PEOPLE WILL STOP SCIENCE FROM HAPPENING!

The biggest stop to science progress is still HUMAN.  Full of politics and a little greed and above all full of competitive spirit.  You ask for help to complete a project, the value of the project does not come first.  Money, who are you, who do you know.  What you may achieve without us? all irrelevent questions will stop progress on research of public health important.  For the Universties, the spirit of competition comes first.
Below  is the perfect example:

"

Thank you very much for your recent  tissue request.  After review, I would like to seek the following information before presenting your request to the committee.

I see that you have now marked the IRB Status as “Exempt.” Can you explain how this research is exempt? You explain in the description that protocols have been approved for both Dr. Kankonde’s and your labs, but do those apply to this specific research protocol/proposal?

Also, are you a named PI on this grant?

Do you have a title at your institution, such as Assistant Professor, Director, Researcher, etc? This should be put in the “Title” section, not “Dr.”

Can you please spell out UTEP and CRBCM? Also, are these the institutions where the research will be performed? I see you are using a gmail address, so am just seeking if this will be done through Dr. K Cancer Clinic instead of at University of Texas El Paso.

Your research plan states that Dr. Kankonde has approval to supply the 50 fresh lung cancer tissue samples.  If so, why are you seeking 50 samples from the bank? Please clarify here, just so the committee is not confused!

Lastly, do you have any preliminary data or significant articles to show those 3 cancer genes are important in establishing early detection of lung cancer?

Thanks,"

---------------------------------------------------------------------------------------------

This is what the CRBCM has to deal with daily to block advances!

"Can you spell out UTEP....instead of at the University of Texas "  This question tell you many things and raises question on INTENTIONS?  How can one request what they know?

NOTCH NOTCH, who's there!?

NOTCH NOTCH NOTCH every single where!

Research at NIH reported that metastasis occur when the cancer cell has created an invasive extension called INVADOPODIA.  To form these invadopodia the cell has to modify its membranous boundaries.
Cancer cells live in a relatively hypoxic milieu which activates HIF-1 the Hypoxia Induced Factor, which of course will go on to induce formation of transcription factors to deal with the hypoxic milieu.  But one of the target  pathways turned on by HIF1 is "THE NOTCH SIGNALING PATHWAY, which an important means of cell to cell communication" (Begona Diaz et al.).   And you just know that the NOTCH is going to do its things in the epigenetic area which include activating c-MYC, inducing  Cytokine formation, inducing growth factors including those involving epidermal growth factor.  Indeed at appropriate Integrins, the NOTCH resulting effect is to FLIP-IN HB-EGF (heparin-binding Epidermal Growth Factor) and FLOP-OUT Metallopreotease.  One of the Integrins involved is ADAMS-12 which is further involved under the metalloproteases effect, amplifying extracellular events and on the membrane, prompting the INVADOPODIA.   According to these authors "ADAMS-12 is an important effector of INVADOPODIA" and ensures the Cross talk NOTCH versus EGFR.  And with the cross talk EGFR versus VEGF. path to Metastatasis enabling is crossed!

The NOTCH, so omnipresent, it is sometimes ignored by distracted scientists! 

HOW MANY TARGETS are listed here!?

ADAM12, an effector of invadopodia signaling
ADAM12 functions in the cell by cutting other proteins. Hypoxia and notch signaling increased the amount of ADAM12 in the cell. Media obtained from hypoxic cells but not cells that lacked ADAM12-induced invadopodia formation in cells growing under normal oxygen levels. Diaz concluded that ADAM12 activity released an invadopodia-promoting factor. One of the potential candidates was heparin-binding epidermal growth factor (HB-EGF).
Crosstalk between notch and EGFR signaling linked by ADAM12
HB-EGF, which can be released from the cell by ADAM12’s activity, activates the epidermal growth factor receptor (EGFR). Adding HB-EGF to normoxic cells promoted invadopodia formation, while inhibiting HB-EGF decreased invadopodia in hypoxic cells. Inhibiting any component of the upstream pathway, Notch or ADAM12, prevented cells from releasing HB-EGF in response to hypoxia.
- See more at: http://beaker.sanfordburnham.org/2013/08/kicking-invasion-up-a-notch/#sthash.xhKP53nR.dpuf

ADAM12, an effector of invadopodia signaling
ADAM12 functions in the cell by cutting other proteins. Hypoxia and notch signaling increased the amount of ADAM12 in the cell. Media obtained from hypoxic cells but not cells that lacked ADAM12-induced invadopodia formation in cells growing under normal oxygen levels. Diaz concluded that ADAM12 activity released an invadopodia-promoting factor. One of the potential candidates was heparin-binding epidermal growth factor (HB-EGF).
Crosstalk between notch and EGFR signaling linked by ADAM12
HB-EGF, which can be released from the cell by ADAM12’s activity, activates the epidermal growth factor receptor (EGFR). Adding HB-EGF to normoxic cells promoted invadopodia formation, while inhibiting HB-EGF decreased invadopodia in hypoxic cells. Inhibiting any component of the upstream pathway, Notch or ADAM12, prevented cells from releasing HB-EGF in response to hypoxia.
- See more at: http://beaker.sanfordburnham.org/2013/08/kicking-invasion-up-a-notch/#sthash.xhKP53nR.dpuf

ADAM12, an effector of invadopodia signaling
ADAM12 functions in the cell by cutting other proteins. Hypoxia and notch signaling increased the amount of ADAM12 in the cell. Media obtained from hypoxic cells but not cells that lacked ADAM12-induced invadopodia formation in cells growing under normal oxygen levels. Diaz concluded that ADAM12 activity released an invadopodia-promoting factor. One of the potential candidates was heparin-binding epidermal growth factor (HB-EGF).
Crosstalk between notch and EGFR signaling linked by ADAM12
HB-EGF, which can be released from the cell by ADAM12’s activity, activates the epidermal growth factor receptor (EGFR). Adding HB-EGF to normoxic cells promoted invadopodia formation, while inhibiting HB-EGF decreased invadopodia in hypoxic cells. Inhibiting any component of the upstream pathway, Notch or ADAM12, prevented cells from releasing HB-EGF in response to hypoxia.
- See more at: http://beaker.sanfordburnham.org/2013/08/kicking-invasion-up-a-notch/#sthash.xhKP53nR.dpuf

OUR FASCINATION WITH THE NOTCH IS JUSTIFIED!

