|
NCCN Flash Update sent March 25, 2013
NCCN has published updates for the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Acute Lymphoblastic Leukemia (ALL). These NCCN Guidelines® are currently available as Version 1.2013.
For the complete updated versions of the NCCN Guidelines, the NCCN Drugs and Biologics Compendium (NCCN Compendium®), and the NCCN Chemotherapy Order Templates (NCCN Templates®), please visit NCCN.org.
To access the NCCN Biomarkers Compendium™, please visit NCCN.org/biomarkers.
To view the NCCN Guidelines for Patients®, please visit NCCN.com.
Free NCCN Guidelines mobile apps for iPad and Android are now available! Visit NCCN.org/mobile/tablet.
|
Monday, April 8, 2013
View all JNCCN CE Opportunities
PUTATIVE TARGETS IN HEPATOMA
------------------------------------------
It is evident that Hepatocarcinoma which develops most of the time within a cirrhotic liver, result from stress
putting the NF-kB, c-JUN and c-Fos front and center into the pathogenesis of this disease. The result is an overexpression of Cyclins and Growth factors (TGF). In fact researchers have reported as a critical step into Hepatogenesis Mutations in the the receptor of TGF. Making Interferon alpha a potential Target therapy. It is often time reported that for the above pathway to perform fully a balance in Polyamines should existence (measured by spermidine and Putresssine in one study). Making Polyamine levels a target for therapy. Recently, Interferon Regulator factor 4 (IRF4 or MUM1) had become a center of research in Melanoma. One may wonder if it has the same importance in Hepatoma. This IRF4 is regulated MITF which we commented on earlier.
The disease will eventually grow and metastasize using standard VEGF/EGFR pathways and Multikinases are now standard of care. The Anti-MEK are waiting in a wing for testing. c-JUN belong to the MAPK family, therefore the MTOR inhibitor are waiting for further testing (May be in combination to interferon).
The genes of hepatic differentiation, the IGF, NF1, hSRC, Axin1, P53,SMAD2-4, TIMP2,Rb1,Bcl-10 and others all appears legitimate target. We have our work cut out, let's go to work!
------------------------------------------
It is evident that Hepatocarcinoma which develops most of the time within a cirrhotic liver, result from stress
putting the NF-kB, c-JUN and c-Fos front and center into the pathogenesis of this disease. The result is an overexpression of Cyclins and Growth factors (TGF). In fact researchers have reported as a critical step into Hepatogenesis Mutations in the the receptor of TGF. Making Interferon alpha a potential Target therapy. It is often time reported that for the above pathway to perform fully a balance in Polyamines should existence (measured by spermidine and Putresssine in one study). Making Polyamine levels a target for therapy. Recently, Interferon Regulator factor 4 (IRF4 or MUM1) had become a center of research in Melanoma. One may wonder if it has the same importance in Hepatoma. This IRF4 is regulated MITF which we commented on earlier.
The disease will eventually grow and metastasize using standard VEGF/EGFR pathways and Multikinases are now standard of care. The Anti-MEK are waiting in a wing for testing. c-JUN belong to the MAPK family, therefore the MTOR inhibitor are waiting for further testing (May be in combination to interferon).
The genes of hepatic differentiation, the IGF, NF1, hSRC, Axin1, P53,SMAD2-4, TIMP2,Rb1,Bcl-10 and others all appears legitimate target. We have our work cut out, let's go to work!
Sunday, April 7, 2013
CELL IN CANCER MODE
In a normal cell, things are operating normally. The cell feeds itself and uses energy to allow its normal functions to unfold, and knowing that hard times will come to it, it even puts some energy aside for reserve. When one looks at Mitochondrial activity, one will find Gluconeogensis in full display. This Normal Metabolism that some have called NORMAL CELLULAR MODE tends to show anabolism and normal oxygen. In clear Hypoxic conditions which are read by the cell as a stress, there is the reversal of the chemical reactions as catabolism ensue and Fatty Acid become the source of energy and Glycolysis enters into play. Under these circumstances, which can occur in normal life, catabolism is accompanied with Glycolysis.
In 1920, Walburg described the Walburg effect which characterizes the CANCER CELL MODE.
Indeed in cancer there is a dissociation of Glycolysis and with Catabolism. In Cancer mode, the cell adopts Glycolysis and Anabolism. Glycolysis is to escape the normal requirements of constant feeding, be in a stress like while Making new proteins (Anabolism) to allow cell division and proliferation. One hundred years after the Walburg effect was described, it is now molecularly explained by Researchers. Indeed, to do this the cell induces a genetic controlled hypoxia by suppressing SIRT3 which overexpresses HIF. This induces Hypoxic conditions in the Mitochondria.
http://onlinedigeditions.com/publication/?i=104782&p=12
The Cancer mode can now be measured
but quantifying:
1 Pyruvate Dehydrogenase kinase
2. Over-expression of GLUT1
3. level of vascular endothelial growth factor
4. level of suppression of SIRT3 and related Increase in ROS1
5. level of HK2, IDH, and SOD3
and if you are very smart, start by including c-JUN, HIF, Myc and TCA (fatty acid)
And as you progress with the clues given you will understand why overexpression of ROS1 could predict resistance to MTOR Inhibitors. And I believe it predicts of low participation of MAPK as a driver of pathogenesis therefore decreasing the value of MTOR inhibitors. more detail to come.
ANOTHER WAY OF INDUCING HIF:
"Description
In 1920, Walburg described the Walburg effect which characterizes the CANCER CELL MODE.
Indeed in cancer there is a dissociation of Glycolysis and with Catabolism. In Cancer mode, the cell adopts Glycolysis and Anabolism. Glycolysis is to escape the normal requirements of constant feeding, be in a stress like while Making new proteins (Anabolism) to allow cell division and proliferation. One hundred years after the Walburg effect was described, it is now molecularly explained by Researchers. Indeed, to do this the cell induces a genetic controlled hypoxia by suppressing SIRT3 which overexpresses HIF. This induces Hypoxic conditions in the Mitochondria.
http://onlinedigeditions.com/publication/?i=104782&p=12
The Cancer mode can now be measured
but quantifying:
1 Pyruvate Dehydrogenase kinase
2. Over-expression of GLUT1
3. level of vascular endothelial growth factor
4. level of suppression of SIRT3 and related Increase in ROS1
5. level of HK2, IDH, and SOD3
and if you are very smart, start by including c-JUN, HIF, Myc and TCA (fatty acid)
And as you progress with the clues given you will understand why overexpression of ROS1 could predict resistance to MTOR Inhibitors. And I believe it predicts of low participation of MAPK as a driver of pathogenesis therefore decreasing the value of MTOR inhibitors. more detail to come.
ANOTHER WAY OF INDUCING HIF:
"Description
Dimethyloxaloylglycine
(DMOG) is an inhibitor of PHF (prolyl hydroxylase, PHD) and asparaginyl
hydroxylase FIH-1 (Factor inhibiting HIF, FIH). DMOG has been observed
to upregulate HIF (hypoxia stabilize) HIF-1α at specific concentrations.
In HMEC-1 cells DMOG attenuated REF-1 (redox factor 1) through
activation of HIF. PHT cells exposed to DMOG were observed to upregulate
the FSTL3 (follistatin-like 3) transcript. Attenuation of myocardial
injury by DMOG was demonstrated in the rabbit ischemia reperfusion
model. In NGF deprived neurons DMOG increased cell survival through
inhibition of cytochrome c release." SOURCE
santa cruz biotechnology, inc.
PLEASE DON'T TAKE DMOG WITHOUT BEING IN A CLINICAL TRIAL! (CRBCM OPINION PROTECTED BY THE FIRST AMENDMENT!)
CANCER CURE IN PHASES /CANCER MODE
------------------------------------------------------
Now it is clear to those that are deep in the fight against cancer that cancer cell can be attacked at different cellular phases or layers:
1. The membrane Phase: where receptors, stimuli, integrins and Actinic based pathways are in actions.
*talking about Receptors on should include notably the Death Receptors which could trigger Caspase cascade at membrane stimulation. It goes without saying that the cell hide these Death receptors well throwing all kind of barriers, inhibitors and decoy receptors. If you find these Death receptors, cure is yours. Cancer cells makes these death Receptor few and far apart by clearly methylating or suppressing the genes involved in their expression. In therapeutic Targeting, Receptors of growth factors have been the most looked at. It is now known that growth factors have both the role of causing cancers by causing secondary amplification of pathways, but also by driving cancer growth by playing an autocrine growth and giving cancer an advantage of growth over surrounding cells. This role is critical in cancer seeding during metastasis. One of the Growth factor that has been insufficiently looked at is the Tumor Necrosis Factor (TNF).
TNF has been poorly looked at because It can induce Necrosis that we can't control. Necrosis is an alternative Apoptosis that is independent of Caspase induced cell death. It is said that when a sepsis is uncontrolled it is because there is too much TNF released and we have no effective way of controlling TNF
to date. Anti TNF product have been introduced cautiously introduced (ENBREL use in psoriasis) but warnings about overall global immune suppression tell you of danger using this modality. And this is mostly aplha receptor suppression. Work is in progress in this area.
Some tumor growth factor actually control or impact the expression of ICAMS, the adhesion molecules including the Cadherins which are decreased prior to cancer Metastasis or readiness to be on the move!
*Stimuli are chemical, traumatic, pressure like but also growth driven. In cancer biology, they involve the pathogenesis of cancers as they leading to causing it (ie. Esophageal and lung cancers), but they also involve cancer growth and cell survival. It is the stimulus interpretated as stress that will reach the c-JUN instead of the regular MAPK pathway. The MTOR will insure cancer or cell survival through their multiple effect which include thier impact of Telomeres!
Through c-JUN, proliferation or overproduction of Cyclins and growth factors will secondarily occur or expand to amplify the actions. Cyclins and growth factors belongs to the Integrins mentioned above. Every molecule belonging to the Integrins is attached a specific family of Metalloproteases. We believe that this is doe through a Flippase and floppase modality (don't forget the scramblase modality). In essence, when cyclin molecule is thrown in the cytoplasm, a Metalloprotease in thrown in the Extracellular space. Metalloproteases act as collagenase and open the road for cell migration. The cell has collagen also in its membrane. It is clear that knowing its metalloprotease, it will make an inhibitor that covers and protect its own Collagen structure. It is believed that the insufficiency of these inhibitors lead to autodistruction of the cell in TTP. But that is another topic.
