PIM1, a powerful target in Cytokine dependent diseases

No gene is deep in the bowel of the cellular Beast having such powerful interactions that leads to cytokine production as this one.  Its relation with the NF-KB and the NFATs is a testimony to how critical a gene it is.
Under the management of NUMA1....(to be continued!)

The secret of triple negative breast cancer

Common sense tells us that events happening in your women when they acquire childbearing age contribute significantly to the happening of triple negative breast cancer.   The young woman has gone through infancy when events here are more related to the setting of class I HLA antigens first for self tolerance, then comes exposure to the outside world and the building of defense mechanisms.  Implying development of class II HLA Antigens which we know by now are very much linked in their variations to racial disparity.  Then the young woman enters puberty which brings in the reign of the Estrogen with its extensive methylation of genes dampening the Class I HLA to prepare the young lady's body to receive the foreign "body" of the potential infant.  We have touched in one of our precedent writings about the effects of Estrogen on the immune system.   We have extensively discussed the interaction of Interferon and TNF /TGFs on receptors of Estrogen (Activation followed by desensitization or lack thereof.  The female individual with autoimmune disease will be much more affected by the surge of cytokines above.  Then come the menses with their resulting Iron deficiency which prones the body to the danger of Reactive Oxidative species.  But as far as genes are a concern, the most important event is the development of the breasts.  It is the reign of the PROLACTINS.....
Indeed, it is Prolactins that will happen on this background of Estrogen/Cytokines effects.   Don't think of Prolactin as a hormone, it is a Cytokine!  Yes, it comes in to not only have a direct effect on the Janus Kinase 2 and induce the JAK-2-STAT pathways, but through its Dopamin Receptor, it will pound on the c-MET effect and exert numerous pounding on the PIK (effect include on its regulators (AGAP2) pathway....If you happen to have another genetic abnormality such as BRCA, or too much free Iron stimulating the HIF or any other failure....something wrong is bound to happen....such as ...triple negative breast cancer.....The point is, don't forget the Prolactin reign!!!

IN THE "EL PASO TIMES"

There is an announcement for the last 2 Sundays,
reporting the Retirement of DR RAY LUNDY, a Dr who has been a pillar in this community.
DR Lundy has chosen the Greater East Cancer Center  (and the CRBCM) to continue the care of his patients.
We are pleased by is careful choice, and promise to continue what he started.  We will make sure patients receive the kind of excellent care they expect from us!

CRITICAL POTENTIAL NOTIONS IN UNDERSTANDING TRIPLE NEGATIVE BREAST CANCERS

It all makes sense that Hypoxia induced by respiratory failure in a predominantly obese population will contribute to generation of Reactive Oxidative Species and that Over eating of sugar based products will worsen the events that will lead to HIF-1 gene excitation and probable amplification, which eventually involve the VHL (justifying the correlation of clear cell Renal cancer with obesity), and eventually amplify angiogenic genes (EGFR,VEGF).  This will end-up through Gerb2 connection gene, amplify the G proteins connected MAPK and could drive to a neoplastic process.  When p38-MAPK is involved there appears that the process will be accompanied by a significant cytokine release leading to an associated inflammatory process.  This is why anti-p38 is more looked into for its anti-inflammatory consequences rather than anti-neoplastic processes. For this inflammatory process to be successful, stimulation of the CREB must be suppressed, which it is in hypoxia. The level of Cyclic-AMP is also dampened as a result.

In the epigenic zone, amplification of the MAPK will ultimately amplify the MIFT (MIFT was first described under these conditions of amplified MAPK) with consequences that lead to dampening of Androgen activity if the MIFT interacts with PATZ1.

