Important genes (from Wikipedia)

1.NMYC interactor (NMI) interacts with NMYC and CMYC (two members of the oncogene Myc family), and other transcription factors containing a Zip, HLH, or HLH-Zip motif. The NMI protein also interacts with all STATs except STAT2 and augments STAT-mediated transcription in response to cytokines IL-2 and IFN-gamma. The NMI mRNA has low expression levels in all human fetal and adult tissues tested except brain and has high expression in cancer cell line-myeloid leukemias.<sup>[3]

THIS ONE GO STRAIGHT TO LEUKEMIA AND LYMPHOBLASTIC LYMPHOMA (BURKITT)
----------------------------------------------------------------------------------------------------------

-------------------</sup>

2.Crk-like protein is a protein that in humans is encoded by the CRKL gene.^[1][2]
v-CRK avian sarcoma virus CT10-homolog-like contains one SH2 domain and two SH3 domains. CRKL has been shown to activate the RAS and JUN kinase signaling pathways and transform fibroblasts in a RAS-dependent fashion. It is a substrate of the BCR-ABL tyrosine kinase and plays a role in fibroblast transformation by BCR-ABL. In addition, CRKL has oncogenic potential.^[3]
CrkL together with Crk participates in the Reelin signaling cascade downstream of DAB1.^[4][5]

REELIN PATHWAY, NOT VERY MUCH TALK ABOUT!
WHEN A GENE PLAYS A ROLE IN SOME KIND OF TRANSFORMATION THAT IS MORPHOLOGICALLY MEANINGFUL, IT IS AN IMPORTANT GENE!
^{--------------------------------------------------------------------------------------------------------------------------------------}
Retinoic Acid Inhibits Serum-stimulated Activator Protein-1

Gene Expressions during

the Vitamin-induced DifferenTIATION (GO TO ARTICLE)

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

3.Alzheimer's Disease

10 SNPs of GAB2 have been associated with late-onset Alzheimer's disease (LOAD).^[14] However, this association is found only in APOE ε4 carriers.^[15] In LOAD brains, GAB2 is overexpressed in neurons, tangle-bearing neurons, and dystrophic neuritis.^[8][15]
GAB2 has been indicated in playing a role in the pathogenesis of Alzheimer's disease via its interaction with tau and amyloid precursor proteins.^[8] GAB2 may prevent neuronal tangle formation characteristic of LOAD by reducing phosphorylation of tau protein via the activation of the PI3K signaling pathway, which activates Akt. Akt inactivates Gsk3, which is responsible for tau phosphorylation.^[8] Mutations in GAB2 could affect Gsk3-dependent phosphorylation of tau and the formation of neurofibrillary tangles.^[8][15][16] Interactions between GAB2-Grb2 and APP are enhanced in AD brains, suggesting an involvement of this coupling in the neuropathogenesis of AD.^[8]

Cancer

GAB2 has been linked to the oncogenesis of many cancers including colon, gastric, breast, and ovarian cancer.^[5][12] Studies suggest that GAB2 is used to amplify the signal of many RTKs implicated in breast cancer development and progression.^[4]
GAB2 has been particularly characterized for its role in leukemia. In chronic myelogenous leukemia (CML), GAB2 interacts with the Bcr-Abl complex and is instrumental in maintaining the oncogenic properties of the complex.^[5][12][17] The Grb2/GAB2 complex is recruited to phosphorylated Y177 of the Bcr-Abl complex leading to Bcr-Abl-mediated transformation and leukemogenesis.^[4] GAB2 also plays a role in juvenile myelomonocytic leukemia (JMML). Studies have shown the protein’s involvement in the disease via the Ras pathway.^[12] In addition, GAB2 appears to play an important role in PTPN11 mutations associated with JMML.<sup>[12]

GAB2, DON'T SAY I DID NOT MENTION PTPN11 AS IMPORTANT
 ----------------------------------------------------------------------------------------------------

4.</sup> In immunohistochemistry, CD31" is used primarily to demonstrate the presence of endothelial cells in histological tissue sections. This can help to evaluate the degree of tumour angiogenesis, which can imply a rapidly growing tumour. Malignant endothelial cells also commonly retain the antigen, so that CD31 immunohistochemistry can also be used to demonstrate both angiomas and angiosarcomas. It can also be demonstrated in small lymphocytic and lymphoblastic lymphomas, although more specific markers are available for these conditions.^[7]"
FOR THOSE WHO LIKE TO QUANTIFY EVERYTHING
HOW MUCH A TUMOR HAS CD31 COULD PREDICT RESPONSE TO AVASTIN? 
---------------------------------------------------------
LAIR1    prevent lysis of cells recognized as self
THIS GENE'S MUTATION NOT GOOD FOR YOU, AUTOIMUNE DISEASE LURKING
--------------------------------------------------

5.PRKCI

From Wikipedia, the free encyclopedia

Jump to: navigation, search

Protein kinase C, iota
PDB rendering based on 1vd2.
Available structures PDB Ortholog search: PDBe, RCSB [show]List of PDB id codes
Identifiers
Symbols	PRKCI; DXS1179E; PKCI; nPKC-iota
External IDs	OMIM: 600539 MGI: 99260 HomoloGene: 37667 ChEMBL: 2598 GeneCards: PRKCI Gene
EC number	2.7.11.13
[show]Gene Ontology
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	5584	18759
Ensembl	ENSG00000163558	ENSMUSG00000037643
UniProt	P41743	Q62074
RefSeq (mRNA)	NM_002740	NM_008857
RefSeq (protein)	NP_002731	NP_032883
Location (UCSC)	Chr 3: 169.94 – 170.02 Mb	Chr 3: 31 – 31.05 Mb
PubMed search	[1]	[2]