*Actinic based pathways lead to a quick notification by the nucleus of what is going on the cell surface. Microtubules act as nerve for the cell and through the Reticulum Endothelium, take the message to the cell faster for initiation of the Nuclear Phase, by-passing the Cytoplasmic phase. The Wnt pathway seems globally to take this approach and is important in Breast and Ovarian Cancer. We will revist this topic at length!
2. Cytoplasmic Phase
Receptors and stimuli are the critical determinants of this phase. And Growth factors, pyrogenes, and various stimuli act on receptors which are transmenbrane (Decoy receptors lack a post membrane section) and therefore can trigger an intramembrane stimulation of the GTPase and other molecule complexes attached to the membrane at the inside surface, the SRC and RAS families are located in this area (to be continued.)
------------------------------------------------------
Now it is clear to those that are deep in the fight against cancer that cancer cell can be attacked at different cellular phases or layers:
1. The membrane Phase: where receptors, stimuli, integrins and Actinic based pathways are in actions.
*talking about Receptors on should include notably the Death Receptors which could trigger Caspase cascade at membrane stimulation. It goes without saying that the cell hide these Death receptors well throwing all kind of barriers, inhibitors and decoy receptors. If you find these Death receptors, cure is yours. Cancer cells makes these death Receptor few and far apart by clearly methylating or suppressing the genes involved in their expression. In therapeutic Targeting, Receptors of growth factors have been the most looked at. It is now known that growth factors have both the role of causing cancers by causing secondary amplification of pathways, but also by driving cancer growth by playing an autocrine growth and giving cancer an advantage of growth over surrounding cells. This role is critical in cancer seeding during metastasis. One of the Growth factor that has been insufficiently looked at is the Tumor Necrosis Factor (TNF).
TNF has been poorly looked at because It can induce Necrosis that we can't control. Necrosis is an alternative Apoptosis that is independent of Caspase induced cell death. It is said that when a sepsis is uncontrolled it is because there is too much TNF released and we have no effective way of controlling TNF
to date. Anti TNF product have been introduced cautiously introduced (ENBREL use in psoriasis) but warnings about overall global immune suppression tell you of danger using this modality. And this is mostly aplha receptor suppression. Work is in progress in this area.
Some tumor growth factor actually control or impact the expression of ICAMS, the adhesion molecules including the Cadherins which are decreased prior to cancer Metastasis or readiness to be on the move!
*Stimuli are chemical, traumatic, pressure like but also growth driven. In cancer biology, they involve the pathogenesis of cancers as they leading to causing it (ie. Esophageal and lung cancers), but they also involve cancer growth and cell survival. It is the stimulus interpretated as stress that will reach the c-JUN instead of the regular MAPK pathway. The MTOR will insure cancer or cell survival through their multiple effect which include thier impact of Telomeres!
Through c-JUN, proliferation or overproduction of Cyclins and growth factors will secondarily occur or expand to amplify the actions. Cyclins and growth factors belongs to the Integrins mentioned above. Every molecule belonging to the Integrins is attached a specific family of Metalloproteases. We believe that this is doe through a Flippase and floppase modality (don't forget the scramblase modality). In essence, when cyclin molecule is thrown in the cytoplasm, a Metalloprotease in thrown in the Extracellular space. Metalloproteases act as collagenase and open the road for cell migration. The cell has collagen also in its membrane. It is clear that knowing its metalloprotease, it will make an inhibitor that covers and protect its own Collagen structure. It is believed that the insufficiency of these inhibitors lead to autodistruction of the cell in TTP. But that is another topic.
*Actinic based pathways lead to a quick notification by the nucleus of what is going on the cell surface. Microtubules act as nerve for the cell and through the Reticulum Endothelium, take the message to the cell faster for initiation of the Nuclear Phase, by-passing the Cytoplasmic phase. The Wnt pathway seems globally to take this approach and is important in Breast and Ovarian Cancer. We will revist this topic at length!
2. Cytoplasmic Phase
Receptors and stimuli are the critical determinants of this phase. And Growth factors, pyrogenes, and various stimuli act on receptors which are transmenbrane (Decoy receptors lack a post membrane section) and therefore can trigger an intramembrane stimulation of the GTPase and other molecule complexes attached to the membrane at the inside surface, the SRC and RAS families are located in this area (to be continued.)
Friday, April 5, 2013
DO NOT CLAIM THAT I DID NOT TELL YOU (FYI)
DO NOT CLAIM THAT I DID NOT TELL YOU (FYI)
From: Health Alert Network (CDC) [mailto:healthalert@cdc.gov]
Sent: Friday, April 05, 2013 1:24 PM
To: Health Alert Network (CDC)
Subject: Errata for CDC HAN 344: Human Infections with Novel Influenza A (H7N9) Viruses
Dear HAN Coordinators,
Please see the two errata below that need to be incorporated into cascaded notification of CDC HAN 344. In the Treatment section the comma between oseltamivir and inhaled zanamivir was removed and replaced with the word or. This change is important for clinical reasons. In the For More Information section the typo in the final link to source should be corrected from Veterans to Veterinarians.
Treatment
For persons hospitalized with suspected influenza, including suspected novel H7N9 virus infection, clinicians should start empiric treatment with influenza antiviral medications (oral oseltamivir or inhaled zanamivir) as soon as possible, without waiting for laboratory confirmation.
For high-risk persons (persons <5 years of age, ≥65 years of age, and those with certain underlying medical conditions) with suspected influenza of any severity , including suspected novel H7N9 virus infection, clinicians should start empiric treatment with influenza antiviral medications (oral oseltamivir or inhaled zanamivir) as soon as possible, without waiting for laboratory confirmation.
For More Information
National Association of State Public Health Veterinarians "Compendium of Measures to Prevent Disease Associated with Animals in Public Settings, 2011" is available as the first bulleted item at http://nasphv.org/documentsCompendiumAnimals.html.
Regards.
CDC HAN Team
Indiana Health Alert Network
This is an Official
Indiana Health Alert Network Advisory Message
From: Health Alert Network (CDC) [mailto:healthalert@cdc.gov]
Sent: Friday, April 05, 2013 1:24 PM
To: Health Alert Network (CDC)
Subject: Errata for CDC HAN 344: Human Infections with Novel Influenza A (H7N9) Viruses
Dear HAN Coordinators,
Please see the two errata below that need to be incorporated into cascaded notification of CDC HAN 344. In the Treatment section the comma between oseltamivir and inhaled zanamivir was removed and replaced with the word or. This change is important for clinical reasons. In the For More Information section the typo in the final link to source should be corrected from Veterans to Veterinarians.
Treatment
For persons hospitalized with suspected influenza, including suspected novel H7N9 virus infection, clinicians should start empiric treatment with influenza antiviral medications (oral oseltamivir or inhaled zanamivir) as soon as possible, without waiting for laboratory confirmation.
For high-risk persons (persons <5 years of age, ≥65 years of age, and those with certain underlying medical conditions) with suspected influenza of any severity , including suspected novel H7N9 virus infection, clinicians should start empiric treatment with influenza antiviral medications (oral oseltamivir or inhaled zanamivir) as soon as possible, without waiting for laboratory confirmation.
For More Information
National Association of State Public Health Veterinarians "Compendium of Measures to Prevent Disease Associated with Animals in Public Settings, 2011" is available as the first bulleted item at http://nasphv.org/documentsCompendiumAnimals.html.
Regards.
CDC HAN Team
Indiana Health Alert Network
This is an Official
Indiana Health Alert Network Advisory Message
STRATIFIN (IN OVARIAN CANCER)
LAM et al.
" Stratifin, also known as 14-3-3 sigma protein, stimulates matrix metalloproteinase (MMP)-1 expression in dermal fibroblasts. Treatment of dermal fibroblasts with stratifin resulted in rapid and transient upregulation of c-jun and c-fos mRNA levels. Stratifin was demonstrated to increase MMP-1 protein levels. Microarray analysis of stratifin-treated fibroblasts shows an increase in Elk4/Sap1 mRNA expression and this finding was confirmed by northern blot analysis. Our results indicate that stratifin markedly increase Elk4/Sap1 mRNA expression in a time-dependent fashion. In conclusion, stratifin stimulates fibroblast MMP-1 levels through the activation of c-fos and MAPK pathway."
Our interpretation is that stratifin is part of an intergrin, its release in the Cytoplasm indeed stimulate MAPK C-JUN and c-fos. This means it is interpretated by the cell as a chemical stressor. The NF-kB is not far away. One of the most important hidden information here is the note by the authors that there is an increase of ELK4/Sap1.
ELK4 has been shown to interact with Serum response factor[4][5] and BRCA1.[6]
Serum response factor has been shown to interact with NFYA,[10] Src,[11] CREB-binding protein,[12] GTF2I,[13][14] ATF6,[15] Nuclear receptor co-repressor 2,[16] CEBPB,[17][18] GATA4,[19][20] Myogenin,[21][22] GTF2F1,[23][24] TEAD1,[25] ELK4,[15][26] Promyelocytic leukemia protein[12] and ASCC3.[27]
(wikipedia)
(PLEASE, WHEN A MOLECULE INTERACT WITH THIS MANY MOLECULE, IT IS A PERFECT, LEGITIMATE TARGET FOR THERAPY, AND SFR DOES)
ELK4 therefore control BRCA1 and serum response factor which control NFYA. This uncover what the cancer cell has to do to start the neoplastic process. It has to derail genetic repair by abrogating the action of BRAC1, but it also has to take controles of CBF complexes and NFYA and ZHXY. Remember CBF complexes control the direction of the metabolism, In essence, when it comes to function in the cell, the role of Core Binding Factors (CBF) is indistinguishable from that of TRANSCRIPTION FACTORS. They all impose the direction that the cell metabolism should take.
Remember also that because the Stratifin engages the MAPK mostly through the certain well selected CDK, it will tend to stop cell division. In Breast cancer, Stratifin is one of the earliest methylated gene slated for silencing.
CDO1:
Cysteine dioxygenase type I, IS A GENE CONTROLLING CYSTEIN METABOLISM. DEEP ANALYSIS BRINGS THIS GENE TO ELECTRON EXCHANGE FOR THE FORMATION OF CYTOCHROME C, THE WAY TO APOPTOSIS. THE CANCER CELL QUICKLY METHYLATES THIS GENE EARLY AND MUTATION HAS BEEN LINKED TO PROGNOSIS
(WORK FROM CORNELL UNIVERSITY)
" Stratifin, also known as 14-3-3 sigma protein, stimulates matrix metalloproteinase (MMP)-1 expression in dermal fibroblasts. Treatment of dermal fibroblasts with stratifin resulted in rapid and transient upregulation of c-jun and c-fos mRNA levels. Stratifin was demonstrated to increase MMP-1 protein levels. Microarray analysis of stratifin-treated fibroblasts shows an increase in Elk4/Sap1 mRNA expression and this finding was confirmed by northern blot analysis. Our results indicate that stratifin markedly increase Elk4/Sap1 mRNA expression in a time-dependent fashion. In conclusion, stratifin stimulates fibroblast MMP-1 levels through the activation of c-fos and MAPK pathway."