If you read carefully with open mind everything we have written about the NOTCH
you may have detected that Mutations at the NOTCH appears to be associated with diseases that not only
are refractory and bent to resist, but also has a "consensus" to progress no matter what!
This is seen with Leukemia, brain tumors,pancreatic cancers, melanoma.
we strongly believe that disturbance at the NOTCH are the reason for the "foolish" mission of cancers to resist no matter what, and to succeed this mission, the NOTCH has to skirt Apoptotic measures!  Mutations at the NOTCH have to involve or block all Apoptosis procedures in order to induce an acute leukemia, and for a "consensus", it has to imprint the message through epigenetic events.
When the NOTCH fails to block all apoptotic phenomena, a Myelodysplasia Occurs.
Remember Myelodysplasia most of the time involve Deletion of Chromosome 7  (where the NOTCH was discovered"NOTCH1 was first described as an oncogene by virtue of its involvement in the t(7;9)translocation found in the subset of patients with T cell Acute Lymphoblastic Leukemia" (Clurman). In Acute Leukemia...the where the NOTCH1 was noted there is "impaired differentiation and ENHANCED SELF RENEWAL" the author adds.  The enhanced self renew is not only prolong survival but a successful shut down of Apoptosis venues.  If the cancerous cell does not shut down successfully the Apoptotic trap, what you get is a Myelodysplasia.   "Accelerated apoptosis is the hallmark of early MDS, which explain the paradoxical finding of Normal or Hypercellular marrow in most patients. The malignant clone has an inherent susceptibility to apoptotic cell death" (Alan List et al)  But as the epigenetic NOTCH activity continues, the resulting disturbances associated with high level of Cytokines and growth factor results in cellular "autodestructions" of receptors ( a desensitization mechanisms).  At the NOTCH which is involved in T cell differentiation, "direct T cell suppression akin to Aplastic Anemia" (List).
This also explain why epigenetic events point to susceptibility to

Anti-thymocyte globulin in MDS.

  When the NOTCH is involved successfully, the result is an acute leukemia nothing less...and Myelofibrosis results from consequent epigenetic activities here leading to cytokine (interleukins) production and disturbances.

A SLEW OF INTERVENTIONS CAN AFFECT THE NOTCH

Rather than sitting in awe before this dangerous phenomena that is the NOTCH, It is time to take a closer look at a comprehensive corrective measures to face it.  Mutations at the NOTCH involve many killer cancers.  Our patients are dying when we "navigate" cautiously with timid treatments!
We know the NOTCH has a Membrane base but "lightning fast" involves  epigenetic and nuclear events.  It is time to take a stand and face this monstrous challenge in a more systematic way.  Again c-MYC is a critical Mediator of the Notch activity, it is therefore a potential good Biomarker of its activity.  This NOTCH first described in Hematologic disease (it is involved with t(7,9) translocation) gives a powerful message of "apoptosis consensus to leukemic cell" most likely by its relations with the AKT/MTOR implications.
It is a Membrane based and act
1.as a Receptors and theirs various Co-factors (affected by CYTOKINES (IL21,granzyme), GROWTH FACTORS (TGF beta), and NEUROFACTORS), Endophilin,MAML1,
2.As a Endocytototic apparatus, indeed the internal portion of these proteins enter the cell after Detachment (FAK involved)
3.It is affected by important molecules at the membranes (Cyclic AMP, secretases, an the Hedghog pathway, ions channels, Rho-GTPase)
It goes on in the Cytosol where transporters must be involved
and affects main pathways  through some anchors and related co-activators/adaptators (Grb2) and interact with wild genes FYN, SMRTR, Six1,dHBP1,TRAF6, HSP60-90,Ctip-2
some of its related proteins will undergo Ubiquilation  E6

It goes on to the Nucleus to affect epigenetic events miR524, c-MYC, SMAD7, HES promoter,

Here is summarized work of many researchers, we thank them for their ccontibutions, but it is time to stop admiring Mutations at NOTCH, and take a stand!

*FBW7/hCDC4, an ubiquitin ligase, a substrate of E3,
It targets c-Myc, c-JUN and Notch for degradation through Ubiquitlation and proteasome degradation.
This is Mutated in grave cancer including Colon cancer and Acute lymphoblastic leukemia.
and of interest c-Myc is a critical Mediator of NOTCH activity.  Putting notch in epigenetic phenomena rather than at the membrane where it is said to drive cellular consensus !  Bad disease are determined to be bad here!

Notch1 involvement (and potentially the Wnt) determine the consensus to be bad in T-cell leukemia despite therapy. It is "a member of the Notch family. Members of this Type 1 transmembrane protein family share structural characteristics including an extracellular domain consisting of multiple epidermal growth factor-like (EGF) repeats, and an intracellular domain consisting of multiple, different domain types. Notch family members play a role in a variety of developmental processes by controlling cell fate decisions."(wikipedia)

Notch power is demonstrated by the fact that it induced Malformation (ie Bicuspid Aortic valve and Aortic Aneurysm). It is the Anti-apoptotic somewhat irreversible power of the Notch which makes this gene a dangerous contender for chemotherapeutic drugs (we suspect).  Researchers are now suggesting that p561ck could be the target to knock down in T-cell to affect the fate of these leukemic cells.   

