Thursday, September 19, 2013

wonders of the NOTCH

Aberrant Activation of Notch Signaling in Human Breast Cancer

"Notch signaling prevents induction of the p53 target genes Puma and Noxa following mitoxantrone treatment. Western blot analysis for JNK activation, Thr⁸¹ phosphorylation of p53, Puma, Noxa, and cleaved caspase-3 levels in parental (lane 1), vector control (lane 2), MCF 10A/RBP-Jκ (lane 3), and MCF 10A/NICD (lane 4) cells treated with mitoxantrone for 16 hours. Activation of JNK and Thr⁸¹ phosphorylation of p53, leading to the up-regulation of Puma and Noxa and cleavage of caspase-3, were observed in parental and vector control cells but not in cells stably expressing RBP-Jκ/VP16 or NICD. Puma, Noxa, and cleaved caspase-3 were undetectable in untreated cells.

=====================================================
THAT'S HOW THE NOTCH ENSURE CELLS DO NOT DIE!
====================================================

Crosstalk Between Vascular Endothelial Growth Factor, Notch, and Transforming Growth Factor-β in Vascular Morphogenesis

Matthew T. Holderfield,
Christopher C.W. Hughes
"
The formation of a new capillary involves endothelial cell activation, migration, alignment, proliferation, tube formation, branching, anastomosis, and maturation of intercellular junctions and the surrounding basement membrane. Each of these stages is either known or suspected to fall under the influence of the vascular endothelial growth factor, notch, and transforming growth factor-β/bone morphogenetic protein signaling pathways. Vascular endothelial growth factor is essential for initiation of angiogenic sprouting, and also regulates migration of capillary tip cells, proliferation of trunk cells, and gene expression in both."
===========================================
NO NEW BLOOD VESSELS WITHOUT THE NOTCH!
SEE IMPLICATIONS FOR STROKE AND TUMOR METASTASIS========
========================================
" The Jagged/Notch signaling pathways control cell fate determination and differentiation, and their dysfunction is associated with human pathologies involving cardiovascular abnormalities."(LINDNER ET AL!)
===================================ARRHYTHMIA AND SUDDEN DEATH IS AN AREA WHERE THE NOTCH IS IMPORTANT (OF COURSE DON'T FORGET THE DYSTROPHIES, CHANNELOPATHIES AND VARIOUS MITOCHONDRIAL DISTURBANCES (MCARDLE DISEASES)

CRAWFORD ET AL " Novel observations showed that focal adhesion kinase and paxillin concentrate at sites of cell-cell adhesion in the epithelial enveloping layer and may associate with actin cytoskeleton at epithelial junctions containing cadherins. Fak is phosphorylated at these epithelial junctions but is not phosphorylated on Tyr³⁹⁷, implicating a noncanonical mechanism of regulation."

WHERE NOTCH PLAYS, THE Wnt /cADHERIN IS NOT VERY FAR
===================================================
FOR ANY ACTIVE MOLECULE, THERE IS ONE THAT TAMPERS IT, SLOW IT DOWN...FOR THE NOTCH IT IS THE "NUMB" MOLECULE THAT "COOLS" IT!

Wednesday, September 18, 2013

so you know!

SUBJECT: Risks associated with the use of XGEVA^® (denosumab 120 mg)

Severe symptomatic hypocalcemia, including fatal cases
Hypersensitivity, including anaphylactic reactions

August 27, 2013

Dear Health Care Professional,

This letter is issued to notify healthcare providers about risks associated with
the use of Xgeva; severe symptomatic hypocalcemia, including fatal cases,
and hypersensitivity, including anaphylactic reactions. Xgeva is indicated for
the prevention of skeletal-related events in patients with bone metastases
from solid tumors and for the treatment of adults and skeletally mature
adolescents with giant cell tumor of bone that is unresectable or where
surgical resection is likely to result in severe morbidity. Xgeva is not indicated
for the prevention of skeletal-related events in patients with multiple myeloma.

Severe symptomatic hypocalcemia, including fatal cases

In the postmarketing setting, in patients with cancer receiving Xgeva for
prevention of skeletal-related events, severe symptomatic hypocalcemia,
including fatal cases, has been reported. Signs and symptoms of these
cases include altered mental status, tetany, seizures and QTc prolongation,
which were temporally associated with Xgeva use and decreased serum calcium levels.
The calculated reporting rate of severe symptomatic hypocalcemia suggests
that the incidence in the postmarketing setting is similar to the rate observed
in clinical trials. During clinical trials, severe hypocalcemia (corrected
serum calcium < 7 mg/dL or < 1.75 mmol/L) occurred in 3.1% of patients
receiving treatment with Xgeva and 1.4% of patients had hypocalcemia reported
as a serious adverse event.

Action being taken by Amgen

To communicate this important safety information, changes have been made
to the US prescribing information (USPI) as described below:

The Contraindications section has been updated to reflect that pre-existing
hypocalcemia must be corrected prior to initiating therapy with Xgeva.
The Warnings and Precautions section has been updated to reflect that
Xgeva can cause severe symptomatic hypocalcemia, and fatal cases have
been reported.
The Adverse Reactions section has been updated to include “severe symptomatic
hypocalcemia, including fatal cases” as a postmarketing adverse drug reaction.