Our interpretation is that stratifin is part of an intergrin, its release in the Cytoplasm indeed stimulate MAPK C-JUN and c-fos. This means it is interpretated by the cell as a chemical stressor. The NF-kB is not far away. One of the most important hidden information here is the note by the authors that there is an increase of ELK4/Sap1.
ELK4 has been shown to interact with Serum response factor[4][5] and BRCA1.[6]
Serum response factor has been shown to interact with NFYA,[10] Src,[11] CREB-binding protein,[12] GTF2I,[13][14] ATF6,[15] Nuclear receptor co-repressor 2,[16] CEBPB,[17][18] GATA4,[19][20] Myogenin,[21][22] GTF2F1,[23][24] TEAD1,[25] ELK4,[15][26] Promyelocytic leukemia protein[12] and ASCC3.[27]
(PLEASE, WHEN A MOLECULE INTERACT WITH THIS MANY MOLECULE, IT IS A PERFECT, LEGITIMATE TARGET FOR THERAPY, AND SFR DOES)
ELK4 therefore control BRCA1 and serum response factor which control NFYA. This uncover what the cancer cell has to do to start the neoplastic process. It has to derail genetic repair by abrogating the action of BRAC1, but it also has to take controles of CBF complexes and NFYA and ZHXY. Remember CBF complexes control the direction of the metabolism, In essence, when it comes to function in the cell, the role of Core Binding Factors (CBF) is indistinguishable from that of TRANSCRIPTION FACTORS. They all impose the direction that the cell metabolism should take.
Remember also that because the Stratifin engages the MAPK mostly through the certain well selected CDK, it will tend to stop cell division. In Breast cancer, Stratifin is one of the earliest methylated gene slated for silencing.
CDO1:
Cysteine dioxygenase type I, IS A GENE CONTROLLING CYSTEIN METABOLISM. DEEP ANALYSIS BRINGS THIS GENE TO ELECTRON EXCHANGE FOR THE FORMATION OF CYTOCHROME C, THE WAY TO APOPTOSIS. THE CANCER CELL QUICKLY METHYLATES THIS GENE EARLY AND MUTATION HAS BEEN LINKED TO PROGNOSIS
(WORK FROM CORNELL UNIVERSITY)
Nomenclature of 2 important genes in Ovarian cancer !
1.RASSF1A: One of the thing cancer cell do is to Methylate some genes in order to block its path to death.
it appears this gene is a critical door to shut or disable. It not only decrease the significance of RAS and MAPK in the pathogenesis of tumor that harbor this mutation. It also remove blockage to proliferation by desensitizing the cell to the effect of P53, Cyclins. Desensitize the cell to Death Receptor 6 and its Fas connection. RASSF1a, demethylation is a valid target in ovarian cancer.
2.HNF1B: " Hepatocyte Nuclear Factor 1α (HNF1α) is an atypical homeodomain-containing transcription factor that transactivates liver-specific genes including albumin, α-1-antitrypsin and α- and β-fibrinogen. Biallelic inactivating mutations of HNF1A have been frequently identified in hepatocellular adenomas (HCA), rare benign liver tumors usually developed in women under oral contraceptives, and in rare cases of hepatocellular carcinomas developed in non-cirrhotic liver. HNF1α-mutated HCA (H-HCA) are characterized by a marked steatosis and show activation of glycolysis, lipogenesis, translational machinery and mTOR pathway. We studied the consequences of HNF1α silencing in hepatic cell lines, HepG2 and Hep3B and we reproduced most of the deregulations identified in H-HCA."
(Laura Pelletier et al)
This gene is the gene of differentiation for liver formation, it has the structure of a CBF (core binding Factor) therefore has a subunit binding the DNA, therefore silencing that portion, and another subunit having locations for enzymatic proteins or molecular structures that directly assume various functions intended by the cell (formation of Albumin, alpha Antitrypsine, and Beta Fibrinogen).
Interestingly enough, Steatosis is a prominent feature here. This structure and gene may be of interest in LIPOSARCOMA?
DOES ACTIVATION OF MTOR DEMONSTRATED HERE OPEN THE DOOR TO THE USE OF MTOR IN LIPOSARCOMA?
it appears this gene is a critical door to shut or disable. It not only decrease the significance of RAS and MAPK in the pathogenesis of tumor that harbor this mutation. It also remove blockage to proliferation by desensitizing the cell to the effect of P53, Cyclins. Desensitize the cell to Death Receptor 6 and its Fas connection. RASSF1a, demethylation is a valid target in ovarian cancer.
2.HNF1B: " Hepatocyte Nuclear Factor 1α (HNF1α) is an atypical homeodomain-containing transcription factor that transactivates liver-specific genes including albumin, α-1-antitrypsin and α- and β-fibrinogen. Biallelic inactivating mutations of HNF1A have been frequently identified in hepatocellular adenomas (HCA), rare benign liver tumors usually developed in women under oral contraceptives, and in rare cases of hepatocellular carcinomas developed in non-cirrhotic liver. HNF1α-mutated HCA (H-HCA) are characterized by a marked steatosis and show activation of glycolysis, lipogenesis, translational machinery and mTOR pathway. We studied the consequences of HNF1α silencing in hepatic cell lines, HepG2 and Hep3B and we reproduced most of the deregulations identified in H-HCA."
(Laura Pelletier et al)
This gene is the gene of differentiation for liver formation, it has the structure of a CBF (core binding Factor) therefore has a subunit binding the DNA, therefore silencing that portion, and another subunit having locations for enzymatic proteins or molecular structures that directly assume various functions intended by the cell (formation of Albumin, alpha Antitrypsine, and Beta Fibrinogen).
Interestingly enough, Steatosis is a prominent feature here. This structure and gene may be of interest in LIPOSARCOMA?
DOES ACTIVATION OF MTOR DEMONSTRATED HERE OPEN THE DOOR TO THE USE OF MTOR IN LIPOSARCOMA?
Thursday, April 4, 2013
WE CONTINUE TO BE STOPPED IN OUR PROGRESS BECAUSE OF LACK OF FUNDING
IN THE UNITED STATES THE SCARCITY OF FUNDING HAS BECOME A HINDRANCE TO THE CURE PROMPTING THE AMERICAN CANCER SOCIETY TO LAUNCH A TELEVISION CAMPAIGN ASKING PEOPLE TO TAKE THIS CAUSE BACK TO THE STREET. THE AMERICAN CONGRESS IS SHACKLED IN DIVISIONS THAT HAVE NOW BECOME VISCERAL AND NONSENSICAL. AMERICA HAS LOST ITS DREAMERS AND THEREFORE ITS INSPIRING IDEALS. UNDER THE PRETENSE OF FINANCIAL PRUDENCE, DREAMS ARE ALLOWED TO DIE, CURE LET TO ESCAPE ONE MORE DAY, AND CANCER VICTIMS ARE LET TO DIE IN THE PROCESS! (WE NEED LINCOLN BACK!)
"LET'S GET LOUD" THE CANCER AGENCY ADVOCATES, AND THE CRBCM SUPPORTS THE MOVEMENT!
ANOTHER COMPONENT TO THE PROBLEM, WITH SCARCITY COME MORE POLITICAL FAVORS, MORE DISCRIMINATION AND DISPARITY IN GRANT ALLOCATIONS. THE CRBCM DOES NOT EXPECT ANYTHING AT PRESENT. THE IRS IS STILL FIGHTING US BY SHACKLING OUR 501 STATUS. SUPPRESSION OF MINORITY RESEARCH POTENTIAL COMES IN ALL UGLY FORMS! WE WILL NOT BACK DOWN UNTIL THEIR PLAY BECOME IRRELEVANT TO THE COURSE OF HISTORY! CPRIT HAS PLAYED FAVORITISM, LOOK WHERE THEY ARE...DO THE RIGHT THING PEOPLE, NO ONE HAS REACHED THE MOON BY FAULTY MATH BECAUSE NATURE IS WATCHING! AT THE CRBCM, THE FIGHT IS ON, WE ARE NOT GOING ANYWHERE AND STAY IN
THE GAME UNTIL OUR VOICE IS HEARD, UNTIL OUR ENEMIES BECOME IRRELEVANT AND UNTIL WE ARE ALLOWED TO RISE!
"LET'S GET LOUD" THE CANCER AGENCY ADVOCATES, AND THE CRBCM SUPPORTS THE MOVEMENT!
ANOTHER COMPONENT TO THE PROBLEM, WITH SCARCITY COME MORE POLITICAL FAVORS, MORE DISCRIMINATION AND DISPARITY IN GRANT ALLOCATIONS. THE CRBCM DOES NOT EXPECT ANYTHING AT PRESENT. THE IRS IS STILL FIGHTING US BY SHACKLING OUR 501 STATUS. SUPPRESSION OF MINORITY RESEARCH POTENTIAL COMES IN ALL UGLY FORMS! WE WILL NOT BACK DOWN UNTIL THEIR PLAY BECOME IRRELEVANT TO THE COURSE OF HISTORY! CPRIT HAS PLAYED FAVORITISM, LOOK WHERE THEY ARE...DO THE RIGHT THING PEOPLE, NO ONE HAS REACHED THE MOON BY FAULTY MATH BECAUSE NATURE IS WATCHING! AT THE CRBCM, THE FIGHT IS ON, WE ARE NOT GOING ANYWHERE AND STAY IN
THE GAME UNTIL OUR VOICE IS HEARD, UNTIL OUR ENEMIES BECOME IRRELEVANT AND UNTIL WE ARE ALLOWED TO RISE!
Nomenclature of some Genes in Ovarian Cancer:
Nomenclature of some Genes in Ovarian Cancer:
BRAC1
BRAC2
CDO1
HER-2
CPG ISLAND
TMS1
ER alpha
PRB
MEK
==============================================================
RASSF1A: One of the thing cancer cell do is to Methylate some genes in order to block its path to death.
it appears this gene is a critical door to shut or disable. It not only decrease the significance of RAS and MAPK in the pathogenesis of tumor that harbor this mutation. It also remove blockage to proliferation by desensitizing the cell to the effect of P53, Cyclins. Desensititize the cell to Death Receptor 6 and its Fas connection. RASSF1a, demethylation is a valid target in ovarian cancer
RARbeta
=============================================================
STRATIFIN.
