Dear Colleague,
It’s with great enthusiasm that the Johns Hopkins Department of Neurosurgery
will be hosting our first Spine Business Forum: Strategies for the Provider, Investor and Innovator on May 18th, 2013 at the Johns Hopkins Chevy Chase Bank Conference Center. This new conference will represent a microcosm of United Stated healthcare changes in general, with ramifications on delivery, cost, investment,innovation and regulation and bring leaders from clinical medicine, biomedical industry, investment banking, venture capital, hospital administration, healthcare consulting, insurance providers, legal and governmental regulation together to present and discuss the current and future issues around spine care. In the last 30 years, there has been great progress in treating spinal disorders and spine care has become a major aspect of clinical medicine, health care expenditures, and innovation throughout the world. Such care in the United States is undergoing drastic changes that may simultaneously provide new obstacles and new avenues for success in the field. However, there is currently no forum that combines leaders from clinical medicine, industry, hospital administration, insurance providers, and legal and governmental regulation. In this conference, we seek to bring leaders in each of these fields together to present and discuss the current and future issues around spine care. In the last 30 years, there has been great progress in treating spinal disorders and spine care has become a major aspect of clinical medicine, health care expenditures, and innovation throughout the world. Such care in the United States is undergoing drastic changes that may simultaneously provide new obstacles and new avenues for success in the field. However, there is currently no forum that combines leaders from clinical medicine, industry, hospital administration, insurance providers, and legal and governmental regulation. In this conference, we seek to bring leaders in each of these fields together to present and discuss the current and future issues around spine care. Speakers include: Doug King (President of Medtronic Spine), Max Reinhardt (Worldwide President of Depuy-Synthes), Rich Grossi (CFO of Johns Hopkins Medicine), Dr. Zeya Gokaslan (Director of the Spine Center at Johns Hopkins), Dr. Christopher Ames (Director of the Spine Center at UCSF), Youseph Yazdi (Executive Director of Johns Hopkins CBID), Anton Dmitriev (Chief of Spine Devices at FDA), Christina Cook (CEO of DC2 Healthcare), Scott Becker(Partner of McGuireWoods LLP, Becker Spine Review), Barry Alexander (Partner of Nelson Mullins Riley & Scarborough LLP), Meg Garrett (Legal Counsel for JH Medicine), and more. I am pleased to invite you, on behalf of Drs. ,Ziya Gokaslan and Daniel Sciubba, to attend the Spine Business Forum on May 18th, 2013 in Baltimore, MD. Please find the attached agenda for the meeting and due to limited seating availability please confirm your attendance at your earliest convenience. In any case; please feel free to forward this invitation to any of your colleagues who may be interested in the conference. If you have additional questions, please do not hesitate to contact me at mmazlum1@jhmi.edu or 433-287-5962.
For registration:
http://www.hopkinscme.edu/CourseDetail.aspx/80031641
For the brochure: /www.hopkinscme.edu/pdfs/80031641.pdf
For the detailed program: http://www.hopkinscme.edu/pdfs/80031641program.pdf
Sincerely,
Mustafa Mazlumoglu Mustafa F Mazlumoglu, MSc, MBA Special Project Manager Johns Hopkins University, School of Medicine Department of Neurosurgery, Spine Center 600 N.Wolfe Street, Meyer 8-148 Baltimore, MD 21287 |
A blog about research, awareness, prevention, treatment and survivorship of Breast Cancer and all cancers, including targeted scientific research and a grassroots approach to increase screening for cancer, especially in the low income and under-insured population of El Paso, Texas, with a view to expand this new health care model to many other 'minority' populations across the United States and beyond
Tuesday, April 16, 2013
KEEPING YOU IN THE LOOP!
DENOSUMAB in Metastatic Castration Resistant Prostate cancer: Rove et al.
"Phase III studies comparing denosumab to the bisphosphonate zoledronic acid with respect to time to development of a first SRE in patients with CRPC and at least one bone metastasis were published in 2010.[22,23] Denosumab improved the median time to development of a first SRE (20.7 months vs 17.1 months for zoledronic acid, a difference of 3.6 months). Rates of osteonecrosis of the jaw were not significantly different between the two study arms, at 2.3% and 1.3%, respectively (P = .09), but hypocalcemia was observed more frequently with denosumab than with zoledronic acid (13% vs 6%). This report showed no difference in overall survival between the two groups."
JUMPING TO CONCLUSION!