Notch Cooperates with the Reelin pathway mainly in the brain
Notch has various co-factors (MAML1)
and acts on several promoters (HES) of genes (see Ankyrin)
Cross talk with Tumor Growth factors and Neurofactors

The NOTCH family of genes are "wild genes":

In a recent publication,

AIP4/Itch Regulates Notch Receptor Degradation in the Absence of Ligand

Patricia Chastagner, Alain Israël, and Christel Brou^{* et al put it this way}

" However it was recently shown that increased Notch signaling in transgenic mice mimics the symptoms of the disease [6]. Various substrates have been described for Itch in mammals: CXCR4 [7], p73, p63 [8], [9] smad 7 [10], Jun [11], Deltex (DTX, [12]) and Endophilin [13]. In general Itch targets its substrates to degradation, with some exceptions: AIP4 regulates the cell surface expression of select TRP channels by enhancing their ubiquitination and endocytosis but without facilitating their degradation [14]. Itch activity on junB is enhanced by Ser/Thr phosphorylation by MEKK1-JNK1 kinases [11], and reduced by Tyr phosphorylation in a fyn-dependent manner [15]. Thus it is difficult to attribute general characteristics to Itch, except that it is located in the endosomal system [7], [13], [16] and that it is autoubiquitinated [12], [17]. Furthermore the type of chains formed on its substrates is not often identified (except for K29-linked polyubiquitin chains on DTX and itself, [12]). Even less is known in Drosophila about the mechanisms controlled by Su(dx), Notch being its unique described target in this organism. Sakata et al. [18] have shown that ubiquitination of Drosophila Notch depends on Nedd4 (an E3 ubiquitin ligase belonging to the same family as Su(dx)) and on the presence of a PPSY motif in the intracellular region of Notch. Nedd4 is involved in the constitutive endocytosis of Notch and regulates its stability. Wilkin et al. [19] have demonstrated that Su(dx) and/or Nedd4 regulate sorting of Notch full-length within the early endosome. However these authors did not determine whether ubiquitination of Notch targets it for degradation, recycling or some other fate."

making the case for a "itch " to the NOTCH and to the variety of interactions that will take days to write about!

"IL-21-stimulated human plasmacytoid dendritic cells secrete granzyme B, which impairs their capacity to induce T-cell proliferation"  a new approach to treating ALL!

Speculations on DPC4 gene!

 "The K-ras oncogene is activated in approximately 90% of pancreatic adenocarcinomas, and the DPC4 (MADH4/SMAD4) tumor suppressor gene is inactivated in approximately 55% of pancreatic adenocarcinomas." McCarthy et al.
===================================================================
Another functional Misnomer the DPC4 gene
It is a growth factor that stops proliferation (GROWTH FACTOR THAT INHIBITS IT!)
It is one of these things that nature has created to balance its growth.   And when the breaks are absent, proliferation of cells will go wild.  I suspect it is one of the genes that comes into effect early at the end of embryogenesis when tissue differentiation has to end.  It got to have links to the NOTCH to be so powerful a gene!  With the NOTCH, this will explain how so determined cancer induced by this deletion will stubbornly progress thinking it is doing the right thing!  NOTCH is the guy that convince cells to agree to the mission! Coupling the determination of the NOTCH with removing break to proliferation makes for one deadly disease!  The cells don't know the mission is destructive!  The KRAS amplification is also a result of removal of breaks!  Indeed reports of repression of EVI1, Mir-96, and even GLUT1 seem to abound in Pancreatic cancer.  What is of fascination is that GLUT 1 that we reported to be linked to HIF-1 and VHL and antioxidants, is said to be "downstream from c-MYC" the gene amplifier! (proliferative by excellence)  DPC4 must act on c-MYC through this conduit!   The VHL will impact EGFR and sure enough angiogenesis could be "depressed" impairing delivery (and effectiveness) of Chemotherapy in these disease.  Only Microtubule effect will come to concur this of course!(affecting the NOTCH!)
It is now evident that to slow down Pancreatic cancer
we should focus on
Disturbing ions channel, watch the FAK, impacting on Actin metabolism, expanding GLUT1, block c-MYC
and let's go to work!

ONE Thing THOUGH, the Devil Wnt is not far (when NOTCH is awaken)!

1.KRAS, " normal tissue signaling, and the mutation of a KRAS gene is an essential step in the development of many cancers.^[3] Like other members of the Ras family, the KRAS protein is a GTPase and is an early player in many signal transduction pathways. KRAS is usually tethered to cell membranes because of the presence of an isoprenyl group on its C-terminus." wikipedia
It is interesting to know that with KRAS activation follow the activation of RALGDS which through the Arrestins wake up the DVL (devil) preparing the cell to early proliferation and metastasis through the Wnt.
(wikipedia)

Activities at CRBCM

*The CRBCM has moved to 11601 Pellicano Drive, suite A2 in EL PASO, same Zip code.  newer building
Here we finally have direct frontage to the street, our lights will shine among other organizations in the fight for survival and expansion.  The location is cheaper, and the management more dynamic and responsive!  This is the right place to be right now !  We have made our debut, now time to be more in the public face!

*Still exploring more expansion, we have now met September 5th Developers and will be part of the plan of new Medical Building.  We thank Developers for inviting us to the table.  El Paso is growing with us!

* Dr Kankonde is now Medical Director at the Grifols/Talecris Plasma laboratory known as EL PASO II.  Training as Medical lab director is in full swing and progressing on target!  We are where it is happening.   Over 16000 donors a year at this location...our team is working well.  We can accommodate  more donors, the need is here now!

*CRBCM has submitted few research proposals, we are waiting to hear...
We are hard at work planning for Breast cancer Month activity...October 2013!

*  Contract with UTEP on work on PCR work on lung cancer progressing well, and should be finalized this week.  The tissue Bank (University of Virginia) is ready to send samples!  And fund from MDHonors have been received (thank you!).  We are ready to embark in our project thanks to Professor Jianying Zhang!

Zhang, Jianying

WE ARE STILL WAITING TO SEE WHAT HAPPENS WITH CPRIT, WATCHING ACTIVITIES THERE!   HOPEFULLY AT LEAST ONE OF OUR PROJECTS WILL BE TO THEIR LIKING! LAST WE HEARD WAS A FOX NEWS REPORT PUBLISHED 8/5/13, GO TO ARTICLE!

In Cancer target therapy, BIG IS NOT NECESSARILY BETTER.

