Our study on lung cancer detection got boosted by UTEP individual efforts, indeed the availability of some Antibodies to certain genes allowed the crew led by DR Chai to screen sera of lung cancer patients for these molecules. This extra efforts allowed us to identify Cyclin B1, NPM1, and 8 other antibodies at various quantities. Suffice is to add that Cyclin B1 was found more frequently in 26 % of patients. We have discussed NPM1 briefly in other blog. But the confirmation of the presence of Cyclin B1 again point to the point that a number of molecular transformations will be occurring once the neoplastic process is underway early in the cascade of cellular events.
One of the first event after the neoplasm is engaged, most likely cigarette induced MDM2 driven changes, is that mitosis should be the general orientation of the now proliferating malignant cell. And Cyclin B1 does this by committing the cell to cancerous proliferation. With Cyclin B1 increased, the cancerous cell is squarely turned to changes favoring division and proliferation. Protection of the Nucleus for chromosomes is broken down to allow spindle formation, this is achieved through Cyclin B1. Clearly under Cyclin B1 cellular division goes wild and natural stops of this process by the APC gene is removed by the shutting down of the Mitosis exit door!
Other gene interacting with Cyclin B1 will engage P53, p38/JNK, MAPK and even the stress related HSP genes. Through CRK, the Reeling and DABK1 is not far behind!
Another observation was a Koc gene amplification. This is another finding pointing to cancer underway. Here again certain RNA need to be shut down to and our friend Koc will do that! This is an attempt to stream line the activities.
Monday, May 5, 2014
Sunday, May 4, 2014
STILL TRYING TO FURTHER PROBE THE LUNG CANCER DATA AT CRBCM
LETTER TO OUR INVESTIGATORS
would you please send us the list of the names of the 10 antibodies that
Dr. Choi has also measured in the lung cancer project?
Also, please let us know when you will have the raw data available as we would like to look at it
and, for example, check if there is a correlation between the expression of MDM2 and the duration and intensity of smoking (years/packs per year) in the lung cancer patients.
CRBCM!
would you please send us the list of the names of the 10 antibodies that
Dr. Choi has also measured in the lung cancer project?
Also, please let us know when you will have the raw data available as we would like to look at it
and, for example, check if there is a correlation between the expression of MDM2 and the duration and intensity of smoking (years/packs per year) in the lung cancer patients.
We are looking forward to doing further analysis of the data
collected and then apply for more funding to run the study with a larger
number of samples.
With our thanks and very best regards,CRBCM!
How about "Embryonal" and "Blastic appearance" inside information
*According to Perez Moreno et al....E2A works in the depression of E-cadherin
a phenomena which intervene in the metastasis of cancer...is fair to conclude the Blocking E2A could decrease metastatic potential of cancers?
*Depression of E-Cadherin may also play a role in Epithelial mesengial transformation or transition, a phenomena that seems to occur early in the neoplastic transformation, could blocking E2A be used in cancer prevention?
*does the embryonal or blastic appearance is linked to the over expression of the HOXb1 and family
or is it linked to the overexpression of PBX1
Memorable possible intricacy
================================================
(TCF3) !- HOXb1------E-Cadherin
*E2A---PBX1---!- MEIS-1-----MLL+PAF----TET1---c-MYB
! !- HOXs
!
CBP/p300----TWIST-1
==================================================
what about SRG3? what do we know?"SRG3 (Smarcc1) is a core subunit of the SWI/SNF complex. In the absence of SRG3, embryonic development ceases during peri-implantation stages," ncbi! could intervene in differentiation arrest?
=================================================
The MEK must be somewhere, and Rho gene!
ARE THESE POTENTIAL TARGETS?
THE HOXS ARE STANDING OUT!
a phenomena which intervene in the metastasis of cancer...is fair to conclude the Blocking E2A could decrease metastatic potential of cancers?
*Depression of E-Cadherin may also play a role in Epithelial mesengial transformation or transition, a phenomena that seems to occur early in the neoplastic transformation, could blocking E2A be used in cancer prevention?
*does the embryonal or blastic appearance is linked to the over expression of the HOXb1 and family
or is it linked to the overexpression of PBX1
Memorable possible intricacy
================================================
(TCF3) !- HOXb1------E-Cadherin
*E2A---PBX1---!- MEIS-1-----MLL+PAF----TET1---c-MYB
! !- HOXs
!
CBP/p300----TWIST-1
==================================================
what about SRG3? what do we know?"SRG3 (Smarcc1) is a core subunit of the SWI/SNF complex. In the absence of SRG3, embryonic development ceases during peri-implantation stages," ncbi! could intervene in differentiation arrest?
=================================================
The MEK must be somewhere, and Rho gene!
ARE THESE POTENTIAL TARGETS?
THE HOXS ARE STANDING OUT!
Friday, May 2, 2014
notes
IN ALL
*Cells are devoided of granules
*presence of CD19, CD22
*leukemia Cutis
----
some of the prognosis factors
elevated LDH
high white count
evidence of CNS involvement?
pro-B cell ALL
*t(4,11), t(8,14), >5 cytogenic abnormalities
t(1,19),t(9,22)
Good prognosis: del-9 and hyperploidy (50-60 Xsomes
=========================================
*Cells are devoided of granules
*presence of CD19, CD22
*leukemia Cutis
----
some of the prognosis factors
elevated LDH
high white count
evidence of CNS involvement?
pro-B cell ALL
*t(4,11), t(8,14), >5 cytogenic abnormalities
t(1,19),t(9,22)
Good prognosis: del-9 and hyperploidy (50-60 Xsomes
=========================================
Thursday, May 1, 2014
Notes on Myeloma, lesson learned (II)
*If del 17 present -give RVD (revlimid, velcade, Decadron)
*After first transplant, your options are:
1.Tandem Therapy Vs Revlimid
2.Maintenance therapy with Revlimid +/- Velcade based on Cytogenetics
whatever drug you choose give until progression of disease.
*In younger patients 3 drug therapy is better
-to increase efficacy, which turn out to be better,
-Maintenance therapy is standard
for high risk patients, think RVD
*for all transplant candidate
Give "triple therapy" for induction
but again for high risk Myeloma, think RVD
*some argue that Myeloma is a curable disease, indeed when you look at survival curb, a plateau exists...meaning aggressive treatment when feasible should be offered to our patients!
*Some start questioning that adding alkylating agent (Cytoxan) to the mix in myeloma may be pouring flame to the Mutations already present, CRBCM agrees! But may be important when del 17 present!
*Obtaining MRD appears important to reduce proportion of non responders to treatment.
and VTD appears beter than TD. the proportion of VGPR 62 Vs 20
*and VTD anihilate the risk of t(4,14) translocation, choose this combination in people with this translocation
*Velcade should no longer be given Intravenously, always give Sub-cutaneously to decrease significantly Neuropathy!
*carfilzomid has definitely entered the frey, combination therapy CRD being offered, see results in the literature!
*One may consider deferring transplant in patient who are reluctant to proceed:(up to 25% of patients who qualify for transplant actually delay therapy believe it or not!)
3 criteria
A-Standard 3 medications used, and no complicated Cytogenetics in play
B-good response to therapy (high VGPR)
C-Good tolerance of treatment!
*CR 1X 10 (power 8)
but can consider by Molecular or flow 1x10(power4)
*Maintenance therapy is definitely standard since it has shown longer progression free and overall survival (HOVON65/GMMG-HD4) Use of Velcade IV vs SC discussed earlier
*Ixazomid best for maintenance therapy since PO, and once a week dose considered, with decreased Neuropathy!
*for maintenance therapy, particularly in bad Cytogenetics, add Velcade to Rev. (please try to avoid Decadron in this setting if possible for side effects!)
*Major development
Velcade is safe in renal failure
and guess what is added to the list Carfilzomib, also safe!
renal failure bad for Pomalidomide!!! do not use!!!
*Most if not all Oncologists will treat laboratory signs of progression of disease
ptions would include
1.RVD
2.Resume Velcade
3.Carfilzomib
4.Pomidomide
5.DOXORUBICIN (+/- Melphalan?)
(All info to be used cautiously after check of literature)
Note I still to come!
CRBCM, tracking the news!lesson learned in LAS VEGAS!CRBCM does not fabricate and does not own this information....but this may help someone somewhere!
