Because of limited resources available in research, society falls short in the management of cancer patients. The notion that cancer patient should be managed by affecting only their driver Mutation has been popular lately and most research has focused on this emphasis. There is a rush to discovering the driver mutation in each disease. The truth is that driver mutation although very effective (ie. BRAF inhibitor) for a short time, are quickly overwhelmed by what we have come to know as "mechanisms of resistance" The point is that cells are constantly exposed to new environmental stimulants. And their natural TASK is to die or adapt. And naturally we try to forget or underestimate the adaptative capability of cells, including neoplastic (cancer) cells. Cure will remain fleeting until a closer look is taken into these adjustment techniques used by the cancer cells. and it is within that contest that I bring this statement to your mind:
" that SHC-1 not only opposes IIS but also activates JNK signaling. Loss of shc-1
function results in accelerated aging and enhanced sensitivity to heat,
oxidative stress, and heavy metals, whereas expression of human p52Shc
rescues the shc-1 mutant phenotype. SHC-1 acts upstream of the
insulin/IGF receptor DAF-2 and the PI3 kinase AGE-1 and directly
interacts with DAF-2. Moreover, SHC-1 activates JNK signaling by binding
to MEK-1 kinase. Both aspects converge on controlling the nuclear
translocation and activation of the FOXO transcription factor DAF-16." Elke Neuman-Haeflin et al.
If you are shocked and troubled by the placement of this statement here, you are completely within the norm! but let's go back and recapitulate. Most cells succumbs to external pressure by cellular environmental stimulations. Hypoxia, autocrine cytokines, chemicals and minerals end up exciting receptors including VEGFRs (the MEK is close by). But really when you speak of the VEGF, you imply SHC1,2 and stimulation of Annexins and from there p52, p42, and the famous p66SHC....then you can understand the above sentence...In Gastric cancer for example, VEGFR2 is stimulated and therefore the effectiveness of Ramucirumab. (CYRAMZA.)
Please note that the statement speak about p52 and does not even address the main RAS cofactor p66 which may affect Cyclin D and deplete MCI-1 the main depletor of SHC-1. (through PTPNs)
RAS autophosphorylation driving the cancerous process may be hidden here.
These facts point to the truth that independent of cancer driven mutation, control of these processes must occur concurrently to improve the cure! cancer deaths are produced by progression of cancer but also involvement of cellular maturation and lifespan determinants that most Oncologist do not measure! (we dance very little away from guidelines (NCCN))...
Sunday, October 12, 2014
Saturday, October 11, 2014
Pathogenesis of Neoplastic transformations.
Speculative sources of Neoplastic disease
As we plan Cancer Prevention, it seems logical to target potential mechanisms that likely could initiate the neoplastic process in order to propose logical steps. And clearly, from a beginner stand of view, and from data screening of various cancer, this task could be daunting. However major patterns have to be proposed as we examine what works, and what are the main metabolic disturbances in each disease.
*In Kidney cancer for example, Here abnormality in the Von Hippel Lindau gene (gene that promote UBIQUINATION) has supported strongly the involvement of an exaggeration of deficient Hypoxia induced factors (HIF) and related proteins. This facts lead to the removal of inhibitor forces leading to the expansion of VEGF and PDGF. It takes blocking the either the the VEGF (Avastin) or blocking the MTOR down the line (Everolimus) to slow down the neoplastic process. Anything in between may have not been efficient. Hypoxic conditions often found in patient with obesity (associated with sleep Apnea) may favor the frequency of this disease. The involvement of VEGF explain the importance of abnormal Angiogenesis in this disease...the tumor is bloody ...Therefore, optimizing Oxygenation (CPAP use in obese patient with sleep Apnea), decreasing or impairing VEGF, could have significant prevention use. Optimizing Iron level may also have a positive impact should studies initiated here further support that iron deficiency may exacerbate the various cellular metabolites. Interferon and IL-2 should be consider under this light (as to their effect on the VEGF-MTOR axe. The involvement of Ubiquination beg the question on whether Velcade and anti-TNF related compound may add to the therapy in Kidney cancer. One thing is for sure, all cancerous transformation try to escape the immune system, and Pembrolizumab could be discussed further within the contest of this disease! our knowledge is rapidly expanding.
*In Lung Cancer, the neoplastic transformation is diverse since some non smokers are known to develop the disease. Here we believe that diet based on high levels of anti-oxidant without sufficient compensatory iron (iron deficiency in women particularly) and HIF gene isoforms may lead to chronic intoxication triggering once again EGFR/VEGF expansion. Susceptibility of these cancers to Cetuximab/ERBITUX strongly support this hypothesis. Detoxification may also be influenced by CYP1A1 and GSTM1.
In standard lung cancer however, not only HIF is involved, but there is now increasing suspicion that alterations at the MDM-2 has entered the possibility of initiating the disease process forcing further Ubiquination or intervening at some point, affecting the P53, c-MYC, NPM1 and even prot 14-3-3 ("Phosphorylation of Cdc25C by CDS1 and CHK1 creates a binding site for the 14-3-3 family of phosphoserine binding proteins. Binding of 14-3-3 has little effect on Cdc25C activity, and it is believed that 14-3-3 regulates Cdc25C by sequestering it to the cytoplasm, thereby preventing the interactions with CycB-Cdk1 that are localized to the nucleus at the G2/M transition.[wikipedia) effect on Ubiquitination should be re-emphasized. With stimulation and amplification of the EGFR/VEGF come the importance of ALK, BRAF, again factors that have enterec lung cancer therapeutics since agents active here have become available (to be continued)
As we plan Cancer Prevention, it seems logical to target potential mechanisms that likely could initiate the neoplastic process in order to propose logical steps. And clearly, from a beginner stand of view, and from data screening of various cancer, this task could be daunting. However major patterns have to be proposed as we examine what works, and what are the main metabolic disturbances in each disease.
*In Kidney cancer for example, Here abnormality in the Von Hippel Lindau gene (gene that promote UBIQUINATION) has supported strongly the involvement of an exaggeration of deficient Hypoxia induced factors (HIF) and related proteins. This facts lead to the removal of inhibitor forces leading to the expansion of VEGF and PDGF. It takes blocking the either the the VEGF (Avastin) or blocking the MTOR down the line (Everolimus) to slow down the neoplastic process. Anything in between may have not been efficient. Hypoxic conditions often found in patient with obesity (associated with sleep Apnea) may favor the frequency of this disease. The involvement of VEGF explain the importance of abnormal Angiogenesis in this disease...the tumor is bloody ...Therefore, optimizing Oxygenation (CPAP use in obese patient with sleep Apnea), decreasing or impairing VEGF, could have significant prevention use. Optimizing Iron level may also have a positive impact should studies initiated here further support that iron deficiency may exacerbate the various cellular metabolites. Interferon and IL-2 should be consider under this light (as to their effect on the VEGF-MTOR axe. The involvement of Ubiquination beg the question on whether Velcade and anti-TNF related compound may add to the therapy in Kidney cancer. One thing is for sure, all cancerous transformation try to escape the immune system, and Pembrolizumab could be discussed further within the contest of this disease! our knowledge is rapidly expanding.
*In Lung Cancer, the neoplastic transformation is diverse since some non smokers are known to develop the disease. Here we believe that diet based on high levels of anti-oxidant without sufficient compensatory iron (iron deficiency in women particularly) and HIF gene isoforms may lead to chronic intoxication triggering once again EGFR/VEGF expansion. Susceptibility of these cancers to Cetuximab/ERBITUX strongly support this hypothesis. Detoxification may also be influenced by CYP1A1 and GSTM1.