Protein kinase C iota type is an enzyme that in humans is encoded by the PRKCI gene.^[1][2][3]
This gene encodes a member of the protein kinase C (PKC) family of serine/threonine protein kinases. The PKC family comprises at least eight members, which are differentially expressed and are involved in a wide variety of cellular processes. This protein kinase is calcium-independent and phospholipid-dependent. It is not activated by phorbolesters or diacylglycerol. This kinase can be recruited to vesicle tubular clusters (VTCs) by direct interaction with the small GTPase RAB2, where this kinase phosphorylates glyceraldehyde-3-phosphate dehydrogenase (GAPD/GAPDH) and plays a role in microtubule dynamics in the early secretory pathway. This kinase is found to be necessary for BCL-ABL-mediated resistance to drug-induced apoptosis and therefore protects leukemia cells against drug-induced apoptosis. There is a single exon pseudogene mapped on chromosome X.<sup>[3]

THIS IS TO LOOK AT DEFINITELY IN ALZHEIMER TOO !
RAISES A GOOD QUESTION, WHAT IS THE ROLE OF PSEUDOGENE?
---------------------------------------------------------------------------------------------------------------</sup>

6.Valosin-containing protein (VCP) is a member of a family that includes putative ATP-binding proteins involved in vesicle transport and fusion, 26S proteasome function, and assembly of peroxisomes. VCP, as a structural protein, is associated with clathrin, and heat-shock protein Hsc70, to form a complex. VCP has been implicated in a number of cellular events that are regulated during mitosis, including homotypic membrane fusion, spindle pole body function, and ubiquitin-dependent protein degradation.<sup>[3]

FOR THOSE WHO LIKED THE LYSOZOME BLOG, HERE IS YOUR GENE
ALL FUNCTION SENT TO EXTRA CELLULAR SPACE THROUGH EXOCYTOSIS CAN BE CHALLENGED THROUGH THIS GENE I PRESUME,  IMPORTANT STUFF
----------------------------------------------------------------------------------------------------------------------------------------------------</sup>

7.AMFR

From Wikipedia, the free encyclopedia

Jump to: navigation, search

Autocrine motility factor receptor, E3 ubiquitin protein ligase
Rendering based on PDB 2EJS.
Available structures PDB Ortholog search: PDBe, RCSB [show]List of PDB id codes
Identifiers
Symbols	AMFR; GP78; RNF45
External IDs	OMIM: 603243 MGI: 1345634 HomoloGene: 888 GeneCards: AMFR Gene
EC number	6.3.2.19
[show]Gene Ontology
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	267	23802
Ensembl	ENSG00000159461	ENSMUSG00000031751
UniProt	Q9UKV5	Q9R049
RefSeq (mRNA)	NM_001144	NM_011787
RefSeq (protein)	NP_001135	NP_035917
Location (UCSC)	Chr 16: 56.4 – 56.46 Mb	Chr 8: 93.97 – 94.01 Mb
PubMed search	[1]	[2]

"Autocrine motility factor receptor, isoform 2 is a protein that in humans is encoded by the AMFR gene.^[1][2]
Autocrine motility factor is a tumor motility-stimulating protein secreted by tumor cells. The protein encoded by this gene is a glycosylated transmembrane protein and a receptor for autocrine motility factor. The receptor, which shows some sequence similarity to tumor protein p53, is localized to the leading and trailing edges of carcinoma cells.<sup>[2]"

CANCER DRIVEN BY AUTOCRINE MECHANISMS COULD BE AFFECTED
 --------------------------------------------------------------------------------------------------------------------------</sup>

8.There is one other NGF receptor besides TrkA, called the "LNGFR" (for "Low Affinity Nerve Growth Factor Receptor"). As opposed to TrkA, the LNGFR plays a somewhat less clear role in NGF biology. Some researchers have shown the LNGFR binds and serves as a "sink" for neurotrophins. Cells which express both the LNGFR and the Trk receptors might therefore have a greater activity – since they have a higher "microconcentration" of the neurotrophin. It has also been shown, however, that in the absence of a co-expressed TrkA, the LNGFR may signal a cell to die via apoptosis – so therefore cells expressing the LNGFR in the absence of Trk receptors may die rather than live in the presence of a neurotrophin."

WATCH THIS ONE, ANTIBODY TO Trka COULD UNLEASH APOPTOSIS THROUGH LNGFR IN THOSE CELLS HAVING BOTH GENES! 
-----------------------------------------------------------------------------------------
9.The Nck (non-catalytic region of tyrosine kinase adaptor protein 1) belongs to the adaptor family of proteins. The nck gene was initially isolated from a human melanoma cDNA library using a monoclonal antibody produced against the human melanoma-associated antigen. The Nck family has two known members in human cells (Nck-1/Nckalpha and NcK2/NcKbeta), two in mouse cells (mNckalpha and mNckbeta/Grb4) and one in drosophila (Dock means dreadlocks-ortholog).
The two murine gene products exhibit 68% amino acid identity to one another, with most of the sequence variation being located to the linker regions between the SH3 and SH2 domains, and are 96% identical to their human counterparts. While human nck-1 gene has been localised to the 3q21 locus of chromosome 3, the nck-2 gene can be found on chromosome 2 at the 2q12 locus.