*After first transplant, your options are:
1.Tandem Therapy Vs Revlimid
2.Maintenance therapy with Revlimid +/- Velcade based on Cytogenetics
whatever drug you choose give until progression of disease.
*In younger patients 3 drug therapy is better
-to increase efficacy, which turn out to be better,
-Maintenance therapy is standard
for high risk patients, think RVD
*for all transplant candidate
Give "triple therapy" for induction
but again for high risk Myeloma, think RVD
*some argue that Myeloma is a curable disease, indeed when you look at survival curb, a plateau exists...meaning aggressive treatment when feasible should be offered to our patients!
*Some start questioning that adding alkylating agent (Cytoxan) to the mix in myeloma may be pouring flame to the Mutations already present, CRBCM agrees! But may be important when del 17 present!
*Obtaining MRD appears important to reduce proportion of non responders to treatment.
and VTD appears beter than TD. the proportion of VGPR 62 Vs 20
*and VTD anihilate the risk of t(4,14) translocation, choose this combination in people with this translocation
*Velcade should no longer be given Intravenously, always give Sub-cutaneously to decrease significantly Neuropathy!
*carfilzomid has definitely entered the frey, combination therapy CRD being offered, see results in the literature!
*One may consider deferring transplant in patient who are reluctant to proceed:(up to 25% of patients who qualify for transplant actually delay therapy believe it or not!)
3 criteria
A-Standard 3 medications used, and no complicated Cytogenetics in play
B-good response to therapy (high VGPR)
C-Good tolerance of treatment!
*CR 1X 10 (power 8)
but can consider by Molecular or flow 1x10(power4)
*Maintenance therapy is definitely standard since it has shown longer progression free and overall survival (HOVON65/GMMG-HD4) Use of Velcade IV vs SC discussed earlier
*Ixazomid best for maintenance therapy since PO, and once a week dose considered, with decreased Neuropathy!
*for maintenance therapy, particularly in bad Cytogenetics, add Velcade to Rev. (please try to avoid Decadron in this setting if possible for side effects!)
*Major development
Velcade is safe in renal failure
and guess what is added to the list Carfilzomib, also safe!
renal failure bad for Pomalidomide!!! do not use!!!
*Most if not all Oncologists will treat laboratory signs of progression of disease
ptions would include
1.RVD
2.Resume Velcade
3.Carfilzomib
4.Pomidomide
5.DOXORUBICIN (+/- Melphalan?)
(All info to be used cautiously after check of literature)
Note I still to come!
CRBCM, tracking the news!lesson learned in LAS VEGAS!CRBCM does not fabricate and does not own this information....but this may help someone somewhere!
Wednesday, April 30, 2014
Natural laws at play in CLL-Theory
In all the pathology, there is no disease that makes so much sense than Chronic Lymphocytic Leukemia disease I will beg to venture. Our understanding of this disease has grown so rapidly that what is left to discover is probably not as much as one may think. What is needed today is a reorganization of what we know and minute details particularly at the Nuclear levels. The disease affects about 15000 people, and kills about a third of our people who happen to have gone in a wrong path because of a genetic failure particularly in our way of managing infections and cellular death. And along these paths, there are laws that need to be followed, and any failure of following these laws leads to these dangerous disease called CLL.
The first observation to remember following this theory is that there is no clear environmental disaster that can induce CLL directly unless people exposed have a genetic failure in their cellular death control! CLL is the only type of leukemia not noted after the Chernobyl Nuclear Reactor incident and there no correlation with CLL with other chemicals or Benzene exposures!
Infections however have a demonstrated activity in CLL occurrence. Scientists will tell you tha disturbances of the NF-KB, NFAT and STATs are commonly found in this disease. With the Infections, one can quickly conclude that Cytokines and growth factors are and must be involved and they are (ie. disturbance at IL4). (Adenopathies'swelling is a result of cytokine activity!) These are common occurrences, why is it that CLL is not why spread?
1.For CLL to occur, you got to have disturbance in the law against cellular death.
The first evidence for this is the fact that mainly and or only disturbance in DAPK 1 (Death receptor) has been clearly and convincingly demonstrated to be found in familial CLL. There is a law of nature that says, "to fight infection, the cell must close the door to programmed death, But Apoptosis must happen when certain circumstances are met". In CLL, This last portion of the law must not be met! The B cell involved, most likely a memory cell, has gotten rid of genes that fulfill this last portion of the law! They forget the notion of death. It is not by mistake that sometime up to 98% of CLL cells have deletion of 13q14 which removes the regulator of Bcl-2 (miR16). And it is not by mistake that there is an expansion of of Bcl-2, bak , Mcl-1 and XIAP reported in the literature. (and try to find bax or caspases, they are profoundly "suppressively" disturbed) All are a consequence of relatively total suppression of Apoptosis. Now wonder why the cells of CLL are mature non dying cells!
2.The law of desensitization.
When an antigen, or any stimulant persists at a receptor, natural laws will kick in to engage desensitization. Nor desensitization has been normally described as decrease in receptors. The reality is just a it more complex. As a matter of facts, decreasing receptors which are proteins assumes decreasing gene or gene expression but the reality can be more severe! Gene could be mutated or silenced, or fully deleted. Sometimes the full arm containing the gene could be lost. There are many deletions in CLL and silencing of promoters (ID4, SFRP family and even DAPK) is notoriously common. Desensitization can start at receptors, G proteins to miRs and Chromosome arms removal! This happens for proteins involve in regulations of cytokines, regulators of many involved genes, and hell, even Glycogene regulation is deranged in the process! The law of desensitization is violated big time here! In presence of chronic stimulation, even The IgVh region is Mutated! (a strong prognosis in CLL)
Abruptly you find yourself facing the inadequacy of current Biomarkers for CLL. But things are coming your way with a vengeance and soon! The CRBCM is following...!
The first observation to remember following this theory is that there is no clear environmental disaster that can induce CLL directly unless people exposed have a genetic failure in their cellular death control! CLL is the only type of leukemia not noted after the Chernobyl Nuclear Reactor incident and there no correlation with CLL with other chemicals or Benzene exposures!
Infections however have a demonstrated activity in CLL occurrence. Scientists will tell you tha disturbances of the NF-KB, NFAT and STATs are commonly found in this disease. With the Infections, one can quickly conclude that Cytokines and growth factors are and must be involved and they are (ie. disturbance at IL4). (Adenopathies'swelling is a result of cytokine activity!) These are common occurrences, why is it that CLL is not why spread?
1.For CLL to occur, you got to have disturbance in the law against cellular death.
The first evidence for this is the fact that mainly and or only disturbance in DAPK 1 (Death receptor) has been clearly and convincingly demonstrated to be found in familial CLL. There is a law of nature that says, "to fight infection, the cell must close the door to programmed death, But Apoptosis must happen when certain circumstances are met". In CLL, This last portion of the law must not be met! The B cell involved, most likely a memory cell, has gotten rid of genes that fulfill this last portion of the law! They forget the notion of death. It is not by mistake that sometime up to 98% of CLL cells have deletion of 13q14 which removes the regulator of Bcl-2 (miR16). And it is not by mistake that there is an expansion of of Bcl-2, bak , Mcl-1 and XIAP reported in the literature. (and try to find bax or caspases, they are profoundly "suppressively" disturbed) All are a consequence of relatively total suppression of Apoptosis. Now wonder why the cells of CLL are mature non dying cells!
2.The law of desensitization.
When an antigen, or any stimulant persists at a receptor, natural laws will kick in to engage desensitization. Nor desensitization has been normally described as decrease in receptors. The reality is just a it more complex. As a matter of facts, decreasing receptors which are proteins assumes decreasing gene or gene expression but the reality can be more severe! Gene could be mutated or silenced, or fully deleted. Sometimes the full arm containing the gene could be lost. There are many deletions in CLL and silencing of promoters (ID4, SFRP family and even DAPK) is notoriously common. Desensitization can start at receptors, G proteins to miRs and Chromosome arms removal! This happens for proteins involve in regulations of cytokines, regulators of many involved genes, and hell, even Glycogene regulation is deranged in the process! The law of desensitization is violated big time here! In presence of chronic stimulation, even The IgVh region is Mutated! (a strong prognosis in CLL)
Abruptly you find yourself facing the inadequacy of current Biomarkers for CLL. But things are coming your way with a vengeance and soon! The CRBCM is following...!