"In summary, denosumab is a fully human monoclonal antibody against RANKL; it inhibits osteoclast activity, limiting bone turnover and resorption. It is approved for the prevention of SREs in high-risk postmenopausal women and men with advanced prostate cancer and bone metastasis. Denosumab does not have any direct antitumor activity, and while there is some recent evidence that denosumab prevents development of bone metastasis, it has not yet been approved for this use. Studies published to date have demonstrated its ability to help prevent and reduce SREs in men with and without bone metastasis, compared with bisphosphonates and placebo, to increase BMD over placebo, and to improve the time to development of a first SRE compared with zoledronic acid. Clinicians will ultimately have to grapple with cost-benefit issues, since denosumab is more expensive than zoledronic acid. Clinicians will also have to weigh the convenience of a subcutaneous injection of denosumab against the intravenous administration of zoledronic acid and fewer cases of renal toxicity with denosumab. As mentioned, in a head-to-head study, denosumab delayed SREs by 3.6 months compared with zoledronic acid."
"
WHAT ABOUT SPLENDA
SPLENDA ALSO "exerted numerous adverse effects, including reduction of beneficial fecal Microflora, increased fecal PH, end enhanced expression levels of P-gp, CYP3A4, and CYP2D1, which are known to limit the bioavailability of orally administered drugs" Abou-Donia MB et al.
TELEONCOLOGY
Most oncology programs or cancer clinics in Texas wish they had TELEONCOLOGY communication with their referral University programs. It would be nice if we could attend some of the discussions of clinical cases at MD ANDERSON or Baylor. Quick feedback would help patientS stay home instead of traveling to Houston away from social support!
"Phase III studies comparing denosumab to the bisphosphonate zoledronic acid with respect to time to development of a first SRE in patients with CRPC and at least one bone metastasis were published in 2010.[22,23] Denosumab improved the median time to development of a first SRE (20.7 months vs 17.1 months for zoledronic acid, a difference of 3.6 months). Rates of osteonecrosis of the jaw were not significantly different between the two study arms, at 2.3% and 1.3%, respectively (P = .09), but hypocalcemia was observed more frequently with denosumab than with zoledronic acid (13% vs 6%). This report showed no difference in overall survival between the two groups."
JUMPING TO CONCLUSION!
"In summary, denosumab is a fully human monoclonal antibody against RANKL; it inhibits osteoclast activity, limiting bone turnover and resorption. It is approved for the prevention of SREs in high-risk postmenopausal women and men with advanced prostate cancer and bone metastasis. Denosumab does not have any direct antitumor activity, and while there is some recent evidence that denosumab prevents development of bone metastasis, it has not yet been approved for this use. Studies published to date have demonstrated its ability to help prevent and reduce SREs in men with and without bone metastasis, compared with bisphosphonates and placebo, to increase BMD over placebo, and to improve the time to development of a first SRE compared with zoledronic acid. Clinicians will ultimately have to grapple with cost-benefit issues, since denosumab is more expensive than zoledronic acid. Clinicians will also have to weigh the convenience of a subcutaneous injection of denosumab against the intravenous administration of zoledronic acid and fewer cases of renal toxicity with denosumab. As mentioned, in a head-to-head study, denosumab delayed SREs by 3.6 months compared with zoledronic acid."
"
WHAT ABOUT SPLENDA
SPLENDA ALSO "exerted numerous adverse effects, including reduction of beneficial fecal Microflora, increased fecal PH, end enhanced expression levels of P-gp, CYP3A4, and CYP2D1, which are known to limit the bioavailability of orally administered drugs" Abou-Donia MB et al.
TELEONCOLOGY
Most oncology programs or cancer clinics in Texas wish they had TELEONCOLOGY communication with their referral University programs. It would be nice if we could attend some of the discussions of clinical cases at MD ANDERSON or Baylor. Quick feedback would help patientS stay home instead of traveling to Houston away from social support!
FROM SIMPLE TO COMPLICATED IN CELLULAR FUNCTION.
The finding of CORE BINDING FACTOR (CBF) has been one of the best finding in modern cellular biology
and my analogy will be that CBF is a BENCH or a room full of purpose!
Let explain this by taking the current international crisis situation where north Korea wants to wage a war against its neighbors and the united states. And the cell wants to resolve this issue.