LAM et al.
" stratifin, also known as 14-3-3 sigma protein, stimulates matrix metalloproteinase (MMP)-1 expression in dermal fibroblasts. Treatment of dermal fibroblasts with stratifin resulted in rapid and transient upregulation of c-jun and c-fos mRNA levels. Stratifin was demonstrated to increase MMP-1 protein levels. Microarray analysis of stratifin-treated fibroblasts shows an increase in Elk4/Sap1 mRNA expression and this finding was confirmed by northern blot analysis. Our results indicate that stratifin markedly increase Elk4/Sap1 mRNA expression in a time-dependent fashion. In conclusion, stratifin stimulates fibroblast MMP-1 levels through the activation of c-fos and MAPK pathway."
Our interpretation is that stratifin is part of an intergrin, its release in the Cytoplasm indeed stimulate MAPK C-JUN and c-fos. This means it is interpretated by the cell as a chemical stressor. The NF-kB is not far away. One of the most important hidden information here is the note by the authors that there is an increase of ELK4/Sap1.
ELK4 has been shown to interact with Serum response factor[4][5] and BRCA1.[6]
Serum response factor has been shown to interact with NFYA,[10] Src,[11] CREB-binding protein,[12] GTF2I,[13][14] ATF6,[15] Nuclear receptor co-repressor 2,[16] CEBPB,[17][18] GATA4,[19][20] Myogenin,[21][22] GTF2F1,[23][24] TEAD1,[25] ELK4,[15][26] Promyelocytic leukemia protein[12] and ASCC3.[27]
(wikipedia)
ELK4 therefore control BRCA1 and serum response factor which control NFYA. This uncover what the cancer cell has to do to start the neoplastic process. It has to derail genetic repair by abrogating the action of BRAC1, but it also has to take controles of CBF complexes and NFYA and ZHXY. Remember CBF complexes control the direction of the metabolism, In essence, when it comes to function in the cell, the role of Core Binding Factors (CBF) is indistinguishable from that of TRANSCRIPTION FACTORS. They all impose the direction that the cell metabolism should take.
Remember also that because the Stratifin engages the MAPK mostly through the certain well selected CDK, it will tend to stop cell division. In Breast cancer, Stratifin is one of the earliest methylated gene slated for silencing.
======================================================================
HNF1B " Hepatocyte Nuclear Factor 1α (HNF1α) is an atypical homeodomain-containing transcription factor that transactivates liver-specific genes including albumin, α-1-antitrypsin and α- and β-fibrinogen. Biallelic inactivating mutations of HNF1A have been frequently identified in hepatocellular adenomas (HCA), rare benign liver tumors usually developed in women under oral contraceptives, and in rare cases of hepatocellular carcinomas developed in non-cirrhotic liver. HNF1α-mutated HCA (H-HCA) are characterized by a marked steatosis and show activation of glycolysis, lipogenesis, translational machinery and mTOR pathway. We studied the consequences of HNF1α silencing in hepatic cell lines, HepG2 and Hep3B and we reproduced most of the deregulations identified in H-HCA."
(Laura Pelletier et al)
This gene is the a gene of differentiation for liver formation, it has the structure of a CBF (core binding Factor) therefore has a subunit binding the DNA therefore silencing that portion, and another subunit having locations for enzymatic proteins or molecular structures that direct assume various functions intended by the cell (formation of Albumin,alpha Antitrypsine, and Beta Fibrinogen) Interestingly enough, Steatosi is a prominent feature here. This structure and gene may be of interest in LIPOSARCOMA.? DOES ACTIVATION OF MTOR DEMONSTRATED HERE OPEN THE DOOR TO USE OF MTOR IN LIPOSARCOMA?
-------------------------------------------------------------------------------------------------------------
p16INK4A
p14
CYCLIN D2
SLIT2
CDH13
PTEN
CLAUDIN 3,4
HE4
MUCIN1 OR MUC1
MESOTHELIN
ApoE, J
PIK3CA
P53 AND CHEK2
MLH1
MSH2,6
PMS2
CA-125
STK11
LKB1
PTCH
ATM
This is just the beginning, lets go to work! love those recurring genes as they cross over with presence in other cancers to strengthen their importance, Please remember those that lead to hypothrophy of muscles and extremities are probably more important for therapeutic intervention. And those with a "q" location on chromosome arm are most likely of poor prognosis or dramatic phenotype expression! Always do remember that Multidrug resistance (MDR-1) is in play HERE!
BRAC1
BRAC2
CDO1
HER-2
CPG ISLAND
TMS1
ER alpha
PRB
MEK
==============================================================
RASSF1A: One of the thing cancer cell do is to Methylate some genes in order to block its path to death.
it appears this gene is a critical door to shut or disable. It not only decrease the significance of RAS and MAPK in the pathogenesis of tumor that harbor this mutation. It also remove blockage to proliferation by desensitizing the cell to the effect of P53, Cyclins. Desensititize the cell to Death Receptor 6 and its Fas connection. RASSF1a, demethylation is a valid target in ovarian cancer
RARbeta
=============================================================
STRATIFIN.
LAM et al.
" stratifin, also known as 14-3-3 sigma protein, stimulates matrix metalloproteinase (MMP)-1 expression in dermal fibroblasts. Treatment of dermal fibroblasts with stratifin resulted in rapid and transient upregulation of c-jun and c-fos mRNA levels. Stratifin was demonstrated to increase MMP-1 protein levels. Microarray analysis of stratifin-treated fibroblasts shows an increase in Elk4/Sap1 mRNA expression and this finding was confirmed by northern blot analysis. Our results indicate that stratifin markedly increase Elk4/Sap1 mRNA expression in a time-dependent fashion. In conclusion, stratifin stimulates fibroblast MMP-1 levels through the activation of c-fos and MAPK pathway."
Our interpretation is that stratifin is part of an intergrin, its release in the Cytoplasm indeed stimulate MAPK C-JUN and c-fos. This means it is interpretated by the cell as a chemical stressor. The NF-kB is not far away. One of the most important hidden information here is the note by the authors that there is an increase of ELK4/Sap1.
ELK4 has been shown to interact with Serum response factor[4][5] and BRCA1.[6]
Serum response factor has been shown to interact with NFYA,[10] Src,[11] CREB-binding protein,[12] GTF2I,[13][14] ATF6,[15] Nuclear receptor co-repressor 2,[16] CEBPB,[17][18] GATA4,[19][20] Myogenin,[21][22] GTF2F1,[23][24] TEAD1,[25] ELK4,[15][26] Promyelocytic leukemia protein[12] and ASCC3.[27]
ELK4 therefore control BRCA1 and serum response factor which control NFYA. This uncover what the cancer cell has to do to start the neoplastic process. It has to derail genetic repair by abrogating the action of BRAC1, but it also has to take controles of CBF complexes and NFYA and ZHXY. Remember CBF complexes control the direction of the metabolism, In essence, when it comes to function in the cell, the role of Core Binding Factors (CBF) is indistinguishable from that of TRANSCRIPTION FACTORS. They all impose the direction that the cell metabolism should take.
Remember also that because the Stratifin engages the MAPK mostly through the certain well selected CDK, it will tend to stop cell division. In Breast cancer, Stratifin is one of the earliest methylated gene slated for silencing.
======================================================================
HNF1B " Hepatocyte Nuclear Factor 1α (HNF1α) is an atypical homeodomain-containing transcription factor that transactivates liver-specific genes including albumin, α-1-antitrypsin and α- and β-fibrinogen. Biallelic inactivating mutations of HNF1A have been frequently identified in hepatocellular adenomas (HCA), rare benign liver tumors usually developed in women under oral contraceptives, and in rare cases of hepatocellular carcinomas developed in non-cirrhotic liver. HNF1α-mutated HCA (H-HCA) are characterized by a marked steatosis and show activation of glycolysis, lipogenesis, translational machinery and mTOR pathway. We studied the consequences of HNF1α silencing in hepatic cell lines, HepG2 and Hep3B and we reproduced most of the deregulations identified in H-HCA."
(Laura Pelletier et al)
This gene is the a gene of differentiation for liver formation, it has the structure of a CBF (core binding Factor) therefore has a subunit binding the DNA therefore silencing that portion, and another subunit having locations for enzymatic proteins or molecular structures that direct assume various functions intended by the cell (formation of Albumin,alpha Antitrypsine, and Beta Fibrinogen) Interestingly enough, Steatosi is a prominent feature here. This structure and gene may be of interest in LIPOSARCOMA.? DOES ACTIVATION OF MTOR DEMONSTRATED HERE OPEN THE DOOR TO USE OF MTOR IN LIPOSARCOMA?
-------------------------------------------------------------------------------------------------------------
p16INK4A
p14
CYCLIN D2
SLIT2
CDH13
PTEN
CLAUDIN 3,4
HE4
MUCIN1 OR MUC1
MESOTHELIN
ApoE, J
PIK3CA
P53 AND CHEK2
MLH1
MSH2,6
PMS2
CA-125
STK11
LKB1
PTCH
ATM
This is just the beginning, lets go to work! love those recurring genes as they cross over with presence in other cancers to strengthen their importance, Please remember those that lead to hypothrophy of muscles and extremities are probably more important for therapeutic intervention. And those with a "q" location on chromosome arm are most likely of poor prognosis or dramatic phenotype expression! Always do remember that Multidrug resistance (MDR-1) is in play HERE!
GENES IN OVARIAN CANCER: (part I)
The notion that there is a particular gene or genes for a specific cancer is attractive, but most of the time only reflects the scientists' tendency to attract the community interest on their findings. There is nothing wrong with that because their work needs recognition. Recent advances in cure and novel therapeutic approaches have occurred to convince the common of mortals that Researchers are hard at work. But by now we know that most standard genetic family abnormalities involve only 5-10% of cancers. That means that no one genetic abnormality stands to justify any specific cancer in-toto. The case of BRCA1 and 2 in Breast cancer.
Breast cancer survivor Women who participated in My talk in El Paso,TX were surprised to learn that 85% of women newly diagnosed with Breast cancer in the US were first in their family. Everybody was assuming that breast cancer happens because of family predisposition. This is clearly an underestimation of the heterogeneity of our genetic material. Don't understand me wrong, there are clear cases of family predispositions, however, we have an approximate 25,000 genes, something and somewhere a significant event can happen anytime. Also, one should know that there is primary and secondary amplification. In some cases it is hard to determine which came first (Chicken and egg dilemma ).