Tuesday, April 29, 2014
Some genes of interest
1.MTNR1B : A MELATONIN GENE
" insulin levels also exhibit a nocturnal drop, which has previously been suggested to be controlled, at least in part, by melatonin. This regulation can be explained by the proposed inhibitory action of melatonin on insulin release." Mulder et al.
This gene has been linked to gestational Diabetes and some have used it to secgregate patient with propensity to Diabetes Mellitus type 2.
2.HHEX
" HHEX serves to repress VEGFA, another protein which is important in endothelial cell development."wikipedia...Can it play a role in angiosarcoma?
PAZ et al " Hhex is a critical regulator of hematopoietic development and is necessary for the maturation and proliferation of the earliest definitive hematopoietic progenitors."
HHEX interacts with SOX13
" SOX13 is known to repress Wnt/TCF signaling by interacting with TCF1. We show that Hhex is able to block the SOX13-dependent repression of Wnt/TCF activity by displacing SOX13 from the SOX13·TCF1 complex."Marfil et al
"Otx2, and Lim1 appear to promote hhex transcription through homeobox sites in a Wnt-responsive element located between −0.65 to −0.55 Kb of the hhex promoter. (2) Siamois/Twin also induce the expression of the BMP-antagonists Chordin and Noggin, " RANKIN et al
for CRBCM, role in pancreatic cancer, liver cancer and thyroid cancer needs further clarification
3.Cytokynes (EPC)-JAKs---STAT 3,5----Bcl-xL ----CYTOCHROMEC---CASPASE9- (WIKIMEDIA)
is this the mechanism of PTSD.?
" insulin levels also exhibit a nocturnal drop, which has previously been suggested to be controlled, at least in part, by melatonin. This regulation can be explained by the proposed inhibitory action of melatonin on insulin release." Mulder et al.
This gene has been linked to gestational Diabetes and some have used it to secgregate patient with propensity to Diabetes Mellitus type 2.
2.HHEX
" HHEX serves to repress VEGFA, another protein which is important in endothelial cell development."wikipedia...Can it play a role in angiosarcoma?
PAZ et al " Hhex is a critical regulator of hematopoietic development and is necessary for the maturation and proliferation of the earliest definitive hematopoietic progenitors."
HHEX interacts with SOX13
" SOX13 is known to repress Wnt/TCF signaling by interacting with TCF1. We show that Hhex is able to block the SOX13-dependent repression of Wnt/TCF activity by displacing SOX13 from the SOX13·TCF1 complex."Marfil et al
"Otx2, and Lim1 appear to promote hhex transcription through homeobox sites in a Wnt-responsive element located between −0.65 to −0.55 Kb of the hhex promoter. (2) Siamois/Twin also induce the expression of the BMP-antagonists Chordin and Noggin, " RANKIN et al
for CRBCM, role in pancreatic cancer, liver cancer and thyroid cancer needs further clarification
3.Cytokynes (EPC)-JAKs---STAT 3,5----Bcl-xL ----CYTOCHROMEC---CASPASE9- (WIKIMEDIA)
is this the mechanism of PTSD.?
Monday, April 28, 2014
Prevention and monitoring following cellular zones
As predominant abnormalities of genes are more described as they are specific to each cancer, most likely location of genes in the cell could further characterize gene location for further development of prevention intervention.
These interventions may include:
-gene modification (morphologic, post translational modifications, and otherwise...)
-gene activation that induce overexpression
-gene suppression which induce deactivation (PTEN)
-gene silencing (through methylation and other complementary molecules)
-etc...
Whether you approach the gene targeted for intervention by standard approach or nanotechnology, it is important to predict where you are more likely to find this gene. Is the gene more likely in the extracellular matrix (Metalloprotease) or in the Nucleus or rether in the epigenic zone. Where is the gene that is more likely to be other mutated, over expressed or suppressed.
Most of the times, given the light speed of interactions and travel down the pathways, where to intervene may not be relevant, but increasing the odds force scientist to locate intervention points. ie, Patient with lobular cancer with history of Familial Gastric cancers are known to have E-Cadherin abnormality, focusing prevention efforts on the membrane, will go a long way than focusing studies on Telomeres...
To be continued.....
These interventions may include:
-gene modification (morphologic, post translational modifications, and otherwise...)
-gene activation that induce overexpression
-gene suppression which induce deactivation (PTEN)
-gene silencing (through methylation and other complementary molecules)
-etc...
Whether you approach the gene targeted for intervention by standard approach or nanotechnology, it is important to predict where you are more likely to find this gene. Is the gene more likely in the extracellular matrix (Metalloprotease) or in the Nucleus or rether in the epigenic zone. Where is the gene that is more likely to be other mutated, over expressed or suppressed.
Most of the times, given the light speed of interactions and travel down the pathways, where to intervene may not be relevant, but increasing the odds force scientist to locate intervention points. ie, Patient with lobular cancer with history of Familial Gastric cancers are known to have E-Cadherin abnormality, focusing prevention efforts on the membrane, will go a long way than focusing studies on Telomeres...
To be continued.....
Sunday, April 27, 2014
OUR OLD EXPERIENCE HELPS ! LAS VEGAS ROCKS!
Yes as a drug gains more indications, the past experience makes it easier for Oncologist practitioner to re-use drugs they have been used to!
For Hepatocellular Carcinoma, the drug on the mind of all oncologists is NEXAVAR, yeah, we have been accustomed to managing its rashes and Diarrhea, and watch its marrow suppression. A combination of weekly visits and then monthly for our patients to start with!
Well it is the same dance once again in Metastatic thyroid cancer, the kind of Metastatic progressing and resistant to Iodine based treatments! NFX1 OR SHOULD WE SAY
NBCI-gene "Inappropriate activation of NFKB has been associated with a number of inflammatory diseases while persistent inhibition of NFKB leads to inappropriate immune cell development or delayed cell growth.'
Jing Du et al:"Correlation analysis revealed that there was a positive relationship between the level of HPV16 E7 and the expression of p65. The correlation between E7 and p53 was also significant, although to a lesser degree"
IT'S NOT JUST P65, BUT P300, P25
AND THE NOTCH1 IS NOT FAR ! MEANING VEGF-A-DELTA,JAGGED1,AND A SLEW OF
MIR (s) AND SF3Bs, NOT TO MENTION TENACIN AND CADHERINS!
For Hepatocellular Carcinoma, the drug on the mind of all oncologists is NEXAVAR, yeah, we have been accustomed to managing its rashes and Diarrhea, and watch its marrow suppression. A combination of weekly visits and then monthly for our patients to start with!
Well it is the same dance once again in Metastatic thyroid cancer, the kind of Metastatic progressing and resistant to Iodine based treatments! NFX1 OR SHOULD WE SAY
NBCI-gene "Inappropriate activation of NFKB has been associated with a number of inflammatory diseases while persistent inhibition of NFKB leads to inappropriate immune cell development or delayed cell growth.'
Jing Du et al:"Correlation analysis revealed that there was a positive relationship between the level of HPV16 E7 and the expression of p65. The correlation between E7 and p53 was also significant, although to a lesser degree"
IT'S NOT JUST P65, BUT P300, P25
AND THE NOTCH1 IS NOT FAR ! MEANING VEGF-A-DELTA,JAGGED1,AND A SLEW OF
MIR (s) AND SF3Bs, NOT TO MENTION TENACIN AND CADHERINS!
LAS VEGAS WILL STAY ON OUR MINDS FOR A WHILE, RESPECT SILTUXIMAB FOR THIS!
*How in the world can you succeed this! But Siltuximab did, BE INDICATED IN A RARE FORM OF A RARE PRESENTATION OF A RARE DISEASE...
EVEN WIKIPEDIA DEFINE :
"Multicentric Castleman disease (MCD) involves growths at multiple sites.[8] About 50% is caused by KSHV, also called HHV-8, a gamma herpesvirus that is also the cause of Kaposi's sarcoma and primary effusion lymphoma, while the remainder of MCD are of unknown cause. The form of MCD most closely associated with KSHV is the plasmacytic form of Castleman disease while another pathologic form, the hyaline-vascular form, is generally negative for this virus."