Summary of Recommendations for Health Care Professional
The risk of severe symptomatic hypocalcemia among patients receiving Xgeva can be
minimized by the following:

Correction of pre-existing hypocalcemia prior to Xgeva treatment.
Administration of calcium and vitamin D as necessary to treat or prevent
hypocalcemia. Monitor calcium levels and administer calcium, magnesium,
and vitamin D as necessary. Monitor levels more frequently when Xgeva is
administered with other drugs that can also lower calcium levels. Advise
patients to contact a healthcare professional for symptoms of hypocalcemia.
Identification of risk factors for hypocalcemia in patients receiving Xgeva.
Based on clinical trials using a lower dose of denosumab (single dose of
60 mg denosumab), patients without cancer and with severe renal impairment
(creatinine clearance less than 30 mL/min) or receiving dialysis were at greater
risk of severe hypocalcemia compared to patients with normal renal function.

Hypersensitivity, including anaphylactic reactions
In the postmarketing setting, two spontaneously reported cases of anaphylactic
reactions were identified and were considered causally related to Xgeva. The calculated
reporting rate of anaphylactic reaction is 5.4 per 100,000 patient-years, which classifies
anaphylactic reaction as a very rare event.
Action being taken by Amgen
To communicate this important safety information, changes have been made to the
US prescribing information (USPI) as described below:

The Contraindications section has been updated to reflect that Xgeva is
contraindicated in
patients with known clinically significant hypersensitivity to Xgeva.
The Warnings and Precautions section and the Adverse Reactions section
have been updated to indicate that clinically significant hypersensitivity
including anaphylactic reactions has been reported with use of Xgeva.

Summary of Recommendations for Health Care Professional
Patients with clinically significant hypersensitivity to Xgeva should not receive Xgeva.
Further Information
These are not the only risks associated with the use of this product. Please see
the full prescribing information for more information about the risks associated
with the use of this product. This information is also available at www.xgeva.com.
Contact details for adverse event reporting or to request further information
Any suspected adverse reactions should be reported to FDA’s MedWatch
Adverse Event Reporting Program:

by phone (1-800-FDA-1088), by facsimile (1-800-FDA-0178),
online (www.fda.gov/medwatch), or
by mail using the MedWatch Form FDA 3500 postage paid form,
to the FDA Medical Products Reporting Program, 5600 Fishers Lane,
Rockville, MD 20852-9787.

Should you have any questions or require additional information regarding the
use of Xgeva, please contact Amgen’s Medical Information Department at
1-800-77-AMGEN.
Sincerely,

Michael Severino, MD
Senior Vice President, Global Development, and Chief Medical Officer
Amgen

Amgen, Inc. | PO Box 681308 | Indianapolis, IN 46268

74864-R1-V1

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Multiple Sclerosis would fit

Multiple sclerosis would fit the model of pathology prompted by failure at the receptor of Interleukins
with resulting increase of Cytokines. In this model the initial insult will be destruction of Glycans at the IL-2,7 receptor resulting in the increase of these cytokines. Although they will fail at the receptors, they will still attract T cell and other relevant inflammatory cell. This is confirmed by the scenario of Traumatic brain injury in which lack of post-synaptic stimulation also result in post synaptic neuron destruction. Failure at the receptors stays the most dangerous cellular event. The triple negative Breast cancer is another example.
The effect of Interferon as a therapeutic intervention confirms that increase of Interleukins is the most significant driving event in the disease! It is driving even the coexisting gliosis found in the disease...

Tuesday, September 17, 2013

ANTI-EGFR, what is the inside story (full story)

Could anti-EGFR effect be simply an intra-tumoral Vasculitis blocking vascular Oxygenation? Can ANCA be a significant Biomarker particularly in those with Dermatitis? Is FAK and Metalloproteases be better biomarkers
text to follow!

"The fact is that anti-EGFR activity is associated with a significant dermatitis. And the dermatitis is associated or has been linked to drug activity. Indeed the more severe the rash, the more the activity of the drug. At skin level, we know as a result of the drug, toxic chemical are liberated to induce the reaction.
Myeloperoxidase (MPO) is a peroxidase enzyme that in humans is encoded by the MPO gene.^[2] Myeloperoxidase is most abundantly expressed in neutrophil granulocytes (a subtype of white blood cells).^[3] It is a lysosomal protein stored in azurophilic granules of the neutrophil. MPO has a heme pigment, which causes its green color in secretions rich in neutrophils, such as pus and some forms of mucus.