For that, the cell will create a BENCH or a Room with 4-5 seating places
for A the united states (TK1)
and B north Korea (TK2)
but also C china (RTK1)
and D south Korea (RTK2
and may E FOR JAPAN (BUS1)
Corresponding seats will be called A', B', C', D' and E'
The bench or room will have these 5 seats ready, and in due time
the 5 will come to sit in the order predetermined by the the Bench preparer, Negotiation will occur and resolution of the conflit will occur.
If you understand this then you know how the cell can control the metabolism.
The Bench or room is the CBF
and Activity from that bench or room will result in Chronic Myelogenous leukemia or war.
Instead of China, let send CONGO to spoil the meeting and let is sit at C'
CONGO has no clue about the issue and will spoil the meeting. That is what Gleevec does.
Gleevec attaches where a leukemia inducing protein should attach. And Nilotinib attachment to the China seat 30 times stronger. Dasatinib, the manufacturer refuses to tell us!
NOW any changes of C' (the seat) may make the person sitting uncofortable and not work as planned creating resistance to the drug.
The core Binding factor or Bench, a easy thing to understand but causing leukemic mayhem !
FOR THE CURE, KNOW ALL THE CBF IN A CELL AND PICK THE ONE TO SPOIL AND YOU GOT IT!
The finding of CORE BINDING FACTOR (CBF) has been one of the best finding in modern cellular biology
and my analogy will be that CBF is a BENCH or a room full of purpose!
Let explain this by taking the current international crisis situation where north Korea wants to wage a war against its neighbors and the united states. And the cell wants to resolve this issue.
For that, the cell will create a BENCH or a Room with 4-5 seating places
for A the united states (TK1)
and B north Korea (TK2)
but also C china (RTK1)
and D south Korea (RTK2
and may E FOR JAPAN (BUS1)
Corresponding seats will be called A', B', C', D' and E'
The bench or room will have these 5 seats ready, and in due time
the 5 will come to sit in the order predetermined by the the Bench preparer, Negotiation will occur and resolution of the conflit will occur.
If you understand this then you know how the cell can control the metabolism.
The Bench or room is the CBF
and Activity from that bench or room will result in Chronic Myelogenous leukemia or war.
Instead of China, let send CONGO to spoil the meeting and let is sit at C'
CONGO has no clue about the issue and will spoil the meeting. That is what Gleevec does.
Gleevec attaches where a leukemia inducing protein should attach. And Nilotinib attachment to the China seat 30 times stronger. Dasatinib, the manufacturer refuses to tell us!
NOW any changes of C' (the seat) may make the person sitting uncofortable and not work as planned creating resistance to the drug.
The core Binding factor or Bench, a easy thing to understand but causing leukemic mayhem !
FOR THE CURE, KNOW ALL THE CBF IN A CELL AND PICK THE ONE TO SPOIL AND YOU GOT IT!
NEWS FROM THE LITERATURE
1.a FEAST to read if you want to know about c-KIT inhibitors
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2. TALKING FYN gene AGAIN
"Dasatinib, at nanomolar concentrations, inhibits the following kinases: BCR-ABL, SRC family (SRC, LCK, YES, FYN), c-KIT, EPHA2, and PDGFRβ. Based on modeling studies, dasatinib is predicted to bind to multiple conformations of the ABL kinase."(FROM THE MANUFACTURER)
aND i BET YOU YOU DOUBTED ME WHEN I TOLD YOU FYN WAS A "CRAZY GENE"
ADD IT TO THE MIXT AND YOU GOT YOURSELF A GREAT DRUG!
-----------------------------------------------------------------------------------
3.FOR LUNG CANCER
Always obtain EGFR, ALK, ROS1,
KRAS remains controversial although it has been used as a surrogate for :
1.a FEAST to read if you want to know about c-KIT inhibitors
Melanoma Research:
December 2011 - Volume 21 - Issue 6 - p 475–482
doi: 10.1097/CMR.0b013e32834b58cf
Review Article
Mucosal melanomas of the head and neck: new aspects of the clinical outcome, molecular pathology, and treatment with c-kit inhibitors
Papaspyrou, Giorgiosa; Garbe, Clausb; Schadendorf, Dirkc; Werner, Jochen A.a; Hauschild, Axeld; Egberts, Friederiked
2. TALKING FYN gene AGAIN
"Dasatinib, at nanomolar concentrations, inhibits the following kinases: BCR-ABL, SRC family (SRC, LCK, YES, FYN), c-KIT, EPHA2, and PDGFRβ. Based on modeling studies, dasatinib is predicted to bind to multiple conformations of the ABL kinase."(FROM THE MANUFACTURER)
aND i BET YOU YOU DOUBTED ME WHEN I TOLD YOU FYN WAS A "CRAZY GENE"
ADD IT TO THE MIXT AND YOU GOT YOURSELF A GREAT DRUG!