BUT SILTUXIMAB IS:
"On April 23, 2014, Siltuximab was FDA approved under the brand name of Sylvant[11] for the treatment of patients with multicentric Castleman’s disease (MCD) who do not have human immunodeficiency virus (HIV) or human herpesvirus-8 (HHV-8).[12][13]"WIKIPIDEA
WATCH THE 2 AND GO FIGURE!
BUT LET'S GRANT IT, IT IS STILL AN ANTI-INTERLEUKIN- 6, A FACT TO BE KEPT IN MIND AS WE LOOK INTO TBI AND PTSD! CRBCM IS WORKING HARD!
EVEN WIKIPEDIA DEFINE :
"Multicentric Castleman disease (MCD) involves growths at multiple sites.[8] About 50% is caused by KSHV, also called HHV-8, a gamma herpesvirus that is also the cause of Kaposi's sarcoma and primary effusion lymphoma, while the remainder of MCD are of unknown cause. The form of MCD most closely associated with KSHV is the plasmacytic form of Castleman disease while another pathologic form, the hyaline-vascular form, is generally negative for this virus."
BUT SILTUXIMAB IS:
"On April 23, 2014, Siltuximab was FDA approved under the brand name of Sylvant[11] for the treatment of patients with multicentric Castleman’s disease (MCD) who do not have human immunodeficiency virus (HIV) or human herpesvirus-8 (HHV-8).[12][13]"WIKIPIDEA
WATCH THE 2 AND GO FIGURE!
BUT LET'S GRANT IT, IT IS STILL AN ANTI-INTERLEUKIN- 6, A FACT TO BE KEPT IN MIND AS WE LOOK INTO TBI AND PTSD! CRBCM IS WORKING HARD!
Saturday, April 26, 2014
LAS VEGAS conference III Mantle cell
We first saw the Death of CHOP/R-CHOP in this disease
Now we see the death of Modified HyperCVAD
Today we see the rise of Ibrutinib-Rituxan in the firt setting of disease treatment
than only come Idelalisib
and ABT-199
and may be HyperCVAD
and if you think of Bendamustine-Rituxan (after failure of Ibritinib), do not forget Maintenance therapy with Rituxan (rather than Interferon)
(as a note, in Europe R-CHOP/R-DHAP but is there a need?) (trying to be controversial here, am I successful?) CRBCM, we take things in strides!
BUT IN THIS DISEASE, BENDAMUSTIN -RITUXAN MAY BE BETTER THE R-CHOP!
*WATCH THE MIPI
SEE
"
Now we see the death of Modified HyperCVAD
Today we see the rise of Ibrutinib-Rituxan in the firt setting of disease treatment
than only come Idelalisib
and ABT-199
and may be HyperCVAD
and if you think of Bendamustine-Rituxan (after failure of Ibritinib), do not forget Maintenance therapy with Rituxan (rather than Interferon)
(as a note, in Europe R-CHOP/R-DHAP but is there a need?) (trying to be controversial here, am I successful?) CRBCM, we take things in strides!
BUT IN THIS DISEASE, BENDAMUSTIN -RITUXAN MAY BE BETTER THE R-CHOP!
*WATCH THE MIPI
SEE
"
The Mantle Cell Lymphoma International Prognostic Index (MIPI) is superior to the International Prognostic Index (IPI) in predicting survival following intensive first-line immunochemotherapy and autologous stem cell transplantation (ASCT)
Christian H. Geisler1" GO TO ARTICLEThe Hematologic malignancy review has been completed in Las Vegas II....CLL
In CLL
*?review role of Thyrosine Kinase in CLL
*Prognosi factor remains the same (17p deletion, 11q dletion, ZAP70, etc.)
*CLL remains an uncurable disease
*FCR better than FC
*FCR better than Bendamustin -Rituxan despite more infection which does not impact mortality ultimately, and particularly in the young? (And who thought FCR lost its luster before Bendamustine-R ? watch for 17p deletion though and pick carefully!)
*17p deletion better treated in clinical trials
*Omecetaxine, an alternative approach to treatment
*Therapeutic choices
1.FCR
2.Benda-Rituxan
3.New anti CD20
4.Ibrutinib
5.Idelalisib
6.BCL-2 antibody
Obinutuzumab always used with Chlorambucil :"The monoclonal anti-CD20 antibody rituximab, combined with chemotherapeutic agents, has been shown to prolong overall survival in physically fit patients with previously untreated chronic lymphocytic leukemia (CLL) but not in those with coexisting conditions. We investigated the benefit of the type 2, glycoengineered antibody obinutuzumab (also known as GA101) as compared with that of rituximab, each combined with chlorambucil, in patients with previously untreated CLL and coexisting conditions." NEJM.
*?review role of Thyrosine Kinase in CLL
*Prognosi factor remains the same (17p deletion, 11q dletion, ZAP70, etc.)
*CLL remains an uncurable disease
*FCR better than FC
*FCR better than Bendamustin -Rituxan despite more infection which does not impact mortality ultimately, and particularly in the young? (And who thought FCR lost its luster before Bendamustine-R ? watch for 17p deletion though and pick carefully!)
*17p deletion better treated in clinical trials
*Omecetaxine, an alternative approach to treatment
*Therapeutic choices
1.FCR
2.Benda-Rituxan
3.New anti CD20
4.Ibrutinib
5.Idelalisib
6.BCL-2 antibody
Obinutuzumab always used with Chlorambucil :"The monoclonal anti-CD20 antibody rituximab, combined with chemotherapeutic agents, has been shown to prolong overall survival in physically fit patients with previously untreated chronic lymphocytic leukemia (CLL) but not in those with coexisting conditions. We investigated the benefit of the type 2, glycoengineered antibody obinutuzumab (also known as GA101) as compared with that of rituximab, each combined with chlorambucil, in patients with previously untreated CLL and coexisting conditions." NEJM.
The Hematologic malignancy review has been completed in Las Vegas I....CML
In CML (Information to be rechecked in the literature)
-Cytogenetic recovery becomes even more important as it guides
1. quality of response at 3,6,12 months and should be 10, 1 and 0.1% of the quantitative PCR
and failure to do so impact of patient survival
(MR less than 10% at 3 months, linked to 96% survival at 4 years whereas more than MMR>10% at 6 months is linked to 69% survival at 4years!)
2. direct impacting the survival
*Failure to meet that end point, particularly at 3 and 6 months, should prompt Cytogenetic Mutations reevaluation and based on Mutation found pick the right TKI
*T3151---definitely Ponatinib or go to transplant (Allogeneic)
*Y253 and others---Dasatinib
*V299 and others---Nilotinib
*At 6 months, if Molecular response not met,
-check for adherence to treatment by the patient, and check for Mutations (ABL kinase domain point Mutation pattern assessment)
That now Major molecular response (MMR) could be expressed as , or MR 4.5
*Recognition that Frontline treatment is changing to 2nd generation TKI (Dasatinib, Nilotinib) but there is recognition that cardiovascular events are more frequent with these agents ( and Pulmonary Hypertension-particularly with Bosutinib?)
*There is a recording of 4 year survival data (Dasison) MR4.
*Reduction in Ponatinib dosage from 45 to 30mg could reduce lvel of Arterial Thrombosis, and hypertension rates ?without questionable effect on response rate.
-Cytogenetic recovery becomes even more important as it guides
1. quality of response at 3,6,12 months and should be 10, 1 and 0.1% of the quantitative PCR
and failure to do so impact of patient survival
(MR less than 10% at 3 months, linked to 96% survival at 4 years whereas more than MMR>10% at 6 months is linked to 69% survival at 4years!)
2. direct impacting the survival
*Failure to meet that end point, particularly at 3 and 6 months, should prompt Cytogenetic Mutations reevaluation and based on Mutation found pick the right TKI
*T3151---definitely Ponatinib or go to transplant (Allogeneic)
*Y253 and others---Dasatinib
*V299 and others---Nilotinib
*At 6 months, if Molecular response not met,
-check for adherence to treatment by the patient, and check for Mutations (ABL kinase domain point Mutation pattern assessment)
That now Major molecular response (MMR) could be expressed as , or MR 4.5
*Recognition that Frontline treatment is changing to 2nd generation TKI (Dasatinib, Nilotinib) but there is recognition that cardiovascular events are more frequent with these agents ( and Pulmonary Hypertension-particularly with Bosutinib?)