As part of the respiratory burst that neutrophils use to kill bacteria, myeloperoxidase converts hydrogen peroxide (H₂O₂) into hypochlorous acid (HOCl). HOCl is the most potent oxidant generated by neutrophils, and can cause significant tissue damage during inflammation. Dapsone arrests myeloperoxidase in an inactive intermediate form, reversibly inhibiting the enzyme. This prevents accumulation of hypochlorous acid, and reduces tissue damage during inflammation" wikipedia

Antibody " against MPO have been implicated in various types of vasculitis, most prominently crescentic glomerulonephritis and Churg-Strauss syndrome. They are detected as perinuclear ANCAs (p-ANCAs), as opposed to the cytoplasmic ANCAs (c-ANCAs) against proteinase-3 (PR3), which are strongly associated with Wegener's granulomatosis. Recent studies have reported an association between myeloperoxidase levels and the severity of coronary artery disease.^[8] It has been suggested that myeloperoxidase plays a significant role in the development of the atherosclerotic lesion and rendering plaques unstable."wikipedia

The above discussion bring to mind that dermatitis seen with use of Drugs aiming at epithelial covering of blood vessel could indeed lead to secretion of molecules such as Cyclo-oxygenease (target of NSAID), MPO such as in this case Dapsone but Anti EGFR dose liberate from other affected cells cytokines of similar products that induced rash as a secondary effect. Should study confirms that MPO is our guy, then ANCA would be a legitimate candidate Bio-Marker.
Certainly during the activity of anti-EGFR, there is significant mambranes activity in terms of shedding proteins/Cytokines, FAK will be over express as a function of this activity and high FAK will be expected, liberations of Metalloproteases and the ADAMS such as 12 will follow the same logic and could join biomarkers of EGFR activity. Elevated stress at the membrane could be associated with HSP 90 amplification...let's go get them in a trial!

SRC-3Delta4 mediates the interaction of EGFR with FAK to promote cell migration.

Long W, Yi P, Amazit L, LaMarca HL, Ashcroft F, Kumar R, Mancini MA, Tsai SY, Tsai MJ, O'Malley BW.

Source

Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030 USA.

Abstract

EGF induces signal transduction between EGFR and FAK, and FAK is required for EGF-induced cell migration. It is unknown, however, what factor mediates the interaction between EGFR and FAK and leads to EGF-induced FAK phosphorylation. Here, we identify SRC-3Delta4, a splicing isoform of the SRC-3 oncogene, as a signaling adaptor that links EGFR and FAK and promotes EGF-induced phosphorylations of FAK and c-Src.

OTHER TARGETS! WHAT IN HELL IS LEUKEMEIA INHIBITOR FACTOR?

THE LIST OF TARGET IS ENDLESS
EVERYWHERE IN THE CELL THERE IS MUCH TO FIND OUT
AND SCIENTISTS ARE SPEECHLESS
LETS DELVE ON THIS ONE
IN MATTER OF INTRODUCTION LET'S GO TO SHARKEY ET AL!

"Transcripts encoding the receptor for c-fms, the receptor for colony-stimulating factor-1 (CSF-1), and c-kit (the receptor for stem cell factor [SCF]) were expressed throughout preimplantation development. Other growth factor ligand and receptor transcripts were expressed in a stage-specific manner: these included receptors for interleukin (IL)-6 (IL-6R), leukemia inhibitory factor (LIFR), tumor necrosis factor alpha (TNF alpha) (TNFRp80 and TNFRp60), and gp130."

THIS STATEMENT UNVEIL gp130 AND ITS VARIOUS CO-FACTOR LOOMING IN THE DARK
DOING ITS THINGS, BUT IMPORTANT IN THE CYTOKINES LIBERATION AND ACTIVITY OF INTERLEUKINS. LEUKEMIA DRIVEN BY INTERLEUKIN-6 CAN BE MODULATED BY ACTING ON ITS RECEPTOR AND TARGETING TO gp130 AND ITS SLEW OF CO-FACTORS!

Monday, September 16, 2013

Key advances

*Microtubule Inhibitors (Taxanes, Ixabepilone, Erubilin)
*Signs of cellular death (Shrinkage of cell, membrane bleb formation, DNA fragmentation)
Pro-Apoptotic BCL-2 are Bax, Bak and Bim. whereas Anti-Apoptotic are BCL ( 2, XL,w)

*BH3 mimiking agents affecting BCL-XL led to significant thrombocytopenia
can this agent be used in Essential thrombocytopenia,
what is the status of BCL-XL in Essential thrombocytopenia, is it amplified?

*Does side effect of chemotherapy due to the drug itself or to cell killed
what cell was killed during the process, are there lymphokines that were liberated and could induce the side effects. Which receptor to target.
for skin reaction a panoply of of receptors could be crossed to steroid affected Receptors to find which one to block.

FDA approved anti JAK
-Tofacinib (anti JAK 1 and 3)
-Ruxolitinib (Anti JAK 1 and 2)

what is the link NOTCH1 and blockage of apoptosis, is it the BCL2, blockage of death receptor, the MTOR or the Telomerase.
or iit the MYC for amplification of genes

Are pro-apoptotic BCL2 increased in MDS, and are they under the influemce of the NOTCH

Does FAK over expression induce Fibroblast growth factor 2 to explain chemoth resistance in patient treated with chemotherapy? how does Fibroblast growth factor2 induce drug resistance?

Meaning of reduction of splenomegaly, ?decreases infltrate of abnormal cells
or Fibroblast growth factor induces fibrosis and transfusion independence is more space for normal producing cell, decrease of opposing (inhibitor ) growth factor effects or reduction of cell death.