Scientists have long understood that our fascination with major pathways in the cell should be modulated
and attention to smaller and intermediary molecules should be heightened.   It is true that driver molecules could be sitting in the main high way of the pathways.  But increasingly, it has become evident that supportive genes that maintain the Pathway flow, those that regulate, modulate, start or maintain the pathways or redirect  differentiation  are just as important and may be at time larger in importance for therapeutic intervention.

The discovery that some major chemotherapy drugs keep some special places in our armamentarium of therapeutic interventions not because of their recognized main effects on genes but rather from their Epigenetic effects, how they affect de-acethylation or methylation, miRNA or other related events, have shown the importance of "secondary" changes they impose!

In Pancreatic cancers, the most recognized Mutation is that involving KRAS ( and secondarily the EGFR).  However attacks or inhibition of KRAS has not assured remarkable successes. Anti-EGFR have not convincingly improved survival although with some effect.  Today Researcher are starting to look at supportive genes: the switch genes, those that keep autophosphorylation on, The Cbl, the Shc, PYK2,
 FAK (cheloid effect), PKB and Lyn, the Grb2, The COT when it comes to MEK.

We have neglected the role of TGF alpha as a stressor in this disease although it is the inducer of EGFR.
We have chosen to ignore AP-1 when it is the major inducer of IL-1 (IL-8) and contributor somehow of exacerbation or a consequence of NF-kB intervention in this disease.

Other aspect is the role of maintenance therapy in metastatic Pancreatic cancers, Indeed we know that Activity at KRAS are somewhat obligatory to the driving of this disease, yet we have not checked the status of the KRAS after completion of primary therapy, and attempted to suppress this this in maintenance setting.

The CRBCM is looking into this also!

(Of note major Mutations still involve  P16ink4A, EGFR, DPC4/SMAD4,BRCA2,MHL1,MSH2,KRAS,CDKN2A,PMS1, and TGF(s)) in pancreatic cancers!

It is time to take it or leave it! SEASONAL FLU VACCINE!

   DATE:          September 4, 2013

 

   SUBJECT:    2013-14 Seasonal Influenza Vaccination Program

 

It's that time again!  Flu season is approaching and all Medical Staff members, employees and volunteers will be required to provide documentation of a current influenza vaccination.  As always, THE Hospital will provide free flu shots to our medical staff in the Employee Health Office at the hospital starting Monday, September 16.  The schedule for ongoing immunization clinics at the hospital is listed in the table below.  If you choose to be vaccinated elsewhere, you must provide proof of that vaccination in writing to the Medical Staff Office. 

 

Any Medical Staff member requiring a medical or religious exemption from vaccination must submit a request for exemption in writing to the Medical Staff Office from their personal physician stating the reason for exemption. 

 

Documentation of vaccination or exemption must be received by the Medical Staff Office by October 15 or the Medical Staff member's privileges will be suspended for the entire influenza season.

 

Thanks as always for helping keep our patients and our coworkers healthier during the influenza season.

 

FROM HYPOXIA TO CANCER/ HTLV1 (RAPID COMPLICATION OF CELLULAR EVENTS)

What is really going on in the tissue is that there is a relative Hypoxia in the tissue.  These Hypoxic conditions are exacerbated in Obese individual because of coexisting sleep apnea.  During sleep Apnea, the body goes into an hypoxic mode because of the frequent Apnea.  At cellular level Hypoxia has to be dealt with  rapidly because the cell use insufficiently Glucose for the generation of ATP the molecular energy.  So Glucose influs is needed to maintain cell life without building up Acids.  There is cellular response to hypoxia which 2 folds
1.  Rapid transcription factor response which leads to increase of GLUT1 the amount of receptors for Glucose.  The cell needs sugar more because it can only produce 3-4 ATP instead of all it can using the Mitochondrial Kreb cycle.  Receptors to Glucose increase sharply, weakening in fact the cell because we now know that Viruses (HTLV1) use the same Receptors to penetrate the cell!  Making GLUT1 a legitimate target during HTLV1 infection.  (watch for Hypertrophy here as cell lose polarity)  (WATCH WHAT TGF IS DOING BY NOW WITH THIS RECEPTOR!  STRESS WILL START HSP90)
2. Exacerbation of Activity the Hypoxic Intrinsic Factor (HIF1).  With a name like this, when else can it acts. Of course in Hpoxic condition.   There is a global perception that Oxygen is needed pronto so this HIF has to do some thing to that effect.  Oxygen has to come from blood, so it figure we have to do something to the blood vessel.  HIF goes to the promoter of VEGF and activates it leading to smooth muscle of blood vessel effect (contributing to Diabetic Retinopathy treated by Avastin)).
Watching all these activities is a big monster in the room called VHL which is linked to VEGF through its interaction with AUF1, and Ubiquitilation of HIF1 is not far away. (If you speak VHL, Renal cancer is ready to start! and the worse kind called "clear cell")

In the global Acidic conditions imposed by Hypoxia followed by ineffective Glycolysis, free radical ensues ready to cause potentially cancer...taking Anti-Oxidants is good to dampen the free Radicals and danger of DNA Adducts production.  But remember Anti-Oxidants activities must occur in safe presence of Iron.  Women with Iron deficiency because of menses could go "viral" here we surmise and develop a weird lung cancer EGFR positive because of the EGFR and VEGF "cross talk".
 Again at cellular level, what start with lack of Oxygen can go "viral" and "neoplastic" on you lightening fast...particularly if it (hypoxia that is) comes to be every time you sleep or dose off!

MORE SUPPUTATIONS IN GENETIC TARGETING THERAPY

My deep investigation into Hypoxia has led to an interesting set of clinical questions
What is again the role of Mitotane in the treatment of Pancreatic cancer?
can Mitotane add to Anti-VEGF in the treatment of Pancreatic or Renal cancers
Is there a role of AUF1 in monitoring Anti-VEGF therapeutic effect
in other words can AUF1 elevation predicts Diabetic retinopathy.
Role of Geldanamycine in pancreatic and esophageal cancers!
Hummm...need to look into these!

