FOXO3 is the reason why inflammatory processes and other causes (such hyperhomocysteinemia) DO NOT INDUCE CELLULAR PROLIFERATION.
DURING INFLAMMATORY DISEASE, BLOCKAGE OF FOXO3 ENTRANCE IN THE NUCLEUS
BLOCK PROLIFERATION, build up of FOX3 may favor autophagia instead
(let's work some more)
Phosphorylation of AKT is closely watched by FOXO3!
Thursday, March 20, 2014
how to stay young
first you have to know all your genes
and every time you want to ingest something, know the genes in what you eat and think that you are about to interact with new genes and reactions with your system will occur
now digestion will occur and what you will eat will be digested
but remember alot we eat ultimately will go through as is particularly small molecules, and will interact with your cells at pure state.
Now it appears that Oxidants have a deeper meaning since they not only induces reactions in your body but they appear to shorten your life by inducing creation of abnormal proteins at mitochondrial levels or by inducing post translational changes to normal proteins. (The so called Mitochondria unfolded protein response). Whether they induce production of cytokines that will have distant effect at cells with special receptors such as the distant substance negria is still debated but will soon come to light once we know the specific cytokine involved (or is it a TGF) !
think like this, with each abnormal proteins secreted you lose a year of your life, or at least some time of your life. This means that with every extra stress, stress created in our mitochondria, you lose some lifespan. And it makes perfect sens, at the core of the Mitochondria is the CRE gene and just tell me what gene does not impact the CRE gene. And remember the CRE gene is in the inflammation, it is in the alcohol metabolism, it is everywhere, it is involved when you are awake and when you sleep, underwatter, or above the ground, in activity of the FOS or Adenyl Cyclase, the HIF or the MTOR. where ever you go, the CRE gene is involved...
Thinking to stay young, look at the FOX, not the gene but the animal FOX, which is full of agility, brightness, and promptitude...in our genes we have the FOXOs, (no clear relation you will rightly say) but if you lack a high level of FOXOs, your life is long! you lack the FOXO you can't stop your life from FLIP-ing to a live state because FLIP is anti-apoptotic for cells. FOXOs elevated will make you killed faster! HIGH FOXOs INCREASES BIM AND PUMA.
ANALOGY WITH THE FOX IS GOOD BECAUSE HIGH FOXY IS ALSO HIGH IN FKHRL1 (youngness)
AND IF YOU ASK ANN BRUNET ET AL " Within the nucleus, FKHRL1 triggers apoptosis most likely by inducing the expression of genes that are critical for cell death, such as the Fas ligand gene."
This FKHRL1 is something to watch closely because of its reported association with 14-3-3. Is this the same protein found in CReutzfeldt Jakob? how come? cellular autophagia? how these fact can be used in a cure of cancer is another chapter! we are digging deeper!
and every time you want to ingest something, know the genes in what you eat and think that you are about to interact with new genes and reactions with your system will occur
now digestion will occur and what you will eat will be digested
but remember alot we eat ultimately will go through as is particularly small molecules, and will interact with your cells at pure state.
Now it appears that Oxidants have a deeper meaning since they not only induces reactions in your body but they appear to shorten your life by inducing creation of abnormal proteins at mitochondrial levels or by inducing post translational changes to normal proteins. (The so called Mitochondria unfolded protein response). Whether they induce production of cytokines that will have distant effect at cells with special receptors such as the distant substance negria is still debated but will soon come to light once we know the specific cytokine involved (or is it a TGF) !
think like this, with each abnormal proteins secreted you lose a year of your life, or at least some time of your life. This means that with every extra stress, stress created in our mitochondria, you lose some lifespan. And it makes perfect sens, at the core of the Mitochondria is the CRE gene and just tell me what gene does not impact the CRE gene. And remember the CRE gene is in the inflammation, it is in the alcohol metabolism, it is everywhere, it is involved when you are awake and when you sleep, underwatter, or above the ground, in activity of the FOS or Adenyl Cyclase, the HIF or the MTOR. where ever you go, the CRE gene is involved...
Thinking to stay young, look at the FOX, not the gene but the animal FOX, which is full of agility, brightness, and promptitude...in our genes we have the FOXOs, (no clear relation you will rightly say) but if you lack a high level of FOXOs, your life is long! you lack the FOXO you can't stop your life from FLIP-ing to a live state because FLIP is anti-apoptotic for cells. FOXOs elevated will make you killed faster! HIGH FOXOs INCREASES BIM AND PUMA.
