No infection is as intriguing as the Herpetic infection. Its interest lays in several facts
1. The mere fact that a Third of the US population may be involved makes this disease one of the most prevalent ones, but it is also feared. Whether the fear is justified or not remains a question.
2. Certainly it has something to do with horrific stories of potential recurrence of horrific burning neuropathic pains that we have heard about. Science does not know for sure whether only specific viral serotypes lead to this or whether certain hosts genes isoforms or inflammatory reactions may be contributing to this presentation.
3. The outbreak is accompanied with guilt and sense of guiltiness that is mostly unjustified...many questions arise after the realization that those painful skin or otherwise lesions could be herpetic...that a partner you have gave this to you and that you may give this to a new partner? Those questions are valid but with the prominence of the prevalence of this disease in the US, who and when one got exposed to Herpes is one of the great mysteries in herpetic disease. Herpes 1 has been linked to Over crowding, and Herpes 2 is the one with a sexual connotation. But one should remember that the Herpetic Virus will invade teguments (particularly abrasions) when contact happens, sexual or not! And very often this happens in our tender ages of infancy. Remember the infection can be symptomatic, but most of the time completely without any clinical manifestations. And enters quietly a dormancy.
4. The dormancy itself is quite a puzzling event! All we know is that the capsule to this double stranded DNA viral particule is from the host! This may help it to be "tolerated " by the host. We can speculate that class I MHC will not be bothered. Only the class II may note the invader most likely and provide the Antibody that we can measure!
5. The exacerbation of the herpetic infection is also puzzling in many ways
-It happens when we are under stress (menstruation and exposure to UV light), pregnancy state and post chemotherapy, the so called state of "when the immune system" is down!
-To the writer this is a state of activity of the c-JUN and Fos, the NF-kB and full epigenetic phenomena as if cyclines and TNF, TGFs are in full swing! Epigenetic events seem to free or unleash genes (regulators or not) that will reactivate the Virus.
-How and where these events occur (Golgi, Nucleus, or cytosolic) remains to be clarified.
(Let raise the eyelid of this dormant disease and look at it through its eyes/pupils without awakening it!)
6. The bad exacerbation could be virally induced or it could be in fact a reaction of the Host (Neutrophilic Grazymes) or Cyclin effects. ie. In post Brain trauma injury (TBI) we know that post synaptic nerve death is due to Cytokins that kill post synaptic nerve, is it the same in this herpetic disease?And if it is, what would be the therapeutic implications?!
Showing posts with label C-JUN. Show all posts
Showing posts with label C-JUN. Show all posts
Thursday, October 3, 2013
Tuesday, March 19, 2013
Ovarian Cancer
*Researchers who conducted the study who conducted the use of Selumetinib in low grade serous Ovarian cancer were still puzzled because its activity did not follow presence of KRAS or BRAF. They have been wondering if it used another pathway. But remember MEK is the revolving door to de-differentiation and to the reversal of mesengialization and as such increase tor susceptibility not only to chemotherapy drugs, but also to the secondary angiogenic potentiation of MEK. That is, with anti-MEK, there is a down regulation of MAPK (as suggested) and therefore the C-JUN and TGF and cyclins, but also down regulation of the VEGF!
They say " Our results suggest that selumetinib is an active agent, but not necessarily because of BRAF or KRAS mutational activation per se,” the authors concluded.
They say " Our results suggest that selumetinib is an active agent, but not necessarily because of BRAF or KRAS mutational activation per se,” the authors concluded.
In an interview, Gershenson said that one reason for the
lack of correlation could be biomarker instability. Among the 52
patients, specimens were available for only 40, mutational analysis was
done in 34, and in 28 of those the tissue was from the primary therapy
and not from the recurrent tumor. “The question arises, are these
biomarkers stable over time or do they change, so that what you find in
the primary tumor may not be what you find in the recurrent tumor,” he
said." They suggesting here that the lack of correlation could be due to a changing nature of Biomarker. But the existence of other factors and pathways could not be be excluded!