Are Neuropathy associated to membrane phenomenon (metalloproteases) in the blood vessel, or fibroblast growth factor like activity inside the neuron, or death of the neuron

JUST TO LET ME KNOW!

Hi MUTOMBO,

In the run up to Target TME (18-20 November, Boston) I've had the chance to speak with and interview researchers working on some of the hottest research projects in the field. One of these projects is Noxxon Pharma’s NOX-A12.

NOX-A12 is a clinical candidate which inhibits CXCL12/SDF-1, which plays a key role in homing and retention of leukemic cells to their protective niches like the bone marrow or the lymph nodes. The biotech company has had some promising results so far which may be of huge interest to you and your work.

When I spoke to Anna Kruschinski, the project leader, she was able to go into much more detail for me:

“We are in Phase II running two proof of concept studies in chronic lymphocytic leukemia (CLL) and multiple myeloma (MM) using NOX-A12 in combination with standard treatment, and we have managed to treat approximately half of the required patients.”

Continue reading

I've made the full interview with Anna into a free downloadable PDF, where she discusses the clinical and PK/PD results they have seen already, as well as their future plans for taking NOX-A12 through the clinic.

Download the Full Interview

Her interview can be found, alongside other free and exclusive content, on our online resource page at http://tumor-microenvironment.com/resources.

I hope you enjoy the interview and find the content useful. Make sure you look out for updates as this week I will be interviewing our chairman Michael Lisanti, Professor and Director, Breakthrough Breast Cancer Centre.

Best wishes,

Emma

Emma Hosgood

Programme Director

Hanson Wade

THEORY IN CANCER PATHOLOGY

Based on pathology findings in Bladder cancer and the progressive genetic abnormalities proclaimed to be happening in colon cancer it appears that cancer pathology starts with an abnormal persistent stimulation of Receptors (FGFR3, FGF2, EGFR) which eventually under persistent stimulation will be eventually destroyed in an effort to to "desensitize" the cells from further stimulation. The Receptor destruction however could induce alterations of glycans covering the surface of receptors but could also cause immediate demise of the cell through death receptors found in the submenbrane layer of the cell. These Death Receptors are associated with Caspase 3. As the stimulation persists and some of the stimulation going through will solicit normal pathways with internalization of the stimuli-Receptor and solicitation of normal pathways such as the RAS leading to transduction of the signal. It also be perceived as stress triggering HSP and the NF-kB / c-JUN. (this pathway can also be stimulated by cytokine altered Receptors) According to the nature of the stimuli and the nature of the tissue, the HRAS (more epidermal-squamous than Adeno) or KRAS (more adeno then epidermal-squamous) pathway will be engaged. As aggression at the membrane continue The FAK, the Wnt and NOTCH induce membrane events as well as epigenetic events to escape the stimulation leading to liberation of further cytokines and growth factors (c-MYC stimulation) that will allow cellular survival and cellular desensitization. But it is not until repair (BRCAs), and regulator/modulators mechanisms failure that the cell becomes engaged in an irreversible proliferative process. Potentially under the these growth factor the p21,p16, MDM2 etc. are knock down. When the process reaches the P52,P53 AND Rb1, Malignancy is declared. (to be edited further) these events could happen concurrently and at various sites.

Stimulation of the MEK /c-MET Vs Epidermal...to come

Sunday, September 15, 2013

Another BAD ACTOR ; a MET derivative!

If you followed our fight for the cure, we are increasingly suggesting that, nature has given us
its laws that we need to harvest and follow to win the cure, yes you need to follow the cellular pathways and select a point of intervention to stop or amplify in order to kill bad cells. We also have to know the nature of the environment of pathways which contain facilitators (enzymes),substrates(Homeobox) and Breakers (Rb1), repair mechanisms (BRCA), CBF(leukemias) or point of traffic signal orienting the reactions(Homeobox/CBF), and amplifiers (c-MYC, growth factor).
Bad cancers are those that:
1-Recruit genes that leads to malformations (DDR2) (FAK) (VEGF)
2-Recruit genes that restore embryonic potentials (c-MET) (STEM CELLS)
3-Recruit genes Regulating reactions or Homeobox (CBF)
4-Recruit the NOTCH, AND THE Wnt
5-KNOCKS OUT Breakers, repair and regulators, induce transcription factors or affect the miRNA or the polymerases.
6-Recruit and command Ubiquitilation machinery or the Helicases.
7-Recruit the Bcl (s)
8-recruit omnipresent co-factors ("wild gene") such as Gerb2. GAB1

It is quite apparent that genes that are associated with a growth factor will be imitating a chronic stimulation (exposure), or a driver situation. The c-MET is a gene that encodes a growth factor, and not just any growth factor,

"c-Met (MET or MNNG HOS Transforming gene) is a proto-oncogene that encodes a protein known as hepatocyte growth factor receptor (HGFR).^[1]^[2] The hepatocyte growth factor receptor protein possesses tyrosine-kinase activity.^[3] The primary single chain precursor protein is post-translationally cleaved to produce the alpha and beta subunits, which are disulfide linked to form the mature receptor."