ANALOGY WITH THE FOX IS GOOD BECAUSE HIGH FOXY IS ALSO HIGH IN FKHRL1 (youngness)
AND IF YOU ASK ANN BRUNET ET AL " Within the nucleus, FKHRL1 triggers apoptosis most likely by inducing the expression of genes that are critical for cell death, such as the Fas ligand gene."
This FKHRL1 is something to watch closely because of its reported association with 14-3-3. Is this the same protein found in CReutzfeldt Jakob? how come? cellular autophagia? how these fact can be used in a cure of cancer is another chapter! we are digging deeper!
Instead of exercising, why not decrease the DAF 2 gene? (suggestions from the literature
"Decreased DAF-2 signaling also causes an increase in life-span." kimura et
al! or is it the Insulin line
"Reduced signaling through the IGF type 1 (IGF-1) receptor increases life span in multiple invertebrate organisms. Studies on mammalian longevity suggest that reducing levels of IGF-1 may also increase life span."Lorenzini et al?
is it Mitochondrial activities as suggested by long et al:
"The traditional view of the role of mitochondria generated reactive oxygen species (ROS) in cellular aging...linked to "...."All of these appear to elicit mitochondrial retrograde signaling processes (defined as signaling from the mitochondria to the rest of the cell, for example, the mitochondrial unfolded protein response, or UPRmt). The effects of mitochondrial retrograde signaling may even spread to other cells/tissues in a noncell autonomous manner by yet unidentified signaling mediators." long et al
are these some forms of cytokines ?
It is assumed that such cytokine effect can act on FOXO3 in the substance Nigra:
"Parkinson's disease (PD) is characterized by the selective degeneration of neuronal populations presumably due to pathogenic interactions between aging and predisposing factors such as increased levels of α-synuclein. Here, we genetically modulate the activity of the transcription factor Forkhead box protein O3 (FOXO3) in adult nigral dopaminergic neurons" Pino et
It is assumed that such cytokine effect can act on FOXO3 in the substance Nigria:
if such cytokine is freed, they induces significant " consequences of their deregulation for tissue function and longevity." wang et al!
other researcher are focusing on UPR:
" In this review, we focus on the mitochondrial unfolded protein response (UPRmt), a response to proteotoxic stress specifically in mitochondria, an organelle with a wide array of fundamental functions, most notably the harvesting of energy from food and the control of cell death." Jovaisaite et al!
THEY IMPLY THE LEVEL OF UPR COULD BE LINKED TO LIFESPAN
How this UPR is linked to Foxo3 or cytokine remains to be clarified...
Katoh et al
"Acceleration of ER-associated degradation in response to the accumulation of unfolded glycoproteins and insufficient interaction with calnexin/calreticulin in the ER lumen likely accounts for the increase of FOSs."
"C-fos but not c-jun expression was also suppressed in the diabetic group" Lu et al
could you follow age by level of c-FOS, we know here we are closer to Foxo3 in the epigenic area!
to be continued!........
al! or is it the Insulin line
"Reduced signaling through the IGF type 1 (IGF-1) receptor increases life span in multiple invertebrate organisms. Studies on mammalian longevity suggest that reducing levels of IGF-1 may also increase life span."Lorenzini et al?
is it Mitochondrial activities as suggested by long et al:
"The traditional view of the role of mitochondria generated reactive oxygen species (ROS) in cellular aging...linked to "...."All of these appear to elicit mitochondrial retrograde signaling processes (defined as signaling from the mitochondria to the rest of the cell, for example, the mitochondrial unfolded protein response, or UPRmt). The effects of mitochondrial retrograde signaling may even spread to other cells/tissues in a noncell autonomous manner by yet unidentified signaling mediators." long et al
are these some forms of cytokines ?
It is assumed that such cytokine effect can act on FOXO3 in the substance Nigra:
"Parkinson's disease (PD) is characterized by the selective degeneration of neuronal populations presumably due to pathogenic interactions between aging and predisposing factors such as increased levels of α-synuclein. Here, we genetically modulate the activity of the transcription factor Forkhead box protein O3 (FOXO3) in adult nigral dopaminergic neurons" Pino et
It is assumed that such cytokine effect can act on FOXO3 in the substance Nigria:
if such cytokine is freed, they induces significant " consequences of their deregulation for tissue function and longevity." wang et al!
other researcher are focusing on UPR:
" In this review, we focus on the mitochondrial unfolded protein response (UPRmt), a response to proteotoxic stress specifically in mitochondria, an organelle with a wide array of fundamental functions, most notably the harvesting of energy from food and the control of cell death." Jovaisaite et al!