In standard lung cancer however, not only HIF is involved, but there is now increasing suspicion that alterations at the MDM-2 has entered the possibility of initiating the disease process forcing further Ubiquination or intervening at some point, affecting the P53, c-MYC, NPM1 and even prot 14-3-3 ("Phosphorylation of Cdc25C by CDS1 and CHK1 creates a binding site for the 14-3-3 family of phosphoserine binding proteins. Binding of 14-3-3 has little effect on Cdc25C activity, and it is believed that 14-3-3 regulates Cdc25C by sequestering it to the cytoplasm, thereby preventing the interactions with CycB-Cdk1 that are localized to the nucleus at the G2/M transition.[wikipedia) effect on Ubiquitination should be re-emphasized. With stimulation and amplification of the EGFR/VEGF come the importance of ALK, BRAF, again factors that have enterec lung cancer therapeutics since agents active here have become available (to be continued)
Friday, October 10, 2014
Warsaw Indiana, an interesting case
We are back in Warsaw Indiana completing obligations here for CRBCM.
This exercise also expose us to local pathology and ways they are managed by local Oncologist.
An interesting case encounter here is that of a 22 year young mother who had 2 c-sections and was referred for Menorrhagia, she had a Biopsy of the Uterus, and a Von-Willebrand screen suggested very elevated Factor VIII (3 times the upper limit). She is obese and suffers from Hypothyroidism. Now elevation of Factor VIII has been identified as an independent factor determining an Hypercoagulable state. We may soon be quantifying related gene. This Hypercoagulable state is however confusing because it is indeed associated with higher risk of stroke and Coronary events. However, independent of thrombotic event, does it really require Anti-Coagulation for life?
The patient has been advised Aspirin, do we justify Xarelto at preventive dosage? Should weight loss be a sufficient intervention, should we look for coexisting Hercoagulable factor such as Factor V leyden, or Homocystein for that matter...we are checking TSH level of course...Elimination of this factor is associated with certain Blood Group, should we type and cross ? Very puzzling case indeed! What are the genes proximate to this gene?
This exercise also expose us to local pathology and ways they are managed by local Oncologist.
An interesting case encounter here is that of a 22 year young mother who had 2 c-sections and was referred for Menorrhagia, she had a Biopsy of the Uterus, and a Von-Willebrand screen suggested very elevated Factor VIII (3 times the upper limit). She is obese and suffers from Hypothyroidism. Now elevation of Factor VIII has been identified as an independent factor determining an Hypercoagulable state. We may soon be quantifying related gene. This Hypercoagulable state is however confusing because it is indeed associated with higher risk of stroke and Coronary events. However, independent of thrombotic event, does it really require Anti-Coagulation for life?
The patient has been advised Aspirin, do we justify Xarelto at preventive dosage? Should weight loss be a sufficient intervention, should we look for coexisting Hercoagulable factor such as Factor V leyden, or Homocystein for that matter...we are checking TSH level of course...Elimination of this factor is associated with certain Blood Group, should we type and cross ? Very puzzling case indeed! What are the genes proximate to this gene?
BREAST CANCER
familial predisposition has been appreciated by the presence of BRCA1 and BRCA2
but increasingly we find young women with breast cancers who do not carry the mutation expected. By their age and family history, we know there must be a genetic predisposition for the particular cancer of the breast to occur.
1.Mutation in the genes regulating or acting in the vicinity of the BRCA.
For medicine to advance and allow better use of limited resources and decrease the burden of side effects for our patients, It would be critical that new sets of genes enter the standard detection/category testing in the management of Breast Cancer. There are over 100 Mutations knwon!
2As far as BRCA2 is concerned, interaction with RAD51 has been suggested. Ween et al:"versican and hyaluronan (HA) which interacts with the HA receptor, CD44, have been shown to play critical roles in ovarian cancer metastasis." These molecule states (isoforms) have been found to be increasingly affected by interaction with growth factors TGF and even PDGF. (early detection of metastatic disease). They should enter biomarker testing.
3.BRCAs are "wild gene" first because there are hundred of these Mutations
and also because Wikipidea describes multiple various interactions:
"BRCA1 has been shown to interact with
familial predisposition has been appreciated by the presence of BRCA1 and BRCA2
but increasingly we find young women with breast cancers who do not carry the mutation expected. By their age and family history, we know there must be a genetic predisposition for the particular cancer of the breast to occur.
1.Mutation in the genes regulating or acting in the vicinity of the BRCA.
For medicine to advance and allow better use of limited resources and decrease the burden of side effects for our patients, It would be critical that new sets of genes enter the standard detection/category testing in the management of Breast Cancer. There are over 100 Mutations knwon!
2As far as BRCA2 is concerned, interaction with RAD51 has been suggested. Ween et al:"versican and hyaluronan (HA) which interacts with the HA receptor, CD44, have been shown to play critical roles in ovarian cancer metastasis." These molecule states (isoforms) have been found to be increasingly affected by interaction with growth factors TGF and even PDGF. (early detection of metastatic disease). They should enter biomarker testing.
3.BRCAs are "wild gene" first because there are hundred of these Mutations
and also because Wikipidea describes multiple various interactions:
"BRCA1 has been shown to interact with
- ABL1,[102]
- AKT1,[103][104]
- AR,[105]
- ATR,[106][107][108][109]
- ATM,[10][106][107][108][109][110][111]
- ATF1,[112]
- AURKA,[113]
- BACH1,[114]
- BARD1,[23][31][35][114][115][116][117][118][119][120][121][122][123][124][125][126][127][128][129][130][131][132][133][134][135][136][137][138][139][140][141][142]
- BRCA2,[120][143][144][145]
- BRCC3,[120]
- BRE,[120]
- BRIP1,[27][146][147][148][149][150]
- C-jun,[151]
- CHEK2,[152][153]
- CLSPN,[154]
- COBRA1,[155]
- CREBBP,[140][156][157][158][159]
- CSNK2B,[160]
- CSTF2,[125][126]
- CDK2,[29][161][162]
- DHX9,[163][164]
- ELK4,[165]
- EP300,[156][158]
- ESR1,[158][166][167][168]
- FANCA,[169]
- FANCD2,[122][144]
- FHL2,[170][171]
- H2AFX,[115][119][172]
- JUNB,[151]
- JunD,[151]
- LMO4,[173][174]
- MAP3K3,[175]
- MED1,[147]
- MED17,[130][147][176]
- MED21,[177]
- MED24,[147]
- MRE11A,[10][130][178][179]
- MSH2,[10][31]
- MSH3,[31][146]
- MSH6,[10][31]
- Myc,[35][180][181][182]
- NBN,[10][130][178]
- NMI,[180]
- NPM1,[121]
- NCOA2,[146][183]
- NUFIP1,[184]
- P53,[120][157][185][186][187]
- PALB2,[188]
- POLR2A,[130][177][189][190]
- PPP1CA,[191]
- Rad50,[10][130][178]
- RAD51,[31][120][143][192]
- RBBP4,[193]
- RBBP7,[193][194][195]
- RBBP8,[136][146][196][197][198][199][200]
- RELA,[140]
- RB1,[193][201][202]
- RBL1,[201]
- RBL2,[201]
- RPL31,[195]
- SMARCA4[203][204]
- SMARCB1,[203]
- STAT1,[205]
- UBE2D1,[115][116][117][118][119][120][121][122][123][124]
- USF2,[206]
- VCP,[207]
- XIST,[208][209]
- ZNF350,[210]"""
- of interest to us at CBCM are interaction with "BARD1,E3,VCP, SWI/SNF,Cobra1,Mir-17, Mir-30,ATM,MRE 11, PARP, PALB2,RAD51"
Monday, October 6, 2014
Getting more training in research, full schedule.....this is my outlook Calendar
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Saturday, October 4, 2014
Treatment in advanced Head and neck cancer
Cetuximab-Cisplatin-5-FU
adding Taxane does not change survival
question maintenance of Cetuximab
weekly Taxol - carbo
Afatinib
weekly Methotrexate
Gemzar - Cisplatin
Pembrolizumab
for early stage of course
------------------------------chemotherapy and weekly Cisplatin +/-Cetuximab
or RT with Cetuximab
Cetuximab-Cisplatin-5-FU
adding Taxane does not change survival
question maintenance of Cetuximab
weekly Taxol - carbo
Afatinib
weekly Methotrexate
Gemzar - Cisplatin
Pembrolizumab
for early stage of course
------------------------------chemotherapy and weekly Cisplatin +/-Cetuximab
or RT with Cetuximab
Monday, September 29, 2014
ROLE OF SOX5, A DRIVER FORCE. FROM EPITHELIALIZATION TO METASTASIS
TWIST1 ------!