*There is a recording of 4 year survival data (Dasison) MR4.
*Reduction in Ponatinib dosage from 45 to 30mg could reduce lvel of Arterial Thrombosis, and hypertension rates ?without questionable effect on response rate.
Potential future collaboration lead at CRBCM!
"Thanks Peggy for your quick response,
As I mentioned to you last week,
there
was a potential collaboration with an oncologist in China. The story
was that I met a clinical oncologist, Dr. Baofa Yu, who used be a
research assistant professor
at UCSD. When I was in Scripps Res. Institute in San Diego, I have
known him quite well. He has returned to China about 10 years ago to
establish private tumor hospitals using a therapeutic approach he
developed to treat cancer patients (He has US and China
Patents) . It was very successful. Currently, he has owned four tumor
hospitals in China (in Beijing and other cities). He has interest in
collaborating with an oncologist in US to use his novel approach to
treat cancer patients. I have introduced our research
collaboration to Dr. Yu on phone last week. He has great interest in
collaborating with Dr. Kankonde. Dr. Yu may come to US for a visit in
this coming July. Maybe we can meet here at El Paso. Dr Yu let me tell
you that if it is possible, Dr. Yu would also
like to invite you to China to visit his cancer hospitals in the near
future."
The CRBCM will be honored to learn from DR Yu...
The future will be bright!And only the future will tell!
Friday, April 25, 2014
CRBCM, on the move again
Flying today to LAS VEGAS for a major hematology conference
for our reader this is the annual update in certain Hematologic conditions
a report will follow I am sure, but its our ways to watch what is driving the mood in Hematology!
Be patient, the news will come to you...If I am not back....I just may have won in Vegas!
And if I don't say a thing! well what happens in Vegas, stay in Vegas......
We are reviewing in the meantime all these good genes HHEX,KCNJ11,PPARG, TCF7, MTNR1, TRAF1....Is there a crystal ball in these?
for our reader this is the annual update in certain Hematologic conditions
a report will follow I am sure, but its our ways to watch what is driving the mood in Hematology!
Be patient, the news will come to you...If I am not back....I just may have won in Vegas!
And if I don't say a thing! well what happens in Vegas, stay in Vegas......
We are reviewing in the meantime all these good genes HHEX,KCNJ11,PPARG, TCF7, MTNR1, TRAF1....Is there a crystal ball in these?
Thursday, April 24, 2014
A critical Function down the neoplastic transformation : NPM1
As we test gene mutations with the UTEP team, one of the Mutation detected in the sera of lung cancer patients was Mutation or over expression of NPM1. The literature suggested that this gene is a critical path to closing of natural ways to apoptosis while exacerbating cell division.
Indeed we all know that cancer is characterized by cellular persistence, and longer life relative to normal cell. This fact is more seen with Leukemic cells and NPM1 will be more present in these diseases as a matter of facts. To escape cellular programmed death, cancer will use NPM1 and related molecules to escape normal death particularly in the presence of abnormal genetic alteration often present in cancer cells!
It is not by mistake that NPM1 will have interactions with
1. BRCA that affect gene repair
2.P53 to close that reflex cellular arrest
3.Runx genes in hematopoietic malignancies (proof of promoters'activities)
ARF, etc... for some, RUNX is a part of CBFs
The activities into suppression of programmed death can even be measure by drop in Caspase 3,8 as reported by bright scientists!
The second fold is of course promotion of cell division mainly through the Nucleoli and division of centromeres. NPM1 expression appears bad prognostic indicators but has been cited in some leukemia of the young as a good prognosis indicator? And that is most likely because it is a secondary events rather than truly a driver mutation?
Clearly it was striking to find it sitting there in Lung cancers!
Indeed we all know that cancer is characterized by cellular persistence, and longer life relative to normal cell. This fact is more seen with Leukemic cells and NPM1 will be more present in these diseases as a matter of facts. To escape cellular programmed death, cancer will use NPM1 and related molecules to escape normal death particularly in the presence of abnormal genetic alteration often present in cancer cells!
It is not by mistake that NPM1 will have interactions with
1. BRCA that affect gene repair
2.P53 to close that reflex cellular arrest
3.Runx genes in hematopoietic malignancies (proof of promoters'activities)
ARF, etc... for some, RUNX is a part of CBFs
The activities into suppression of programmed death can even be measure by drop in Caspase 3,8 as reported by bright scientists!
The second fold is of course promotion of cell division mainly through the Nucleoli and division of centromeres. NPM1 expression appears bad prognostic indicators but has been cited in some leukemia of the young as a good prognosis indicator? And that is most likely because it is a secondary events rather than truly a driver mutation?
Clearly it was striking to find it sitting there in Lung cancers!
Wednesday, April 23, 2014
And progress continues on CRBCM Blog! More than 40,000 reviews....
Coalition for the Reversal of Breast Cancer Mortality in African American Women · Stats › Overview
May 2007 – April 2014
|
More than 40.000 reviews in less than 2 years! The CRBCM!
With over 40,000 reviews, the CRBCM is advancing slowly but deliberately
our cause is just that is why we are still alive,
will stay alive long enough until enemies become irrelevant!
We are still advancing as more is being done,
and somehow we keep staying alive by the grace of God!
40,000 reviews and counting in less than 2 years ...we can be proud and the need is there!
we will keep on progressing until we get to the promised "land"....
our cause is just that is why we are still alive,
will stay alive long enough until enemies become irrelevant!
We are still advancing as more is being done,
and somehow we keep staying alive by the grace of God!
40,000 reviews and counting in less than 2 years ...we can be proud and the need is there!
we will keep on progressing until we get to the promised "land"....
Ramucirumab, FDA approved in Metastatic GE Junction and gastric cancer, but is-it all?
May be Ramucirumab will work
At CRBCM we have a patient who has Angiosarcoma in the liver who had a rapid progression on Gem-Taxane (in fact she had a very powerful allergic reaction to Taxane) and again progressed on MAID
She was switched to Avastin alone since the reaction to Taxane was strong. The disease remains stble for 1 year. She has now vaginal bleed and acute SOB that responded only to steroid, Avastin has benn on hold
It is unclear if she will tolerate it again.
Alternative Pazopanib?
?Trabectedin (unavailable in the US?)
Cediranib?
or is-it the new Ramucirumab? will try with Lilly!
At CRBCM we have a patient who has Angiosarcoma in the liver who had a rapid progression on Gem-Taxane (in fact she had a very powerful allergic reaction to Taxane) and again progressed on MAID
She was switched to Avastin alone since the reaction to Taxane was strong. The disease remains stble for 1 year. She has now vaginal bleed and acute SOB that responded only to steroid, Avastin has benn on hold
It is unclear if she will tolerate it again.
Alternative Pazopanib?
?Trabectedin (unavailable in the US?)
Cediranib?
or is-it the new Ramucirumab? will try with Lilly!
Monday, April 21, 2014
The process of Neoplasia in lung cancer, potential for screening through blood!
Lung cancer, one of the leading deadly cancers for which screening has not clearly be established, has been one of the target of many researches. To this day, only radiological evaluations have creeped up to a level of screening. With the advance of technology, we have gone from Chest Xray to low-dose cat scans for this indication. And this despite our progress in the knowledge of genetics.
Quite frankly it seems that much of preliminary genetic knowledge has been developed. The amount of information available on genes of cancer is impressive. What is missing is boldness of our scientists to form theories of progression of this disease which kill many victims each year. The neoplastic process however continues to occur steadily, and year after year, new lung cancers are being brought to light through detection that is characteristically late. There are many lung cancers and none appears to have the same pathophysiologic occurrence mechanism. So in this maze of mechanisms, finding a steady gene abnormality that does vary very much through stages of cancer appears a significant fact! Indeed the MDM-2 Mutation appears steadily throughout the stages of certain lung cancers, particularly the Adenocarcinomas. Mouse double minute 2 homolog (MDM2) also known as E3 ubiquitin-protein ligase is the gene in question! In our sample, this gene was the highest present and its presence seemed to vary little both on cancer tissues and in the serum of diseased patients. These specimen were provided to CRBCM and the UTEP biologic research laboratory by LCBRN -VA university tissue bank (under MDHONORS funding).