This GROWTH FACTOR will affect all major "wild gene" and amplify them like the "CAPS LOCK" button of your computers!

The like of FGF2, HGFR is another dangerous trigger to protecting affected cells from dying! It is found in all dangerous cancers from Melanoma to hepatoma. Aside from Anti-MET, only IL-2, and Interferon can reach these. Although anti-P85 could play a role! It involves the NOTCH and the Wnt as well as the CRKL (reelin) through GAB1 the binder to Grb2! It involves the HIF1 and VHL, and everything else dangerous !

Saturday, September 14, 2013

Some of the interesting Basic questions in Oncology

1.Understanding side effects better in order to design a response or treatment strategy!
--------------------------------------------------------------------------------------
There nothing annoying more the Oncologist and of course the cancer patient who is victimized than chemotherapy side effects. To me this is a experienced as a "let down" from sometimes a good drug. Here we are having a good response or even a stable disease, but the side effect pushes the treatment to a halt.
And quite frankly, current literature aside from listing the side effect, does not provide much in terms of why the side effect happened in the first place. And I understand it is difficult to say, but let it ride is not always the best option. It leaves in the mind of the Oncologist an unexplained "caveat". One of the thing driving medication prescription patterns is not only response to therapy based on phase II or III randomized studies, but rates of response to treatment and panoply and intensity of side effects of the drug. These factors determine the level of "comfort" with the drug. And with that level of comfort comes the "selling" of the drug to our patients who are the ultimate consumer.
The point is that deciphering the mechanisms underlying a side effect is not clear.
1-Is the side effect a direct effect from the drug
2.Is the side effect due to subsequently released cytokines
3.does patient have to have a deficiency in their genes (gene Heterozygosity ) to experience it
4.Is the side effect a bystander effect
etc...
At CRBCM, we are interested in deciphering the mechanism(s) of RASHES during the use Anti-EGFR and various Kinases. It is said that the worse the RASH the higher the response to Cetuximab and Tareceva for that matter. BUT THE WHY HAS BEEN LEFT FOR US TO GUESS!

DIARRHEA WITH CPT-11 OR THE ANTI-EGFR AND THE SUNITINIB (TKIs)

THE NEUROPATHY
----------------------.Now Neuropathy is an interesting one.!!
ie. post synaptic Neuron death during post Brain or nerve injury has been partly attributed to inflammatory Cytokines liberated in supportive glial cells. But we know that in Diabetics that obliteration of vasa vasorum or more clearly in (the nerve) small vessel feeding the nerve (vasa nervosa I am suggesting1) may play a role. There is no question in my mind that drugs such as the Taxanes will induce epigenetic consequences liberating some nocive Interleukins...
Bleeding from Avastin is an intriging one, somewhere I remember that an cofactor gene or anchor to the VEGF is affected. will sharpen my understanding again before delving further into this discussion.
Gene wise this is an interesting area since most of the target therapy since to share these side effect.

ONE OF THE INTRIGUING SET OF SIDE EFFECTS RESEARCH, IS THE DIFFERENCE OF IN THE PANOPLY OF SIDE EFFECTS BETWEEN AN ANTI-BRAF AGENT AND AN ANTI-MEK.
THE SLEW OF SIDE EFFECTS IS SIMILAR HOWEVER, THE ANTI-BRAF GIVES YOU A SURPRISING SIDE EFFECT. NOT ONLY IT GIVES YOU A DERMATITIS/RASH BUT IT PUSHES THE ENVELOP FURTHER TO GIVE YOU A SQUAMOUS CELL CANCER OF THE SKIN! AS IF NOW THE NF-kB IS INVOLVED? AS IF THE HSP 90 (OR IS-IT HSP 60 ) AND OF COURSE THE Wnt AND NOTCH? OR MAY BE REPAIR MECHANISMS OF SKIN DAMAGE CAN'T HANDLE THE CYTOKINES AFFECTING THE EPIDERMAL RECEPTORS? DAMAGE TO RECEPTORS? REALLY A TEASER WHEN IT COMES TO EXCITED RESEARCHERS!

2.WHICH ONE DOES WHAT?
=======================
FDA approved anti JAK
-Tofacinib (anti JAK 1 and 3)
-Ruxolitinib (Anti JAK 1 and 2)

One of the reality in the cell, is the issue of Heterozygosity of genes which affect how we respond to drugs and stimuli, a fact clearly affecting our prognosis. But surprisingly, some form of genes give squarely the opposing effect! Basically we could be death or alive because the same gene has a minimal molecular change. (the story of Sickle cell comes running in my mind). Another interesting set of fact is that some cellular molecule belong to a "same family" but could play opposing role Interleukin 4 vs Interleukin-1 for example. And now the JAK, the Metalloproteases, the TGFs,the Interferons, the MUC gene,THE SRC, the STATs and it goes on and on. We need mapping of these things to design a strategy of Use.AND AS I USUALLY SAY, COMPUTER CAN HELP. LET'S FACE IT ONE MIND CANNOT DO WHAT A PC CAN!