Gene-Expression Profiling May Help Select Best Drugs for Pancreatic Cancer
Friday, February 22, 2013
NEXT TO THE MTOR,
We are getting closer to the cure every day, we are clearly at the door of the cure acquiring process,
just learning the language spoken by the cell. Already it seems we are overwhelmed by what we find.
There are things we are learning though, and fast:
1. That forces within the cell can be followed through laws of nature, as grouped here: THAT AMPLIFICATION, PROLIFERATION AND DIFFERENTIATION ARE GOVERNED BY SETS OF GENES AND HAVE VARIOUS LEVELS OF EXPRESSION.
2. That treatment strategies can be made following different steps in pathways
3. That Death traps are located at the membrane, cytoplasm, mitochondria and Nucleus
4. That downstream targets inhibition can overcome resistance to earlier target inhibition
5. That Inactivation and down-regulation of gene expression appears to be more important in Oncogenesis
6. That most of the time MAPK amplification results from the down regulation of PI3K/PTEN
7. That MTOR inhibition is deeper than EGFR/VEGF and PI3k inhibition
8. That VELCADE or antiproteasome will disturb all the pathways of which products need Ubiquitination for degradation
9. That Velcade may worsen VHL depedent syndromes
10. Then, even deeper, that MTOR, are Histone de-acyl- transferases
BUT WHAT WE HAVE NOT TALKED ABOUT ENOUGH IS THE POSSIBILITY OF CURE HIDDEN EVEN DEEPER IN THE DIFFERENTIATION.: HERE ARE HIDDEN THE SO- CALLED "PATHWAYS OF SECONDARY METABOLISM" AND SURPRISE SURPRISE THAT THE ROLE OF ANTIBIOTICS RE-EMERGES!
HERE, WE LOOK FOR DIMBOA PATHWAYS AND DNA REPLICATION
ASSOCIATION WITH STRESS (FOS, C-JUN)
ASSOCIATION WITH P450
ASSOCIATION WITH UDPG GLUCOSYL TRANSFERASES AND SOME DIOXYGENASE
WE NEED TO EXPLORE ANTIBIOTICS COMING FROM FUNGI.
LET ME COME TO THE CHASE OF BX1, BX2, AS THEY ARE TIED TO U11, U12, AND CHROMOSOME 4. THIS IS THE NEW BATTLEGROUND!
RESEARCHERS, PLEASE GO BACK TO WORK!
We are getting closer to the cure every day, we are clearly at the door of the cure acquiring process,
just learning the language spoken by the cell. Already it seems we are overwhelmed by what we find.
There are things we are learning though, and fast:
1. That forces within the cell can be followed through laws of nature, as grouped here: THAT AMPLIFICATION, PROLIFERATION AND DIFFERENTIATION ARE GOVERNED BY SETS OF GENES AND HAVE VARIOUS LEVELS OF EXPRESSION.
2. That treatment strategies can be made following different steps in pathways
3. That Death traps are located at the membrane, cytoplasm, mitochondria and Nucleus
4. That downstream targets inhibition can overcome resistance to earlier target inhibition
5. That Inactivation and down-regulation of gene expression appears to be more important in Oncogenesis
6. That most of the time MAPK amplification results from the down regulation of PI3K/PTEN
7. That MTOR inhibition is deeper than EGFR/VEGF and PI3k inhibition
8. That VELCADE or antiproteasome will disturb all the pathways of which products need Ubiquitination for degradation
9. That Velcade may worsen VHL depedent syndromes
10. Then, even deeper, that MTOR, are Histone de-acyl- transferases
BUT WHAT WE HAVE NOT TALKED ABOUT ENOUGH IS THE POSSIBILITY OF CURE HIDDEN EVEN DEEPER IN THE DIFFERENTIATION.: HERE ARE HIDDEN THE SO- CALLED "PATHWAYS OF SECONDARY METABOLISM" AND SURPRISE SURPRISE THAT THE ROLE OF ANTIBIOTICS RE-EMERGES!