 If  MIFT interaction is mediated via PIAS3 binding^,, ER will be next to be knocked out


Wikipedia: "This interaction is mediated via PIAS3 binding to the STAT3 DNA binding domain. Hence, STAT3 transcriptional activity is inhibited by the physical prevention of its binding to target genes. Subsequently, PIAS3 was also found to be a regulator protein of other key transcription factors, including MITF,^[6] NFκB,^[7] SMAD ^[8] and estrogen receptor.^[9] PIAS3 protein also functions as a SUMO (small ubiquitin-like modifier)-E3 ligase"

Pretty soon, you have yourself a triple negative breast cancer!!!
(leading to the question is IL6 elevated in this disease?

MIFT involvement with TFE3 will engage HMGA-2 and prop the metastatic propensity in this disease (triple negative breast cancer).

The involvement of MIFT is obligatory since it will unlock the chromatin to allow access to nuclear material by chromatin modulation

TO BE CONTINUED

An interesting Observation

 Contact QIAGEN OUR SOURCE FOR QUESTIONS!

 A study on a  BRAF(V600E) melanoma cell line treated with RAF, MEK, ERK or combined RAF-MEK inhibitors revealed a cAMP-dependent melanocytic signaling network not previously associated with drug resistance, including G-protein-coupled receptors (GPCRs), adenyl cyclase, protein kinase A (PKA) and cAMP response element binding protein (CREB).
" histone-deacetylase inhibitors suppressed MITF expression and cAMP-mediated resistance (Nature, December 2013" QUIAGEN


This observation from journal nature reported to us by QIAGEN
tells us
1. a second look at a old story does not hurt
BRAF INHIBITION IS A NEW THING HAPPENING TO A OLD STORY
AND LOOK WE HAVE BEEN SITTING ON OUR HANDS IN MELANOMA UNTIL IT SUNK ON US TO TARGET THERAPY! NOW LET'S ENJOY THE SUCCESS OF VEMURAFENIB IN OUR FIGHT FOR THE CURE!
2.THIS IDEA THAT  MITF AND c-AMP MAY HAVE THE POWER IN THEM TO CAUSE DRUG RESISTANCE IS EXTREMELY IMPORTANT, IT MAY BE THE JUSTIFICATION OF 2 IMPORTANT PHENOMENA
2.1 THAT EGFR/VEGF INHIBITION IS TEMPORARY, THAT ULTIMATELY AVASTING WILL FAIL BECAUSE OF THESE ACTORS (OR ARE THEY BYSTANDERS?)
2.2 THAT MTOR INHIBITION CAN STOP THIS RESISTANCE ONCE IT IS DOCUMENTED BY AMPLIFICATION OF THESE 2 GENES.  SO YOU GIVE AVASTIN, AND WATCH THESE 2 GENES, AND IF THEY CREEP UP, YOU KNOW AVASTIN RESISTANCE IS IN PLACE, AND HOP! YOU GIVE MTOR INHIBITOR!  WHAT'S THIS FOR A CONCEPT TO BE PROVEN!

LET'S GO TO WORK!

GENES IN MELANOMA

ERCC6
DDB2
POLH
RAD2
p16/CDKN2A, p14ARF
CDK4
MCIR
NRAS
BRAF
KIT
MITF
PTEN
GNAQ
GNA11
XPA
BRCA
miRNA

1.does amplification of Grb2 influence c-KIT biomarker function...or response to Imitanib/Dasatinib
is Mutation or amplification of Grb2 necessary to predict response to treatment.
2.what is the therapeutic, prognosis roles of Cytokines in triple negative breast cancers and Melanoma for that matter.  We know CyclinD is involved,  But are theyr other Cytokine, Status of Ornithin?  Polygluthamine, Melanine derivative?level of Ketoacids in both serum and Urine?

Words of caution!