Coming back to the MDM-2:
------------------------------
When one lean on this finding in depth, the puzzle for the involvement of the MDM-2 runs deeper than first suspected. And clearly lays in the dawn of the neoplastic process. And as we lean further, new suspicions rise that the onset of the neoplasia for some cancers is here! Several facts contribute to this perception. We all know that cigarette smoking is a common cause of lung cancer, and now this known fact...
Dr Yurong Chai, our investigator stressed that Cigarette smoke "increase the risk of alternative MDM-2 splicing" a fact that establishes the initial event that will trigger so much subsequent genetic calamities. MDM-2 happens to be the regulator of P53. It also has a competitive partner, the FKBP25,
OCHOKA"
"The p53 tumour suppressor protein is tightly controlled by the E3 ubiquitin ligase, mouse double minute 2 (MDM2), but maintains MDM2 expression as part of a negative feedback loop. We have identified the immunophilin, 25kDa FK506-binding protein (FKBP25), previously shown to be regulated by p53-mediated repression, as an MDM2-interacting partner. We show that FKBP25 stimulates auto-ubiquitylation and proteasomal degradation of MDM2, leading to the induction of p53. Depletion of FKBP25 by siRNA leads to increased levels of MDM2 and a corresponding reduction in p53 and p21 levels. These data are consistent with the idea that FKBP25 contributes to regulation of the p53-MDM2 negative feedback loop." The impact on a member of the FK506 family has deep implications both on the disease process and therapeutically as we may discuss.
The involvement of disturbances of the MDM-2 has even deeper consequences, because of independent MDM-2 activity directly on initiation of DNA replication and through its activity on Cyclin-depedent Kinases! The MDM-2 rise quickly as a biomarker of Cancer initiation and therefore a major Biomarker of the danger of smoking! And its presence no matter the stage of disease has several implications including that of how you appreciate curability! (to be continued)
Quite frankly it seems that much of preliminary genetic knowledge has been developed. The amount of information available on genes of cancer is impressive. What is missing is boldness of our scientists to form theories of progression of this disease which kill many victims each year. The neoplastic process however continues to occur steadily, and year after year, new lung cancers are being brought to light through detection that is characteristically late. There are many lung cancers and none appears to have the same pathophysiologic occurrence mechanism. So in this maze of mechanisms, finding a steady gene abnormality that does vary very much through stages of cancer appears a significant fact! Indeed the MDM-2 Mutation appears steadily throughout the stages of certain lung cancers, particularly the Adenocarcinomas. Mouse double minute 2 homolog (MDM2) also known as E3 ubiquitin-protein ligase is the gene in question! In our sample, this gene was the highest present and its presence seemed to vary little both on cancer tissues and in the serum of diseased patients. These specimen were provided to CRBCM and the UTEP biologic research laboratory by LCBRN -VA university tissue bank (under MDHONORS funding).
Coming back to the MDM-2:
------------------------------
When one lean on this finding in depth, the puzzle for the involvement of the MDM-2 runs deeper than first suspected. And clearly lays in the dawn of the neoplastic process. And as we lean further, new suspicions rise that the onset of the neoplasia for some cancers is here! Several facts contribute to this perception. We all know that cigarette smoking is a common cause of lung cancer, and now this known fact...
Dr Yurong Chai, our investigator stressed that Cigarette smoke "increase the risk of alternative MDM-2 splicing" a fact that establishes the initial event that will trigger so much subsequent genetic calamities. MDM-2 happens to be the regulator of P53. It also has a competitive partner, the FKBP25,
OCHOKA"
"The p53 tumour suppressor protein is tightly controlled by the E3 ubiquitin ligase, mouse double minute 2 (MDM2), but maintains MDM2 expression as part of a negative feedback loop. We have identified the immunophilin, 25kDa FK506-binding protein (FKBP25), previously shown to be regulated by p53-mediated repression, as an MDM2-interacting partner. We show that FKBP25 stimulates auto-ubiquitylation and proteasomal degradation of MDM2, leading to the induction of p53. Depletion of FKBP25 by siRNA leads to increased levels of MDM2 and a corresponding reduction in p53 and p21 levels. These data are consistent with the idea that FKBP25 contributes to regulation of the p53-MDM2 negative feedback loop." The impact on a member of the FK506 family has deep implications both on the disease process and therapeutically as we may discuss.
The involvement of disturbances of the MDM-2 has even deeper consequences, because of independent MDM-2 activity directly on initiation of DNA replication and through its activity on Cyclin-depedent Kinases! The MDM-2 rise quickly as a biomarker of Cancer initiation and therefore a major Biomarker of the danger of smoking! And its presence no matter the stage of disease has several implications including that of how you appreciate curability! (to be continued)
Friday, April 18, 2014
We had our last meeting with DR CHOI at UTEP!
Yes yesterday was our last face to face meeting with DR Choi a brilliant scientist working at UTEP
with DR Zhang. She is returning to China within a week. She transformed our world of suspicions into real events. She has been a dominant force and a matter of facts woman who has key to our project on lung cancer detection kit development project.
She did the PCR work needed and open us up to new perspective on the 3 genes looked at that not only confirms our suspicions, but opened new perspectives for future research questions related to the 3 genes.
Her findings have reaffirmed that we are in the right path and raises significantly the importance of target therapy, strengthen the notion that Ubiquitylation is critical in the initiation of lung cancers (and other cancers)
and could probably be a potent biomarker ( by its disturbances) to smoking danger to initiate lung cancers.
In the sera of patients with lung cancers, her findings have been just as stunning and intriguing. From high Cyclin presence to the presence of antibody for NPM1, p16 and even in minutes amount the presence of 14-3-3 (the same found in Creutzfeld Jacob disease ?). All these findings were captivating and raising new questions about the specificity and sensitivity of some of our tests.
The level of amplification of these abnormal genes certainly call for a cut of point for amplification that could be primary and be suspected to be neoplastic, or secondary that could be an unintended event subsequent to other gene's amplification whether malignant or not.
When it comes to Antibody, what we suspected was confirmed. Indeed since the antibody secretion is function of fluctuating lymphocyte reaction, or cellular use of genes involved in raising attraction of the white cells, the levels of antibody is fleeting or not correlating with the presence of gene amplification. But our findings is that in cancer the presence of antibody is confirmed. This may help in early detection...
Our discussion also brought to mind the difficulty of perceiving or detecting gene suppression unless your sets include normal tissue (we were offered biopsies of surrounding tissue luckily). Finding genes that are less expressed is critical. The example would be the suppression of PTEN in lung cancer, a well published event. Unless you are comparing with surrounding tissues in the same individual, establishing repressed gene could elude your observation. And we know how important such an observation represents as in major neoplasia, regulator genes could be suppressed! Our work is still preliminary, and may be revisiting, but clearly new perspectives have been open and our work will continue no matter what!
CRBCM is progressing deliberately. Please wait for the publication as it is being finalized!
with DR Zhang. She is returning to China within a week. She transformed our world of suspicions into real events. She has been a dominant force and a matter of facts woman who has key to our project on lung cancer detection kit development project.
She did the PCR work needed and open us up to new perspective on the 3 genes looked at that not only confirms our suspicions, but opened new perspectives for future research questions related to the 3 genes.
Her findings have reaffirmed that we are in the right path and raises significantly the importance of target therapy, strengthen the notion that Ubiquitylation is critical in the initiation of lung cancers (and other cancers)
and could probably be a potent biomarker ( by its disturbances) to smoking danger to initiate lung cancers.
In the sera of patients with lung cancers, her findings have been just as stunning and intriguing. From high Cyclin presence to the presence of antibody for NPM1, p16 and even in minutes amount the presence of 14-3-3 (the same found in Creutzfeld Jacob disease ?). All these findings were captivating and raising new questions about the specificity and sensitivity of some of our tests.
The level of amplification of these abnormal genes certainly call for a cut of point for amplification that could be primary and be suspected to be neoplastic, or secondary that could be an unintended event subsequent to other gene's amplification whether malignant or not.