THIS ONE IS A TRUE CRITICAL GENE, CHECK OUT ITS INTERACTIONS!
----------------------------------------------------------------------

10. KHDRBS1

From Wikipedia, the free encyclopedia

Jump to: navigation, search

KH domain containing, RNA binding, signal transduction associated 1
Available structures PDB Ortholog search: PDBe, RCSB [show]List of PDB id codes
Identifiers
Symbols	KHDRBS1; Sam68; p62; p68
External IDs	OMIM: 602489 MGI: 893579 HomoloGene: 4781 ChEMBL: 1795190 GeneCards: KHDRBS1 Gene
[show]Gene Ontology
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	10657	20218
Ensembl	ENSG00000121774	ENSMUSG00000028790
UniProt	Q07666	Q60749
RefSeq (mRNA)	NM_001271878	NM_011317
RefSeq (protein)	NP_001258807	NP_035447
Location (UCSC)	Chr 1: 32.48 – 32.53 Mb	Chr 4: 129.7 – 129.74 Mb
PubMed search	[1]	[2]
This box: view talk edit

KH domain-containing, RNA-binding, signal transduction-associated protein 1 is a protein that in humans is encoded by the KHDRBS1 gene.^[1][2]
This gene encodes a member of the K homology domain-containing, RNA-binding, signal transduction-associated protein family. The encoded protein appears to have many functions and may be involved in a variety of cellular processes, including alternative splicing, cell cycle regulation, RNA 3'-end formation, tumorigenesis, and regulation of human immunodeficiency virus gene expression.^[3]
---------------
DISCUSSED

TARGETING OF IMPORTANT GENES

TARGETING OF IMPORTANT GENES.
==============================
What makes a gene critical for targeting is not only that it is clearly established as a driver gene of which Mutation is clearly a critical determinant in the pathogenesis of a particular cancer, but also that its inhibition can ultimately cause the cancer to choose the road to program cell death.  For cancer to choose Apoptosis,
the cancerous cell has to find no way of escaping, adapting, or otherwise survive with the challenge inflicted.
Apoptosis can be induced directly when Death receptors (FAS,BAX) are stimulated, or through pathways ultimately blocking growth factor stimulation.  When the cell sees its adaptation mechanism blocked (NF-kB) blocked or severe block to its Nuclear structure.  So basically, there are several ways to cell Death.  Apoptosis, Necrosis, Anoikis etc. are just some cell death mechanisms.   Our Task is to unveil these death pathways in the cell.
This is easier said than done!  Cells are made to survive and Adapt, assuring longevity.  The cell will use Decoys to hide death receptors, it will use Loopholes to detract pathways to death, it will use build in protein MDR (Multiple drug resistance) proteins which are already existing in certain tissue cells, or it will adapt to new conditions by unveiling new potential genes (Mutations) such as in Sickle cell Anemia.  Or it will escape the local condition if the "abnormal" stimuli is localized.  Wherever it stays, it will make its own grown factor to help its survival!
Important genes are those that belong to a critical family of genes, that sits at the Junction of pathways, that drive a pathway critical in cell live, that is a link to other pathways, that is induced by Receptor or otherwise are part of such receptor, that are activator of pathways or are transcription factors or open the door to Apoptosis directly or indirectly.
We would like to propose to you 10 such genes that interfer with the FYN gene, one of the "crazy gene"!

Gene 1.  AP-1 gene
It regulates gene expression in response to a variety of stimuli, including cytokines, growth factors, stress, and bacterial and viral infections.  This is a critical gene in the management of response to these agents, "
heterodimeric protein composed of proteins belonging to the c-Fos, c-Jun, ATF and JDP families. It regulates gene expression in response to a variety of stimuli, including cytokines, growth factors, stress, and bacterial and viral infections."  you block this gene, the cell can't handle new stress!
------------------------------------------------------------------------------------------------
Gene2  KHDRBS1.
'KH domain-containing, RNA-binding, signal transduction-associated protein 1 is a protein that in humans is encoded by the KHDRBS1 gene.^[1][2]
This gene encodes a member of the K homology domain-containing, RNA-binding, signal transduction-associated protein family. The encoded protein appears to have many functions and may be involved in a variety of cellular processes, including alternative splicing, cell cycle regulation, RNA 3'-end formation, tumorigenesis, and regulation of human immunodeficiency virus gene expression.<sup>[3]'

Here you are in the nucleus
this the kind of target for Leukemia and tough to treat
verification of over-expression is needed.
---------------------------------------------------------------------------------------------
Gene 3  NMI   (see next)</sup>

 

 

A WHITE WOMAN TO THE CONGO | JuntoBox Films

A WHITE WOMAN TO THE CONGO | JuntoBox Films

This film can be funded if you register and like
you can even apply to be an actor
join the movement, we need 5000 registrations, take a minute, it's all that matter
over 1000 have done so
it is anonymous, and cost you nothing but time
your support will make this film a reality
do count and make a difference
A white woman in Congo, a clash of culture, an unusual scenario, but real  posssibilty
join the movement and make it real, read the script!

DR Kankonde....

SPECULATION ON PATHOGENESIS OF HEMATOLOGIC MALIGNANCY.

As one review the pathogenesis of Hematologic Malignancy, there is a fundamental difference between a group of Malignancies started by a Gene Mutation driving the disease such has a Myelodysplatic syndrome, and those driven by a Fusion protein (ie Chronic Myelogenous Leukemia or some of the ALK driven lymphoma).  Fusion protein point to the existence of a Core Binding Protein where resulting proteins line up to direct the metabolism of the cell, and in this case a cancer generating Metabolism!  The second group of leukemic process provide many opportunities for treatment.  Blocking the protein to dock onto the CBF is already a significant intervention because it disrupt the trends of the Metabolism.  If you don't believe me, well that's what Gleevec does to cure CML!   I don't want to bore you now with my discussion of CDK and p(number) inhibiting gene, but do you know that with every fusion gene come a particular set of CDK (see CDC2 in CML) and a particular p inhibitor?  we are looking into this !  May be targeting one specific CDK may be all we need in a specific proliferative disease.
Malignancy driver by a gene Mutation still need an anti-histone deacetylator, or an alkylating agents.  But there will be a time when PACHA, DROSHA and DICER will be our focus !  Remember Leukemia are driven by level of expression of regulator genes/enzymes, MiR203 role needs to be further assess!