A formidable opponent in the fight for the cure!

The only purpose of the cell is to survive, and to do so it has ability to not only live without resources or Oxygen for that matter for a while at least, through autophagia, the cell can live for a period of time without outside influx of nutrients. The cell can escape its environment to friendly shores, it can proliferate to increase the odds that at least one of the daughter cells can survive, through the years, the cell has learned to keep record of what mechanisms that helped it survive "bad weathers". It has build in Homeobox or Core binding Factors made of specific catalysts for only certain reactions and their determined sequence to orient the way metabolism should go. It has a wide variety of repair genes and regulators to temper rates of reactions and correct mistakes, It has a number of Paracrine or Autocrine secretions to maintain its growth (and this despite an incredible variety of Receptors and various exposures to a gamut of stimuli...One such paracrine and autocrine Molecule is: FGF2 which belong to the family of:

"Fibroblast growth factors, or FGFs, are a family of growth factors, with members involved in angiogenesis, wound healing, embryonic development and various endocrine signaling pathways. The FGFs are heparin-binding proteins and interactions with cell-surface-associated heparan sulfate proteoglycans have been shown to be essential for FGF signal transduction. FGFs are key players in the processes of proliferation and differentiation of wide variety of cells and tissues." wikipedia

FGF2 is a powerful defense against cellular death. It has been also accused of conferring resistance to chemotherapy. Through its link with JAK 2 which promotes it, FGF2 has risen to become one of the most formidable challenge to treating hematologic malignancies. It is reminiscent to IL-1, and its wound healing activities put it squarely at the FAK, its Heparan sulfate covered receptor is reminiscent of failing receptors of the triple negative Breast cancer. It confers Chemotherapy resistance such the one seen in Sarcoma,. Its angiogenesis activity put it in the metastatic cellular potentials. Its membrane localization put it closer to the Notch and Wnt. And has a growth factor and through the JAK-STAT, it has ample epigenetic consequences. FGF2, a Biomarker to deal with absolutely in the fight for the cure!

Friday, September 13, 2013

fighting secondary malignancy post BRAF therapy

To avoid secondary malignancy BRAF inhibitor should be associated
to anti HSP90 (reduce stress associated side effects)
or the MTOR Inhibitors
or drugs that may affect the VHL/HIF-1 .

Is MEK inhibition a marker of RASK, it is the site of endothelial - epithelial interchange?

Next fight in the gene battle/computer models needed!

Yes we have decipher the human genome
But the epigenetic Zone is where things are happening
what are the patterns of Methylated genes, what is the miRNA patterns and quantity,
what are the active Regulators, Genetic repair genes, what is mutated, what is secondarily amplified, what is primarily amplified, what Receptors is altered, what ion-channels, is there cheloid factor activity involving the FAK, the NOTCH the Wnt, what pathways is activated, these are the questions that really matter, what CBF or Homebox are expressed, is there new translocations?
Each Neoplastic cell need this level of report!
Computer models needed!

fighting the Cytokines!

As we advance in our knowledge, it will be increasingly apparent that new biomarkers of disease will be defined for a variety of diseases. The increasing role of Cytokine and growth factors will be recognised. Indeed the inclusion of Obesity as a disease state can only be ascertain only because it is accompnied by abnornal level of Cytokins, growth factor and a number of Metabolic protein capable of inducing a disease state.
We also know that not all Cytokines are equal. Inhibition at the receptor of these specific receptor will be increasingly a way to address specific increase of these Cytokine. This fight had already started in Asthma where Interleukins 4, and 13
"Pitrakinra (Aerovant) is a human recombinant protein. It is an IL-4 and IL-13 antagonist in phase IIa studies for asthma. Its mechanism of action is by interruption of the Th2 lymphocyte immune response that underlies the inflammatory hyperresponsiveness in the airway epithelium of asthmatics.
Asthma results from a dysregulated, hyperresponsive immune response in the airways. Some immune cells in allergic asthmatics respond aggressively to foreign allergens with the release of IL-4 and -13, two key mediators that initiate a cycle of inflammation in the lung. Aerovant is an IL4Ra receptor antagonist that blocks the inflammatory effects of interleukins-4 and -13 (IL-4 and IL-13), thereby promoting a more balanced immune response." wikipedia

A cautious note though, IL 4 has been noted by some to be a good guy! IL-4 may be protective, so go easy. If you decrease it much, the ratio may break the balance (we are still looking into this!).
Aging is full of deleterious Cytokines, we believe a balance should be carefully maintain....Caution, just because it is increased does not means it is bad, homeostasis sometime require elevated protection or "protective Cytokines". Let's be discriminatory when it comes to Cytokines...the interferon story support our cautionary tale!

Recognition at CRBCM

Dear Dr. Mutombo Kankonde,

You are one of the many valued members within our community celebrating a birthday this month. At the Physicians Consulting Network, we would like to take this opportunity to wish you a very Happy Birthday. In addition, we would like to take this opportunity to celebrate you for the contributions you have made to our research and hopefully will continue to make over the coming year.