THEY IMPLY THE LEVEL OF UPR COULD BE LINKED TO LIFESPAN
How this UPR is linked to Foxo3 or cytokine remains to be clarified...
Katoh et al
"Acceleration of ER-associated degradation in response to the accumulation of unfolded glycoproteins and insufficient interaction with calnexin/calreticulin in the ER lumen likely accounts for the increase of FOSs."
"C-fos but not c-jun expression was also suppressed in the diabetic group" Lu et al
could you follow age by level of c-FOS, we know here we are closer to Foxo3 in the epigenic area!
to be continued!........
Wednesday, March 19, 2014
questions of the day in stroke or myocardial events
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?
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?
Tuesday, March 18, 2014
And Researchers have done the work
And as we have suggested, down the belly of the beast, the dance was uncovered...and for triple negative breast cancer, we now know that the main event is the surge in prolactin which is aimed at stimulating breast development but secondarily promote Casein genes. And we have described Casein genes as they lead to random phosphorylation of other genes.
One model shows Casein phosphorylation of CHEK1 which in turn phosphorylates CDC25 inhibiting it for removing the Phosphate brought by wee1 to stop Mitosis promotion. Putting this as a control of mitosis (but not hyperplasia) in the breast.
Explaining how my achondroplastic woman developed breast cancer became a little easier since Achondroplasia is 99 percent due to FGFR gene abnormalities, and that FGFR interacts with FGF1 which in turn interacts directly with the Casein Kinase 2, and within the presence of BRCA1, Achondroplasia will lead to cdc25 within million seconds!
It is nice to note that Achondroplasia is the thing about not only disturbance of connective tissue through the FGFR3 but also associated calcium distribution (as it occurs on mammogram for breast cancer diagnosis), may be through activity of the SYT-1, or is it S100A.
Note the action of FGF1 on CSNKs!
One model shows Casein phosphorylation of CHEK1 which in turn phosphorylates CDC25 inhibiting it for removing the Phosphate brought by wee1 to stop Mitosis promotion. Putting this as a control of mitosis (but not hyperplasia) in the breast.
Explaining how my achondroplastic woman developed breast cancer became a little easier since Achondroplasia is 99 percent due to FGFR gene abnormalities, and that FGFR interacts with FGF1 which in turn interacts directly with the Casein Kinase 2, and within the presence of BRCA1, Achondroplasia will lead to cdc25 within million seconds!
It is nice to note that Achondroplasia is the thing about not only disturbance of connective tissue through the FGFR3 but also associated calcium distribution (as it occurs on mammogram for breast cancer diagnosis), may be through activity of the SYT-1, or is it S100A.
Note the action of FGF1 on CSNKs!
Monday, March 17, 2014
An interesting Target: The Cullins
" the F-box protein p45(SKP2) is required for S phase and forms stable
complexes with p19(SKP1) and cyclin A-cyclin-dependent kinase (CDK)2." Lisztwan et al...he went on to say:"CUL-1, a member of the cullin family, and the ubiquitin-conjugating enzyme CDC34 as additional partners of p45(SKP2) in vivo."
----------------------------------------------
IT IMPLIES THAT THE CULLINS INTERVENE IN
1.PROMOTION OF UBIQUITILATION THROUGH CONTROL OF REGULATORS
2.SPEED OF OCCURRENCE OF S-PHASE.
BY AFFECTING E2 OR E3 FUNCTION, THE CULLING MAY AFFECT ANY PROTEIN DEGRADATION THAT COULD EXTEND TO THE CYTOKINES AND CYCLINS! "This implies that most cullins may use a SKP1/F-box-independent pathway to facilitate protein degradation."
--------------------------------------------------
XIONG ET AL "
Cullin 4 is said to cause " G1 cell cycle arrest and an increased protein level of the CDK inhibitor Dacapo." and said "E ligase"
TO BE CONTINUED: " WHY THE CULLINS"
----------------------------------------------
IT IMPLIES THAT THE CULLINS INTERVENE IN
1.PROMOTION OF UBIQUITILATION THROUGH CONTROL OF REGULATORS
2.SPEED OF OCCURRENCE OF S-PHASE.
BY AFFECTING E2 OR E3 FUNCTION, THE CULLING MAY AFFECT ANY PROTEIN DEGRADATION THAT COULD EXTEND TO THE CYTOKINES AND CYCLINS! "This implies that most cullins may use a SKP1/F-box-independent pathway to facilitate protein degradation."