! !
! !..................E-CADHERIN
! ! !
SOX5--------! !
! miR125B - - - SNAIL-1------FGF
! ! !
! ! !
! SIP-1 MMP
!
!
_______________________!__________________________________
! ! ! ! ! !
COL2A AGC-1 PPARs AP-1 ATF1 C-jun
Saturday, September 27, 2014
Mutombo Kankonde, MD11601 Pellicano Rd
El Apso, TX 79936
Certificate
Dannemiller certifies that the above individual has participated in the enduring material titled Evolving Strategies for Management of Early-Stage and Metastatic Triple-Negative Breast Cancer on September 27, 2014 and is awarded 2.00 AMA PRA Category 1 Credit(s)™.
Michelle Montgomery, MA, CCMEP
Director of Continuing Education
Director of Continuing Education
5711 Northwest Parkway – San Antonio, TX 78249 – Tel: (800) 328-2308 – Fax: (210) 641-8329
Breast cancer/TNBC
*when a woman expected to have BRCA1,or 2 fails to have it
should we go on to find PALB2
*for TNBC
1,Taxol or Taxotere weekly
+Carboplatin AUC6 Q4weeks
or
Eribulin (1.4mg/m2 day 1,8 Q21 ) + Carbo
or
Ixabepilone
or Gem-Carbo + Iniparib or olaparib
VELIPARIB +CARBO+TAXOL
should we go on to find PALB2
*for TNBC
1,Taxol or Taxotere weekly
+Carboplatin AUC6 Q4weeks
or
Eribulin (1.4mg/m2 day 1,8 Q21 ) + Carbo
or
Ixabepilone
or Gem-Carbo + Iniparib or olaparib
VELIPARIB +CARBO+TAXOL
Friday, September 26, 2014
Origin of solid/epithelial and some hematologic tumors: disturbance of Ubiquitilation...
Although there seem to come from every single where,
life seems to try to hide from us the single origin of sufficient disturbance that lead to neoplastic transformation, but every where you turn seems to impose upon us that the single most important process involved in the neoplastic process start as a deficiency in the Ubiquilation process!
Yes one of the E3 (or partner) is involved in many cancer.
The involvement may not be directly involving the cellular E(s), however in many instances, molecules containing a E receptor or attachment site will be involved.
In Breast cancer, the SWI/SNF HAS AN UBIQUITININ BINDING DOMAIN:
"SWI/SNF mutations were widespread across diverse human cancers, with an excess of deleterious mutations, and an overall frequency approaching TP53 mutation. Mutations occurred most commonly in the SMARCA4 enzymatic subunit, and in subunits thought to confer functional specificity (ARID1A, ARID1B, PBRM1, and ARID2). SWI/SNF mutations were not mutually-exclusive of other mutated cancer genes, including TP53 and EZH2 (both previously linked to SWI/SNF). Our findings implicate SWI/SNF as an important but under-recognized tumor suppressor in diverse human cancers, and provide a key resource to guide future investigations." HUNTER SHAIN et al.
"Remarkably, mutations in SWI/SNF were present at high frequency across many different tumor types (Fig. 1A). The cancers with the highest SWI/SNF mutation rates were ovarian clear cell carcinoma (75%), clear cell renal cell carcinoma (57%), hepatocellular carcinoma (40%), gastric cancer (36%), melanoma (34%), and pancreatic cancer (26%). Across all tumor types, the average frequency of SWI/SNF mutations (19%) approached that of TP53 (26%; shown for comparison in Fig. 1A), the single-most mutated tumor suppressor gene." SHAIN AND JOHNATAN POLLACK
"
Mammalian SWI/SNF-A Subunit BAF250/ARID1 Is an E3 Ubiquitin Ligase That Targets Histone H2B
Xuan Shirley L et al" " together with cullin 2 and Roc1, assemble into an E3 ubiquitin ligase. The BAF250b BC box mutant protein was unstable in vivo
and was autoubiquitinated in a manner similar to that for the VHL BC
box mutants. The discovery that BAF250 is part of an E3 ubiquitin ligase
adds an enzymatic function to the chromatin-remodeling complex
SWI/SNF-A."
The part were the SWI/SNF has Histone modulation activity is a relevant one since it points to new creation of sets of molecules that are going to help in the neoplastic transformation. That in this part of the Silenced DNA, activity at the Ligase will "Unsilence" several genes that will be determinant to the future of the new cell.
=========================================================
In lung cancers, effects at the MDM-2 has now been recognized by studies by DR Zhang (UTEP) that this is one of the most amplified genetic mutation. Putting the MDM-2 at the onset of cancer pathogenic production. Yes the disease seems to start here with further secondary amplification of the NPM1 as a result:
Robert Amson et al
"TPT1"
and
"recruitment of phosphorylated NPM1 to site of DNA damage through RNF-8-dependent Ubiquitin conjugates" Ayaka Koike et al!
implicating BRCA-1 ....
===========================================
The high response rate of Velcade in Myeloma has provided further proof that ubiquitination is a major pathways in this disease
===========================================
In renal cancer
the answer is obvious,
life seems to try to hide from us the single origin of sufficient disturbance that lead to neoplastic transformation, but every where you turn seems to impose upon us that the single most important process involved in the neoplastic process start as a deficiency in the Ubiquilation process!
Yes one of the E3 (or partner) is involved in many cancer.
The involvement may not be directly involving the cellular E(s), however in many instances, molecules containing a E receptor or attachment site will be involved.
In Breast cancer, the SWI/SNF HAS AN UBIQUITININ BINDING DOMAIN:
"SWI/SNF mutations were widespread across diverse human cancers, with an excess of deleterious mutations, and an overall frequency approaching TP53 mutation. Mutations occurred most commonly in the SMARCA4 enzymatic subunit, and in subunits thought to confer functional specificity (ARID1A, ARID1B, PBRM1, and ARID2). SWI/SNF mutations were not mutually-exclusive of other mutated cancer genes, including TP53 and EZH2 (both previously linked to SWI/SNF). Our findings implicate SWI/SNF as an important but under-recognized tumor suppressor in diverse human cancers, and provide a key resource to guide future investigations." HUNTER SHAIN et al.
"Remarkably, mutations in SWI/SNF were present at high frequency across many different tumor types (Fig. 1A). The cancers with the highest SWI/SNF mutation rates were ovarian clear cell carcinoma (75%), clear cell renal cell carcinoma (57%), hepatocellular carcinoma (40%), gastric cancer (36%), melanoma (34%), and pancreatic cancer (26%). Across all tumor types, the average frequency of SWI/SNF mutations (19%) approached that of TP53 (26%; shown for comparison in Fig. 1A), the single-most mutated tumor suppressor gene." SHAIN AND JOHNATAN POLLACK
"
Mammalian SWI/SNF-A Subunit BAF250/ARID1 Is an E3 Ubiquitin Ligase That Targets Histone H2B![[down-pointing small open triangle]](http://www.ncbi.nlm.nih.gov/corehtml/pmc/pmcents/x25BF.gif)
Xuan Shirley L et al" " together with cullin 2 and Roc1, assemble into an E3 ubiquitin ligase. The BAF250b BC box mutant protein was unstable in vivo
and was autoubiquitinated in a manner similar to that for the VHL BC
box mutants. The discovery that BAF250 is part of an E3 ubiquitin ligase
adds an enzymatic function to the chromatin-remodeling complex
SWI/SNF-A."The part were the SWI/SNF has Histone modulation activity is a relevant one since it points to new creation of sets of molecules that are going to help in the neoplastic transformation. That in this part of the Silenced DNA, activity at the Ligase will "Unsilence" several genes that will be determinant to the future of the new cell.