When it comes to Antibody, what we suspected was confirmed. Indeed since the antibody secretion is function of fluctuating lymphocyte reaction, or cellular use of genes involved in raising attraction of the white cells, the levels of antibody is fleeting or not correlating with the presence of gene amplification. But our findings is that in cancer the presence of antibody is confirmed. This may help in early detection...
Our discussion also brought to mind the difficulty of perceiving or detecting gene suppression unless your sets include normal tissue (we were offered biopsies of surrounding tissue luckily). Finding genes that are less expressed is critical. The example would be the suppression of PTEN in lung cancer, a well published event. Unless you are comparing with surrounding tissues in the same individual, establishing repressed gene could elude your observation. And we know how important such an observation represents as in major neoplasia, regulator genes could be suppressed! Our work is still preliminary, and may be revisiting, but clearly new perspectives have been open and our work will continue no matter what!
CRBCM is progressing deliberately. Please wait for the publication as it is being finalized!
Thursday, April 17, 2014
Dangerous precedent about VIAGRA, its connection to Melanoma!
The risk association of Melanoma with Viagra raises significant fear for those who have no genetic background because Melanoma is still one of the most dangerous and untreatable cancer at advanced stage. For the scientist, this open the door to further research into gene interactions.
Melanoma is a disease that raises fear in the community given its fatality in advanced stage. In the Untited states it kills close to 9000 lives yearly or more than 10% of affected individual globally. The gene involved is p16/CDKN2A which encodes for both p16 and p14ARF. It is worth mentioning that Xeroderma pigmentosum and BRCA2 predispose to this disease. Also loss of PTEN has been cited for association with Melanoma. GNAQ/GNA11 has been associated with Uveal Melanoma. c-KIT has been cited in Lentigo maligna Melanoma.
Viagra, suppressor of the enzyme phosphodiesterase type 5 (PDE5),will block degradation of Cyclic GMP necessary for Erection performance. What this has to do with PTEN. CDKN2A, and may be p14ARF or BRCA2 becomes of interest. Other then standard Erection dysfunction, Viagra has been used more chronically in patients who have Pulmonary Hypertension, a silently deadly condition.
This elevated risk of melanoma does not come as a surprise however and more discoveries are upcoming for certain since the Cyclic GMP, like Cyclic AMP are "second messengers" affecting many pathways given their position early in these pathways. The observation also point to the danger of chronic exacerbations of genes in any pathways. The reactions occurring in a cell to adjust to excited gene could be deleterious as it can either exacerbate or suppress compensatory pathways, leading to cancers. Another independent fact is the fact that "second messengers" have been used in the past for Biomarker of chemical molecule activity...and Cyclic GMP is a "messenger", a clear Biomarker of event to come in a cell!
Melanoma is a disease that raises fear in the community given its fatality in advanced stage. In the Untited states it kills close to 9000 lives yearly or more than 10% of affected individual globally. The gene involved is p16/CDKN2A which encodes for both p16 and p14ARF. It is worth mentioning that Xeroderma pigmentosum and BRCA2 predispose to this disease. Also loss of PTEN has been cited for association with Melanoma. GNAQ/GNA11 has been associated with Uveal Melanoma. c-KIT has been cited in Lentigo maligna Melanoma.
Viagra, suppressor of the enzyme phosphodiesterase type 5 (PDE5),will block degradation of Cyclic GMP necessary for Erection performance. What this has to do with PTEN. CDKN2A, and may be p14ARF or BRCA2 becomes of interest. Other then standard Erection dysfunction, Viagra has been used more chronically in patients who have Pulmonary Hypertension, a silently deadly condition.
This elevated risk of melanoma does not come as a surprise however and more discoveries are upcoming for certain since the Cyclic GMP, like Cyclic AMP are "second messengers" affecting many pathways given their position early in these pathways. The observation also point to the danger of chronic exacerbations of genes in any pathways. The reactions occurring in a cell to adjust to excited gene could be deleterious as it can either exacerbate or suppress compensatory pathways, leading to cancers. Another independent fact is the fact that "second messengers" have been used in the past for Biomarker of chemical molecule activity...and Cyclic GMP is a "messenger", a clear Biomarker of event to come in a cell!
Monday, April 14, 2014
Hyperlipidemia "under the microscope", REDUCING RISK OF CORONARY AND BLOOD VESSEL DISEASES
-does Xanthelasma, Corneal arcus, provide clues in triglyceride deposition in the artery
-does minimal pancreatitis and similar induced inflammatory disease induced by hyperlipidemia contributes to Coronary disease
-what type of inflammatory process are produced by free fatty acids and related lipid molecules
-?associated Pulmonary hypertension
-Dysbetalipoproteinemia provides more clues to pathophysiology?
-Cytokines involved in Neurologic syndrome of Chylomicronemia or is it direct disruption of lipogenesis/lysis
-What is the role of IL-6 in all this mess, can controlling IL-1 & 6 help (ie preserve elasticity of blood vessel) could vascular cellular preservation slow down Arteriosclerotic phenomena (preservation of elastin and related compounds)
-what is the role of cytokines in vascular transformations (AS CYTOKINES INDUCED BY FFA)
-should closer elective follow-up of the pancreas serve as a biomarker of hyperlipidemia
-should early xanthoma be allowed to alert of Coronary event due to hyperlipidemia, FFA levels?
-what is the role of TSH, and the thyroid?
-what in the urine analysis predict a coronary events (as it relates to lipid)
-What Vitamins have to do with this? Vitamin D role?
-Eruptive Vs tuberous XANTHOMAS (FAT VS CHOLESTEROL) WHY AND WHEN?
-how to consume debris of lipolysis without causing a "Cytokine storm" or an autoimmune disease
is it through IL-6
-how does specific medicines works to minimize cytokine storm?
-How does Ileal bypass affect the cytokines, vascular transformation, should it be routine at a certain age to reduce Coronary risk
-can sonogram of the pancreas, specific artery gives a clue on coronary disease due to lipid disruption
-does minimal pancreatitis and similar induced inflammatory disease induced by hyperlipidemia contributes to Coronary disease
-what type of inflammatory process are produced by free fatty acids and related lipid molecules
-?associated Pulmonary hypertension
-Dysbetalipoproteinemia provides more clues to pathophysiology?
-Cytokines involved in Neurologic syndrome of Chylomicronemia or is it direct disruption of lipogenesis/lysis
-What is the role of IL-6 in all this mess, can controlling IL-1 & 6 help (ie preserve elasticity of blood vessel) could vascular cellular preservation slow down Arteriosclerotic phenomena (preservation of elastin and related compounds)
-what is the role of cytokines in vascular transformations (AS CYTOKINES INDUCED BY FFA)
-should closer elective follow-up of the pancreas serve as a biomarker of hyperlipidemia
-should early xanthoma be allowed to alert of Coronary event due to hyperlipidemia, FFA levels?
-what is the role of TSH, and the thyroid?
-what in the urine analysis predict a coronary events (as it relates to lipid)
-What Vitamins have to do with this? Vitamin D role?
-Eruptive Vs tuberous XANTHOMAS (FAT VS CHOLESTEROL) WHY AND WHEN?
-how to consume debris of lipolysis without causing a "Cytokine storm" or an autoimmune disease
is it through IL-6
-how does specific medicines works to minimize cytokine storm?
-How does Ileal bypass affect the cytokines, vascular transformation, should it be routine at a certain age to reduce Coronary risk
-can sonogram of the pancreas, specific artery gives a clue on coronary disease due to lipid disruption
Genes to Eternal life
According to the US Government on Aging (at least seems to suggest)
to have eternal life you have to have or know some of the genes for these functions:
-Gene(s) to avoid unhealthy choices (ie. blocking Glucogen,controlling lipid,MTOR, CRE gene)
-Genes to keep life sparks (hormones,cytokine,physical exercise,what to eat)let's go find them!
Sunday, April 13, 2014
related questions? Personal record mind you!
*Can use of Atra/retinoic acid improves Nexavar?
*could decreasing Zinc by a chelator increase or decrease Metastic progression in the liver
*Could blocking Prostaglandins affect metastatic progression in the liver
*can inflammatory parameters be useful in measuring progression of metastatic disease in the liver?
*defining role of Anti-Adenyl CYCLASE in both inflammatory and neoplastic disease in the liver
*and now what is the exact role of Protein Kinase C
*N-Acetyl cystein? what may be other roles...