--------------------------------------------------
XIONG ET AL "
Cullin 4 is said to cause " G1 cell cycle arrest and an increased protein level of the CDK inhibitor Dacapo." and said "E ligase"
TO BE CONTINUED: " WHY THE CULLINS"
Saturday, March 15, 2014
Activity at CRBCM
As we plan another Visit to the Indianapolis Area this week-end the CRBCM has rapidly grown to meet an accelerating demand of immediate patient care and other positive administration requirements. So much so that genetic work had suffered some delays. But gene work is where the future is, and where our soul rest. So do not be surprised that we shall comeback with a vengeance and progress.
The SBIR/NCI is currently reviewing one of the proposal submitted by CRBCM, and in this world of thousand hypotheses, catch the eyes of investigators is already a victory for CRBCM.
In the clinic, we continue to meet interesting new cases as we move deliberately with formulation of new Hypotheses. This week, a 42 year hispanic achondroplastic (malformation) woman presented with bilateral breast cancer. It is true that this case is the type that beg for gene evaluation first as to the presence of BRCA 1&2 because of her age and bilateral mastectomy needs. How to raise issue of need of bilateral Oophorectomy for Breast-Ovarian cancer possibility, and potential interactions between the Achondroplastic gene and the BRCAs. And how the Achondroplastic gene is linked to VEGF, how to bring in Avastin and the MTOR inhibitor eventually. Her cancer is early and she is currently on Letrozole for adjuvant therapy. But how to gear ourselves for an eventual progression. How the breast cancer biomarkers will behave in this case and how to best follow her, are unique questions. Is the RELA gene involved? These are unique questions making our current practice below what it should be in terms of current insurance limitations in terms of testing. The future will be better. Yes I could test BRCAs but the Achondroplastic gene relation with BRCA is out of Boundaries even though it could point to interesting driver Mutation genes that would have benefited this lady! Is targeting the MEK a potential benefit in case progression to Metastasis occurred? These are unanswered questions that may remain so under the current insurance pressures!
New challenges have also presented themselves as a 62 year old hispanic man walked in with a severe back pain with evidence of L1 involvement by a mass which turned out to be an Adenocarcinoma with GI features in a patient who was treated just 3 years ago for a locally advanced Prostate cancer. The mass was negative for Alkaline Phosphatase and PSA markers. The Colonoscopy is pending and so is the result of several biomarkers. But the severity of the Back pain and knowledge of the impeding vertebral involvement wisked this man into Radiation's hand as we have yet to determine a final plan. Will it be FOLFOX or a DCF model to include still Taxotere given the recent Prostate cancer fight. Is this still a non hormone progression of prostate cancer despite the pathologist suggestions. And yes a PET is not an option because the patient is uninsured and the family cannot pay for this. Yet they feel he may qualify for a new P53 inhibitor which it will take another month to check if this is the driver mutation (can we ? is such a test necessary?). Should we add Avastin in the setting of unknown primary?
These are some of the clinical challenges met a CRBCM, and supputations continue to go on at CRBCM.
Next month we will be in Las Vegas to attend an update in Hematology, we will see what is cooking ....
The SBIR/NCI is currently reviewing one of the proposal submitted by CRBCM, and in this world of thousand hypotheses, catch the eyes of investigators is already a victory for CRBCM.
In the clinic, we continue to meet interesting new cases as we move deliberately with formulation of new Hypotheses. This week, a 42 year hispanic achondroplastic (malformation) woman presented with bilateral breast cancer. It is true that this case is the type that beg for gene evaluation first as to the presence of BRCA 1&2 because of her age and bilateral mastectomy needs. How to raise issue of need of bilateral Oophorectomy for Breast-Ovarian cancer possibility, and potential interactions between the Achondroplastic gene and the BRCAs. And how the Achondroplastic gene is linked to VEGF, how to bring in Avastin and the MTOR inhibitor eventually. Her cancer is early and she is currently on Letrozole for adjuvant therapy. But how to gear ourselves for an eventual progression. How the breast cancer biomarkers will behave in this case and how to best follow her, are unique questions. Is the RELA gene involved? These are unique questions making our current practice below what it should be in terms of current insurance limitations in terms of testing. The future will be better. Yes I could test BRCAs but the Achondroplastic gene relation with BRCA is out of Boundaries even though it could point to interesting driver Mutation genes that would have benefited this lady! Is targeting the MEK a potential benefit in case progression to Metastasis occurred? These are unanswered questions that may remain so under the current insurance pressures!