=========================================================
In lung cancers, effects at the MDM-2 has now been recognized by studies by DR Zhang (UTEP) that this is one of the most amplified genetic mutation. Putting the MDM-2 at the onset of cancer pathogenic production. Yes the disease seems to start here with further secondary amplification of the NPM1 as a result:
Robert Amson et al
"TPT1"
and
"recruitment of phosphorylated NPM1 to site of DNA damage through RNF-8-dependent Ubiquitin conjugates" Ayaka Koike et al!
implicating BRCA-1 ....
===========================================
The high response rate of Velcade in Myeloma has provided further proof that ubiquitination is a major pathways in this disease
===========================================
In renal cancer
the answer is obvious,
Thursday, September 25, 2014
from ASCO 2014: Treatment of renal cancer
Renal cell cancer
setting phase III Alternative
Sunitinib
1st line Good or Intermediate Avastin HD-IL-2
Interferon-alpha
Pazopanib
Poor risk Tamsirolimus
================================================================
Prior Cytokine Sorafenib Sunitinib
Pazopanib Avastin
2nd line Prior EGFR Everolimus
therapy inhibitor Axitinib clinical trial
Prior MTOR Clinical trial
From ASCO
setting phase III Alternative
Sunitinib
1st line Good or Intermediate Avastin HD-IL-2
Interferon-alpha
Pazopanib
Poor risk Tamsirolimus
================================================================
Prior Cytokine Sorafenib Sunitinib
Pazopanib Avastin
2nd line Prior EGFR Everolimus
therapy inhibitor Axitinib clinical trial
Prior MTOR Clinical trial
From ASCO
Challenges in treating immunocompromised patients
One of the many challenges in treating immunocompromised patient is the lack of predictive bio-markers that help guide treatments of these patients while they are undergoing chemotherapy or any other immunocompromising treatment. In most cases, the treatment is reactive that is we wait until the patient is sick and proceed on to catch up by giving him a combination of Antibiotics, anti-fungals, and other available anti-virals.
We know the patients have either a cellular deficiency or an humoral dysfunction linked to the primary hematologic disease or to treatment. But we still can't predict what if any infection will be developed. Perturbation of the integrity of the Gastro-intestinal or pulmonary membranes that could be induced by our therapeutic interventions, and dormant viral (CMV, HH-6,)and bacterial infections (Syphilis,Tuberculosis), all could contribute to an infection outbreak, but no predictive bio-markers are available for current clinical use!
The longer the patient remains neutropenic also impact on what infection can set in! Briefly, we have no predictive definite Biomarkers to predict what infection will be developed, and in specific cases, in patient undergoing treatment preventive or otherwise. Ongoing treatment on Tacrolimus or Cyclosporine must be monitored with specific biomarkers that will allow closer monitoring of these patients. Current medical practice does not allow clear measurement indicators predicting what will happen to the patients.
Another component of these issues, is predicting who will develop a sweet syndrome in our neutropenic patients, and who are susceptible to other rare event such as the PRES (posterior reversible Encephalopathy Syndrome). Genetic Bio-markers must be out there, our point is just to go get them to declare our readiness for future medicine....
We know the patients have either a cellular deficiency or an humoral dysfunction linked to the primary hematologic disease or to treatment. But we still can't predict what if any infection will be developed. Perturbation of the integrity of the Gastro-intestinal or pulmonary membranes that could be induced by our therapeutic interventions, and dormant viral (CMV, HH-6,)and bacterial infections (Syphilis,Tuberculosis), all could contribute to an infection outbreak, but no predictive bio-markers are available for current clinical use!
The longer the patient remains neutropenic also impact on what infection can set in! Briefly, we have no predictive definite Biomarkers to predict what infection will be developed, and in specific cases, in patient undergoing treatment preventive or otherwise. Ongoing treatment on Tacrolimus or Cyclosporine must be monitored with specific biomarkers that will allow closer monitoring of these patients. Current medical practice does not allow clear measurement indicators predicting what will happen to the patients.
Another component of these issues, is predicting who will develop a sweet syndrome in our neutropenic patients, and who are susceptible to other rare event such as the PRES (posterior reversible Encephalopathy Syndrome). Genetic Bio-markers must be out there, our point is just to go get them to declare our readiness for future medicine....
Monday, September 22, 2014
So we said!
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!
Saturday, September 20, 2014
News in Prostate Cancer! Getting hot in Las Vegas!
With all the new options for therapy in Prostate cancer, one may wonder if there is still interesting topics and areas of unknown in Prostate cancer. One thing is for certain, there is no definitive cure for Prostate Cancer and therefore research and progress in this field remain to be accomplished. And with each conference, one continue to learn new areas of research emphasis. In Prostate cancer, data free Zones continue to abound as discoveries are made!
Areas of Data free Zone!
------------------------------This is where in clinical practice things are done although there is no clear data to support our practice.
1.Although we all know that patient who fail Lupron should go onto "withdraw", there is no biomarkers to determine who should be chosen for this option. Often we bypass this withdraw as an option to jump now to Abiraterone or Enzalutamide because we can! This is however an important period of no therapy that our patients can enjoy with no therapy or side effects!
2.How to determine the most efficacious treatment? or what are the most predictive Bio-markers?
3.Are combination therapy better than sequential use of major therapeutic options
4.Is deterioration of performance status a clear indication of exclusion of spileucel-T use since this drug may take up to 6 months before the curb separation to indicate benefit, should Performance status be used for early initiation of chemotherapy...?
4.what is the role of new immune markers?
CD54 upregulation has been used for the appropriateness of use of spileucel-T? what about CTC - ARv7 the so called "negative Predictor Biomarker"?
5.Given the impact of the marrow, should RAD 223 come always prior to Chemotherapy or after this? should documented radiological progression in the bone be the indicator of RAD 223 in a pain bearing patient with metastatic Prostate cancer patient? And how to interpret PSA fluctuation in RAD 223 treated patient? Should we always continue to associate Lupron or other anti-androgen treatment that adress non bone disease (or visceral disease) while on RAD 223?
6. What in hell is "liquified semen" while on treatment for Prostate cancer? And now the role of Eosinophilia in so called "good responders" ? should alkaline Phosphatase, or PAP be better biomarker in patient treated will spileucel-T. Or is-it PA-2024? Could proof of long term memory by T-cell be evidence of further role for a boost in Spileucel-T. What is the role of "Antigen spread"? and what that has to do with Cancer preservation and resistance?
7Notion of AR Variant that apparantly lack a binding domain for membrane area activity but can still act deeper into the Nucleus, and is -t here that Enzutamide may be more effective since it impairs deep localisation at AR cellular path...and what are the co-factors allowing this deep action of the variant AR. Should we really look for AKT/PI3K upregulation in resistant diseases? And actually which gene cross-talk with the AR in resistant cancers? And the role of combination therapy in these setting...
8.Instead of fighting all these side effect, should we just push further Orchiectomy?
9.role of Gleason once treatment has been started?
10. Is testosterone level <50ng better than 20ng to define hormone resistance disease?
11. how to appreciate cardiac risk in patient on treatment for metastatic Prostate cancer
EH! patient on Abiraterone, always use Prednisone
but you don't have to for Enzalutamide
and always use GCSF while on Cabazitaxel because the one who died fron this chemotherapy did so after the first cycle of chemotherapy! experimenting without it at your own risk!
etc...and I can go on for days...at CRBCM, we keep ourselves informed! still a lot of work even in Prostate cancer....
Areas of Data free Zone!
------------------------------This is where in clinical practice things are done although there is no clear data to support our practice.
1.Although we all know that patient who fail Lupron should go onto "withdraw", there is no biomarkers to determine who should be chosen for this option. Often we bypass this withdraw as an option to jump now to Abiraterone or Enzalutamide because we can! This is however an important period of no therapy that our patients can enjoy with no therapy or side effects!