The trenches of stress

Whether the stimuli to stress be physical (heat, radiation, cold etc) or autoimmune or infectious(Interleukins, TNF,other cytokines and cyclins, etc.).deep into the "bowel" of the cell these events have a chemical effect involving genes that are also involved in proliferation, amplification, cellular differentiation, division etc.   Cellular stress potentially could lead to Apoptosis. Therefore anti-apoptotic genes are also stimulated to stop the cell from dying from a "benign and non overwhelming " stress.  Anti-Apoptotic genes include those that directly stops Apoptosis from Happening (GADD45, MyD118, Ing1p33inca etc) but also those involved in DNA repair XRCC1, PARP1,2,APEX1,PCNA.

• APEX1,^[4]
• APTX,^[5][6]
• OGG1,^[7]
• PARP2,^[8]
• PCNA,^[9]
• PNKP,^[10][11]
• POLB,^{[12][9][13][14]} and
• PARP1.^{[6][15]wikipedia} 
•  PCNA has been shown to interact with Ku70,^[13][14] MSH3,^[13][15][16] Werner syndrome ATP-dependent helicase,^[17][18] RFC2,^[13][19][20] RFC3,^[13][21] RFC1,^{[13][22][23][24][25]} RFC4,^[13][19] RFC5,^[13][19][24] GADD45G,^[26][27] CDC25C,^[28] MUTYH,^[29] Flap structure-specific endonuclease 1,^{[30][31][32][33][34][35][36]} Cyclin O,^[13][37] CHTF18,^[13] Y box binding protein 1,^[38] Cyclin D1,^[39][40] Annexin A2,^[13] MSH6,^[13][15][16] DNMT1,^[41][42][43] HDAC1,^[44] KCTD13,^[45] XRCC1,^[46] Cyclin-dependent kinase 4,^[40][47] Ku80,^[13][14][48] HUS1,^[49] GADD45A,^{[50][51][52][53][54]} POLD2,^[55] ING1,^[56] POLH,^[57] KIAA0101,^[36] POLDIP2,^[58] EP300,^[59] MCL1,^[60] POLD3,^[13][61] Cyclin-dependent kinase inhibitor 1C,^[62] POLL,^[63][64][65] Ubiquitin C^[66][67][68] and P21.^{[23][32][36][62][69][70][71][72]wikipedia}
•  
•     DNA damage repair and those involved in containment of Oxidative attacks are very much part of genetic coping mechanisms against stress induced damages to the cell.   Suffice is to say that these events are epigenetic and will also involve the MeCTR and DNMT1 as mentioned above.

Dealing with stress is very much molecular at cell level!
of note, this section identify PCNA, a series of polymerase cofactor enzymes/proteins, as an important target for intervention!and Ing1 protects against UV induced Apoptosis per researchers!

Genes involved in stressful events

PATTERNS OF STRESS

It is by now evident that there is multiple types of stress
all of which have different genetic basis
The variety of stresses seems mostly determined by stimuli inducing them.
Indeed stress induced by an a new infection is different than that induced by a stressful job interview. Stress leading to a constant level of subluminal anxiety seems to be the most life threatening as it stimulate a set of of genes that are either directly linked to survival or secondary linked to its pathway.
globally, No stress is the same.
Various stresses:
1.stress due to an interview
2.stress due to pressure of a deadline
3. stress due to an undefined fear
4.stress due to an infection
5.stress imposed by immunization to our systems
6.the Somogyi effect
7. fear and flight reaction
8.stress imposed by hard jobs, "needed but not liked" jobs, tasks, or bosses (and some times spouses).
9.Stress imposed by inflammatory bowel diseases or autoimmune syndromes!stress of chronic diseases (Obesity, Hypertension, etc.) and other non curable diseases
etc.
our abilities to cope
the sudden or length nature and duration of the stimuli,
acknowledging the stress
our response to the stress and whether or ot we achieve complete or partial remission to the stress
all these factors impact both short and long term consequences of stress in our systems.
MOST IMPORTANTLY AS FAR AS OUR SURVIVAL IS CONCERNED, THE GENES SOLICITED DURING AND AFTER THE EVENT/STIMULI ARE CLEAR DETERMINANTS AND MOST IMPORTANT FOR LONG TERM OUTCOME.

GENES INVOLVED IN  STRESSES
=========================
Depending on the sudden-acuteness or chronicity of the stimuli, we use various genes.  There are genes involved in immediate reaction to the stimuli, genes due to receptor-stimuli interactions,  pathways elicited whether necessary or not, downstream consequences of elicited pathways, and of course cycline effects as a result.  Hormonal involvement is often part or the initial stimulation, but other hormone disturbances are a result of persistent cyclins'effects.  Mechanisms of coping include not only genes meant to provide us potential to process and adjust to the stimuli, but also pre-printed patterns in the epigenetic zone, and ratios of hormones which prone us to coping evenly and sanely to the stimuli.

The importance of the nature of stimulation cannot be "stressed" enough.

ie. when the stress is an autoimmune disease, the role of TNF, and TGF cannot be over-emphasized,
ie. when it is an infection, although TNF and TGFs play an important role, Cyclins (IL-1, IL-6, 10,12,13 and even 23) comes into play.  (remember the protective IL-4)
ie. sudden inducing fear events stimulate the fear and flight reaction (Adrenaline, noradrenaline,steroids(including the Androgen receptor gene) and even somatostatins and other GI "Enterokines"  etc).
In the Brain, Oxycytosin, serotonin, and other neuro-factors (BDNF).
It cannot be a surprise that Hypertension will involve vasopressin, neurotensin
and some stimuli will involve IGF-1, PON-1,PR4 like genes and ATF4, to list just a few genes!
It is interesting that genes involved in stress management not only include the NF-kB but genes known to immunize or protect good cells from chemotherapeutic drugs!
The critical involvement of Actin-dependent pathways is worth being noted!
Mitochondrial glycolytic and Oxidative participation is very much related to the nature of the stimuli...and so is the MTOR participation which way heavily on survival impact!

full list of genes to follow!