New challenges have also presented themselves as a 62 year old hispanic man walked in with a severe back pain with evidence of L1 involvement by a mass which turned out to be an Adenocarcinoma with GI features in a patient who was treated just 3 years ago for a locally advanced Prostate cancer. The mass was negative for Alkaline Phosphatase and PSA markers. The Colonoscopy is pending and so is the result of several biomarkers. But the severity of the Back pain and knowledge of the impeding vertebral involvement wisked this man into Radiation's hand as we have yet to determine a final plan. Will it be FOLFOX or a DCF model to include still Taxotere given the recent Prostate cancer fight. Is this still a non hormone progression of prostate cancer despite the pathologist suggestions. And yes a PET is not an option because the patient is uninsured and the family cannot pay for this. Yet they feel he may qualify for a new P53 inhibitor which it will take another month to check if this is the driver mutation (can we ? is such a test necessary?). Should we add Avastin in the setting of unknown primary?
These are some of the clinical challenges met a CRBCM, and supputations continue to go on at CRBCM.
Next month we will be in Las Vegas to attend an update in Hematology, we will see what is cooking ....
Tuesday, March 11, 2014
Questions in Pancreatitis
1.Complications from pancreatitis results when a Cytokine storm complicate the clinical tableau,
which Cytokine?
can we stop the buckling by Early input of Hydrocortisone or Interferon?
2.Does predisposition to Pancreatitis a G protein issue (when exposed to Alcohol or Tobacco?)
3.What is the exact role of PRSS1, CFTR, and SPINK genes, thier contribution to Pancreatitis
4.Most Pancreatitis lead to fibrosis, are genes guiding fibrosis the best monitor of inflammatory resolution,
what are these genes, cytokines, Metalloproteases, Integrins?
5.The dance between PRSS1 and SPINK1 shows the importance of Stoppers or breaker
any activators (PRSS1) needs stoppers/breakers (SPINK1) or regulators in human physiology
(remember the story of Factor V in Coagulation unstoppable cascade!)
6.Is IG4 only valuable in Autoimmune Pancreatitis
7.can you "block" pancreatic enzymes while feeding the patient in acute setting?
which Cytokine?
can we stop the buckling by Early input of Hydrocortisone or Interferon?
2.Does predisposition to Pancreatitis a G protein issue (when exposed to Alcohol or Tobacco?)
3.What is the exact role of PRSS1, CFTR, and SPINK genes, thier contribution to Pancreatitis
4.Most Pancreatitis lead to fibrosis, are genes guiding fibrosis the best monitor of inflammatory resolution,
what are these genes, cytokines, Metalloproteases, Integrins?
5.The dance between PRSS1 and SPINK1 shows the importance of Stoppers or breaker
any activators (PRSS1) needs stoppers/breakers (SPINK1) or regulators in human physiology
(remember the story of Factor V in Coagulation unstoppable cascade!)
6.Is IG4 only valuable in Autoimmune Pancreatitis
7.can you "block" pancreatic enzymes while feeding the patient in acute setting?
Monday, March 10, 2014
CRBCM keeping alive is a battle in a cut throat world!
This email is to inform you that your Attestation for the Medicare
Electronic Health Record (EHR) Incentive Program is 'Accepted'.
Attestation Tracking Information
______________________________
Attestation Confirmation Number: 1000524208
Name: Mutombo Kankonde
NPI: xxxxxxxxx
EHR Certification Number: 30000004H0RCEA0
EHR Reporting Period: 01/01/2013 - 12/31/2013
Program Year: 2013
Attestation Status Date: 03/07/2014
Attestation Tracking Information
______________________________
Attestation Confirmation Number: 1000524208
Name: Mutombo Kankonde
NPI: xxxxxxxxx
EHR Certification Number: 30000004H0RCEA0
EHR Reporting Period: 01/01/2013 - 12/31/2013
Program Year: 2013
Attestation Status Date: 03/07/2014
================================================
don't ask me how we got here,struggle at CRBCM, it is the name of the game!
Sunday, March 9, 2014
speculations in lung cancers
1.TTF-1 and CK 7 held as biomarkers of lung origin, how does MUC 7 compare?
2.how does T790M confer resistance to EGFR positive lung cancer
3.what target therapy becomes possible after EGFR resistance,meaning what mechanism of escape is now on to allow now sequential treatment.
is it Afatinib
is it Dabrafenib
please if you find a Mutation that will compromise the result of your therapy, don't challenge it with a known medication to which it is meant to resist. Well because it is there to exercise its muscles and in the process open new avenue.
4.Inhibitor of the anti-MEK appear certainly attractive
but be sure not to use an upstream blocker to affect its effects
and always think inhibitor of MTOR post anti EGFR! the cell relies on this to escape.
eh by the way bothering the CRE always work!