2.How to determine the most efficacious treatment? or what are the most predictive Bio-markers?
3.Are combination therapy better than sequential use of major therapeutic options
4.Is deterioration of performance status a clear indication of exclusion of spileucel-T use since this drug may take up to 6 months before the curb separation to indicate benefit, should Performance status be used for early initiation of chemotherapy...?
4.what is the role of new immune markers?
CD54 upregulation has been used for the appropriateness of use of spileucel-T? what about CTC - ARv7 the so called "negative Predictor Biomarker"?
5.Given the impact of the marrow, should RAD 223 come always prior to Chemotherapy or after this? should documented radiological progression in the bone be the indicator of RAD 223 in a pain bearing patient with metastatic Prostate cancer patient? And how to interpret PSA fluctuation in RAD 223 treated patient? Should we always continue to associate Lupron or other anti-androgen treatment that adress non bone disease (or visceral disease) while on RAD 223?
6. What in hell is "liquified semen" while on treatment for Prostate cancer? And now the role of Eosinophilia in so called "good responders" ? should alkaline Phosphatase, or PAP be better biomarker in patient treated will spileucel-T. Or is-it PA-2024? Could proof of long term memory by T-cell be evidence of further role for a boost in Spileucel-T. What is the role of "Antigen spread"? and what that has to do with Cancer preservation and resistance?
7Notion of AR Variant that apparantly lack a binding domain for membrane area activity but can still act deeper into the Nucleus, and is -t here that Enzutamide may be more effective since it impairs deep localisation at AR cellular path...and what are the co-factors allowing this deep action of the variant AR. Should we really look for AKT/PI3K upregulation in resistant diseases? And actually which gene cross-talk with the AR in resistant cancers? And the role of combination therapy in these setting...
8.Instead of fighting all these side effect, should we just push further Orchiectomy?
9.role of Gleason once treatment has been started?
10. Is testosterone level <50ng better than 20ng to define hormone resistance disease?
11. how to appreciate cardiac risk in patient on treatment for metastatic Prostate cancer
EH! patient on Abiraterone, always use Prednisone
but you don't have to for Enzalutamide
and always use GCSF while on Cabazitaxel because the one who died fron this chemotherapy did so after the first cycle of chemotherapy! experimenting without it at your own risk!
etc...and I can go on for days...at CRBCM, we keep ourselves informed! still a lot of work even in Prostate cancer....
Friday, September 19, 2014
Wynn Las Vegas, a review on Prostate Cancer...
The CRBCM is back in Las Vegas to sharpen its knowledge on Prostate Cancer
what is new ? Is there a new sequence to treating Prostate cancer...are there new bio-markers, new guidelines, new genes to be aware of? these are the few questions that we have forward. The actual conference will be tomorrow. Here at the Wynn...the setting is perfect...we will update you as quickly as we get the info....for now just let's enjoy the Wynn...
what is new ? Is there a new sequence to treating Prostate cancer...are there new bio-markers, new guidelines, new genes to be aware of? these are the few questions that we have forward. The actual conference will be tomorrow. Here at the Wynn...the setting is perfect...we will update you as quickly as we get the info....for now just let's enjoy the Wynn...
Tuesday, September 16, 2014
Interesting case at CRBCM: Acute Myeloid Leukemia with myelomonocytic differentiation in a patient with possible Lupus
This is a 74 YOHM who presented to Sierra Providence with vomiting, nausea , poor appetite and weight loss, he was found with a severe anemia. A bone marrow biopsy obtained on 08/11/2014 suggested a Hypercellular Marrow involved with Acute myelogenous leukemia with myelomonocytic differentiation. There was 70 to 80 % of myeloblasts by morphology and flow. Further cytogenetic studies revealed a positive inversion 16 ( MYH1) with 7q- (DS486). The CBFB was found in 90% of cells and RUNX1-I mutation in 90% of cells.
Of note: The ANA was positive. HIV negative.
The patient received a course of hydroxyurea prior to a standard 7+3 induction therapy with Daunarubicin and ARA-C. A new bone marrow biopsy obtained on 09/02/2014 suggests residual disease with 3% blasts 10 to 15% myelomonoblasts. the patient will need a reinduction therapy with Idarubicin and ARA-C.
Prior to this admission, the patient, an old teacher, was otherwise healthy. He has no history of hypertension, diabetes or asthma.
Of interest: The patient's sister has an open Lupus.
===================================================
This case is very interesting as it suggests progression of Lupus into a monocytic AML
did RUNX-1 under various pressure go awry,
did presence of RUNX-1 suggest activity of Etoposide or may be just activity of Decitabine.
but this is an inversion 16 case, should we forgo standard induction because of the patient age? But he did tolerate induction treatment at the local Hospital. He had the 7q minus deletion and therefore a bad prognosis indicator mitigating the Inv(16) presence. Could he have transplant in good hands...the man has a good performance status and flew through his first attempt to induction!
your feed back appreciated!
Ida will do (
"Idarubicin /ˌaɪdəˈruːbɨsɪn/ or 4-demethoxydaunorubicin is an anthracycline antileukemic drug. It inserts itself into DNA and prevents DNA from unwinding by interfering with the enzyme topoisomerase II. It is an analog of daunorubicin, but the absence of a methoxy group increases its fat solubility and cellular uptake.[1] Similar to other anthracyclines, it also induces histone eviction from chromatin.[2]" wikipedia
Of note: The ANA was positive. HIV negative.
The patient received a course of hydroxyurea prior to a standard 7+3 induction therapy with Daunarubicin and ARA-C. A new bone marrow biopsy obtained on 09/02/2014 suggests residual disease with 3% blasts 10 to 15% myelomonoblasts. the patient will need a reinduction therapy with Idarubicin and ARA-C.
Prior to this admission, the patient, an old teacher, was otherwise healthy. He has no history of hypertension, diabetes or asthma.
Of interest: The patient's sister has an open Lupus.
===================================================
This case is very interesting as it suggests progression of Lupus into a monocytic AML
did RUNX-1 under various pressure go awry,
did presence of RUNX-1 suggest activity of Etoposide or may be just activity of Decitabine.
but this is an inversion 16 case, should we forgo standard induction because of the patient age? But he did tolerate induction treatment at the local Hospital. He had the 7q minus deletion and therefore a bad prognosis indicator mitigating the Inv(16) presence. Could he have transplant in good hands...the man has a good performance status and flew through his first attempt to induction!
your feed back appreciated!
Ida will do (
"Idarubicin /ˌaɪdəˈruːbɨsɪn/ or 4-demethoxydaunorubicin is an anthracycline antileukemic drug. It inserts itself into DNA and prevents DNA from unwinding by interfering with the enzyme topoisomerase II. It is an analog of daunorubicin, but the absence of a methoxy group increases its fat solubility and cellular uptake.[1] Similar to other anthracyclines, it also induces histone eviction from chromatin.[2]" wikipedia
So it is! from the Indiana State commissionaire
State Health Commissioner
_______________________________________________
Physicians mailing list
Physicians@lists.in.gov
http://lists.in.gov/mailman/listinfo/physicians
To
Today at 7:58 AM
The
Indiana State Department of Health (ISDH) has identified four confirmed
cases of respiratory enterovirus EV-D68 among Indiana residents.
Testing was performed at
the Centers for Disease Control and Prevention (CDC). Several other
suspect cases are pending testing at the Indiana State Department of
Health Laboratory. Syndromic surveillance of hospital emergency
department chief complaints has indicated a higher than
expected level of respiratory illness statewide for this time of year.
Several other states, including Colorado, Illinois, Iowa, Kentucky,
Kansas, and Missouri, have also identified confirmed EV-D68 cases.
EV-D68 infections can be mild and self-limited, but children with asthma are at risk for
severe respiratory illness and may require hospitalization to receive intensive supportive therapy.
Patients
with asthma should carefully maintain their current medical management
and follow their asthma action plan to monitor for early signs of
exacerbation. People who smoke are
also at higher risk for severe enterovirus infections.