ADAPTER PROTEINS: A CLASS OF "WILD GENES"

We have venture to define "wild genes" as class of genes that have multiple interactions leading to uncontrolled neoplastic processes.   A particular note has to be noted about Adapter proteins (ie.Gerb2)
The notion that their standard description suggests they do not have intrinsic enzymatic properties tend to minimize their actual role.  Indeed these genes act as "obligatory cofactors" in many cancers.  Kantarjian et al discussing Chronic Myeloid leukemia reported: "Many of these interactions are mediated through tyrosine phosphorylation and require binding of the BCR-ABL to adapter proteins such as the Grb2, CRK, CRK like proteins(CRKL), and SCR-homology containing proteins (SHC)".  In fact, downstream events will not effectively happen without these "enablers", making them an equal partner in crime.
Now going after these Adapters may prove dicey as it is assumed that they are also extensively found in normal tissue but who really knows until all phases of trials are completed.
Wikipedia:
"Signal transducing adaptor proteins are proteins which are accessory to main proteins in a signal transduction pathway. Adaptor proteins contain a variety of protein-binding modules that link protein-binding partners together and facilitate the creation of larger signaling complexes. These proteins tend to lack any intrinsic enzymatic activity themselves^[1] but instead mediate specific protein–protein interactions that drive the formation of protein complexes. Examples of adaptor proteins include MyD88, Grb2 and SHC1."

and the list goes on:


Genes encoding adaptor proteins include:

• BCAR3 – Breast cancer anti-estrogen resistance protein 3
• GRAP – GRB2-related adaptor protein
• GRAP2 – GRB2-related adaptor protein 2
• LDLRAP1 – low density lipoprotein receptor adaptor protein 1
• NCK1 – NCK adaptor protein 1
• NCK2 – NCK adaptor protein 2
• NOS1AP – nitric oxide synthase 1 (neuronal) adaptor protein
• PIK3AP1 – phosphoinositide-3-kinase adaptor protein 1
• SH2B1 – SH2B adaptor protein 1
• SH2B2 – SH2B adaptor protein 2
• SH2B3 – SH2B adaptor protein 3
• SH2D3A -SH2 domain containing 3A
• SH2D3C – SH2 domain containing 3C
• SHB – Src homology 2 domain containing adaptor protein B
• SLC4A1AP – solute carrier family 4 (anion exchanger), member 1, adaptor protein
• GAB2 – GRB2-associated binding protein 2--wikipedia

Ignoring these "adapters" is a gross mistake
look at this one for example"

NSP1 Defines a Novel Family of Adaptor Proteins Linking Integrin and Tyrosine Kinase Receptors to the c-Jun N-terminal Kinase/Stress-activated Protein Kinase Signaling Pathway*

1. Yanmei Lu,
2. Jennifer Brush and
3. Timothy A. Stewart‡

Basically this one tells you, without me c-JUN will not be stimulated and Neoplastic processes induced by prolonged c-JUN stimulation will not occur!
" In contrast, cell contact with fibronectin results in Cas phosphorylation and a transient dissociation of NSP1 from p130^Cas. Increased expression of NSP1 in 293 cells induces activation of JNK1, but not of ERK2. Consistent with this observation, NSP1 increases the activity of an AP-1-containing promoter. Thus, we have described a novel family of adaptor proteins, one of which may be involved in the process by which receptor tyrosine kinase and integrin receptors control the c-Jun N-terminal kinase/stress-activated protein kinase pathway." an interesting observation, conclusion by the authors...

OF INTEREST ALSO IS THE BCAR3 IS PROPOSED IN THE RESISTANCE OF BREAST CANCERS TO TAMOXIFEN, IS IT A FACTOR OR MECHANISM OF DESENSITIZATION?

SUFFICE IS TO SAY THAT OUR EVOLVING UNDERSTANDING OF THESE ADAPTERS SHOULD BE OFTEN REVISITED. BECAUSE THEY ARE INDEED "WILD GENES"...

(ARE THEY THE REASONS FOR ALOPECIA OR SKIN/DERMATITIS  SIDE EFFECTS OF THERAPEUTIC DRUGS?-NAUGHTY OBSERVATION TO TEASE RESEARCHERS AROUND THE WORLD!)

STUNTED HEART

If only death at old age is acceptable as it seems in people interviewed, then geneticist need to spell out phenomena occurring during "stunted heart"...is it the Notch, or is it stoppage of ion channel flow...to be continued!

Untapped new interventions in Traget therapy.

There are phenomena that only nature knows to do well such as
1.Aging of a cell
2.Apoptosis, a controlled programmed death
3.keeping a cell alive or active without a nucleus (Red cell)
4.deleting a gene in a living cell to fully commit it to a function ( T cell Vs B cell differentiation)
5.The differentiation itself...
and many more function.
The funny thing is we are always behind trying to catch-up.
We know from experience that a rotten fruit need to be removed from a bunch because the one in contact with them will also go "awry" as if talked to by the rotten one!  Is it the NOTCH or is-it just timing intervention of MTOR for aging?
There is deep in a cell a language or a voice that tell it to do something because it it is time, and we know this is a chemical message.  Scientist are trying to learn this language still today...Can we ask a Melanoma cell to remove its nucleus like the red cell does, can we master this process, can we ask a Sarcoma cell to delete a gene that prove to be driving the neoplastic process. Is ubiquitylation effective in this process.  So far globally, our targeting therapy is focused at one level (one or multiple kinase attack on the same pathways) and combining therapies is a way of hitting even higher number of pathways.  But today these combinations some time work opposite to one another, mitigating our results or simply not being additive in terms of result achieved.  We need an "integrated staged " attack, and here we need computer models...

NEED FOR BIOMARKERS

"Cardiovascular Autonomic Dysfunction Predicts Outcomes in Diabetes

Marlene Busko

OULU, FINLAND AND GYEONGGI-DO, SOUTH KOREA — Among patients with stable CAD and type 2 diabetes, measures of autonomic function--such as heart-rate recovery after exercise--may help predict the risk of short-term adverse cardiovascular events, a new study hints^[1]. A second study reports that autonomic dysfunction is strongly linked with a greater risk of severe hypoglycemia in patients with type 2 diabetes^[2]".(MEDSCAPE) GO TO ARTICLE FOR FULL INFORMATION.