Another compounding factor complicating our interpretation in rare cases, is the notion that the cause of cancer can be located in the promoter gene which all of a sudden becomes difficult to methylate or suppress, causing secondary amplification of a gene or of its regulators.
When one wants to look at the genes involved in ovarian cancers, it is good to focus on particular genes (HNF1B) as clearly publicized, but we can't ignore the story of BRCAs, and other family syndromes which harbor Ovarian cancer as a component of the syndrome. Therapies that are being developed and being effective in Ovarian cancer (Anti MEK) are also pointing to relevant genes. The story of lung cancer with its ever expanding list of DRIVER MUTATIONS and the advent of MULTIPLEX gene screening is just another proof of the danger of claiming to have discovered THE GENE for a specific cancer!
GENES OF OVARIAN CANCER (to follow)
Breast cancer survivor Women who participated in My talk in El Paso,TX were surprised to learn that 85% of women newly diagnosed with Breast cancer in the US were first in their family. Everybody was assuming that breast cancer happens because of family predisposition. This is clearly an underestimation of the heterogeneity of our genetic material. Don't understand me wrong, there are clear cases of family predispositions, however, we have an approximate 25,000 genes, something and somewhere a significant event can happen anytime. Also, one should know that there is primary and secondary amplification. In some cases it is hard to determine which came first (Chicken and egg dilemma ).
Another compounding factor complicating our interpretation in rare cases, is the notion that the cause of cancer can be located in the promoter gene which all of a sudden becomes difficult to methylate or suppress, causing secondary amplification of a gene or of its regulators.
When one wants to look at the genes involved in ovarian cancers, it is good to focus on particular genes (HNF1B) as clearly publicized, but we can't ignore the story of BRCAs, and other family syndromes which harbor Ovarian cancer as a component of the syndrome. Therapies that are being developed and being effective in Ovarian cancer (Anti MEK) are also pointing to relevant genes. The story of lung cancer with its ever expanding list of DRIVER MUTATIONS and the advent of MULTIPLEX gene screening is just another proof of the danger of claiming to have discovered THE GENE for a specific cancer!
GENES OF OVARIAN CANCER (to follow)
Tuesday, April 2, 2013
Secondary Hematologic Malignancies
Japanese researchers suggested in a retrospective study of patients treated with Temodar for Glioma, that there is an increased occurrence of secondary Myelodysplasia, leukemias and particularly Acute Lymphoblastic Leukemia. It is interesting to look further, beyond the simple observation and speculate as to what leads to such a transformation at the gene level.
Leukemias are a disease not only of pathways, but of deep derangement at the Histone-DNA level and include particularly not only protein complexes similar to core binding factors, but also regulator genes which appear to be specifically amplified in leukemias!
It is pertinent to also look closer at Proteins Kinases affecting or interacting with DNA. Temodar is an Alkylating agent per the researcher's report.
The interval between the treatment and the occurrence is also interesting, and suggests that the secondary Leukemia results from a secondary amplification of proliferative genes after the onslaught on cellular receptors by the chemical stimulus. The NK-kB, c-JUN must be in play. Blocking these pathways could prevent such malignant occurrence. We will soon find that secondary malignancy could be prevented by simply blocking some tumor growth factors. We don't need to accept these complications any more. I learned that my first patient who was diagnosed with Hodgkin disease, a curable disease, died later on with an Acute Leukemia. She was free of Hodgkin disease. Our current follow-up is inadequate in this regard, as we sit and wait for secondary leukemia to set in. Lets look into blocking Tumor growth factors to stop secondary leukemias!
Leukemias are a disease not only of pathways, but of deep derangement at the Histone-DNA level and include particularly not only protein complexes similar to core binding factors, but also regulator genes which appear to be specifically amplified in leukemias!
It is pertinent to also look closer at Proteins Kinases affecting or interacting with DNA. Temodar is an Alkylating agent per the researcher's report.
The interval between the treatment and the occurrence is also interesting, and suggests that the secondary Leukemia results from a secondary amplification of proliferative genes after the onslaught on cellular receptors by the chemical stimulus. The NK-kB, c-JUN must be in play. Blocking these pathways could prevent such malignant occurrence. We will soon find that secondary malignancy could be prevented by simply blocking some tumor growth factors. We don't need to accept these complications any more. I learned that my first patient who was diagnosed with Hodgkin disease, a curable disease, died later on with an Acute Leukemia. She was free of Hodgkin disease. Our current follow-up is inadequate in this regard, as we sit and wait for secondary leukemia to set in. Lets look into blocking Tumor growth factors to stop secondary leukemias!
CRITICAL GENES IN (SECONDARY) LEUKEMIA
Aside from the the genes that can block Tumor Growth factors, our discussion on leukemia had shown that Leukemia is driven also by proteins located at CBF. Indeed we now know that the proteins found in the CBF indeed determine the direction and intensity of the the neoplastic process. Attacking growth factors effectiveness at stimulating its relevant receptor appears to be a decent strategy. However there are other gene that should be in the focus of our attention.
AP-1
TFE-3
SMAD2-4
FOXG1
and at the border JARID1B
(we will add some gene regulators to this list)
==========================================================
'"The SMAD4 gene provides instructions for making a protein involved in transmitting chemical signals from the cell surface to the nucleus. This signaling pathway, called the transforming growth factor beta (TGF-β) pathway, allows the environment outside the cell to affect how the cell produces other proteins. The signaling process begins when a TGF-β protein attaches (binds) to a receptor on the cell surface, which activates a group of related SMAD proteins. The SMAD proteins bind to the SMAD4 protein and form a protein complex, which then moves to the cell nucleus. In the nucleus, the SMAD protein complex binds to specific areas of DNA where it controls the activity of particular genes and regulates cell growth and division (proliferation).
(NIH)
AP-1
TFE-3
SMAD2-4
FOXG1
and at the border JARID1B
(we will add some gene regulators to this list)
==========================================================
'"The SMAD4 gene provides instructions for making a protein involved in transmitting chemical signals from the cell surface to the nucleus. This signaling pathway, called the transforming growth factor beta (TGF-β) pathway, allows the environment outside the cell to affect how the cell produces other proteins. The signaling process begins when a TGF-β protein attaches (binds) to a receptor on the cell surface, which activates a group of related SMAD proteins. The SMAD proteins bind to the SMAD4 protein and form a protein complex, which then moves to the cell nucleus. In the nucleus, the SMAD protein complex binds to specific areas of DNA where it controls the activity of particular genes and regulates cell growth and division (proliferation).
By controlling gene activity and regulating cell proliferation, the
SMAD4 protein serves both as a transcription factor and as a tumor
suppressor. Transcription factors help control the activity of
particular genes, and tumor suppressors keep cells from growing and
dividing too fast or in an uncontrolled way.
Does the SMAD4 gene share characteristics with other genes?
"The SMAD4 gene belongs to a family of genes called SMAD (SMAD, mothers against DPP homologs).
A gene family is a group of genes that share important characteristics. Classifying individual genes into families helps researchers describe how genes are related to each other. For more information, see What are gene families? in the Handbook."
"Common SMAD (co-SMAD) is the coactivator and mediator of signal
transduction by TGF-beta (transforming growth factor). Component of the
heterotrimeric SMAD2/SMAD3-SMAD4 complex that forms in the nucleus and
is required for the TGF-mediated signaling. Promotes binding of the
SMAD2/SMAD4/FAST-1 complex to DNA and provides an activation function
required for SMAD1 or SMAD2 to stimulate transcription. Component of the
multimeric SMAD3/SMAD4/JUN/FOS complex which forms at the AP1 promoter
site; required for syngernistic transcriptional activity in response to
TGF-beta. May act as a tumor suppressor. Positively regulates PDPK1
kinase activity by stimulating its dissociation from the 14-3-3 protein
YWHAQ which acts as a negative regulator."A gene family is a group of genes that share important characteristics. Classifying individual genes into families helps researchers describe how genes are related to each other. For more information, see What are gene families? in the Handbook."
(NIH)
MSR1, ASCC1, and CTHRC1 (Nomenclature of Genes in Esophageal cancer)
CTHRC1" is a protein that has the ability to inhibit collagen matrix synthesis.
Expression of Cthrc1 is increased in fibroblasts and chondrocytic cells in response to TGF-beta family members including BMP4, BMP2 and TGF-beta. Cthrc1 is also upregulated during tumorigenesis and metastasis;
CTHRC1 has been linked to major signaling pathways such as Wnt and TGF-beta. The ability of CTHRC1 to inhibit TGF-beta signaling via a reduction in Smad 2/Smad 3 (is to be noted!)
Location 8q22.3. (Leclair at al )
Once again this comment suggests that stimulation of growth factor induced secondarily by NF-kB /c-JUn amplification leads to secondary amplification which in this case happens to this gene. This gene comes into play in vascular remodeling suggesting invasiveness of the cancer. This is the stuff used by neurone to find their way down their passage. If it is expressed it marks cellular invasiveness. Please pay marked attention to the pathway with witch it is identified, a pathway we believe is very important but neglected. The Wnt pathway. This is the metastasis pathways, it correlates with metastatic disease and is the stuff you find in triple negative Breast cancer!
Suppression of Smad2 could prevent cancer induced by Irritations? and may be secondary cancers?
2.ASCC1.
This gene encodes a subunit of the activating signal cointegrator 1 (ASC-1) complex. The ASC-1 complex is a transcriptional coactivator that plays an important role in gene transactivation by multiple transcription factors including activating protein 1 (AP-1), nuclear factor kappa-B (NF-kB) and serum response factor (SRF). The encoded protein contains an N-terminal KH-type RNA-binding motif which is required for AP-1 transactivation by the ASC-1 complex. Mutations in this gene are associated with Barrett esophagus and esophageal adenocarcinoma. Alternatively spliced transcripts encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Dec 2011]"" (danielsen et al!)
Activating signal cointegrator 1 complex subunit 1 (ASCC1) is a subunit of the activating signal cointegrator 1 (ASC-1) complex. The ASC-1 complex is a transcriptional coactivator that plays an important role in gene transactivation by multiple transcription factors including activating protein 1 (AP-1), nuclear factor kappa-B (NF-kB) and serum response factor (SRF). ASCC1 contains an N-terminal KH-type RNA-binding motif which is required for AP-1 transactivation by the ASC-1 complex. Mutations in the ASCC1 gene are associated with Barrett esophagus and esophageal adenocarcinoma [taken from NCBI Entrez Gene (Gene ID: 51008)].