THE COST OF LACK OF FUNDING FOR  BASIC RESEARCH!
A CHICKEN AND EGG SITUATION , WHICH COMES FIRST!

Our life is governed by well intended politicians who sometimes, and I don't know why, comes to the wrong conclusions now and then! This nation is what it is through its innovations.  And innovation comes from basic research.  So to cut funds for basic research is to severely compromise the future that these funding cuts is suppose to protect.  It is through fundamental research that comes wealth.  Ask Bill Gate where is money comes from and he will give you the answer!   Cutting research funds not only close the doors to potential wealth but alter significantly the life of our children.  We live the kind of life we have today because people before us invested in the kind of research that put us here.

Politicians are claiming that to borrow more today will shift the burden of reimbursement to our children.  That is only true if we give to our children the same world we have today.  If we give them more technology, these costs will have been an investment that would yield benefits 100 times over!

To take an example let's come back to Alzheimer dementia which affects individual at various age leading to years of quality of life deterioration and loss of years of production, the current state of affair and treatment of this disease is nothing to what it should be now, and clearly this is not what we need to give our children.  Current treatment have not started to address the pathogenesis of the disease.   Today's treatments try to increase acetyl choline the chemical stimulating the post-synaptic receptor of the nerve, other  treatment offer stimulate the nerve in these location non specifically to maintain it (yes chronic glutamate stimulation gives impetus to life of neuron) but the hold on the cell by the Neurofibrillary tangles continue to remain non addressed!  Plaques are still forming, and phosphorylation of tau proteins is unchallenged and victims are still dying.  This is not the state of affairs we want to leave the children.  We need to live them a world were the inhibitors of MTOR (activity through PTEN/MMAC1 &  +/- GAC1)  role in Alzheimer prevention is understood clearly, where TENC1 gene with its liberation of phosphatase role in Alzheimer has been visited, how we can act on AXL gene to improve this disease, and fully define the role of inhibiting Calpain, what about Auxilin. We even have not clarified the potential supportive role of ACE inhibitors and interferon. All this work need funding.  And one break through will give us more money and more clear minds around the world!  That is what is at stake!  

Investment in research now, and big reward to come!  What world do you want to leave behind for the sake of savings and sounding good?  (join our discussion)

CRBCM IS NOT THE ONLY ONE DISCUSSING ALZHEIMER, CHECK-OUT MEDSCAPE


"Jacques Hugon, MD, PhD, Professor of Neurology at Saint-Louis Lariboisière Fernand-Widal Hospital in Paris, France, about a biomarker with the potential to aid in AD diagnosis. It's not amyloid beta or tau.
Medscape: Dr. Hugon, what can you tell us about PKR?
Dr. Hugon: PKR is a kinase that has been shown to play a role in recognizing and signaling viral infection, but its activity has also been shown to be altered in several neurologic disorders in which it negatively modulates memory.^[1] Once overactivated, PKR becomes a toxic kinase. As we have shown in our study,^[2] PKR accumulates in the brain of patients with AD and can induce the death of neurons. We have seen that the PKR level in the cerebrospinal fluid (CSF) and the activity of PKR in the brain are highly elevated in patients with AD compared with non-AD patients. Our study showed that the mean level of PKR and phosphorylated PKR in the CSF was 300% higher in patients with AD. Sensitivity was 91.1% and the specificity was 94.3%."

BUT IS THIS AS GOOD AS S100B OR SIMPLY THE METALLOPROTEASES?   A CLINICAL TRIAL IS NEEDED!

What we have learned from the conference on Prostate cancer
=========================================

*That despite detection of Progression of disease
1. Increase in PSA
2.Radiologic Means of progression detection (bone scan, PET, CT)
3.symptomatic deterioration (mostly Pain, and decrease of performance)

Most Oncologists and Urologists at the meeting are still driven by Increase in PSA to make therapeutic decisions.

*That 30% of Men not thought to have Metastatic disease, were found to have positive bone scan
  750/2516 pushing for an early proper radiologic staging particularly when PSA is greater than 10.
*That Lupron +Casodex or flutamide are still the first intervention for primary intervention
followed by initiation  of Provenge.  We heard about this brave urologist who has given already 0ver 30 times Spileucel-T (provenge) insisting it is category 1 NCCN recommendation.  Most Oncologists agree but cost and practicality of doing Apharesis and infusions by dedicated locations make this drug still a difficult option.   Provenge may be more effective given early when the Cancer or tumor burden is lower (of note some patient in the trial had received chemotherapy, so this remain an option even after chemotherapy had been given!  That Provenge had shown 22.5% decrease of risk of death from Prostate cancer (Improving survival by 4 months!
*Abiraterone (Zytiga) came 3rd after progreesion on Sipuleucel-T (Provenge) should the disease progresses

• The most common side effects of ZYTIGA^® include:
  • Weakness
  • Joint swelling or pain
  • Swelling in your legs or feet
  • Hot flushes
  • Diarrhea
  • Vomiting
  • Cough
  • High blood pressure
  • Shortness of breath
  • Urinary tract infection
  • Bruising
  • Low red blood cells (anemia) and low blood potassium levels
  • High blood sugar levels, high blood cholesterol and triglycerides
  • Certain other abnormal blood tests  (from the manufacturer)
  • 
    ================================================== After Zytiga came chemotherapy with Docetaxel+Prednisone (option that has given up competing as everyone is fighting to come before it.  Even Enzalutamide (THE BETTER ANDROGEN RECEPTOR BLOCKER)  IS TRYING TO COME FIRST TO CHEMOTHERAPY.
  •  
  • ========================================Docetaxel is now coming after Zytiga failures and Enzalutamide is coming before Cabazitaxel in those who are asymptomatic with increase of PSA only  whereas symptomatic patients are going to Cabazitaxel more often 
  • BUT WHATEVER YOU DO CONTINUE LUPRON BECAUSE THE STUDIES DID!
  • ALSO START ZOMETA OR BETTER YET DENOSUMAB AS SOON AS BONE METASTASIS ARE DOCUMENTED
  • 
    