========================================================

This article examplify what we are talking about
autonomic dysfunction is home to the Wnt, Notch,ion channel,  and related membrane
ions channel, NEDD4, and all the FAKs.  Best we can come with is Heart rate reovery after exercise for autonomic dysfunction monitoring...
Medical revolution is needed!!!!

Wikipedia
"E3 ubiquitin-protein ligase NEDD4 also known as neural precursor cell expressed developmentally down-regulated protein 4 (NEDD-4) is an enzyme that in humans is encoded by the NEDD4 gene.^[1][2] NEDD4 has been shown to ubiquitinate and therefore down regulate the epithelial sodium channel in the collecting ducts of the kidneys, therefore opposing the actions of aldosterone and increasing salt excretion. In Liddle's Syndrome NEDD4 is unable to bind to the ENaC and uncontrolled natriuresis occurs."

Clinical questions in Essential Hypertension (Gene basis)

Status of the RET gene in Hypertension induced stroke
Let's be frank about this our current understanding of Hypertension and its various therapeutic intervention is not adequate. Strokes appear to occur in a rampant way and the current treatments  are clearly insufficient.The epidemic of Obesity is complicating our progress even more.  Yes obesity is a clear threat to Hypertension control as fat tissue is known to produce ingredients that worsen our autonomic control of blood pressure (we know for example that Sortilin is expressed in testis muscles and fat).
The point is that we can't predict when the autonomic system protecting the brain may deem that enough elevation of blood pressure is too much to "close" the blood vessel long enough to cause an Ischemic stroke!  We suspect that the up and down of Blood pressures cause damages to blood vessels, possibly contributing to a subsequent weakening of the vessel structure prior to some of the bleeding strokes.  But we have no way of predicting these events or estimating the damages early enough to predict a stroke.  (Are there better Biomarkers out there?
One speculation comes to mind, most of the growth factors of the autonomic system have a cystein block, can deacetylation be an effective prevention?  can we measure these compound as Biomarkers  ? can Interferon be used in the prevention of stroke?
You heard me before about the Wnt and the Notch!
But I am not kidding this is where it is all playing out!
There is a tone to blood vessel that is under autonomic control, not our will...And the closest gene controlling these nerve that we know of is VEGF and RET.  Frankly let's look closely at this RET gene now since we have inhibitors (ie Vandetanib).  One of the side effect of Avastin is high blood pressure, did any one care to measure if those with high blood pressure have elevated or amplification of RET?  This RET is a member of the cadherin family (and the Wnt is not to far as you can see!)...what we need to do is to take a group of willing people with hypertension and test them for level of proteins from the GDNF family, and find new biomarkers! (Neurotensin included of course)
Let's go to work people!

(RET gene is a potential tumor inducer because it interacts with a "wild gene" Grb2)

IT'S IN THE NEWS!

JAKAFI (RUXOLITINIB)IMPROVED SURVIVAL WHEN GIVEN WITH XELODA IN RECURRENT AND REFRACTORY METASTATIC PANCREATIC CANCER,OPENING NEW DOORS TO NEW CLINICAL TRIALS IN THIS DISEASE!

JAKAFIRuxolitinib Improves Survival When Given with Capecitabine in Recurrent or Refractory Pancreatic Cancer

Published Online: Friday, August 23, 2013

The survival rate of patients with recurrent or treatment-refractory pancreatic cancer was improved when patients were treated with a combination of ruxolitinib (Jakafi) and the chemotherapy agent capecitabine compared to patients who were treated with capecitabine alone, according to results of a phase II proof-of-concept study.

The drug’s manufacturer, Incyte, announced the results on Wednesday. Full results from the study are expected to be presented at a future scientific meeting.

Ruxolitinib is a potent and selective oral JAK1 and JAK2 inhibitor that was approved by the FDA in 2011 for the treatment of myelofibrosis, a form of blood cancer characterized by bone marrow failure and spleen enlargement.

- See more at: http://www.targetedhc.com/articles/Ruxolitinib-Improves-Survival-When-Given-with-Capecitabine-in-Recurrent-or-Refractory-Pancreatic-Cancer#sthash.P1CrDDpt.dpuf

Ruxolitinib Improves Survival When Given with Capecitabine in Recurrent or Refractory Pancreatic Cancer

Published Online: Friday, August 23, 2013

The survival rate of patients with recurrent or treatment-refractory pancreatic cancer was improved when patients were treated with a combination of ruxolitinib (Jakafi) and the chemotherapy agent capecitabine compared to patients who were treated with capecitabine alone, according to results of a phase II proof-of-concept study.

The drug’s manufacturer, Incyte, announced the results on Wednesday. Full results from the study are expected to be presented at a future scientific meeting.

Ruxolitinib is a potent and selective oral JAK1 and JAK2 inhibitor that was approved by the FDA in 2011 for the treatment of myelofibrosis, a form of blood cancer characterized by bone marrow failure and spleen enlargement.

- See more at: http://www.targetedhc.com/articles/Ruxolitinib-Improves-Survival-When-Given-with-Capecitabine-in-Recurrent-or-Refractory-Pancreatic-Cancer#sthash.P1CrDDpt.dpuf

Ruxolitinib Improves Survival When Given with Capecitabine in Recurrent or Refractory Pancreatic Cancer

Published Online: Friday, August 23, 2013

The survival rate of patients with recurrent or treatment-refractory pancreatic cancer was improved when patients were treated with a combination of ruxolitinib (Jakafi) and the chemotherapy agent capecitabine compared to patients who were treated with capecitabine alone, according to results of a phase II proof-of-concept study.

The drug’s manufacturer, Incyte, announced the results on Wednesday. Full results from the study are expected to be presented at a future scientific meeting.

Ruxolitinib is a potent and selective oral JAK1 and JAK2 inhibitor that was approved by the FDA in 2011 for the treatment of myelofibrosis, a form of blood cancer characterized by bone marrow failure and spleen enlargement.