The
CDC recommends hospitals use standard, contact, and droplet precautions
when caring for patients. Alcohol-based hand sanitizers are not
effective against EV-D68.
Bleach-based disinfectants, like those used for rhinovirus and
norovirus, are effective for environmental cleaning.
Clinicians
are advised to suspect enterovirus infection in patients hospitalized
with asthma exacerbations or severe respiratory illness. To confirm the
presence of
EV-D68 in Indiana and further characterize this illness, the ISDH
Laboratory is temporarily requesting that clinicians send nasopharyngeal
and oropharyngeal swabs in the same transport medium or upper
respiratory aspirates:
·
Patients
must test positive for rhinovirus/enterovirus
before submission to the ISDH Laboratory. Indicate
this positive test result and the test method on the specimen
submission form. Specimen submissions lacking this information will not
be tested.
·
Specimens from patients who test positive for rhinovirus/enterovirus do not need prior authorization.
·
Specimens do not need to be tested for influenza and respiratory syncytial virus (RSV) prior to submission.
Sequencing will be conducted to identify the specific viral strain.
Instructions for specimen submissions to ISDH for testing are located on the ISDH enterovirus page at
http://www.in.gov/isdh/26487.htm
under the laboratory specimen information section.
Specimens should arrive at the ISDH Laboratory Monday-Friday excluding
state holidays within three
days of the collection date. Specimens
must
be submitted using LIMSNET. To sign up for a LIMSNET account, contact the ISDH LIMS HelpDesk at 317-921-5506 or 1-888-535-0011.
Healthcare providers
who identify outbreaks or unusual occurrences of respiratory illness
should contact Shawn Richards, Outbreak Supervisor,
at srichard@isdh.in.gov or 317.233.7125 to inquire about specimen submission and further investigation to identify the cause of these outbreaks.
Most
enterovirus infections in the U.S. occur seasonally during the summer
and fall, and enterovirus outbreaks tend to occur in several-year
cycles. Respiratory enteroviruses
include EV-D68 and rhinovirus and are transmitted through contact with
secretions from the eyes, nose, and mouth (saliva, mucus, sputum) of an
infected person; having close contact with an infected person, such as
touching or shaking hands; and touching objects
or surfaces that have been contaminated with infectious secretions.
No
vaccine is available to prevent infection with respiratory
enteroviruses, and no antiviral medication is available. Health care
providers should recommend the following:
·
Clean: wash hands often with soap and water for 20 seconds
·
Cover: cover sneezes and coughs with your sleeve or a tissue
·
Contain: prevent spreading illness to others by staying home if you are sick
·
Avoid close contact and sharing cups or eating utensils with those who are ill
·
Disinfect frequently touched surfaces
·
Avoid smoking or exposure to second-hand smoke
For questions regarding epidemiology/surveillance, please contact Shawn Richards at
srichard@isdh.in.gov or 317.233.7740. For questions on specimen collection or submission please contact Stephanie Dearth at
stdearth@isdh.in.gov or 317.921.5843.
For more information on enteroviruses, please visit the following websites:
Indiana State Department of Health website at
http://www.in.gov/isdh/26487.htm.
Centers for Disease Control and Prevention (CDC) website at
http://www.cdc.gov/non-polio-enterovirus.
William C. VanNess II, MD
State Health Commissioner
_______________________________________________
Physicians mailing list
Physicians@lists.in.gov
http://lists.in.gov/mailman/listinfo/physicians
Wednesday, September 10, 2014
life in a nutshell
Without further details, and in general
from the time we are born, one seem to cross 4-5 critical phases
first phase:
1. After conception, there seems to be priority to cellular Multiplication, and as the fetus is being formed, cellular multiplication will be the preponderant direction of metabolic and physiologic reactions. These metabolic reactions will be limited by rules of differentiation and location of cell in developing tissue. It seems that gene silencing by methylation or otherwise (shutting down of Histone-DNA modulation, or miRNA amplification) will be a driving forces in many location...
Self recognition will be one of the many driving forces marking this period as the Fetus expand...HLA A, B
2. As we are born, HLA C & D will go to play
As defense mechanisms mature against foreign bodies and organisms, there is a parallel growth and maturation of tissues started after conception. And early organs particularly of the endocrine origin start and expand production and activities, shaping further the new "man". This burst of life will continue into the adolescence
3.Then come "the sexual revolution" as the organisms prepare to make new "man" and leave legacy. The burst of sexual hormones appears one of the most important stage of life as reproductive life will have a deep effect of our HLA C, D. Particularly in women, Estrogen will while expanding sexual organs, will shut down rejection of a potential baby who may be "foreign" (carrying partial natural father genes) to the woman body!
HLA A, B will see themselves dampened, At gene level, significant disturbance of DNA Modulation and Methylation will be driven from Estrogen. So much so, this is the time of diagnosis and worsening of Autoimmune diseases (with thyroid dysfunction following)...genes disturbances driven by these Estrogen or sex hormones'effects may include exposure of genetic abnormalities (BRCAs, and in men, the germ cells and other congenital genetic disturbances) and early cancers! Any one treating Autoimmune diseases, will have the run for their money when following patients in this age range (reproductive stage).
4.Cessation of the reproductive phase is even more dangerous, adding fire to injury. Estrogen cessation or major decrease will have a violent effects on lipids, endothelial cell membranes (made of lipids) and their main components (the various integrins and Cytokines). Indeed membranes are the storage of these molecules and various membranes will drive death phenomena such as stroke and cardiac events. Inflammatory processes and ultimately membrane related genes (ie. MUCs ) could lead to neoplastic transformations in many cases!
5. And as life continues, The cytokines and various integrins will become increasingly important, unleashing muscle deterioration, lipid dysfuction, immune failures, further drop of hormones, dementia and memory issue that we have to call "phase of senescence". "consensus" to cell sudden death and "remain dead" justifies sudden death and is a membrane event (NOTCH)! (in some case it may involve only the Brain, and of course the Heart!).
to be continued!
The CRBCM...working hard with perspective!
4.
from the time we are born, one seem to cross 4-5 critical phases
first phase:
1. After conception, there seems to be priority to cellular Multiplication, and as the fetus is being formed, cellular multiplication will be the preponderant direction of metabolic and physiologic reactions. These metabolic reactions will be limited by rules of differentiation and location of cell in developing tissue. It seems that gene silencing by methylation or otherwise (shutting down of Histone-DNA modulation, or miRNA amplification) will be a driving forces in many location...
Self recognition will be one of the many driving forces marking this period as the Fetus expand...HLA A, B
2. As we are born, HLA C & D will go to play
As defense mechanisms mature against foreign bodies and organisms, there is a parallel growth and maturation of tissues started after conception. And early organs particularly of the endocrine origin start and expand production and activities, shaping further the new "man". This burst of life will continue into the adolescence
3.Then come "the sexual revolution" as the organisms prepare to make new "man" and leave legacy. The burst of sexual hormones appears one of the most important stage of life as reproductive life will have a deep effect of our HLA C, D. Particularly in women, Estrogen will while expanding sexual organs, will shut down rejection of a potential baby who may be "foreign" (carrying partial natural father genes) to the woman body!
HLA A, B will see themselves dampened, At gene level, significant disturbance of DNA Modulation and Methylation will be driven from Estrogen. So much so, this is the time of diagnosis and worsening of Autoimmune diseases (with thyroid dysfunction following)...genes disturbances driven by these Estrogen or sex hormones'effects may include exposure of genetic abnormalities (BRCAs, and in men, the germ cells and other congenital genetic disturbances) and early cancers! Any one treating Autoimmune diseases, will have the run for their money when following patients in this age range (reproductive stage).
4.Cessation of the reproductive phase is even more dangerous, adding fire to injury. Estrogen cessation or major decrease will have a violent effects on lipids, endothelial cell membranes (made of lipids) and their main components (the various integrins and Cytokines). Indeed membranes are the storage of these molecules and various membranes will drive death phenomena such as stroke and cardiac events. Inflammatory processes and ultimately membrane related genes (ie. MUCs ) could lead to neoplastic transformations in many cases!