  • ===============================WATCH OUT NOW ONCOLOGISTS ARE BEING SUED FOR NOT OBTAINING DEXA SCAN AND NOT GIVING CALCIUM AND VITAMIN D TO THEIR CASTRATE REFRACTORY PROSTATE CANCER PATIENTS
  • 
    
  • 
    
  • 
    
  • 
    
  • SO ON EVERY ONE ON TREATMENT KEEP
  • -Calcium and Vit D
  • -weight bearing exercice
  • -Cardiovascular risk record (controlled DM, HTN and Cholesterol level)
  • -avoidance of Alcohol/Tobacco documentation
  • -FRAX score
  • -DEXA Scan
  • 
    
  • or be sued!
  • 
    
  • 
    
  • other alternative treatments discussed, Radium 223 (Alpharadin)
  • 
    
  • Still open!
    

    A Study of Alpharadin® With Docetaxel in Patients With Bone Metastasis From Castration-Resistant Prostate Cancer (CRPC)

     NCT01106352

    register your patients! 

     

    biggest concern with Enzalutamide, fatigue and seizures in 8% of treated patients.  check Brain MRI since rare brain mets seems to contribute to their occurrence!

LAS VEGAS IS STILL A PLACE TO BE
There are now a few soul left
the night was busy
of the new places, ARIA is the most flamboyant
the blue men is still playing
of the new souvenirs, I like the canister for Alcohol (hard whiskey) with LAS VEGAS city
I don't drink Alcohol but I will hide my Splenda coffee in that canister for fun
a new building with a French name on it Be..., will run to the street to tell you
finally 5:56 AM the escalators are running empty
They have been busy all night
from my window, at the Mandarin, I have seen them transporting shadows to where they want to go
I did all my losing at the "NEW YORK, NEW YORK" and the new castle like structure THERE close to the monorail track.
ME, TODAY I AM THINKING WHAT WILL BE SAID AT THE CONFERENCE ON PROSTATE CANCER!
LAS VEGAS is still alive! 

The YES1 gene.

Until we become very familiar with some of the genes, it is very difficult to understand to place new discovered genes in the general context of the cell function.  and yes the YES1 gene is one that one will not see as important until you find out what other gene are in proximity, and what other gene it interact with.
We picked the YES gene randomly, or may be because of its name, but soon we find out that this gene is an important.
The NCBI define this gene as:
"This gene is the cellular homolog of the Yamaguchi sarcoma virus oncogene. The encoded protein has tyrosine kinase activity and belongs to the src family of proteins. This gene lies in close proximity to thymidylate synthase gene on chromosome 18, and a corresponding pseudogene has been found on chromosome 22. [provided by RefSeq, Jul 2008]"

From an Oncology stand point, we go from a gene that has a Unique name, very attractive name to potentially a gene that may be important in Sarcoma, a difficult tumor type that we have difficulty treating.  But the exact role of this gene in sarcoma cannot be defined just by the information here!  And frankly, nothing assure us that this is useful target in our quest for the cure.  Yet another clue is given here, its proximity to Thymidylate Synthase.  The relationship as defined here is just proximity and nothing else.  But why that proximity remains an unanswered question.  Are these gene associated in a Linkage?   Do they participate in a similar function? or does the Thymidilate Synthase activity uses the proteins from the YES gene?  Remember Thymidilate Synthase is the molecule used in DNA repair (Folate) and as we shall see YES1 may be involved in a scaffolding important in the preservation of the cell morphology and potentially in the transfer of information to the Nucleus.   The information that there is a pseudogene on chromosome 18, brings to the mind the notion that there is always a bad gene and its corresponding mitigated isoform equivalent.  Somehow nature knows that to bad things there should be a milder version to and frankly we have not used this notion to its full potential!  (the q arm Vs p arm discussion is not far if you know me!)

Just as we become comfortable, Wikipedia adds a new layer to our discussion about the YES1 gene
"Proto-oncogene tyrosine-protein kinase Yes is an enzyme that in humans is encoded by the YES1 gene.^[1][2]
This gene is the cellular homolog of the Yamaguchi sarcoma virus oncogene. The encoded protein has tyrosine kinase activity and belongs to the src family of proteins. This gene lies in close proximity to thymidylate synthase gene on chromosome 18, and a corresponding pseudogene has been found on chromosome 22.^[2]

Interactions

YES1 has been shown to interact with Janus kinase 2,^[3] CTNND1,^[4] RPL10^[5] and Occludin.^[6]"
"
The Thyrosine Kinase notion brings a careful smile.  We indeed have "beaucoup" of anti-kinases available, and may be we can try these anti/MultiKinase inhibitors in Sarcoma.  Or may be a anti-kinase to yes specifically would be more useful to try in Sarcoma. 
More importantly however is with what gene YES1 interact with.
JAK-2, we are now talking hematologic proliferation.  Now we are deep into Myelofibrosis and and polycythemia.  Now we understand that Sarcoma was probably just a distorsion or quick conclusion that in fact we are talking of stuff downstream the Erythropoietin receptor.  That YES1 is the pathway upstream of JAK2.   The involvement of the CTNND1 (E-cadherin is in the wing) makes sense because the cell needs to stay mobile such as do hematologic malignancies.  It has to stay fluid.  But if we stick to sarcoma, this information will be relevant to metastasis.  Mutation here will involve disease progression and YES1 becomes a clear potential target for the cure!   Or even more importance is my revelation to you that CTNND1 interact with the "crazy gene" FYN we discussed yesterday.  Now YES1 importance becomes even more meaningful because it is upstream the crazy gene!

