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!

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: News Calendar of events A job listing of the region’s life sciences job openings Announcements of grant RFPs, calls for papers, invitations for applications, etc.  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: Your email address will be kept private. Add synapse@mcamericas.org to your email address book to keep Synapse from being routed to your junk folder.  Headlines are color-coded by topic to help you find the news that matters most to you. 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 (E): neyha.sehgal@redskytx.com

This invitation was sent to drkcancerclinic@gmail.com by Medical Center of the Americas the organizer. To stop receiving invitations from this organizer, you can unsubscribe.
Eventbrite | 651 Brannan St. Suite 110 | San Franci

MICROGLIAL SENSOME/ SHARING WITH OUR READERS AS ORDERED!

[ Print | E-mail ] Share [ Close Window ]

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.

---

[ Print | E-mail Share ] [ Close Window ]

 

AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert! system.

HOME   DISCLAIMER   PRIVACY POLICY   TERMS & CONDITIONS   CONTACT US   TOP Copyright ©2013 by AAAS, the science society.

The CRBCM, over 30,000 pageviews in a year!

Pageviews today            5 Pageviews yesterday    68 Pageviews last month  2,823 Pageviews all time history  30,425  only 1 year!

A slew of Other countrie with less than 93, they just stop counting!

Entry	Pageviews
United States	19174
Russia	2130
Germany	1313
France	671
United Kingdom	461
Ukraine	440
Malaysia	375
Poland	347
China	267
South Korea	93

Cooperative research at CRBCM

From: Zhang, Jianying <jzhang@utep.edu<mailto:jzhang@utep.edu>>
Date: Tue, Nov 19, 2013 at 11:06 AM
Subject: FW: Lung cancer project preliminary data
To: Mutombo Kankonde <drkcancerclinic@gmail.com<

mailto:drkcancerclinic@gmail.com>>
Cc: chaiyurong <yrchai@live.cn<mailto:yrchai@live.cn>>, "Zhang, Jianying" <jzhang@utep.edu<mailto:jzhang@utep.edu>>


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>

<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>>

Email: jzhang@utep.edu<mailto:jzhang@utep.edu>

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 G_i. In addition to activating G_i, 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

Maximilien Murone^{1,2ET AL!}

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!

PTCH1 gene

WNT3A

IRF6

GLI

TGF-beta

TrkC: Neurotropin -Receptor

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 !