Be careful when targeting these genes, some of them are "wild genes", meaning that they could be leading to the activation of many more genes. As we discussed, handle these with care because you will not be able to control their side effects....Other genes are just critical to so many functions ie. the ELK-1 gene.  You may use it for pro-apotosis, but it is a gene that, once knocked down, can lead to Alzheimer dementia and many more neurologic disturbances.  So read carefully before targeting these genes.  Some could lead to seizures or sudden Neurologic dysfunction, so pick and choose carefully and be prepared to handle Neurologic or cardiac complications...and always start with Phase I as per standard....Indeed you are in the belly of the beast, tread carefully!

Deep in the belly of the beast, ARE HIDDEN NICE THERAPEUTIC TARGETS!

As we examine deeper for possible targets for therapy, we are not swayed by media or political pressures which are mounting, but we look at real facts that are scientific and based on real data and deep studies of pathways: 6 targets come out either because they are at the intersection of pathways or because they are critical, obligatory steps to either DNA proliferation or cytokine production.   They are: JNK, P38, ERK, SRF, c-fos, CRE, ELK-1, NLK, oh hell did I say 6...my mistake  but depending on the neoplasia under consideration, the list can be prolonged. 
It will include: Sap1a, NFAT, JUN-D,atf2,p53,GADD53,PRAK,MAX,HSP27/72,PP3C,
GOOD HUNTING!
 SNIFF THE BEST AND TAKE YOUR PICK!  AND GUESS WHAT: THE DEVIL IS NOT VERY FAR (I MEAN THE DVL GENE) !

Interesting genetic concepts

* Immediately post brain trauma,  Blocking DISC1 --- GSK-3 INTERACTION
could affect post traumatic brain disorder.  I wonder if early administration of Cyclosporin can have this effect by affecting the NFAT pathway?

* In small cell, I wonder if the YWHAE and CDK5 should be the focus of our attention?   Definitively looking into the Noonan disease gene since it induces malformation.
Inhibitor of the CDK5 should be the focus since the experience with the Melanoma has brought light on these inhibitors (p16/CDK2A/CDK4)!

* Could Disturbance of DISC1 explain post Radiation syndrome or "chemo-Brain"?
* Could Cyclosporin and various interventions decrease post Radiation encephalopathy?

*Is there a surge in peripheral blood cytokines post Radiation as experienced in Traumatic brain injury? And what cytokine is being observed?

CELLULAR PLAY

I strongly believe the cell has multiple plays to hide from us its intrinsic play when it comes to neoplastic process.  I believe we have the cards and each of us has a hand of cards to play with. I believe we have before us confused facts, we need just to make the next step.  yes we have the basic facts, we just need to read them correctly. We know all the genes, and know most of their main roles.  And we have solid leads...

We know that stress leads to Gastric cancer, and we know the NF-kB is wild at play but so far our examination has been incomplete, and clearly we would benefit by looking at this pathway deliberately and completely since that approach would yield various culprit genes and potential targets to treat the ailment.

We know that in triple negative breast cancer the NF-kB must be implicated with disruption at hormone receptors.  BRCA and its full pathways of co-factors and downstream molecules (ie.BABAM-1, HTATIP and  ETV-6). And now the role of Androgen in luminal form of this cancer, the WISP3 in inflammatory Breast.  All these messages have not resounded in our head enough to excite us to cross the bridge...

We have the "wild genes" CRE,Gerb,Lyn,MyH or MyB, Flyn, Ep300, AR, etc.. Basically we know when things reach here, everything goes!

We know full differentiation requires the NOTCH, and MEK is the door to de-diferentiation (under the NOTCH control of the MAPK through the ADAMS10).  We know Ubiquitination is also under NOTCH influence...But we don't still use fully the Info!

Using the "master integrator" to its full potential too in cancer prevention to dampen Reactive Oxide species and reduce EGFR positive lung cancer in non smokers would be a significant new approach.
All this is on the desk at CRBCM as we start 2014.   Wish us luck, the fight is still ahead.

Looking at an earlier find in Melanoma!