The story of the YES1 gene becomes more and more interesting when you follow its interaction with RPL10

RPL10

From Wikipedia, the free encyclopedia

Jump to: navigation, search

Ribosomal protein L10
Available structures PDB Ortholog search: PDBe, RCSB [show]List of PDB id codes
Identifiers
Symbols	RPL10; AUTSX5; DXS648; DXS648E; L10; NOV; QM
External IDs	OMIM: 312173 MGI: 105943 HomoloGene: 130456 GeneCards: RPL10 Gene
[show]Gene Ontology
Orthologs
Species	Human	Mouse
Entrez	6134	434434
Ensembl	ENSG00000147403	ENSMUSG00000008682
UniProt	P27635	Q6ZWV3
RefSeq (mRNA)	NM_001256577	XM_003086757
RefSeq (protein)	NP_001243506	XP_003086805
Location (UCSC)	Chr HG1497_PATCH: 153.6 – 153.62 Mb	Chr 9: 50.34 – 50.34 Mb
PubMed search	[1]	[2]

60S ribosomal protein L10 is a protein that in humans is encoded by the RPL10 gene.^[1][2]
Ribosomes, the organelles that catalyze protein synthesis, consist of a small 40S subunit and a large 60S subunit. Together these subunits are composed of 4 RNA species and approximately 80 structurally distinct proteins. This gene encodes a ribosomal protein that is a component of the 60S subunit. The protein belongs to the L10E family of ribosomal proteins. It is located in the cytoplasm. In vitro studies have shown that the chicken protein can bind to c-Jun and can repress c-Jun-mediated transcriptional activation, but these activities have not been demonstrated in vivo. This gene was initially identified as a candidate for a Wilms tumor suppressor gene, but later studies determined that this gene is not involved in the suppression of Wilms tumor. This gene has been referred to as 'laminin receptor homolog' because a chimeric transcript consisting of sequence from this gene and sequence from the laminin receptor gene was isolated; however, it is not believed that this gene encodes a laminin receptor. Transcript variants utilizing alternative polyA signals exist. The variant with the longest 3' UTR overlaps the deoxyribonuclease I-like 1 gene on the opposite strand. This gene is co-transcribed with the small nucleolar RNA gene U70, which is located in its fifth intron. As is typical for genes encoding ribosomal proteins, there are multiple processed pseudogenes of this gene dispersed through the genome.^[2]
" WIKIPEDIA

-------------------------------NOW YOU ARE BACK INTO SARCOMA, AND ITO BLOKING C-JUN THE CAUSE OF ALL CANCERS CAUSED BY CHRONIC IRRITATIONS AND CHEMICAL EXPOSURES!  NOW YOU ARE THINKING, BLOCKING YES1 CAN BE USED IN CANCER PREVENTION EVEN AGAINST PANCREATIC CANCERS!  NOW YOU ARE THINKING RIBOSOMAL FUNCTION CAN BE ALTERED BY BLOCKING THE YES1.  AND YOU MAY BE RIGHT!

INTERACTION WITH OCCLUDIN ADRESSES THE SHAPE OF THE CELL AND PROVIDE THAT SCAFFOLDING WE WERE TALKING ABOUT.  AND BELIEVE ME IN A ERYTHROCYTE, THE SCAFFOLDING IS CRITICAL (THINK SPHEROCYTOSIS AND ITS PHYSIOLOGIC CONSEQUENCE).

IT IS JUST A MATTER OF WHEN YOU WANT TO STOP FOLLOWING THE MONEY.

And yes, the YES1 gene is like a gift that keeps on giving
and may be an important target in some described cancers (see above!)

FEW POINTS

*The notion that Interferon kills virus some time by stimulating a Ribonuclease which then destroy all RNA that sustain the life of that virus, has left me thinking.  Why don't we master this.  By excluding us from funding, why don't you do it then.  Yes here it is published that interferon can do this.  Cure is here, let use this!

*SEQUESTRATION has cut 85 billions across the board
deeply cut cancer research funding, and reduced the budget of critical agencies engaged in the advancement of the cure, and has reduced access to care for Medicare and Medicaid patients.  I told the reason we do not reach the cure is man made.  The political games have deep implications in day to day life of people, and cancer is laughing all the way to the bank!  If we have seen progress in cancer cure, these advances will be jeopardized or will be difficult to implement without financial support.  We are close but undercutting ourselves and for what?  It is an amazing thing to see it on and on, people dying for an idea which soon or later prove to be false!  These cut are being driven by a political climate.  where are the true thinkers who will not cut and run from social challenges.

*In a second review recently reported, Abiraterone, a CYP17 inhibitor that block Androgen biosynthesis, continued to show survival advantage in patient with metastatic castrate-resistant Prostate Cancers.  This benefit was seem in patients who had not have chemotherapy, moving Abiraterone in front of chemotherapy as an option for patients described above!  the trial from which these observation was made, was an international trial (COU-AA-302).  Abiraterone was reported to decrease death risk by 20% at least!

*It is fair to say that given what we know today, oncologists who offered Gemzar alone to patients with Metastatic  Pancreatic cancers have some explaining to do.  Today,  GEMZAR (1000mg/m2) and Abraxane (125mg/m2) appears to be better then Gemzar alone.   The paradigm has shifted.
This combination will need to be comapared with Folfoxiri  which has taken the lead in Metastatic Pancreatic cancer but has been received has a burning hot potato by the Oncology community because of its side effect profile.   GEMZAR -Tarceva will also have to face the music!

