN INJURY (TBI) : EARLY USE OF BUTEIN, A SIRTUIN ACTIVATOR IN TRAUMATIC BRAIN INJURY!
JOIN THE AUDIENCE AT THE UNIVERSITY MEDICAL CENTER IN EL PASO on DECEMBER 5TH, 2013. 10:00 AM.
FOR DIRECTIONS CALL 915-307-3354.
WE ARE PROUD TO ANNOUNCE THAT WE HAVE BEEN INVITED TO PRESENT AND DEFEND OUR POSTER RELATED TO TRAUMATIC BRAIN INJURY (TBI) : EARLY USE OF BUTEIN, A SIRTUIN ACTIVATOR IN TRAUMATIC BRAIN INJURY!
JOIN THE AUDIENCE AT THE UNIVERSITY MEDICAL CENTER IN EL PASO on DECEMBER 5TH, 2013. 10:00 AM.
FOR DIRECTIONS CALL 915-307-3354.
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