For the longest time in Melanoma therapy, only DTIC and interferon were cited in Melanoma therapy.  Interferon was given in adjuvant setting Mostly and DTIC in Metastatic diseases from Melanoma.             Despite our understanding of the working of Interferon, there no clear biomarker that would predict which melanoma would be more snsitive to Interferon.  Therefore integration of Interferon into new combinations with new Target therapies such as Ipilimumab and Vemurafenib, remains a hot topic of investigation.
Interferons can act on tumor cell through the direct JAK-STAT pathway, but for some other reasons, go through the ISGF/GAS/PE-1/p91 pathways.  The interferon can recruit stimulation of the IRF pathways as well as activating the MHC class I to immunologically block progression in Melanoma.   How this will impact the effects of newly found pathways of Ipilimumab and Vemurafenib is anybody guess and a matter of current trials.  It appears that we now have to play catch-up, since earlier investigations to define predictive biomarkers for interferon/DTIC responses were not timely completed.  Turning and returning a old stone needs once again to be completed!

BURNING QUESTIONS!

1. OH! let me come out and say it!
Don't you believe by now that there is this suspicion that interfering with Iron Receptors could decrease the rate of metastatic disease to the lungs?  Would it be grand to actually prove you could slow down Hepatoma or breast cancers from moving to the lungs by sending an Antibody against Iron receptor?  Let's look closer into the data!  and reconvene in the coming year to get an update!  At the CRBCM, we are working overtime!

2. Could gene interference with EP300 boost anti-VEGF Medication?  It is after all a co-Activator of HIF-1, isn't it?

3. Cataract prevention: what is the standing of the CRYAB gene? What about the RPGRIP-1 gene in retinal damage?

DANCING WITH A GIANT NAMED: "THE SMALL HETERODIMER PARTNER"

There are 25000 genes in human cell approximately or give and/or take they say!
and only 20% are active at one given time they estimate.   But make no mistake about it, the rule of "company you keep" has not been as strong at play as it has in genes!   The Small Heterodimer PARTNER (SHP) really in the thick of it.  See it plays with one of the gene involved with a tissue which, once cancerous, lead to incurable cancer.   SHP interacts with non other than Hepatocyte nuclear factor 4 alpha (HNF4A).  And through this gene, it will reach a "wild gene" called "CREB-binding" which affects in its dealing to close to 50 genes ( Hell! all genes since it it is involved in the "breathing" of the cell!)  This small Heterodimer Partner is a misnomer, it is a GREAT Partner important in the function of all major Hormone from Androgen to Estrogen!  Touch this one, and you will feel the vibe!  If you know What I imply...

ACTIVITY AT CRBCM

ONE COULD NOT STAND THE BEAUTY OF OUR POSTER, WE CAME BACK WITHOUT OUR POSTER ON TRAUMATIC BRAIN INJURY PROJECT, STOLEN AT THE CONFERENCE.
 I GUESS IT IMPRESSED A HECK OUT OF SOMEONE!  STOLEN POSTER, THAT'S JUST IMPRESSIVE AN ACHIEVEMENT FOR ANY POSTER!  LUCKILY, WE STILL HAVE IT ON A MEMORY CHIP!

WHO CARES ABOUT THE TISSUE OF ORIGIN WHEN YOU HAVE THE GENETIC PROFILE OF CANCER?

TIVANTINIB, anti-c-MET
OBINUTUZUMAB, AN ANTI-CD20, FDA APPROVED IN CLL
NINTEDANIB, anti-EGFR
PONATINIB, NOW "DEFUNCT" BECAUSE OF THROMBOTIC COMPLICATIONS

========================================
WHO CARES ABOUT THE ORIGIN OF THE CANCER WHEN YOU KNOW THE DRIVER MUTATIONS?