*THE DRUG THAT KEEPS ON GIVING!
REGORAFENIB recently approved for refractory Metastatic Colon cancer, has now been approved for GIST that is also refractory!  It is a tough little drug fighting hard when the going get tough, it keeps on giving!
watch out though, 1% of patients may get bad side effects(liver damage, hand-foot syndrome,and bleeding!).

*Multiple myeloma is seen an increase in options
Among the Immunomodulators, after Thalidomid and Revlimid, has come the POmalidomide
Among the Proteasome inhibitors, after Velcade come Carfilzomib and now Oprozomib  & Ixazomib.

*Don't forget in Gastric cancer, check out Ramucirumab!   (Always bring up Immunotherapy in difficult cases that have failed several therapies and you will look sharp!)

QUESTION OF THE DAY

In the brain, there are NG2 cell that have still a potential differentiatiation to either oligodendrocytic or other glial cells.   That power to differentiate one way or the other must be exploited as differentiation decreases proliferation. A growth factor must be behind the push toward one specific direction of differentiation.  We need to specify which growth factor for which differentiation.   Another intriguing fact is that these cells appear to be located in only 2 locations, one of which is very close to blood vessel as if the may have or can be influence by VEGF.  we will be looking very closely into this.

Alzheimer dementia seems to be due to increase of Amyloid deposits.  The cause of this accumulation of Amyloid compound seems to involve either production which is favored when with aging there seems to be a decrease of phosphatase activity, leaving phosphorylation intact to involve the Amyloid product.  Phosphorylation and calcification involve microtubule entangling into Neurofibbrillary bundles that characterize the disease.  Is Methylation of genes prompting the initial event? 
there are 2 main roads to calcification, one by influx of calcium though the calcium channels, and the other through the APOE.  Do you believe blocking the APOE by gene intervention or though immune intervention will slow down Neurofibrillary formation and slow down the dementia process?

The 3rd intervention is of course boosting the scavenger who can clean up the mess created by the Amyloid
what is the equivalent of macrophages in the Brain again?

The Amyloid are found in the extra-cellular matrix through activity of Exosome, is there here an opportunity for intervention, let's look closely into the formation and activity of the exosome!

NOMENCLATURE OF Genes in Prostate cancers    
==================
The CRBCM does not have a significant laboratory. fOR ANY RESEARCH WORK, we have to contract with our local university (UTEP) and we intend to do so.  The gene discussed here in are easily found in the literature  What we bring to the discussion is our unique perspective that most of the time is still to be proven but appears sound based on available evidence.  We provide this opinion anyway in order to tease researchers around the world to prove us wrong or right.  We do not make up stuff.  We offer an interpretation of facts.   When you look at the genes involved in the pathogenesis of Prostate cancer

1. HPC1.
controversy has marred this one but it is found in several familial Prostate cancer.  Some has advocated this gene as a screening tool for familial Prostate cancer.  Clearly it is not the only one! 

"RNase L is now implicated in protecting the central nervous system against viral-induced demyelination. A role in tumor suppression was inferred by mapping of the RNase L gene to the hereditary prostate cancer 1 (HPC1) gene,
It encodes a ribonuclease that mediates the antiviral and apoptotic activities of interferons." (wikipedia)

2.CAPB

 "Perlecan is a proteoglycan that regulates extracellular and stromal accessibility to growth factors such as SHH, thus allowing for the maintenance of SHH signaling under growth factor limiting conditions. This proteoglycan represents an important central regulator of SHH activity and presents an ideal drug target for blocking SHH effects."
This open the door to use of anti Hedgehog agent such as the one used in Basal cell skin cancer in the treatment of prostate cancer!?

3.BRCA 1,2

" The protein encoded by the BRCA1 gene combines with other tumor suppressors, DNA damage sensors, and signal transducers to form a large multi-subunit protein complex known as the BRCA1-associated genome surveillance complex (BASC).^[9] The BRCA1 protein associates with RNA polymerase II, and through the C-terminal domain, also interacts with histone deacetylase complexes. Thus, this protein plays a role in transcription, DNA repair of double-stranded breaks^[8] ubiquitination, transcriptional regulation as well as other functions.^[10]The BARD1/BRCA1 interaction is disrupted by tumorigenic amino acid substitutions in BRCA1, implying that the formation of a stable complex between these proteins may be an essential aspect of BRCA1 tumor suppression.^[19] The ring domain is an important element of ubiquitin E3 ligases which catalyse protein ubiquitination2. Ubiquitin is a small regulatory protein

  BRCA1 interacts with the NELF-B (COBRA1) subunit of the NELF complex.^[29]

  the BRCA1 protein interacts with RAD51 during repair of DNA double-strand breaks.[26
Wikipedia and related sources
sources have reported that one form of aggressive prostate cancer was characterized by Mutated BRCA2.
DOES THIS OPEN THE DOOR TO PLATINUM AS THE ANSWER TO THESE TYPE OF CANCERS LIKE IN BREAST CANCER?


^{4. Androgen Receptor genes}

"The androgen receptor (AR), also known as NR3C4 (nuclear receptor subfamily 3, group C, member 4), is a type of nuclear receptor^[6] that is activated by binding of either of the androgenic hormones testosterone or dihydrotestosterone ^[7] in the cytoplasm and then translocating into the nucleus. The androgen receptor is most closely related to the progesterone receptor, and progestins in higher dosages can block the androgen receptor.^[8][9]
The main function of the androgen receptor is as a DNA-binding transcription factor that regulates gene expression;^[10] however, the androgen receptor has other functions as well.^[11] Androgen regulated genes are critical for the development and maintenance of the male sexual phenotype.

testosterone is converted by 5-alpha-reductase to dihydrotestosterone, an even more potent agonist for androgen receptor activation.^[12]

  normal male sexual development
 receptors allow the body to respond appropriately to these hormones." WIKIPEDIA AND RELATED SOURCE

