Showing posts with label NF-kB. Show all posts
Showing posts with label NF-kB. Show all posts

Thursday, October 3, 2013

Interesting aspects of Herpetic Infections

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?!

Thursday, August 22, 2013

Example of neoplastic phenomena at work.

One example  of constant  stimulation is an estrogenic supply which leads to type I endometrial cancers. It appears that constantly giving Estrogens unopposed by progestins  leads to the stimulation of many genes including Grb2, a" wild gene" that provokes amplification of critical genes that are controlling the epithelium of the Uterus (Catenins and Muc1) leading to the disturbance of cell polarity and adhesions, events that are preceding hypertrophic transformation.  MUC 1 amplification will shield the cell from immune detection.  How much Sp1, EP 300, and RELA play to further broaden NF-kB amplification in this process remains to be further defined.
RELA is another "wild gene" very much in control of epigenetic phenomena induced by amplification of the NF-kB.
"RELA has been shown to interact with:

Wednesday, May 1, 2013

A novel virus genome discovered in an extreme environment suggests recombination between unrelated groups of RNA and DNA viruses

A novel virus genome discovered in an extreme environment suggests recombination between unrelated groups of RNA and DNA viruses

Geoffrey S Diemer and Kenneth M Stedman*
GO to the article ! 

This story truly deserve the reward given to those scientists
it is the story introducing the 9th law of nature
which is the law of adaptation to unusual conditions by adjusting genetic potential, by the power of recombination, and using cellular heterogeneity, and by activating NF-kB.
cells have an incredible versatility potential if given the time and if the programmed death is not triggered by an overwhelming stimulant... to adapt and develop new function ready to deal with change in the environment.  These changes could be dramatic! ie we lost our tail for god sake!
The reversal of mesenchymal transformation is another of change to adaptation and is the underlying reason of deviation of epithelialization driving the Barrett transformation in the lower 3rd of the Esophagus.  These changes are benign until receptor become desensitized to an overwhelming and relentless stimulation leading to the HSP (heat stroke protein ) gets as well as the provoked!  Prevention of progression to cancer should dampen growth factors and decrease HSP actions!
We have recently hypothesized that the MEK action  as well as the Wnt were membrane located and followed the Reticulum Endothelium tract to reach the nucleus.   With the involvement of the Hedgehog, Basaloid morphology resulted in triple negative breast cancer!  (Again if it is strong enough to induce a morphologic change, it is strong enough to cause an abnormality so significant as a neoplastic process.-even Fanconi abnormality associated with morphology changes (microcephaly) will lead to a Myelodysplastic  Syndrome.  (and we contend that these type of syndrome will respond to Revlimid and Thalidomide type of drugs).  We promise to discuss the gene involved in the 9th law soon but this text tells you already where we are going to fish them!

Monday, March 11, 2013


Mechanisms of Resistance to Anti-Angiogenic Therapy and Development of Third-Generation Anti-Angiogenic Drug Candidates
  1. Peter Carmeliet
+ Author Affiliations
  1. Vesalius Research Center (VRC), Leuven, Belgium
  1. P. Carmeliet, MD, PhD, Vesalius Research Center, VIB, K.U. Leuven, Campus Gasthuisberg, Herestraat 49, B-3000, Leuven, Belgium Email:
  2. -----------------------------------------------------------------------------------------
  5. Suffice is to say that the concerns mentioned in this review, which is an excellent review, unveils in pretty good details the insufficiency of a monotherapy attacking an essential function of the cells. Not only will the cell have an answer such as dummy receptors, secondary amplification of transcription factors of growth factors, but escape mechanisms that include escape of the area leading to metastasis.  I should confess that recruiting other cells to help fight the attacker (Myeloid and endothelial cells) showed clearly how much angiogenesis is globally needed.  I would think that the reaction by the NF-kB would be sufficient; with its secondary growth  factor production, induction would be the predictable way.  But clearly, the cell wants restoration of the angiogenic function and finally wins, making Avastin effects short lived.  By inducing Hypoxia, stress becomes a secondary impetus and c-JUN enters the dance and fights again with resulting amplification of growth factor and various dislocation of various cyclins at integrin locations including the Angiopoietins.
  6. One of the things that needs to be emphasized or not looked at or discussed in your piece are events happening at the MEK.  You know by now that MEK is clearly amplified either by the cancerous process or in reaction to the blockage or consumption at VEGF.  Tracking MEK is important, because if amplified and mutated it may reverse mesengial transformation and render the cell more omnipotent.  It may be at the center of the observation that blocking both EGFR and VEGF reduces the progression free survival. Events at the MEK need to be scrutinized.
  7. You also realize that, in the long run,  MTOR will be secondarily stimulated leading to Telomere preservation (stabilization) and cell surviva
  8. The quick restoration of the angiogenic function after cessation of the treatment marks the importance of VEGF.
Your discussion has not only brought up in details the predicted failure of mono-target-therapies, but in the case of an important/critical cellular function being impaired by Avastin, and the resulting multitude of cellular responses. I really thank the authors for this important piece!
Clearly, Avastin is never meant to be a monotherapy, that is the answer!  To all action, there is a reaction. And cells expect action, it is built for them!

Thursday, January 17, 2013


The rise of the role of antiproteasome in the treatment of hematologic malignancies such Multiple Myeloma
requires us to stop a bit and reflect on the basic role of proteasomes which is to destroy used proteins.  To be recognized as old proteins ready for destruction, the protein is Ubiquitinated and ready for disposal.  The anti-proteasomes in effect block this plan.  And sure enough, Ubiquitinated proteins stay alive longer and guess what, it is an ubiquitinated proteins that seems to contribute to the negative effect on Modulators of pathways.   Ubiquitinated proteins forms stops transcriptions factors at check points, block the NF-kB, and drives the effects of Antiproteasomes.
Can a simple infusion of ubiquitinated TNF blocks its effects, can we start just ubiquitinating growth factors and infuse them to stop infectious process or cancer growth?  Remember, DRIVER Pathways are driven most of the time by regulators who seems to have a negative feedback from UBIQUITINATED specific pathway proteins in general terms (rare exception will exist)! What do you think?  Can a polyubiquitinated growth factor still stimulate effectively its receptor or will it dampen the stimulation and slow the devastating effect of say, TNF?