When you treat triple negative Breast cancer luminal type with Bicalutamide, when you treat Angiosarcoma in the liver with Avastin, even Melanoma with Yervoy, lung cancer with Crizotinib, who really cares about the tissue of origin?  We are now at the stage where chemotherapy will need to be dictated not by the Oncologist, but by a Central Pathology department giving us the gene profile for each cancer diagnosed in town!
The Europeans are now planning this move as we heard from the grapevine!  are we ready?...it will be cost effective and reportedly better for our patient outcome as suggested in recent studies (for the hard believers!).  "New Paradigm" = Not the tissue of origin, but the genes!  Medicine is a shifting field and new technology is rolling in...I got to go to that Nano meeting planned in March...Europe here we come!

Creating a new path like the CRBCM!

Each time we turn around, people rush to discourage CRBCM that this and that has been studied and therefore there is no point to revisit the question.  It is a weakness to believe that when it comes to cancer biology, revisiting a topic at molecular level always unveil an interesting aspect that had remain hidden or overlooked.  Surprises are everywhere, you just have to keep your eyes open and remain suspicious of the evident...The Retinoic Acid Receptor has been known for long time, but the story of ATRA in Promyelocytic Leukemia does not date that long.  As a matter off fact the story of Targeting therapy is not that old.  It took a second look with new technologies to uncover new aspect of the same story.  For a sole Researcher, going it your way may pay big.  Shackled in large institutions, you have to follow the direction of the chief!  But on your own, just pick up and go, surprises are still awaiting!  There are 25000 genes, each with its habits, reactions and adaptations that are not fully uncovered. To believe otherwise is foolish, work hard and keep at it!  The CRBCM is on that path...we believe is the future!  Passion will take us there!

I was just reading about Lung cancer and what pathological Biomarkers have entered standard therapy (EGFR, ALK, ROS-1,etc...). These are for therapy decision, is that means our patients have stopped their need to know about for early diagnosis, no!  Is that means we don't want to know about prognosis? No...if you work in this area, just keep on plugging along,  until those who doubt come to recognize they are short sighted...things are awaiting your discovery everywhere your mind and heart take you...just keep at it!

ACTIVITY AT CRBCM: BIG DAY TODAY ONCE AGAIN

We are presenting our TBI project at the scrutiny of the staff at the University Medical Center and Faculties at both Texas Tech.and the Paul L.Foster School of Medicine.  We have 15 minutes to convince our audience that Butein an Activator of Sirtuins could limit post traumatic events at gene level that broaden brain lesions.  The task at end is huge because it does not only involve the trauma but extensive genes from regulation of Calcium store in the ER to the involvement of Maf, ICER, p21SFT, GATA, EGR, to OCT, HNF3,IRF4 to the NEF2.

Also DR Ray Lundy has officially announced his Retirement, and Greater East will be taking over his operation, we will be double busy!

The preliminary results on the 5 lung cancer tissues is now available for review with DR Jangh.
CRBCM, advancing in a resisting world but our fight is just!

WE ARE READY TO PRESENT ON TBI TOMORROW

Hello all,

Please provide me with your PowerPoint Presentation by today at 3:00pm.  UMC Nursing needs your presentation in advance to in order to provide credit.

Kindly,

Cynthia Ogaz, MBA

Lead Analyst

Office of Continuing Medical Education

TTUHSC – Paul L. Foster School of Medicine
===================================
NOW FULL REHEARSAL INTO MOTION AT CRBCM!

Conformational molecular Targeting wanted.

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...

Presenting our TBI project !

14th Annual Rio Grande Trauma Conference & Pediatric Update- Abstract Presentation Information

Ogaz, Cynthia	11:20 AM (8 hours ago)

Please see attached Abstract presentation schedule. May you please be 20 minutes prior to your presentation time in AEC Auditorium A and B.  For those that will bring poster for this conference, you will need to set up your posters by 8:00 am on Thursday, December 5, 2013 and pick them up by 4:45pm on Friday, December 6, 2013.  Feel free to contact me if you have any questions. 

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)

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!

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!

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!

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!

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!

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.

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!

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!

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!