ANDROGEN DEPRIVATION IS OF COURSE THE MAIN SOURCE.  REFRACTORINESS IS SEEN IN ADVANCED CANCER WITH ASSOCIATED MUTATIONS TO THE AR  GENE.  BYPASSING THE RECEPTOR AND ACTING ON THE SUBSTRATE OF THESE RECEPTOR IS BEING LOOKED AT.  FOR THE AR TO WORK IT HAS TO BE TRANSFERRED TO THE NUCLEUS,  CYTOPLASMIC MISLOCATION OF THESE AR IS BEING LOOKED AT AS A WAY TO IMPROVE ON ANTI ANDROGEN  (HERE GNB2L1 IS A TARGET)

GOOD CONTROVERSY
 " a DNA segment known as CAG is repeated multiple times. This CAG segment is called a triplet or trinucleotide repeat. In most people, the number of CAG repeats in the AR gene ranges from fewer than 10 to about 36.Researchers have considered a possible relationship between the length of the CAG repeat region in the AR gene and a woman's chance of developing breast cancer. The results of research studies have been mixed. Some studies have suggested that a long CAG repeat region is associated with an increased risk of breast cancer in women,
 Some studies have shown an increased risk of prostate cancer in men with a short CAG repeat region in the AR gene;

Transcriptional activity is enhanced by binding to RANBP9.
The level of tyrosine phosphorylation may serve as a diagnostic tool to predict patient outcome in response to hormone-ablation therapy. Inhibition of tyrosine phosphorylation may be an effective intervention target for hormone-refractory prostate cancer."

PLENTY OF TARGETS!!!

(SIMILARITY FOR AR )  Belongs to the nuclear hormone receptor family. NR3 subfamily.
Contains 1 nuclear receptor DNA-binding domain.
---------------------------------
Related AND UNDER THE THUMBS OF THE AR gene are the TMPRSS-ERG, and ETS,ETV1,  TMPRSS-ERG fusion  (WE DISCUSSED THESE EARLIER)

5.ELAC2
----------------
6. ERG
7.PSA:  strategy here is to use this prominent protein to selectively deliver a powerful chemotherapy drug like in the T-DM1 experience
8.chrXq27.3
9.PCAP
10.MRS1
11.GALACTIN-1
12.SNP
13TGFB1
15NCOA1
16HIPK3
17ZIPK/DAPK3
18GNB2L1
19EFCAB6/DJBP
20NR0B2 AND PELP1

Underclinical investigation you find more the HER-2, Bcl-2, VEGF, Endothelin receptor gene, and the PSA

(several quotes are left intact here to tell you we don't make this stuff up!)

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Join me at RNA-Seq 2013

Paul Kayne	11:05 AM (1 hour ago)
to me

  Dear MUTOMBO,

If one was so inclined, RNA-seq could be considered in the context of a symphony. The first movement, as with Beethoven’s Symphony No. 5 in C minor, started with an Allegro con brio, “with vigor”. The advent of next generation sequencing empowered pioneers to look into the life of cells with unprecedented resolution.  Details of new species of RNA, allele specific expression, and more began to emerge, with a new discovery almost every day. That we were only in the first movement likewise became clear. How to prepare samples, what platform to choose, how to work with the data, were questions without easy answers. Just as conductors fought over the correct interpretation of Beethoven’s score, so scientists brought their individual perspective to RNA-seq. Second movements in symphonies are typically slower, but Beethoven chose an Andante con moto, “with movement and certain quickness”, describing well the state of RNA-seq today. Our field is moving forward deliberately now, towards answers as to how best to use these new capabilities, with exciting discoveries along the way. And you have the opportunity to further your part in the symphony. I invite you to join me at RNA-Seq 2013 in Boston, June 18-20, 2013. You will hear from leaders using this technology to drive research and make decisions. Presentations will address sample prep methods, analysis methods, platform choices, characterizing complicated expression patterns, choosing solution providers, application to drug discovery and more. Add your voice to our panel discussion on customizing analysis to meet your needs. Join us as we move towards the next movement in RNA-seq. I understand that early registration closes in a month so book soon to get the best prices. You can see the full agenda and speaker line up here: www.rna-seqsummit.com.  I look forward to seeing you there. Kind regards, Paul Paul Kayne Senior Principal Scientist, Head of Genomic Technologies Bristol Myers-Squibb

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WE ESCAPED SMARTLY IN THE MELI-MELO OF AGING JUST TO DIVERT OUR ATTENTION ON GENES INVOLVED IN ALZHEIMER. DON'T ASK ME WHY, BUT WE DID. WE CAME OUT MORE PUZZLED THEN ANYTHING ELSE!

MANY QUESTIONS THOUGH:

Many of the striking things and questions

1.Can calcium inhibitors slow down Alzheimer progression?
2. Is Namenda's role to slow down apoptosis in neurons by giving non specific stimulation to Glutamate receptors ?  Or this really by counterbalancing or increasing the effect of cholinesterase inhibitors? We know that when the disease is advanced and cell death has occurred, Namenda does not do much.
3. Can S100B be a more reliable way of monitoring Alzheimer's progression?
4. Does Alzheimer reflects a deficiency of Macrophage function and therefore Colony stimulating factors a way of treatment?
5. What is the effect of GM-CSF on NG2 glial cell and can this slow down Alzheimer?
6. What can slow down tau-protein phosphorylation, will ubiquitination work in detoxifying cells ?
7. What is the effect of disrupting the exosome, could this cause abnormal cell to be cleaned up earlier...? ....before plaque build up!
8. What is the real relation between Vit. D and DAG (diacyl glycerol), the phosphorylator, APOE and Presenilin?

Many question to struggle with...but the challenge is thrown at you, let's go to work!