HERE, WE LOOK FOR DIMBOA PATHWAYS AND DNA REPLICATION
ASSOCIATION WITH STRESS (FOS, C-JUN)
ASSOCIATION WITH P450
ASSOCIATION WITH UDPG GLUCOSYL TRANSFERASES AND SOME DIOXYGENASE
WE NEED TO EXPLORE ANTIBIOTICS COMING FROM FUNGI.
LET ME COME TO THE CHASE OF BX1, BX2, AS THEY ARE TIED TO U11, U12, AND CHROMOSOME 4. THIS IS THE NEW BATTLEGROUND!
RESEARCHERS, PLEASE GO BACK TO WORK!
Friday, January 4, 2013
REVISITING THE FIRST LAW OF NATURE AND IDENTIFYING THERAPEUTIC TARGETS.
As we proposed earlier, there are major forces in the cell that once unleashed drive cellular metabolic pathways in certain direction to preserve life. We coined these laws of nature because they cannot be changed fundamentally. The first one is that DNA aberrancies will trigger activation of P53 and stoppage of cell cycle to allow correction. If those corrections are insufficient, cell death is triggered both downstream (toward the nucleus), but also upstream (toward death receptors). Indeed, one of the ways the P53 leads to cell death is through modulation of death receptors to induce the Caspase 8 machinery of programmed death.
Modulation of Death receptor is an interesting phenomenon. it goes to the basic notion of sensitization and desensitization. Dilute active receptors and you have less effect. Death receptors once stimulated usually by Tumor Necrosis Factor, lead to Caspase 8 activation (through FADD dependent or independent route). To decrease the chance of Random stimulation of Death Domains, the cell makes Decoy Receptors which divert the stimulant toward them instead of the Death Domain. The more the decoy or mimic receptors, the less the chance the stimulant will reach the Death Receptor (DR). The best Dummy (Decoy) Receptor does not have any intracellular portion of the Receptor, therefore no induction of intracellular signals is initiated. Another protection is the Silencer Of the Death Domain (SODD) which does exactly what its name says!
Toning down the TNF machinery is one of the modulation mechanism.
4 important observations:
1. Activated Caspases attack
-laminins reportedly leading to Nuclear Shrinkage and Chromatin condensation
-destroy inhibitors to Endonucleases release leading to further DNA Break down
-MOST importantly, Caspases attack the Cytoskeleton (Actin, Pletin, ROCK1, Gelsolin,Microtubules and all filamentous structures, THIS TRIGGERS THE UNFOLDING OF THE 2ND LAW OF NATURE WITH LIBERATION OF CYTOCHROME C FROM THE MITOCHONDRIAL MEMBRANE INTO THE CYTOSOL, AND ACTIVATION OF CASPASE 9 AND ALL SUBSEQUENT CASPASES, SETTING AN IRREVERSIBLE COURSE TO PROGRAMMED DEATH.
2. You note that the 2nd law is downstream the 1st law, therefore targets driving the 2nd law will bypass the mechanisms of resistance in place to stop the progression of the 1st law. This includes the Bcl-2.
3.Many targets are located here in the functions of Death Receptors. These include the Receptor itself (CD95), but they also include CD 120, AP03, P55, P60, P75 (NERVE), C-JUN (STRESS), FADD, APO2L, AND OF COURSE THE SILENCER (SODD).
4. The gene encoding the Death Receptor and several Decoys has been traced to 8p21-24. THE QUESTION IS, WILL PRESENCE OF MUTATION OF 8p PREDICT FOR RESPONSE TO INTERLEUKINS, INTERFERON OR TO SOME BIOLOGIC INTERVENTION? IS OSTEOPROTEGERIN (8q23-24) PRESENCE SUCH A PREDICTOR?