MSR1
already discussed
Expression of Cthrc1 is increased in fibroblasts and chondrocytic cells in response to TGF-beta family members including BMP4, BMP2 and TGF-beta. Cthrc1 is also upregulated during tumorigenesis and metastasis;
CTHRC1 has been linked to major signaling pathways such as Wnt and TGF-beta. The ability of CTHRC1 to inhibit TGF-beta signaling via a reduction in Smad 2/Smad 3 (is to be noted!)
Location 8q22.3. (Leclair at al )
Once again this comment suggests that stimulation of growth factor induced secondarily by NF-kB /c-JUn amplification leads to secondary amplification which in this case happens to this gene. This gene comes into play in vascular remodeling suggesting invasiveness of the cancer. This is the stuff used by neurone to find their way down their passage. If it is expressed it marks cellular invasiveness. Please pay marked attention to the pathway with witch it is identified, a pathway we believe is very important but neglected. The Wnt pathway. This is the metastasis pathways, it correlates with metastatic disease and is the stuff you find in triple negative Breast cancer!
Suppression of Smad2 could prevent cancer induced by Irritations? and may be secondary cancers?
2.ASCC1.
This gene encodes a subunit of the activating signal cointegrator 1 (ASC-1) complex. The ASC-1 complex is a transcriptional coactivator that plays an important role in gene transactivation by multiple transcription factors including activating protein 1 (AP-1), nuclear factor kappa-B (NF-kB) and serum response factor (SRF). The encoded protein contains an N-terminal KH-type RNA-binding motif which is required for AP-1 transactivation by the ASC-1 complex. Mutations in this gene are associated with Barrett esophagus and esophageal adenocarcinoma. Alternatively spliced transcripts encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Dec 2011]"" (danielsen et al!)
Activating signal cointegrator 1 complex subunit 1 (ASCC1) is a subunit of the activating signal cointegrator 1 (ASC-1) complex. The ASC-1 complex is a transcriptional coactivator that plays an important role in gene transactivation by multiple transcription factors including activating protein 1 (AP-1), nuclear factor kappa-B (NF-kB) and serum response factor (SRF). ASCC1 contains an N-terminal KH-type RNA-binding motif which is required for AP-1 transactivation by the ASC-1 complex. Mutations in the ASCC1 gene are associated with Barrett esophagus and esophageal adenocarcinoma [taken from NCBI Entrez Gene (Gene ID: 51008)].
Alternative names for ASCC1 Antibody include activating signal cointegrator 1 complex subunit 1 antibody, ASC-1 complex subunit p50 antibody, Trip4 complex subunit p50 antibody, p50 antibody, CGI-18 antibody, ASC1p50 antibody.
I refuse to comment on this one because it is so obvious, this is at the core of pathogenesis where chronic stimuli act through the NF-kB and C-JUN to induce growth factors which eventually stimulate a secondary amplification that leads to the pathogenesis of cancer, additional mutations such as that occurring in CTHRC1 will complete the dance. This ASCC1 appears to be a CBF like molecular complex driving this transformation and therefore it is a valid target for therapy.MSR1
already discussed
Update on CPRIT Grant Moratorium
Update on CPRIT Grant Moratorium
In a March 19 letter to the Oversight Committee, the Governor, Lieutenant Governor, and Speaker of the House authorized CPRIT to move forward with the 25 researcher recruitment grants approved by the Oversight Committee in August and December 2012.
Once information becomes available regarding the remaining August and December awards that are awaiting final contracts, an update will be posted on CPRIT’s website.
We are grateful to the Governor, Lt. Governor, and Speaker for allowing CPRIT to proceed with these important recruitment awards. We will continue to work with them and all members of the Legislature to make sure they have the information they need to determine how they want CPRIT to operate going forward. We have worked hard to regain trust with our elected officials and the citizens of Texas. We take this action as evidence that some progress has been made and we will continue to work to strengthen this trust during the coming weeks and months.
In a March 19 letter to the Oversight Committee, the Governor, Lieutenant Governor, and Speaker of the House authorized CPRIT to move forward with the 25 researcher recruitment grants approved by the Oversight Committee in August and December 2012.
Once information becomes available regarding the remaining August and December awards that are awaiting final contracts, an update will be posted on CPRIT’s website.
The following is a statement released March 20 from Wayne Roberts, Interim Executive Director of CPRIT:
The Cancer Prevention and Research Institute of Texas has been informed that state leadership has authorized the agency to move forward with the 25 researcher recruitment grants approved by the CPRIT Oversight Committee in August and December. These grants have been awaiting final contracts, pursuant to the moratorium instituted by the Governor, Lt. Governor and Speaker on December 18. Each of these grants has been certified as being reviewed and approved using appropriate processes and procedures.We are grateful to the Governor, Lt. Governor, and Speaker for allowing CPRIT to proceed with these important recruitment awards. We will continue to work with them and all members of the Legislature to make sure they have the information they need to determine how they want CPRIT to operate going forward. We have worked hard to regain trust with our elected officials and the citizens of Texas. We take this action as evidence that some progress has been made and we will continue to work to strengthen this trust during the coming weeks and months.
Nomenclature of genes in Esophageal cancer (continued)
FEZ1 , fasciculation and Elongation protein Zeta,
a significant gene intervening in the motility of the Esophagus.
Alteration of this gene also increases cancer susceptibility to viral infection (HIV).
It interacts with NBR1, a gene that confers a certain refractoriness to this cancer
and supports the Idea that Cisplatin may be essential to treatment in this disease.
In fact, several neurological receptors are involved in Esophageal cancer
and may contribute to the disease's poor prognosis and epithelial morphology presentation.
RHBF2
--------
a significant gene intervening in the motility of the Esophagus.
Alteration of this gene also increases cancer susceptibility to viral infection (HIV).
It interacts with NBR1, a gene that confers a certain refractoriness to this cancer
and supports the Idea that Cisplatin may be essential to treatment in this disease.
In fact, several neurological receptors are involved in Esophageal cancer
and may contribute to the disease's poor prognosis and epithelial morphology presentation.
RHBF2
--------
Monday, April 1, 2013
Adverse event: Diarrhea - General Guidelines by Pfizer
Adverse
event
Description
General
guidelines
Diarrhea
Diarrhea is an abnormal increase in stool liquidity
and frequency (4 to 6 stools or more per day
over baseline) with or without nocturnal bowel
movements and/or moderate abdominal
cramping. Diarrhea is a common side effect of
many cancer regimens. It can cause depletion of
fluids and electrolytes, malnutrition, dehydration,
and hospitalization and therefore can interfere
with cancer treatment, causing dosing delays or
reductions.
1
Patient education strategies
•
Emphasize the importance of maximizing oral
hydration strategies to avoid dehydration and
electrolyte imbalances
2
•
Educate patients about the likelihood that diarrhea
will develop
3-5
Management tips for patients
•
Diarrhea may be managed through diet as well
as pharmacologic treatment when necessary,
based on the clinical judgment of the treating
healthcare provider (HCP).
1,3,4
The first step in
treatment is dietary management
3,5,6
:
–
Yogurt containing probiotics
–
Soluble fiber
–
Small but frequent meals
–
Fluids, such as water, diluted cranberry juice,
broth, decaffeinated tea or coffee
•
Over-the-counter and Rx agents may also be
used, according to labeling
1,3,4
Hypertension
Hypertension is the term used to describe high blood
pressure (BP). In general, hypertension is repeated
BP elevation exceeding 140 mm Hg systolic blood
pressure (SBP) and 90 mm Hg diastolic blood
pressure (DBP).
7
Hypertension is a commonly
reported AE in cancer patients receiving antivascular
endothelial growth factor (VEGF) drugs.
8
Patient education strategies
•
Take antihypertensive medications as prescribed
4
•
Recognize signs of potentially dangerous
high BP (eg, severe headache, shortness of
breath, nosebleeds)
9
•
Follow healthy lifestyle choices: regular exercise,
weight control, moderate alcohol consumption,
sodium restriction
4
Sunday, March 31, 2013
At the CRBCM, we keep learning continously!
CONTINUING MEDICAL EDUCATION CERTIFICATE
certifies that
Mutombo Kankonde, MD
2400 Trawood Drive
Suite 303
El Paso, TX 79936
2400 Trawood Drive
Suite 303
El Paso, TX 79936
has participated in the enduring material titled
Mechanisms and Actions of HER2-Targeting Agents in Breast Cancer
April 1, 2013
and is awarded
0.50
AMA PRA Category 1 Credit(s)™.
Medscape, LLC designates this enduring material for a maximum of 0.50 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.
Medscape, LLC is accredited by the Accreditation Council for
Continuing Medical Education (ACCME) to provide continuing medical
education for physicians.
For information on
applicability and acceptance of continuing education credit for this
activity, please consult your professional licensing board.
| Certificate Number: 42523061 |  Cyndi Grimes Director, Continuing Medical Education Medscape, LLC |
==============================================================
Options to Her2 positive tumors after Herceptin!
T-DM1
pertuzumab
lapatinib +Xeloda
combination with Everolimus Neratinib
Options to Her2 positive tumors after Herceptin!
T-DM1
pertuzumab
lapatinib +Xeloda
combination with Everolimus Neratinib
Saturday, March 30, 2013
CANCER CELLS AND THE CURE
These cellular reactions respect basic chemical laws of ion and atom interactions. However, the general direction from reactions is imposed by the cellular mission which is clearly determined by the location of the cell in a tissue or organ and the expected function to be performed by the organ. At any given point in time, the cell is either in differentiation or proliferation, or changing to adapt to current circumstances of the cell. These functions and adaptations are caused by environmental stimuli reaching the cell.
These stimuli could be chemical, hormonal, traumatic or electric and they reach receptors which cross the cellular boundaries or membrane, and affect the molecules belonging to a signal transduction pathway. The signal goes on to affect genes in the nucleus of the cell where DNA will be replicated to achieve or respond to the stimuli accordingly. All reactions follow a certain flow to achieve a purpose for the cell. To control the general direction of reaction the cell uses several methods: the first is to silence un-needed genes and to amplify the expression of needed genes that carry the code for the mission to be performed.
The cell will enter division and proliferation of those genes to impose the general direction or flow of the reaction. The second method used to impose the general direction is the formation of genes that can catalyze or force the reaction to go a certain way: these are called "enzymes" for that particular reaction. If an enzyme is not formed, the reaction is not allowed to progress. Therefore, the control of what is happening is occurring this way. A third way to control the flow of direction is to promote proteins called "regulators". The more the regulators in a reaction, the more likely that regulated reaction can occur in a controlled fashion. The fourth way of controlling reaction is mole fraction which puts together certain regulators and enzymes or proteins in general which are aligned in a chain and forces molecules to go from one protein to another in the mole in a certain direction so that the output is what is needed for the mission.