2.how does T790M confer resistance to EGFR positive lung cancer
3.what target therapy becomes possible after EGFR resistance,meaning what mechanism of escape is now on to allow now sequential treatment.
is it Afatinib
is it Dabrafenib
please if you find a Mutation that will compromise the result of your therapy, don't challenge it with a known medication to which it is meant to resist. Well because it is there to exercise its muscles and in the process open new avenue.
4.Inhibitor of the anti-MEK appear certainly attractive
but be sure not to use an upstream blocker to affect its effects
and always think inhibitor of MTOR post anti EGFR! the cell relies on this to escape.
eh by the way bothering the CRE always work!
Saturday, March 8, 2014
Progress in leukemias with the CAR-T Cell
Genetically engineered autologous T cell fight blood cell cancers seem to attract attention of researcher lately. these cell work with CD19 and include a viral component. Chimeric Antigen Receptor-T or CAR-T has been reported to represent another ex-vivo preparation of the patient own T-Cell genetically engineered to attack a new cancer cells notoriously resistant such as those of Acute Lymphoblastic Leukemia and Burkitt disease. In the heels of Ibrutinib, this appears to be a major advance in cancer therapy.
Van Zelm et al:
"The CD19 protein forms a complex with CD21, CD81, and CD225 in the membrane of mature B cells. Together with the B-cell antigen receptor, this complex signals the B cell to decrease its threshold for activation by the antigen."
In a way disruption of CD19, may also lead to trouble in this complex formation.
previous investigations had suggested that disruption at CD80, 81 could be used in Ovarian cancer treatment. Therefore such a complex could be important indeed as more technologies are being developed. These new developments are strengthening the Immunologic option in both solid and hematologic cancers.
Other function of CD19
Watanabe et al:
"CD19 serves as a positive B-cell response regulator that defines signaling thresholds critical for B-cell responses."
Chen et al:
" Conditional deletion of Foxo1 in B cells resulted in an increased percentage of marginal zone B cells and a decrease in follicular B cells. In addition, Foxo1 deficiency corrected the absence of marginal zone B cells that occurs in CD19-deficient mice. These findings show that Foxo1 regulates the balance of mature B cell subsets and is required for the marginal zone B-cell deficiency phenotype of mice lacking CD19."
This further point to the strength of CD19, that is despite the fact that it has a role in a complex to orient cellular functions, it also lead to malformation as it determine what scientist call morphologically a "Marginal zone". Any gene affecting structure shape has been one of our criteria for importance. And clearly, immunologic deficiencies are characterized by congenital malformations.
May be this CAR-T will actually have the most effect here ...in the Marginal Zone!
Van Zelm et al:
"The CD19 protein forms a complex with CD21, CD81, and CD225 in the membrane of mature B cells. Together with the B-cell antigen receptor, this complex signals the B cell to decrease its threshold for activation by the antigen."
In a way disruption of CD19, may also lead to trouble in this complex formation.
previous investigations had suggested that disruption at CD80, 81 could be used in Ovarian cancer treatment. Therefore such a complex could be important indeed as more technologies are being developed. These new developments are strengthening the Immunologic option in both solid and hematologic cancers.
Other function of CD19
Watanabe et al:
"CD19 serves as a positive B-cell response regulator that defines signaling thresholds critical for B-cell responses."
Chen et al:
" Conditional deletion of Foxo1 in B cells resulted in an increased percentage of marginal zone B cells and a decrease in follicular B cells. In addition, Foxo1 deficiency corrected the absence of marginal zone B cells that occurs in CD19-deficient mice. These findings show that Foxo1 regulates the balance of mature B cell subsets and is required for the marginal zone B-cell deficiency phenotype of mice lacking CD19."
This further point to the strength of CD19, that is despite the fact that it has a role in a complex to orient cellular functions, it also lead to malformation as it determine what scientist call morphologically a "Marginal zone". Any gene affecting structure shape has been one of our criteria for importance. And clearly, immunologic deficiencies are characterized by congenital malformations.
May be this CAR-T will actually have the most effect here ...in the Marginal Zone!
The
patient’s own T-cells are extracted and genetically engineered ex vivo
to target the CD19 antigen present on cancer cells; a viral vector is
inserted, and the cells are reinfused into the patient via a single
infusion where they are designed to expand and attack cancer cells like a
“smart bomb.” Currently, it takes approximately 10 days to engineer the
cells.
“It looks like the disease has disappeared after a single infusion of these engineered T-cells,” reported James N. Kochenderfer, MD, from the Experimental Transplantation and Immunology Branch of the National Cancer Institute (NCI).