FOR BASAL CELL LIKE BREAST CANCER PATIENTS, IS MYC (8q24.12) PRESENCE A SIGNAL THAT TUMOR GROWTH FACTOR ARE THE MAIN DRIVING FORCE? IS AVASTIN AND RELATED ANTI-GROWTH FACTORS IMPORTANT IN THE THERAPEUTIC STRATEGY?
WE ARE HARD AT WORK AT CRBCM!
As we proposed earlier, there are major forces in the cell that once unleashed drive cellular metabolic pathways in certain direction to preserve life. We coined these laws of nature because they cannot be changed fundamentally. The first one is that DNA aberrancies will trigger activation of P53 and stoppage of cell cycle to allow correction. If those corrections are insufficient, cell death is triggered both downstream (toward the nucleus), but also upstream (toward death receptors). Indeed, one of the ways the P53 leads to cell death is through modulation of death receptors to induce the Caspase 8 machinery of programmed death.
Modulation of Death receptor is an interesting phenomenon. it goes to the basic notion of sensitization and desensitization. Dilute active receptors and you have less effect. Death receptors once stimulated usually by Tumor Necrosis Factor, lead to Caspase 8 activation (through FADD dependent or independent route). To decrease the chance of Random stimulation of Death Domains, the cell makes Decoy Receptors which divert the stimulant toward them instead of the Death Domain. The more the decoy or mimic receptors, the less the chance the stimulant will reach the Death Receptor (DR). The best Dummy (Decoy) Receptor does not have any intracellular portion of the Receptor, therefore no induction of intracellular signals is initiated. Another protection is the Silencer Of the Death Domain (SODD) which does exactly what its name says!
Toning down the TNF machinery is one of the modulation mechanism.
4 important observations:
1. Activated Caspases attack
-laminins reportedly leading to Nuclear Shrinkage and Chromatin condensation
-destroy inhibitors to Endonucleases release leading to further DNA Break down
-MOST importantly, Caspases attack the Cytoskeleton (Actin, Pletin, ROCK1, Gelsolin,Microtubules and all filamentous structures, THIS TRIGGERS THE UNFOLDING OF THE 2ND LAW OF NATURE WITH LIBERATION OF CYTOCHROME C FROM THE MITOCHONDRIAL MEMBRANE INTO THE CYTOSOL, AND ACTIVATION OF CASPASE 9 AND ALL SUBSEQUENT CASPASES, SETTING AN IRREVERSIBLE COURSE TO PROGRAMMED DEATH.
2. You note that the 2nd law is downstream the 1st law, therefore targets driving the 2nd law will bypass the mechanisms of resistance in place to stop the progression of the 1st law. This includes the Bcl-2.
3.Many targets are located here in the functions of Death Receptors. These include the Receptor itself (CD95), but they also include CD 120, AP03, P55, P60, P75 (NERVE), C-JUN (STRESS), FADD, APO2L, AND OF COURSE THE SILENCER (SODD).
4. The gene encoding the Death Receptor and several Decoys has been traced to 8p21-24. THE QUESTION IS, WILL PRESENCE OF MUTATION OF 8p PREDICT FOR RESPONSE TO INTERLEUKINS, INTERFERON OR TO SOME BIOLOGIC INTERVENTION? IS OSTEOPROTEGERIN (8q23-24) PRESENCE SUCH A PREDICTOR?
FOR BASAL CELL LIKE BREAST CANCER PATIENTS, IS MYC (8q24.12) PRESENCE A SIGNAL THAT TUMOR GROWTH FACTOR ARE THE MAIN DRIVING FORCE? IS AVASTIN AND RELATED ANTI-GROWTH FACTORS IMPORTANT IN THE THERAPEUTIC STRATEGY?
WE ARE HARD AT WORK AT CRBCM!
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