These mole-like complexes of proteins are called "core binding factors". Any protein function not needed will not be incorporated in the complex. Genes are silenced by methylation, or simply by being attached to patches of molecules that belong to the histones, the histones that cover genetic material. At any given point, when a gene is needed, the cover can be re-opened or pulled back, which is called "gene remodeling". A cancer cell will tend to move away from the location where it is located not because of its intention to kill the host, but because in that location the nutrients and local conditions will be inadequate eventually to allow further growth. It will seek another location to survive. Before it moves away, it has to take steps to protect its survival. It will break adhesion to surrounding cells; this is mostly achieved by decreasing its surface adhesion molecules. It will secrete proteins that can break fibers on its way in order to get through and detection of these proteins called “metalloproteases” can signal doctors that the disease, the cancer, is on the move. In certain circumstances, it produces a mucus to protect itself against detection by the immune system.
When it arrives in the new location, the cell will produce a hormone or growth factor which gives itself advantage over the already present cells in that location. This is generally called a “tumor growth factor”. The potential for proliferation, division and growth advantage is driven through the signal transduction pathway inside the cell. This is generally achieved by the expression of a driver gene which is amplified or over-expressed forcing reaction for downstream pathways. This is called a “driver mutation”.
Experience with chemotherapy which was like a bomb with an indiscriminate effect affecting both good and bad cells of the host has only been able to achieve 20 to 30% of cure. Today, scientists are targeting the driver mutations to stop pathways of growth of cancer cells. We are now getting higher response rates and starting to see response in cancers that were resistant to chemotherapy, e.g. melanoma. People used to talk about cure without believing in their own statement, but with the advance of target therapy, cure is a real possibility. We are just at the beginning of our understanding of the various targets. Cure will be achieved.
PTGS2 & MSR1
PTGS2:
The very existence of the amplification of this gene attests to the fact that in Esophageal cancer the stress imposed by chemical and traumatic irritants will involve inflammatory pathways and over-expression of Cyclins and growth Factors. Over-expression of COX-2 that this gene amplification represents leads to the formation of prostaglandins which decrease membrane protection by PGH2 and PGI2, with ulceration at the tumor level resulting. When you see an ulcerated cancer in the stomach or at the base of the Esophagus, you understand what happened!
It points to the potential importance of Interferon treatment as an adjunct therapy.
MSR1 (Macrophage Scavanger Receptor 1):
This gene amplification may stop Macrophages from removing irritated and altered cancer cells,. Irritated neoplastic cells often contain HSP (Heat shock proteins) altered proteins that should trigger action by the scavenger. But Mutation at MRS1 leads to a tolerance of the existence of these neoplastic cells. The HSP are normally generated by HSPA1A, a gene " located in the major histocompatibility complex class III region, in a cluster with two closely related genes which encode similar proteins."(wikipedia)
In a normal cell, HSP will interact with ASK1 (Apoptosis Signal-Regulating Kinase1) and trigger independently Apoptosis, or use the same molecule as MAP3K5 to stimulate c-JUN (the stress pathway). And don't tell me we didn't warn you that, in the pathogenesis of Esophageal cancers, irritants will stimulate C-JUN the stress related family member of the MAP Kinases. ASK1 interacts with TNF alpha Receptor and a bunch of DNA protein Kinases that will lead to the production of inflammatory factors including the Autoimmune Antigen Ku!
There you have it, do not be surprised that HSP has much to do with other altered proteins called Amyloids...and you start getting the right idea that Alzheimer's disease is around the corner! Yes, the tolerance induced by Mutated MSR1 and HSP has something to do with the disposition of Amyloid deposits!
The very existence of the amplification of this gene attests to the fact that in Esophageal cancer the stress imposed by chemical and traumatic irritants will involve inflammatory pathways and over-expression of Cyclins and growth Factors. Over-expression of COX-2 that this gene amplification represents leads to the formation of prostaglandins which decrease membrane protection by PGH2 and PGI2, with ulceration at the tumor level resulting. When you see an ulcerated cancer in the stomach or at the base of the Esophagus, you understand what happened!
It points to the potential importance of Interferon treatment as an adjunct therapy.
MSR1 (Macrophage Scavanger Receptor 1):
This gene amplification may stop Macrophages from removing irritated and altered cancer cells,. Irritated neoplastic cells often contain HSP (Heat shock proteins) altered proteins that should trigger action by the scavenger. But Mutation at MRS1 leads to a tolerance of the existence of these neoplastic cells. The HSP are normally generated by HSPA1A, a gene " located in the major histocompatibility complex class III region, in a cluster with two closely related genes which encode similar proteins."(wikipedia)
In a normal cell, HSP will interact with ASK1 (Apoptosis Signal-Regulating Kinase1) and trigger independently Apoptosis, or use the same molecule as MAP3K5 to stimulate c-JUN (the stress pathway). And don't tell me we didn't warn you that, in the pathogenesis of Esophageal cancers, irritants will stimulate C-JUN the stress related family member of the MAP Kinases. ASK1 interacts with TNF alpha Receptor and a bunch of DNA protein Kinases that will lead to the production of inflammatory factors including the Autoimmune Antigen Ku!
There you have it, do not be surprised that HSP has much to do with other altered proteins called Amyloids...and you start getting the right idea that Alzheimer's disease is around the corner! Yes, the tolerance induced by Mutated MSR1 and HSP has something to do with the disposition of Amyloid deposits!
Esophageal Cancer (continued)
We have discussed that chemical, traumatic and sometimes burns from caustic solutions that people ingest unfortunately, that will stimulate the cellular membrane receptors which in turn will stimulate RAS, which in turn will amplify PI3K, MAP Kinase and RAL/CDC42. But remember these are stressful stimulations, so instead of the standard MAPK, the stimulation is imposing on RAS to awake the NFkB pathway, the c_JUN and at nuclear level the FOS which results in inflammatory proteins stimulation including cyclin production or liberation from membranes with extracellular release of Metalloproteases. Cyclins combining to CDCs will exacerbate cell divisions and proliferation, growth factors will promote cell growth, there is an associated ligase proliferation that will impact P53 (through MDM2) and c-MYC, NOTCH, and even c_JUN itself through FBW7/hCDC4. This is how the proteasomes come into play!
By now you now
1. that amplification of c-MYC exacerbate proliferation by allowing progression of cells int S-phase and bolster DNA replication, imparting bad prognosis to cancer cells.
(nature is kind and gies you a chance to affect here by freeing RB1 and increasing FBW7. Oh! also find MYCN and the p isoform to q for answers!)
2 Rb1 does sequester E2F. you can look at it both ways. that E2F stabilize Rb1 instead, whichever way one stop the other for acting! Remember E2F activates CPP32 which increase APOPTOSIS! (DRUM UP THOSE TARGET THERAPY!)
3.REMEMBER RAS NEEDS A FATTY ACID MOIETY TO STAY AT THE MEMBRANE FOR ITS ACTIVITY (THIS IS ITS SO CALLED POST-TRANSLATIONAL MODIFICATION) BY THIS PHRENYLATION IS IMPAIRED BY THE FARNESYL TRANSFERASE INHIBITOR
(ie. TIPIFARNIB) THAT WE DO NOT USE ENOUGH I FEEL! ALTHOUGH I AGREE THAT SIDE EFFECTS MAY BE PROHIBITIVE GIVEN THE EXTENT OF WHICH NORMAL CELLS WILL ALSO BE COMPROMISED. BUT IT GOES TO THE FACT THAT WE NEED TO FURTHER TWEAK THIS MODALITY TO MAKE IT USABLE IN CANCERS!
ANTI-MEK HAVE DEMONSTRATED USE IN KRAS MUTATION CANCERS! MAY BE ESOPHAGEAL CANCERS WILL BENEFIT HERE!
4Role of combining Velcade and Carfilzomib in Esophageal cancer to see if c-Myc can be affected? Will it increase the right Ligand (FBW7)?
By now you now
1. that amplification of c-MYC exacerbate proliferation by allowing progression of cells int S-phase and bolster DNA replication, imparting bad prognosis to cancer cells.
(nature is kind and gies you a chance to affect here by freeing RB1 and increasing FBW7. Oh! also find MYCN and the p isoform to q for answers!)
2 Rb1 does sequester E2F. you can look at it both ways. that E2F stabilize Rb1 instead, whichever way one stop the other for acting! Remember E2F activates CPP32 which increase APOPTOSIS! (DRUM UP THOSE TARGET THERAPY!)
3.REMEMBER RAS NEEDS A FATTY ACID MOIETY TO STAY AT THE MEMBRANE FOR ITS ACTIVITY (THIS IS ITS SO CALLED POST-TRANSLATIONAL MODIFICATION) BY THIS PHRENYLATION IS IMPAIRED BY THE FARNESYL TRANSFERASE INHIBITOR
(ie. TIPIFARNIB) THAT WE DO NOT USE ENOUGH I FEEL! ALTHOUGH I AGREE THAT SIDE EFFECTS MAY BE PROHIBITIVE GIVEN THE EXTENT OF WHICH NORMAL CELLS WILL ALSO BE COMPROMISED. BUT IT GOES TO THE FACT THAT WE NEED TO FURTHER TWEAK THIS MODALITY TO MAKE IT USABLE IN CANCERS!
ANTI-MEK HAVE DEMONSTRATED USE IN KRAS MUTATION CANCERS! MAY BE ESOPHAGEAL CANCERS WILL BENEFIT HERE!
4Role of combining Velcade and Carfilzomib in Esophageal cancer to see if c-Myc can be affected? Will it increase the right Ligand (FBW7)?
ESOPHAGEAL CANCER
Whether you consider Adenocarcinoma or squamous cell cancer of the Esophagus, you will have to come to the realization that you are looking at the result of a chronic irritation on Esophageal mucosa. The irritation in chemical when it comes to Gastric Acid for the Adenocarcinoma of the Gastro-esophageal (G-E) junction, or it could be traumatic as rough stuffs are swallowed, this include chemicals and alcohols (these days you cannot imagine what people put in their mouth-live scorpions even!) So chemical and rough stuff induce a squamous cell cancer in the upper Esophagus while Gastric reflux lead to an An Adenocarcinoma. However you get their the insult will be register at cell level through our membrane receptors which are trans-membrane structures. In some of these receptors, there is portion facing the cytoplasm called RTK (receptor Tyrosine Kinase) which dimerize on stimulation and/or autophosphorylate, , and This commotion attracts the Sons of the Sevenless which lights up the RAS by bringing in the Erb2 to attach to he RTK. My sons of the Sevenless gives off a Guanine that activates RAS. And here we go with Ras and related molecule amplifications. RAS is known to amplify 3 pathways
1. the MAP Kinase pathways which will go on to stimulate formation of transcription factors that will make proteins structures to deal with the situation, or tell the cell what directions things will go or manage the challenge globally!