5. And as life continues, The cytokines and various integrins will become increasingly important, unleashing muscle deterioration, lipid dysfuction, immune failures, further drop of hormones, dementia and memory issue that we have to call "phase of senescence". "consensus" to cell sudden death and "remain dead" justifies sudden death and is a membrane event (NOTCH)! (in some case it may involve only the Brain, and of course the Heart!).
to be continued!
The CRBCM...working hard with perspective!
4.
Tuesday, September 9, 2014
Sunday, September 7, 2014
Bold proposed study in the fight against Colorectal cancer!
Proposed study to reduce Colon cancer
"Combination of Ciprofloxacin and Motrin for 6 days every 2 months for 2-3 years could reduce by half frequency of colon cancers in people over 50 years in the next 10 years following the 3 years of the study medication administration"
The study is based on a suggested understanding that insidious infection and inflammatory process due to growth of undue infection brewing in the Colon of sedentary adults generates a number of Cytokines that lead to polyps and cancer production. The study assumes that by reducing an infection by the use of Ciprofloxacin, inflammatory processes will be significantly reduced, and that the use of anti-inflammatory could further reduce cytokine exposure to significantly reduce cancer transformation of colonic cells!
Target Population: above 50 years old
as compared to similar cohort of the general population located in same city.
Observed cohort will undergo colonoscopy at year 3, 8, 13.
Corollary events to be observed stroke and Cardiovascular in the observed population Vs the cohort in the general local population. We anticipate a small reduction here also.
Now these kinds of scientific observations are more done in scandinavian countries which are more immersed with these statistical technics while others will see the downfall first! science data are waiting...and colon cancer frequency remain unaltered. I even suspect that cancer of the stomach could also be reduced!
"Combination of Ciprofloxacin and Motrin for 6 days every 2 months for 2-3 years could reduce by half frequency of colon cancers in people over 50 years in the next 10 years following the 3 years of the study medication administration"
The study is based on a suggested understanding that insidious infection and inflammatory process due to growth of undue infection brewing in the Colon of sedentary adults generates a number of Cytokines that lead to polyps and cancer production. The study assumes that by reducing an infection by the use of Ciprofloxacin, inflammatory processes will be significantly reduced, and that the use of anti-inflammatory could further reduce cytokine exposure to significantly reduce cancer transformation of colonic cells!
Target Population: above 50 years old
as compared to similar cohort of the general population located in same city.
Observed cohort will undergo colonoscopy at year 3, 8, 13.
Corollary events to be observed stroke and Cardiovascular in the observed population Vs the cohort in the general local population. We anticipate a small reduction here also.
Now these kinds of scientific observations are more done in scandinavian countries which are more immersed with these statistical technics while others will see the downfall first! science data are waiting...and colon cancer frequency remain unaltered. I even suspect that cancer of the stomach could also be reduced!
Friday, September 5, 2014
What should happen, happened!
The FDA has approved Pembrolizumab in advanced and metastatic Melanoma
Wednesday, September 3, 2014
One thing about Cytokines
One of the misconception about cytokines is that not only that they are supposed to act like Hormones or even Vitamins to specific receptors but that they need sufficient detectable concentrations to induce incremental changes in the body physiology. In cancers, TGB does need to be very noticeable to have a autocrine function for a particular neoplastic cell, helping its growth. In laboratory however acting directly against its receptors may have tangible effect. It may control metastatic spread of disease.
Another interesting aspect is at various levels of the cytokines, the physiologic effect could be contrary to the original effect, that is a Cytokine could be excitatory at low dose, and inhibitory at high level.
Cytokine can affect metabolism so that only a certain direction is imposed to the metabolism such what happens in dementia (ie: effect on Phosphatases). Whether the G proteins have a dramatic role is clearly suggested! And may prone one to open dementia. It is quite clear that the Cytokine found in elderly are different then in the young as if there is a switch from Hormone preponderence to a Cytokine phase. Also a greater Mitochondrial abnormal physiology seems to characterize senility leading to susceptibilty to deadly tone of common infections.
At higher doses, cytokines enleash further actions as if affecting non conventional effects. (ie high dose interferon and high dose IL-2) It is as if at these doses new set of receptors (death receptors, PD-1) become better reachable directly or indirectly. And of course the muscles and vascular receptors are by now overwhelmed and appears the most affected. And here comes depression and memory deficiency the hallmark of these diseases. Increasingly it is now thought that in patients with high blood pressure and diabetic patient, it is the increasing disturbance in Cytokine that lead to stroke and Heart attacks...the dreadful transition from hormone preponderance to the Cytokine kingdom is followed by unhealthy consequences and deterioration of protective effect of hormone is as a result!
The effect on Mitochondrial activities overall push forward immunomodulation and anti-inflammatory role promoting the role of NSAID. But this role is muddled by the various impacts of various agents on JUNK and c-FOS....
to be continued...
CRBCM always continuing its progress! And the circle will be soon closed!
see previous blog
What weakens the blood vessel for stroke to occur
is it an acute process
is it a long standing transformation due to or inducing cytokine release (can we capture the moment?)
what about the the role of the HIF gene? the MTOR, CRE and the Adenyl Cyclase
what is the exact role of VEGF (or the various VEGF)
what is the role of the endothelial genes/integrins/what A4Beta.
what is the level of metalloproteases before and at rupture
stress on the Cateins
can the FGF-1 tell us a thing
what is the PDGFR reaction
secretion of platelet during clotting at blood vessel
what is happening in the endothelial cells, what can preclude the secondary incident that happens within a year
is the therapeutic response adequate
does Aspirin good as an universal response (based on impact on the c-jun--c-fos taken indiviual or by ratio)
what is the c-fos and c-jun behavior ?
Role of Avastin if any
what cytokines are involved?
level of coagulation factors
what factor V has to to
what about the homocystein?
does vitamin D level affected or induces it?
Another interesting aspect is at various levels of the cytokines, the physiologic effect could be contrary to the original effect, that is a Cytokine could be excitatory at low dose, and inhibitory at high level.
Cytokine can affect metabolism so that only a certain direction is imposed to the metabolism such what happens in dementia (ie: effect on Phosphatases). Whether the G proteins have a dramatic role is clearly suggested! And may prone one to open dementia. It is quite clear that the Cytokine found in elderly are different then in the young as if there is a switch from Hormone preponderence to a Cytokine phase. Also a greater Mitochondrial abnormal physiology seems to characterize senility leading to susceptibilty to deadly tone of common infections.
At higher doses, cytokines enleash further actions as if affecting non conventional effects. (ie high dose interferon and high dose IL-2) It is as if at these doses new set of receptors (death receptors, PD-1) become better reachable directly or indirectly. And of course the muscles and vascular receptors are by now overwhelmed and appears the most affected. And here comes depression and memory deficiency the hallmark of these diseases. Increasingly it is now thought that in patients with high blood pressure and diabetic patient, it is the increasing disturbance in Cytokine that lead to stroke and Heart attacks...the dreadful transition from hormone preponderance to the Cytokine kingdom is followed by unhealthy consequences and deterioration of protective effect of hormone is as a result!
The effect on Mitochondrial activities overall push forward immunomodulation and anti-inflammatory role promoting the role of NSAID. But this role is muddled by the various impacts of various agents on JUNK and c-FOS....
to be continued...
CRBCM always continuing its progress! And the circle will be soon closed!
see previous blog
What weakens the blood vessel for stroke to occur
is it an acute process
is it a long standing transformation due to or inducing cytokine release (can we capture the moment?)
what about the the role of the HIF gene? the MTOR, CRE and the Adenyl Cyclase
what is the exact role of VEGF (or the various VEGF)
what is the role of the endothelial genes/integrins/what A4Beta.
what is the level of metalloproteases before and at rupture
stress on the Cateins
can the FGF-1 tell us a thing
what is the PDGFR reaction
secretion of platelet during clotting at blood vessel
what is happening in the endothelial cells, what can preclude the secondary incident that happens within a year
is the therapeutic response adequate
does Aspirin good as an universal response (based on impact on the c-jun--c-fos taken indiviual or by ratio)
what is the c-fos and c-jun behavior ?