- See more at: http://www.targetedhc.com/articles/Ruxolitinib-Improves-Survival-When-Given-with-Capecitabine-in-Recurrent-or-Refractory-Pancreatic-Cancer#sthash.6YZwYBXR.dpuf

Ruxolitinib Improves Survival When Given with Capecitabine in Recurrent or Refractory Pancreatic Cancer

Published Online: Friday, August 23, 2013

The survival rate of patients with recurrent or treatment-refractory pancreatic cancer was improved when patients were treated with a combination of ruxolitinib (Jakafi) and the chemotherapy agent capecitabine compared to patients who were treated with capecitabine alone, according to results of a phase II proof-of-concept study.

The drug’s manufacturer, Incyte, announced the results on Wednesday. Full results from the study are expected to be presented at a future scientific meeting.

Ruxolitinib is a potent and selective oral JAK1 and JAK2 inhibitor that was approved by the FDA in 2011 for the treatment of myelofibrosis, a form of blood cancer characterized by bone marrow failure and spleen enlargement.

- See more at: http://www.targetedhc.com/articles/Ruxolitinib-Improves-Survival-When-Given-with-Capecitabine-in-Recurrent-or-Refractory-Pancreatic-Cancer#sthash.6YZwYBXR.dpuf

estrogen receptor, another wild gene

 Estrogen receptor is another  "wild gene"
 (Interacts with so many other genes to hide its full effect, wild genes will eventually hit another gene or a silent mutation, enough to lead to a neoplastic process).

WIKIPIDIA TELLS

"Genomic

In the absence of hormone, estrogen receptors are largely located in the cytosol. Hormone binding to the receptor triggers a number of events starting with migration of the receptor from the cytosol into the nucleus, dimerization of the receptor, and subsequent binding of the receptor dimer to specific sequences of DNA known as hormone response elements. The DNA/receptor complex then recruits other proteins that are responsible for the transcription of downstream DNA into mRNA and finally protein that results in a change in cell function. Estrogen receptors also occur within the cell nucleus, and both estrogen receptor subtypes have a DNA-binding domain and can function as transcription factors to regulate the production of proteins.
The receptor also interacts with activator protein 1 and Sp-1 to promote transcription, via several coactivators such as PELP-1.^[2]
Direct acetylation of the estrogen receptor alpha at the lysine residues in hinge region by p300 regulates transactivation and hormone sensitivity.^[19]"
"
AT CRBCM, WE WOU;D LIKE TO STRESS THAT ONE OF THE MOST SIGNIFICANT EFFECT OF ESTROGEN IS ITS INDUCTION OF PROFOUND INDUCTION OF EPIGENETIC CHANGES BY A COMPLETE MAKE OVER OF PATTERNS OF METHYLATION, AND ITS CO-PARTNER, THE PATTERN OF miRNA(s), AS IF THIS HORMONE ATTACHES TO mRNA OR TO POLYMERASES.  ONE OF THE MOST AFFECTED GROUP OF GENE THE CLASS I ANTIGENS HLA-A AND B.  THIS SINGLE FACT (ESTROGEN SURGE AND SUBSEQUENT CHANGE IN METHYLATION PATTERNS  ) CONTROLS THE WORSENING OF MOST AUTOIMMUNE DISEASES IN WOMEN ENTERING AGE OF FERTILITY (LUPUS IS BAD BETWEEN 15-45 YEARS OF AGE IN WOMEN) . IT IS ALSO THE CAUSE OF ENDOMETRIAL CANCER IN UNOPPOSED ESTROGENIC EXPOSURE, AND ACTUALLY KILLS WOMEN BY MYOCARDIAL SILENT ATTACK AT MENOPAUSE!


ESTROGEN GENE :  "
Binds DNA as a homodimer. Can form a heterodimer with ESR2. Isoform 3 can probably homodimerize or heterodimerize with isoform 1 and ESR2. Interacts with FOXC2, MAP1S, SLC30A9, UBE1C and NCOA3 coactivator By similarity. Interacts with EP300; the interaction is estrogen-dependent and enhanced by CITED1. Interacts with CITED1; the interaction is estrogen-dependent. Interacts with NCOA5 and NCOA6 coactivators. Interacts with NCOA7; the interaction is a ligand-inducible. Interacts with PHB2, PELP1 and UBE1C. Interacts with AKAP13. Interacts with CUEDC2. Interacts with KDM5A. Interacts with SMARD1. Interacts with HEXIM1. Interacts with PBXIP1. Interaction with MUC1 is stimulated by 7 beta-estradiol (E2) and enhances ERS1-mediated transcription. Interacts with DNTTIP2, FAM120B and UIMC1. Interacts with isoform 4 of TXNRD1. Interacts with KMT2D/MLL2. Interacts with ATAD2 and this interaction is enhanced by estradiol. Interacts with KIF18A and LDB1. Interacts with RLIM (via C-terminus). Interacts with MACROD1. Interacts with SH2D4A and PLCG. Interaction with SH2D4A blocks binding to PLCG and inhibits estrogen-induced cell proliferation. Interacts with DYNLL1. Interacts with CCDC62 in the presence of estradiol/E2; this interaction seems to enhance the transcription of target genes. Interacts with NR2C1; the interaction prevents homodimerization of ESR1 and suppresses its transcriptional activity and cell growth. Interacts with DYX1C1. Interacts with PRMT2. Interacts with PI3KR1 or PI3KR2, SRC and PTK2/FAK1. Interacts with RBFOX2. Interacts with STK3/MST2 only in the presence of SAV1 and vice-versa. Binds to CSNK1D. Interacts with NCOA2; NCOA2 can interact with ESE1 AF-1 and AF-2 domains simultaneously and mediate their transcriptional synergy. Interacts with DDX5. Interacts with NCOA1; the interaction seems to require a self-association of N-terminal and C-terminal regions. Interacts with ZNF366, DDX17, NFKB1, RELA, SP1 and SP3. Interacts with NRIP1 By similarity. "( UniProtKB/Swiss-Prot)

=======================A CAREFUL REVIEW OF EACH CITED GENE IS WARRANTED TO UNDERSTAND THE FULL SCOPE OF ESTROGEN INFLUENCE===============