2. the RAL/CDC42 pathways that send message to the Cytoskeleton (the nervous system at cell level)
we are talking about stand up and fight Vs flight management. This system by following the Actininic cytoskeleton through the mambrane and the Reticulum endothelium (RE) reaches in a flash the Nucleus (that's where RE goes ) We are talking in a flash the cell is informed at Histone level and is ready to process the info and react!
3. The PI3K pathways which readies the cellular response which include needed protein response but also include initiating programmed death if that is an appropriate response! (The FOX (o) is hidden behind the MTOR down this pathway! FOXO hold the key to survival of the cell!
REMEMBER RAS CAN NOT GO WILD EXCITING THESE PATHWAYS, IT IS TEMPERED BY NF1 WHICH BELONG TO THE FAMILY OF GAP, GIVING A GAP (BREAK) OF FUNCTION TO RAS . IF THERE IS NO GAP, AND RAS GOES WILD, YOU GOT YOURSELF A NEUROFIBROMATOSIS ON YOUR HAND TO DEAL WITH! IT IS WORTH NOTING THAT GAP CAN BE DECREASED RELATIVELY TO GEF. THAT IS TO MUCH GEF IS TRANSLATED AS A DECREASED GAP AS GEF TAKES CONTROL. SO ONE WAY TO AFFECT RAS IS TO INCREASE GEF (THE BALANCE WILL BE BROKEN TO THE DISADVANTAGE OF GAP) AND RAS WILL BE HYPERSTIMULATED! (TARGET THERAPY)
AFTER THIS VERIFICATION OF THE NOTION THAT THINGS START SIMPLY BUT GET OUT OF HAND QUICKLY IN CELLULAR METABOLISM, LETS GO BACK TO ESOPHAGEAL CANCER AND PATHWAYS STIMULATION.
(WILL CONTINUE)
Whether you consider Adenocarcinoma or squamous cell cancer of the Esophagus, you will have to come to the realization that you are looking at the result of a chronic irritation on Esophageal mucosa. The irritation in chemical when it comes to Gastric Acid for the Adenocarcinoma of the Gastro-esophageal (G-E) junction, or it could be traumatic as rough stuffs are swallowed, this include chemicals and alcohols (these days you cannot imagine what people put in their mouth-live scorpions even!) So chemical and rough stuff induce a squamous cell cancer in the upper Esophagus while Gastric reflux lead to an An Adenocarcinoma. However you get their the insult will be register at cell level through our membrane receptors which are trans-membrane structures. In some of these receptors, there is portion facing the cytoplasm called RTK (receptor Tyrosine Kinase) which dimerize on stimulation and/or autophosphorylate, , and This commotion attracts the Sons of the Sevenless which lights up the RAS by bringing in the Erb2 to attach to he RTK. My sons of the Sevenless gives off a Guanine that activates RAS. And here we go with Ras and related molecule amplifications. RAS is known to amplify 3 pathways
1. the MAP Kinase pathways which will go on to stimulate formation of transcription factors that will make proteins structures to deal with the situation, or tell the cell what directions things will go or manage the challenge globally!
2. the RAL/CDC42 pathways that send message to the Cytoskeleton (the nervous system at cell level)
we are talking about stand up and fight Vs flight management. This system by following the Actininic cytoskeleton through the mambrane and the Reticulum endothelium (RE) reaches in a flash the Nucleus (that's where RE goes ) We are talking in a flash the cell is informed at Histone level and is ready to process the info and react!
3. The PI3K pathways which readies the cellular response which include needed protein response but also include initiating programmed death if that is an appropriate response! (The FOX (o) is hidden behind the MTOR down this pathway! FOXO hold the key to survival of the cell!
REMEMBER RAS CAN NOT GO WILD EXCITING THESE PATHWAYS, IT IS TEMPERED BY NF1 WHICH BELONG TO THE FAMILY OF GAP, GIVING A GAP (BREAK) OF FUNCTION TO RAS . IF THERE IS NO GAP, AND RAS GOES WILD, YOU GOT YOURSELF A NEUROFIBROMATOSIS ON YOUR HAND TO DEAL WITH! IT IS WORTH NOTING THAT GAP CAN BE DECREASED RELATIVELY TO GEF. THAT IS TO MUCH GEF IS TRANSLATED AS A DECREASED GAP AS GEF TAKES CONTROL. SO ONE WAY TO AFFECT RAS IS TO INCREASE GEF (THE BALANCE WILL BE BROKEN TO THE DISADVANTAGE OF GAP) AND RAS WILL BE HYPERSTIMULATED! (TARGET THERAPY)
AFTER THIS VERIFICATION OF THE NOTION THAT THINGS START SIMPLY BUT GET OUT OF HAND QUICKLY IN CELLULAR METABOLISM, LETS GO BACK TO ESOPHAGEAL CANCER AND PATHWAYS STIMULATION.
(WILL CONTINUE)
Friday, March 29, 2013
DISCUSSING GENES IN ESOPHAGEAL CANCERS
* Esophageal cancers varies by types, and types are related to location
with the squamous cell cancer involving most of the upper 2 thirds of the Esophagus. It is this cancer that is linked to patients who are black, to Achalasia, caustic injury, Plummer -Vinson disease smoking and excessive alcohol consumption and to HPV. Adenocarcinoma are linked to GERD, Barrettt Esophagus, white race, smoking and obesity. It is also characteriZed by Metaplasia and Barett morphology
(to be continued)
Genes in esophageal cancers
Mutation of Rb1
and overexpression of Cyclin D1
MSR1, ASCC1, and CTHRC1
CDK4 and CDK6
* Esophageal cancers varies by types, and types are related to location
with the squamous cell cancer involving most of the upper 2 thirds of the Esophagus. It is this cancer that is linked to patients who are black, to Achalasia, caustic injury, Plummer -Vinson disease smoking and excessive alcohol consumption and to HPV. Adenocarcinoma are linked to GERD, Barrettt Esophagus, white race, smoking and obesity. It is also characteriZed by Metaplasia and Barett morphology
(to be continued)
Genes in esophageal cancers
Mutation of Rb1
and overexpression of Cyclin D1
MSR1, ASCC1, and CTHRC1
CDK4 and CDK6
RHBDF2 gene EGFR MET DLEC1
PTGS2 FEZ1 DMBT1 p16 p14
ODC1 CDK4 CDK6 CD9 E2F
SPARC p33 p53 Rb1 SLP1 c-MYC
NK4 HGF MDM2 PPRP UPRT p21WAF1 CIP
New Medications in Refractory Myeloma
After failure of Revlimid, Velcade and Dexamethasone
particularly in Del 17 patient
4 options:
1. Elotuzumab + Revlimid + Dex
2. Elotuzumab + Velcade + Dex
3. Carfilzomib +Dex
4.Pomalidomid + Velcade + Dex
Newer options
- ARRY-520 +/- Low dose Revlimid +Dex
-DARATUMUMAB
-ANTI - CD 38 MONOCLONAL ANTIBODY.
NEW COMBINATION : REVLIMID+THALIDOMID +dex IN BAD PROGNOSIS PATIENTS
After failure of Revlimid, Velcade and Dexamethasone
particularly in Del 17 patient
4 options:
1. Elotuzumab + Revlimid + Dex
2. Elotuzumab + Velcade + Dex
3. Carfilzomib +Dex
4.Pomalidomid + Velcade + Dex
Newer options
- ARRY-520 +/- Low dose Revlimid +Dex
-DARATUMUMAB
-ANTI - CD 38 MONOCLONAL ANTIBODY.
NEW COMBINATION : REVLIMID+THALIDOMID +dex IN BAD PROGNOSIS PATIENTS
BREAKING NEWS: New CPRIT Oversight Committee Proposals Kill Commercialization Arm Of Organization
Posted Friday , March 15,2013 from www.statesman.com › Business
A set of newly-published proposals put forth by the CPRIT
oversight committee strips out the Chief Commercialization Officer and
related committees, suggesting that the cancer fighting organization
will no longer be permitted to attract new biotech companies into Texas.A sweeping set of new proposals posted today on the Texas Register by the CPRIT oversight committee seeks to make wide-ranging changes to the cancer research funding organization by effectively eliminating its role in using Texas taxpayer dollars to foster biotech startups in the state, as well as attract major biotech corporations to relocate. The new statues, which propose changes to virtually every aspect of the organization, appears to replace the entire commercialization arm with new compliance and oversight officers, as represented in Section 703.2 of the document:
Section 703.2 adds the definitions for “chief product development officer”, “compliance officer”, “product development review council”, and “product development prospects.” The section proposes to delete references to the “chief commercialization officer”, the “commercialization review council”, and “commercial prospects”. The section also clarifies the definition of “cancer research” to include research into the prevention of cancer.Deleting references to the “chief commercialization officer,” “commercialization review council,” and “commercial prospects,” suggests that CPRIT’s new organizational structure will not include its once robust operations to attract private biotech companies into the state. These changes would lay to waste incubator programs designed to help foster new start-ups within Texas, as well as significant relocations of biotech operations.
Conversely, the addition of roles such as “chief product development officer,” “product development review council,” and “product development prospects” would suggest that the commercialization arm will now be more limited in scope, and focus on smaller, in-state product development projects, rather than attracting entire business and operations into the state. The new document describes the role of chief product development officer as: “. . . the individual employed by the Institute to oversee the review and evaluation of grant applications for the development of drugs, biological, diagnostics, or devices arising from cancer research and prevention activities.”
Similarly, the designation of product development prospects is described as: “the potential for development of products, services, or infrastructure to support cancer research efforts, including but not limited to pre-clinical, clinical, manufacturing, and scale up activities.”
It is particularly interesting that this section juxtaposes the deletion of CPRIT’s commercialization arm with the addition of a compliance officer — a detail that only further suggests that these proposals constitute a sea change in the scope and direction that CPRIT will take in the foreseeable future, should these proposals be passed by the Texas legislature.
Download a .pdf of the CPRIT Oversight Committee’s proposed amendments.
Be sure to subscribe to BioNews Texas and receive instant notifications of updates to the CPRIT story and more!
Let us know in the comment section below what you think of this proposed change to the way that CPRIT operates.
Related News Articles:
Subscribe to:
Posts (Atom)