Role of Avastin if any
what cytokines are involved?
level of coagulation factors
what factor V has to to
what about the homocystein?
does vitamin D level affected or induces it?
Monday, September 1, 2014
Important aspect of immunomodulation, the case of the T-reg!
T cell Regulator have plenty of expression of FOXP3 (Scurfin) and this statement summarize the power of Foxp3,
Roli Khattri et al "express glucocorticoid-induced tumor-necrosis factor receptor–related (GITR) protein. The forced expression of Foxp3 also delays disease in CTLA-4-/- mice, indicating that the Scurfin and CTLA-4 pathways may intersect and providing further insight into the TR cell lineage."
Use of Azacytidine and other Histone modulating agents seems to increase Treg cells and therefore TNF receptor stimulation yielding an uncontrolled inflammatory effect leading to some level of Apoptosis. The involvement of CTLA-4 must be clearly noticed!
What triggers the expansion of Foxp3 expressing cell is being debated :" the influence of solely TGF-β, so the difference between a proinflammatory and a pro-regulatory scenario is the presence of a single interleukin. IL-6 or IL-21 is being debated by immunology laboratories as the definitive signaling molecule. It seems so far that murine studies point to IL-6 whereas human studies have shown IL-21." Wikipedia
could Vidaza induced expansion of Treg be compared with IL-21 induced Treg expansion for further answers? Remembering that MGUS is TNF driven, is there a role here?
Could association of IL-23 expands the force of Ipilimumab? or can Vidaza do it since there is a clear proclaimed link?
wait a minute, it gets better" Two lines of functional evidence strongly supported that FoxP3 serves as tumour suppressive transcription factor in cancer development. First, FoxP3 represses expression of HER2, Skp2, SATB1 and MYC oncogenes and induces expression of tumour suppressor genes P21 and LATS2 in breast and prostate cancer cells. Second, over-expression of FoxP3 in melanoma,[12] glioma, breast, prostate and ovarian cancer cell lines induces profound growth inhibitory effects in vitro and in vivo. However, this hypothesis need to be further investigated in future studies." Wikipedia
Is that means
1.In Her-2 negative disease, Vidaza may have a supportive role?
2.what in hell Skp2 add to this
3.MYC is proliferation in chief
4.LATS2 ?????
5. and of course P21, who saw this coming!
Then come this from Marsha Willis-Karp et al:"Tim-3, a member of the T cell immunoglobulin mucin family, is expressed by TH1 cells. Analysis of Tim-3–Tim3 ligand signaling now shows this pathway is intimately involved in the counter-regulation of T helper type 1 immune responses."
DOES THIS MEANS TIM-3 ENTERS THE PATHOGENESIS OF MUCINOUS CARCINOMA? THESE TUMOR ARE NOTICED LATE AND GENERALLY MORE ADVANCED AT TIME OF DIAGNOSIS.
FUN LOOKING IN ALL THIS!
Roli Khattri et al "express glucocorticoid-induced tumor-necrosis factor receptor–related (GITR) protein. The forced expression of Foxp3 also delays disease in CTLA-4-/- mice, indicating that the Scurfin and CTLA-4 pathways may intersect and providing further insight into the TR cell lineage."
Use of Azacytidine and other Histone modulating agents seems to increase Treg cells and therefore TNF receptor stimulation yielding an uncontrolled inflammatory effect leading to some level of Apoptosis. The involvement of CTLA-4 must be clearly noticed!
What triggers the expansion of Foxp3 expressing cell is being debated :" the influence of solely TGF-β, so the difference between a proinflammatory and a pro-regulatory scenario is the presence of a single interleukin. IL-6 or IL-21 is being debated by immunology laboratories as the definitive signaling molecule. It seems so far that murine studies point to IL-6 whereas human studies have shown IL-21." Wikipedia
could Vidaza induced expansion of Treg be compared with IL-21 induced Treg expansion for further answers? Remembering that MGUS is TNF driven, is there a role here?
Could association of IL-23 expands the force of Ipilimumab? or can Vidaza do it since there is a clear proclaimed link?
wait a minute, it gets better" Two lines of functional evidence strongly supported that FoxP3 serves as tumour suppressive transcription factor in cancer development. First, FoxP3 represses expression of HER2, Skp2, SATB1 and MYC oncogenes and induces expression of tumour suppressor genes P21 and LATS2 in breast and prostate cancer cells. Second, over-expression of FoxP3 in melanoma,[12] glioma, breast, prostate and ovarian cancer cell lines induces profound growth inhibitory effects in vitro and in vivo. However, this hypothesis need to be further investigated in future studies." Wikipedia
Is that means
1.In Her-2 negative disease, Vidaza may have a supportive role?
2.what in hell Skp2 add to this
3.MYC is proliferation in chief
4.LATS2 ?????
5. and of course P21, who saw this coming!
Then come this from Marsha Willis-Karp et al:"Tim-3, a member of the T cell immunoglobulin mucin family, is expressed by TH1 cells. Analysis of Tim-3–Tim3 ligand signaling now shows this pathway is intimately involved in the counter-regulation of T helper type 1 immune responses."
DOES THIS MEANS TIM-3 ENTERS THE PATHOGENESIS OF MUCINOUS CARCINOMA? THESE TUMOR ARE NOTICED LATE AND GENERALLY MORE ADVANCED AT TIME OF DIAGNOSIS.
FUN LOOKING IN ALL THIS!
Activities at CRBCM
Our long endeavors continue
we have heard from NIH, they need more details for our research grant application for c-Myc and c-FOS, we are going to continue this line of research since so much is at stake!
we have concluded our mission in Indiana, will complete submissions.
work at the Plasma center has drastically increased as more involvement is required now to achieve the same role, we continue to follow-up on request for further Cytokine research needs here. These places have significant access to plasma and Cytokines...Part of this work may include creation of a school of Biomedical Research in El Paso (part of an integral lab development)! Prospective studies underway!
46 patients planned to be seen this week in clinic and 15 day calls, expansion is arriving, we will skip the trip to Indiana in September...
In October, it is confirmed we will be back at Kosciusko hospital,Warsaw Indiana, for more Oncology work...
This next Month, CRBCM will welcome the help of Orianne Brunet for the finalization of our work completed 1 year ago at Cielo Vista Mall. Orianne will help set up our immunization program!
CRBCM is looking into ensuring independently access to care by indigent cancer patients!
CRCBM will closely follow CPRIT deliberations coming this Sept 3rd in Houston...
We are looking to publish within the next 2-3 months our work on lung cancer...CRBCM...research work continua...
we have heard from NIH, they need more details for our research grant application for c-Myc and c-FOS, we are going to continue this line of research since so much is at stake!
we have concluded our mission in Indiana, will complete submissions.
work at the Plasma center has drastically increased as more involvement is required now to achieve the same role, we continue to follow-up on request for further Cytokine research needs here. These places have significant access to plasma and Cytokines...Part of this work may include creation of a school of Biomedical Research in El Paso (part of an integral lab development)! Prospective studies underway!
46 patients planned to be seen this week in clinic and 15 day calls, expansion is arriving, we will skip the trip to Indiana in September...
In October, it is confirmed we will be back at Kosciusko hospital,Warsaw Indiana, for more Oncology work...
This next Month, CRBCM will welcome the help of Orianne Brunet for the finalization of our work completed 1 year ago at Cielo Vista Mall. Orianne will help set up our immunization program!
CRBCM is looking into ensuring independently access to care by indigent cancer patients!
CRCBM will closely follow CPRIT deliberations coming this Sept 3rd in Houston...
We are looking to publish within the next 2-3 months our work on lung cancer...CRBCM...research work continua...
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