Please click on the following link so we can further extend our best wishes to you.
http://marketing.gfkamerica.com/121112-1342/index_bd.html

Important Reminders About Our December 2012 Integration

· Our New Website: www.askpcn.com

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

and thank you!

we continue our work through the years to come

Dr kankonde.

Thursday, September 12, 2013

Melanoma: the chiken and egg story once more!

If you read about Melanoma pathophysiology, the emphasis is clearly on p16/CDK2A and on p14ARF. Other will emphasize the BRAF and PTENand BRCA2. But when you think about this, These are important modulator of cell division processes which in this disease are gone awry.

Transforming growth factor beta stabilizes p15INK4B protein, increases p15INK4B-cdk4 complexes, and inhibits cyclin D1-cdk4 association in human mammary epithelial cells.

C Sandhu, J Garbe,
-------------------------------------------------------
wikipedia:
"The protein (p16) is a cyclin-dependent kinase (CDK) inhibitor that slows down the progression of the cell cycle by inactivating the Cyclin dependent kinase that phosphorylates the retinoblastoma protein (pRb). Both p16 and retinoblastoma (pRb) are important tumor suppressors that regulate the cell cycle. In addition to protein p16, pRB there are many other important tumor suppressors that regulate the cell cycle and one of them is protein p53. Cyclin D1 promotes the progression of the cell cycle to the S phase by cyclin D-dependent kinases (CDK4/CDK6). However, the activities of CDK4/CDK6 are restricted by protein p16 since protein p16 is a potent inhibitor of CDKs. Protein Rb, p16 and cyclin D1 are major restriction factors of the cell cycle restriction check points. The progression of cells from G1 phase to S phase is blocked by protein p16, which is a potential tumor suppressor that acts to disrupt the complex cyclin D1 and CDK 4 or 6. The most critical point in cell cycle regulation is the G1 checkpoint and it is at this checkpoint, that the complex cyclin D1 interactions take place to determine whether the cell cycle goes back into a quiescent state (G0) phase or enter into the S phase, where cells are destined to divide. when cells enter into the S phase the cells divide uncontrollably and that leads to cancer. It is important to note that Cyclin D1 is not a kinase but it activates kinases and it also appears to be most strongly implicated in human carcinogenesis."

=======================================
The point is that by the time these regulators of cell cycle enter the game, and their role magnified, TUMOR GROWTH factor amplification is already in effect driving this madness neoplastic process. and the lack of breaks due to mutations in these named genes become a critical failure to stop cell division. One should therefore ask what started the the growth factor in the first place.
Growth cycle amplification result from high activity of Epigenetic phenomena. UV light perturbs not the necessarily the p16 molecules, but membrane structures including WNT and NOTCH and various Receptors. At the receptors, stress will induce response including HSP-90, NK-kB, c-JUN which will start epigenetic phenomena including TGF and c-MYC (remember c-MYC is a "critical mediator of the NOTCH").

Interferon at high dose is the only therapeutic intervention in adjuvant setting because it affect cytokines and the TGF of the cellular world.
Failure to repair cellular damage will exacerbate the FAK, NOTCH and the WNT. Cellular loss of polarization,and deformation leading to warts and Nevi clearly involve membranous phenomena.
========================= The involvement of the GNAQ gene in Uveal Melanoma further re-enforces the notion that the initial insult is at the membrane.

you tell me what comes first, the chicken or the egg or p16 or the TGF and epigenetic disturbances?
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"Guanine nucleotide-binding protein G(q) subunit alpha is a protein that in humans is encoded by the GNAQ gene.^[1]
Guanine nucleotide-binding proteins are a family of heterotrimeric proteins that couple cell surface, 7-transmembrane domain receptors to intracellular signaling pathways".(wikipedia)

And, I am still heard!

Hello Clement Albert,

You have unused Play Credits in your account! Get your music in rotation by allocating them to one of your songs - every week we'll give you more.

We think you'll agree that Radio Airplay is a better promotional tool than ever. More than 50,000 artists rely on Airplay to get their music out there, and here's why:

If you are diabetic, water is your friend!

It is really true that we keep we keep emphasizing that in Diabetes Mellitus sugar cannot be allowed in the cell, and that without the sugar in the cell the intra-cellular milieu will use fat (which is Acid) to make energy molecules. There is in the diabetic body cells a build up of Acid within the cell that why we nee the Insulin to open the door to sugar into the cell to decrease the Use of Fatty Acid for energy production.

As sugar we ingest reaches the blood, It becomes unable to go into the cells where it is needed for Energy (ATP) production because Insulin is missing to open cellular doors. The sugar quickly build-up in our. at the And you know something has got to give. Well at the kidney level, the kidney can only keep so much sugar inside us, at one point the flood gates open, and our kidney let go the sugar though its gates because the sugar rise to intolerable levels. And with the sugar goes WATER...WATER.
Diabetes (going through) was not about sugar, it was about Water going through! And we keep loosing that part of the story! Water-Water Water is really really important. With less water we lose the tone of of the blood vessel and with less tone in our blood vessel, small blood vessels close and the Organ where this happens suffer dearly. In your eyes, injury occur you can go blind! In your nerves, loss of tone of blood vessel feeding the nerve itself, leads to Neuropathy. Yes drinking plenty as a diabetic will lead to increased Urination, an inconvenience, but remember life of your Organs depend on it as long as you keep sugar under control (with Medications if need be!)
Water, Water, AND WATER FOR THE PROTECTION OF THE TONE IN BLOOD VESSELS!
Remember what protect the kidney is a well known medication called Lisinopril (ACE Inhibitor) which by reducing the TONE in the Kidney blood vessel, let Water come through to flush them! Water good for you all around!
It is sad that we do not monitor this as closely (tight) as we should in modern medical practice!