- See more at: http://www.valuebasedcancer.com/article/novel-car-t-therapy-shows-impressive-results-aggressive-leukemia-lymphoma#sthash.I8Q2ynHK.dpuf
“It looks like the disease has disappeared after a single infusion of these engineered T-cells,” reported James N. Kochenderfer, MD, from the Experimental Transplantation and Immunology Branch of the National Cancer Institute (NCI).
- See more at: http://www.valuebasedcancer.com/article/novel-car-t-therapy-shows-impressive-results-aggressive-leukemia-lymphoma#sthash.I8Q2ynHK.dpuf
The
patient’s own T-cells are extracted and genetically engineered ex vivo
to target the CD19 antigen present on cancer cells; a viral vector is
inserted, and the cells are reinfused into the patient via a single
infusion where they are designed to expand and attack cancer cells like a
“smart bomb.” Currently, it takes approximately 10 days to engineer the
cells.
“It looks like the disease has disappeared after a single infusion of these engineered T-cells,” reported James N. Kochenderfer, MD, from the Experimental Transplantation and Immunology Branch of the National Cancer Institute (NCI).
- See more at: http://www.valuebasedcancer.com/article/novel-car-t-therapy-shows-impressive-results-aggressive-leukemia-lymphoma#sthash.I8Q2ynHK.dpuf
“It looks like the disease has disappeared after a single infusion of these engineered T-cells,” reported James N. Kochenderfer, MD, from the Experimental Transplantation and Immunology Branch of the National Cancer Institute (NCI).
- See more at: http://www.valuebasedcancer.com/article/novel-car-t-therapy-shows-impressive-results-aggressive-leukemia-lymphoma#sthash.I8Q2ynHK.dpuf
Friday, March 7, 2014
Authors working quickly on the TRB3, a center gene for rapid understanding!
Homocystein can block cell proliferation by upregulating p27 which reportedly increases phosphorylation of AKT.Phosphorylation of the AKT also happens with upregulation by Homocystein of TRB3, however the consequential effect of TRB3 upregulation leads to Endoplasmic Reticulum stress (Zou et al). It is unclear that when TRB3 is busy intervening in the cell proliferation blockage, it also effectively causes the stress mentioned above. We know that homocystein induced hypercoagulation, ?does reticulum induces stress at the center of Atheroma deposit in blood vessel? putting TRIB3 blockage at the center of events?'Homocysteine-induced TRB3 expression was mediated by the cAMP/cAMP response element-binding protein (CREB) pathway." per Zou.
giving 3 ways to affect
1.suppression of TRIB directly by gene interference
or by troubling the CREB as noted by Zou et al.
2.blocking phosphorylation of the AKT
3.blocking p27
4.Zhang et al "However, expression of p-AKT protein increased when TRB3 was inhibited by TRB3 shRNA inhibition." proving blocking RNA could prove effective in preventing Atheroma and cell proliferation through homocystein effect
This TRB3 does not stop there!
Cravero et al:"TRB3, a tribbles homolog, has been shown to inhibit IGF-1-mediated activation of Akt in HEK 293 cells. This study was undertaken to determine if TRB3 is expressed in chondrocytes, and whether the chondrocyte response to IGF-1 is reduced by TRB3."
By targeting or acting with the "terrible" IGF1, TRB3 is in the nix of pathologies
its interactions with the NOTCH and CSNK2B are under close review....
how this TRB3 associate with TIAF1 and RELA
well will see as this story unfolds
What is the TRB3 behavior in the Cordon? and how this may affect the stem cells?
giving 3 ways to affect
1.suppression of TRIB directly by gene interference
or by troubling the CREB as noted by Zou et al.
2.blocking phosphorylation of the AKT
3.blocking p27
4.Zhang et al "However, expression of p-AKT protein increased when TRB3 was inhibited by TRB3 shRNA inhibition." proving blocking RNA could prove effective in preventing Atheroma and cell proliferation through homocystein effect
This TRB3 does not stop there!
Cravero et al:"TRB3, a tribbles homolog, has been shown to inhibit IGF-1-mediated activation of Akt in HEK 293 cells. This study was undertaken to determine if TRB3 is expressed in chondrocytes, and whether the chondrocyte response to IGF-1 is reduced by TRB3."
By targeting or acting with the "terrible" IGF1, TRB3 is in the nix of pathologies
its interactions with the NOTCH and CSNK2B are under close review....
how this TRB3 associate with TIAF1 and RELA
well will see as this story unfolds
What is the TRB3 behavior in the Cordon? and how this may affect the stem cells?