-----------------------------------------------------------------------------------
3.FOR LUNG CANCER
Always obtain EGFR, ALK, ROS1,
KRAS remains controversial although it has been used as a surrogate for :
- Death With Dignity Program Well Accepted by Cancer Patients
- Preventing Heart Damage From Chemotherapy: OVERCOME Trial
- Mutation Status May Guide Treatment for HER2 Breast Cancer
- Doctors Fail to Counsel Lung Cancer Patients to Quit Smoking
Selumetinib Plus Docetaxel for KRAS-Mutant Advanced Non-Small-Cell Lung Cancer: A Randomised, Multicentre, Placebo-Controlled, Phase 2 Study
Jänne PA, Shaw AT, Pereira JR, et alMonday, April 15, 2013
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.[3]
THIS ONE GO STRAIGHT TO LEUKEMIA AND LYMPHOBLASTIC LYMPHOMA (BURKITT)
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-------------------
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!
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Retinoic Acid Inhibits Serum-stimulated Activator Protein-1
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]
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.[12]
GAB2, DON'T SAY I DID NOT MENTION PTPN11 AS IMPORTANT
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4. 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
--------------------------------------------------
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.[3]
THIS IS TO LOOK AT DEFINITELY IN ALZHEIMER TOO !
RAISES A GOOD QUESTION, WHAT IS THE ROLE OF PSEUDOGENE?
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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.[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
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"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.[2]"
CANCER DRIVEN BY AUTOCRINE MECHANISMS COULD BE AFFECTED
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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!
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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!
----------------------------------------------------------------------
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
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.[3]
THIS ONE GO STRAIGHT TO LEUKEMIA AND LYMPHOBLASTIC LYMPHOMA (BURKITT)
----------------------------------------------------------------------------------------------------------
-------------------
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!
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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.[12]
GAB2, DON'T SAY I DID NOT MENTION PTPN11 AS IMPORTANT
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4. 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 | |||||||||||
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PDB rendering based on 1vd2. |
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|
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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 | ||||||||||
|
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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] | |||||||||
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.[3]
THIS IS TO LOOK AT DEFINITELY IN ALZHEIMER TOO !
RAISES A GOOD QUESTION, WHAT IS THE ROLE OF PSEUDOGENE?
---------------------------------------------------------------------------------------------------------------
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.[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
----------------------------------------------------------------------------------------------------------------------------------------------------
7.AMFR
From Wikipedia, the free encyclopedia
Jump to: navigation, search
Autocrine motility factor receptor, E3 ubiquitin protein ligase | |||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|
Rendering based on PDB 2EJS. |
|||||||||||
|
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Identifiers | |||||||||||
Symbols | AMFR; GP78; RNF45 | ||||||||||
External IDs | OMIM: 603243 MGI: 1345634 HomoloGene: 888 GeneCards: AMFR Gene | ||||||||||
EC number | 6.3.2.19 | ||||||||||
|
|||||||||||
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 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.[2]"
CANCER DRIVEN BY AUTOCRINE MECHANISMS COULD BE AFFECTED
--------------------------------------------------------------------------------------------------------------------------
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 | |||||||||||
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Identifiers | |||||||||||
Symbols | KHDRBS1; Sam68; p62; p68 | ||||||||||
External IDs | OMIM: 602489 MGI: 893579 HomoloGene: 4781 ChEMBL: 1795190 GeneCards: KHDRBS1 Gene | ||||||||||
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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 |
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PubMed search | [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.[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)
==============================
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.[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)
Sunday, April 14, 2013
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....
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!
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)
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!
"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
=========================================
*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!
Saturday, April 13, 2013
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!
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]
"
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
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!)
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
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Ribosomal protein L10 | |||||||||||
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Identifiers | |||||||||||
Symbols | RPL10; AUTSX5; DXS648; DXS648E; L10; NOV; QM | ||||||||||
External IDs | OMIM: 312173 MGI: 105943 HomoloGene: 130456 GeneCards: RPL10 Gene | ||||||||||
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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 |
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PubMed search | [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!)
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