*What is more important in TBI, IL-1 or IL6?
what is it again ----Arylhydrocarbon?let's dwelve into these
*could decreasing Zinc by a chelator increase or decrease Metastic progression in the liver
*Could blocking Prostaglandins affect metastatic progression in the liver
*can inflammatory parameters be useful in measuring progression of metastatic disease in the liver?
*defining role of Anti-Adenyl CYCLASE in both inflammatory and neoplastic disease in the liver
*and now what is the exact role of Protein Kinase C
*N-Acetyl cystein? what may be other roles...
*What is more important in TBI, IL-1 or IL6?
what is it again ----Arylhydrocarbon?let's dwelve into these
What I got from the literature, if you didn't get it, you did not get it!
That Inflammatory forces will
1. Increase
-Fibrinogen/Fibronectin
-alpha-Antitrypsin
-Serum Amyloid A
-C-Reactive Protein
-Complement protein factor B
- C3
-ESR
and may Be Adenyl-Cyclase
2.Decrease
-Albumin
-Transferrin
-?P450
-AHH
3.Major forces
Zinc level---and level of EGF?
activity of kinase-C
PMA
Prostaglandins (E)
EGF
ICAM1
Neurotensin
look into these
C-Met, EGF, HGFR,GLP1R, NOD-1,P2Y,C5a,NF4R,ASGP-Receptors
something is here, got to find it! if you didn't get it, you didn't get it!
1. Increase
-Fibrinogen/Fibronectin
-alpha-Antitrypsin
-Serum Amyloid A
-C-Reactive Protein
-Complement protein factor B
- C3
-ESR
and may Be Adenyl-Cyclase
2.Decrease
-Albumin
-Transferrin
-?P450
-AHH
3.Major forces
Zinc level---and level of EGF?
activity of kinase-C
PMA
Prostaglandins (E)
EGF
ICAM1
Neurotensin
look into these
C-Met, EGF, HGFR,GLP1R, NOD-1,P2Y,C5a,NF4R,ASGP-Receptors
something is here, got to find it! if you didn't get it, you didn't get it!
Thursday, April 10, 2014
search for the "OBLONG" pill.
"Oblong man" rather than "circle man" infers less obesity
Obesity is a growing issue in the United States and many want to find an answer to obesity by coming up with a "pill" that will make people lose weight...the "Oblong Pill" is such a pill.
while many reports "fighting" against obesity, few patients with autoimmune diseases are reporting to us for inability to gain weight! In Autoimmune diseases, we surmise that cytokines induced in this disease significant perturbation of both glucogenesis and lipogenesis-lysis. The logical conclusion is that isolating the cytokines involved may help with weight management. But in autoimmune disease we could also localize relevant biomarkers that mark the increase in cytokines. We could also test why cellular proliferation does not occur (is it through FOXO3), and measure transformation in lymphoproliferative disorders (is it through the LYN, RELA etc?). Should we avoid these types of development and what would be the type of warning that these mechanisms are elicited .
Bani-Sadr et al "Weight loss is reported by more than 20% of hepatitis C virus (HCV)-monoinfected patients treated with the peg-interferon (peg-IFN) and ribavirin combination." and indeed chronic use of interferon is accompanied by weight loss. Interferon belong to the Cytokines, another proof that Cytokine may be an answer to Obesity if controlled and managed carefully!
Obesity is a growing issue in the United States and many want to find an answer to obesity by coming up with a "pill" that will make people lose weight...the "Oblong Pill" is such a pill.
while many reports "fighting" against obesity, few patients with autoimmune diseases are reporting to us for inability to gain weight! In Autoimmune diseases, we surmise that cytokines induced in this disease significant perturbation of both glucogenesis and lipogenesis-lysis. The logical conclusion is that isolating the cytokines involved may help with weight management. But in autoimmune disease we could also localize relevant biomarkers that mark the increase in cytokines. We could also test why cellular proliferation does not occur (is it through FOXO3), and measure transformation in lymphoproliferative disorders (is it through the LYN, RELA etc?). Should we avoid these types of development and what would be the type of warning that these mechanisms are elicited .
Bani-Sadr et al "Weight loss is reported by more than 20% of hepatitis C virus (HCV)-monoinfected patients treated with the peg-interferon (peg-IFN) and ribavirin combination." and indeed chronic use of interferon is accompanied by weight loss. Interferon belong to the Cytokines, another proof that Cytokine may be an answer to Obesity if controlled and managed carefully!
Wednesday, April 9, 2014
Mechanism of targeting for therapy
*Receptor Inhibitor
*ATP competitor inhibitor
*DNA repair
*Amplification of certain gene or proteins (EMSY)
*Hypermethylation of certain gene
*Inhibition of critical enzymes
*Inhibition of pathways'genes
*ATP competitor inhibitor
*DNA repair
*Amplification of certain gene or proteins (EMSY)
*Hypermethylation of certain gene
*Inhibition of critical enzymes
*Inhibition of pathways'genes
Tuesday, April 8, 2014
Be There! from PER
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Monday, April 7, 2014
role of TPI gene in cancers
OROSZ et al:
"One of these, triosephosphate isomerase (TPI) deficiency, is unique among the glycolytic enzyme defects since it is associated with progressive neurological dysfunction and frequently with childhood death. The physiological function of TPI is to adjust the rapid equilibrium between dihydroxyacetone phosphate and glyceraldehyde-3-phosphate produced by aldolase in glycolysis, which is interconnected to the pentose phosphate pathway and to lipid metabolism via triosephosphates."
*SABiosciences Regulatory transcription factor binding sites in the TPI1 gene promoter:
c-Fos PPAR-gamma1 AP-1 ATF-2 PPAR-gamma2 c-Jun c-Ets-1
Other transcription factors
*development of Giardiasis is a potent sign of this disturbance
*Is TPI involved in salivary gland cancers
*does supplying G3P +DHAP resulting product correct this disease?
*what is the expression of REB1,RAP1,GCR1 in salivary gland cancers?
stephens et al: on Adenoid Cystic Cancer ( fusions of the MYB-NFIB genes)
"We identified multiple mutated genes that, combined, implicate chromatin deregulation in half of cases. Further, mutations were identified in known cancer genes, including PIK3CA, ATM, CDKN2A, SF3B1, SUFU, TSC1, and CYLD. Mutations in NOTCH1/2 were identified in 3 cases, and we identify the negative NOTCH signaling regulator, SPEN, as a new cancer gene in ACC with mutations in 5 cases. Finally, the identification of 3 likely activating mutations in the tyrosine kinase receptor FGFR2, analogous to those reported in ovarian and endometrial carcinoma, point to potential therapeutic avenues for a subset of cases."
"One of these, triosephosphate isomerase (TPI) deficiency, is unique among the glycolytic enzyme defects since it is associated with progressive neurological dysfunction and frequently with childhood death. The physiological function of TPI is to adjust the rapid equilibrium between dihydroxyacetone phosphate and glyceraldehyde-3-phosphate produced by aldolase in glycolysis, which is interconnected to the pentose phosphate pathway and to lipid metabolism via triosephosphates."
*SABiosciences Regulatory transcription factor binding sites in the TPI1 gene promoter:
c-Fos PPAR-gamma1 AP-1 ATF-2 PPAR-gamma2 c-Jun c-Ets-1
Other transcription factors
*development of Giardiasis is a potent sign of this disturbance
*Is TPI involved in salivary gland cancers
*does supplying G3P +DHAP resulting product correct this disease?
*what is the expression of REB1,RAP1,GCR1 in salivary gland cancers?
stephens et al: on Adenoid Cystic Cancer ( fusions of the MYB-NFIB genes)
"We identified multiple mutated genes that, combined, implicate chromatin deregulation in half of cases. Further, mutations were identified in known cancer genes, including PIK3CA, ATM, CDKN2A, SF3B1, SUFU, TSC1, and CYLD. Mutations in NOTCH1/2 were identified in 3 cases, and we identify the negative NOTCH signaling regulator, SPEN, as a new cancer gene in ACC with mutations in 5 cases. Finally, the identification of 3 likely activating mutations in the tyrosine kinase receptor FGFR2, analogous to those reported in ovarian and endometrial carcinoma, point to potential therapeutic avenues for a subset of cases."
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