Wednesday, September 11, 2013

WHAT'S IN THE NEWS!

*reportedly dose dense Taxol carbo
with Taxol given weekly at 80mg/m2 day 1,8,15
and Carbo full dose AUC -6 given every 3 weeks
for 6 Cycles showing better results in Ovarian cancer

benefit 10 months difference Vs conventional chemoth. Q3weeks.
631 pts registered
stage II-IV

Dose dense in Ovarian Cancer!!!

*Once again no risk difference of treatment of breast cancer in pregnancy confirmed.

*Now old story
Metastatic Lung cancer
1st line if squamous---Gemzar cisplatin

1st line if non squamous -Premetrex-Cisplatin (AVASTIN)

BUT REMEMBER TARGET THERAPY SCREEN FOR EGFR, ROS,ALK
ADD CETUXIMAB (TO VINORELBINE CISPLATIN PER FLEX)
CRIZOTINIB
NOW BEING CONDISERED LIGAND OF PDL-1.

*WHAT IS DOT1L ?

*GANETESPIB, AN ANTI HEAT SHOCK PROTEIN INHIBITOR, THIS DRUG MUST BE MORE IMPORTANT IN LUNG CANCER PREVENTION!?

Tuesday, September 10, 2013

Clinical genetic questions in Hepatitis

As we discuss deeper about the NOTCH and its activity, one of the disease syndrome that comes to mind is the pathobiology of conditions such as Hepatitis. we know the NOTCH is involved in both cellular membrane events as well epigenetic phenomena in the cell. By epigenetic phenomena, we would consider cytokines/growth factors production as a result of gene activity in this are of the cell. The NOTCH delve into these activities heavily. Cell to cell contacts and adhesion, loss of tissue boundaries and eventual transformation in recalcitrant Neoplasms are all potential activities of the NOTCH at liver lesion.
In Hepatitis, "liver injury is thought to be mediated by a strong cytotoxic T cell mediated reaction against infected hepatocytes that express viral Antigens at their surface". (Wedemer et al). Well T cell differentiation is ensured by The NOTCH.
Viral entrance in the cell occurs at the menbrane, the cell membrane where the NOTCH is ultimately located, the cell membrane where all receptors, Metalloproteases and ADAMS12 have been discussed to be active. The NOTCH is very much present.
Other aspects of interest in this disease are the chronicity of certain viral hepatitis and their leading to Cirrhosis which include an unfortunate commitment to disorderly nodular regeneration as if pushed by the NOTCH. The fact that it does not occur in Hepatitis A is an exciting observation. Is there links to the single RNA nature of the Virus instead of a larger Double stranded gene material of the Hepatitis B. Is this linked to certain the silencing of certain Histocompatibility Antigens. We know that Fulminant disease expression might be linked to HLA expression as well as patterns of gene silencing by epigenetic events. Attack of cytokines of self tolerance mechanisms of defense have been insufficiently studied, basically until we re-examine this disease at molecular level, progress in this are will be profoundly limited. We tend to stop our interest as soon as a vaccine has been developed (such as in in Hepatitis A ).
NOTCH activity in this disease is a legitimate target of studies...At CRBCM, we keep this in mind while fighting BAYLOR University Tissue bank which until now is trying to stop our research progress, using CPRIT funds (Texans'money). In life never dismiss the weak!
A coalition will fight until the end for its cause...let it be known!

UPDATE AFTER 1 YEAR OF CRBCM EXISTENCE!

UPDATE OF FOLLOWERS/REVIEWS IN 1 YEAR OF CRBCM EXISTENCE ,

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OVER 20 OTHER COUNTRIES FOLLOWING WITH LESS FREQUENCY

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WITH OVER 25,000 VIEWS, THE CRBCM IS IN THE THICK OF THE FIGHT FOR THE CURE!

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?

Monday, September 9, 2013

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

Sunday, September 8, 2013

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.

Saturday, September 7, 2013

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 . Various substrates have been described for Itch in mammals: CXCR4 , p73, p63 , smad 7 , Jun , Deltex (DTX, ) and Endophilin . 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 . Itch activity on junB is enhanced by Ser/Thr phosphorylation by MEKK1-JNK1 kinases , and reduced by Tyr phosphorylation in a fyn-dependent manner . Thus it is difficult to attribute general characteristics to Itch, except that it is located in the endosomal system , , and that it is autoubiquitinated , . Furthermore the type of chains formed on its substrates is not often identified (except for K29-linked polyubiquitin chains on DTX and itself, ). 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. 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. 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!