Thursday, March 6, 2014
Still at work, the CRBCM...
It is conceptually correct that main events such as Heart attack or strokes be preceded by an outburst
or an overall increase of either an hormone or a burst of Cytokine (s). This is a critical event because this information may help with prevention. Best place to look at this time is into vascular or platelet receptors. It is also true that lipid receptors must be included in the model to include activity at the Thrombus. Another interesting component to this fact is that there are other events that follow the primary ischemic events that can be fatal. Ie, the high risk of a stroke after another stroke within the following period past a primary stroke. How to prevent the secondary event now that we have had one appears to be critical.... The CRBCM is on the task...reviewing some Cytokines/Hormone receptors and their related genes!
or an overall increase of either an hormone or a burst of Cytokine (s). This is a critical event because this information may help with prevention. Best place to look at this time is into vascular or platelet receptors. It is also true that lipid receptors must be included in the model to include activity at the Thrombus. Another interesting component to this fact is that there are other events that follow the primary ischemic events that can be fatal. Ie, the high risk of a stroke after another stroke within the following period past a primary stroke. How to prevent the secondary event now that we have had one appears to be critical.... The CRBCM is on the task...reviewing some Cytokines/Hormone receptors and their related genes!
Questions in limited Area of knowledge, focus on Vitamin D
1.Does intake of high dose Vitamin D decrease sensitivity to Androgen
Meaning Could it help in Prostate cancer Prevention
2.could dimerization to Retinoid X receptor be a self limiting event enough to preclude toxicity and limit activity of High dose Vit D.
3.Should patient being treated with Promyelocytic Leukemeia be precluded from taking Vit D since it interacts with both ZBRB16 and the Retinoid X receptor
4.Is over expression of STAT1,RACK1 enough of biomarkers for Interferon Activity
and could Vitamin D increases activity of Interferon when given sequencially? Vit D given for 1 to 2 weeks before starting Interferon to stimulate the epigenetic terrain!
5.Should women with STAT1 Breast cancer over expression avoid or take Vit D after remission
could intake of Vitamin D impact BRCA1 expression? Could Vitamin D precipitate or slowdown Breast cancer occurrence in patients known to have BRCA 1 positivity (could it be preventative ?)
6. key words by Researchers:
-Zhao et al: " We show that Bim is a direct target of E2F1 and that HDAC inhibition promotes the recruitment of E2F1 to the Bim promoter." as they explained HDAC inhibitor's apoptosis...
-What P73 a biomarker of? Activity of P53, resistance to P53 inhibitor, or it is time to use a E2F1 inhibitor?
-Kitagawa et al:"Nutlin-3 is a selective inhibitor of the p53-Mdm2 interaction, and inhibits growth in most tumor cells with wild-type p53."
7.Can increase in IgM predict lymphoma recurrence?
8.Can P73, CD154,RNF128 mark recurrence of cancers?
Meaning Could it help in Prostate cancer Prevention
2.could dimerization to Retinoid X receptor be a self limiting event enough to preclude toxicity and limit activity of High dose Vit D.
3.Should patient being treated with Promyelocytic Leukemeia be precluded from taking Vit D since it interacts with both ZBRB16 and the Retinoid X receptor
4.Is over expression of STAT1,RACK1 enough of biomarkers for Interferon Activity
and could Vitamin D increases activity of Interferon when given sequencially? Vit D given for 1 to 2 weeks before starting Interferon to stimulate the epigenetic terrain!
5.Should women with STAT1 Breast cancer over expression avoid or take Vit D after remission
could intake of Vitamin D impact BRCA1 expression? Could Vitamin D precipitate or slowdown Breast cancer occurrence in patients known to have BRCA 1 positivity (could it be preventative ?)
6. key words by Researchers:
-Zhao et al: " We show that Bim is a direct target of E2F1 and that HDAC inhibition promotes the recruitment of E2F1 to the Bim promoter." as they explained HDAC inhibitor's apoptosis...
-What P73 a biomarker of? Activity of P53, resistance to P53 inhibitor, or it is time to use a E2F1 inhibitor?
-Kitagawa et al:"Nutlin-3 is a selective inhibitor of the p53-Mdm2 interaction, and inhibits growth in most tumor cells with wild-type p53."
7.Can increase in IgM predict lymphoma recurrence?
8.Can P73, CD154,RNF128 mark recurrence of cancers?
Wednesday, March 5, 2014
Activities at CRBCM
1.We have been busy, extremely so....
new patients in the work
1. Patient with Polycystic Kidney, Hypertension, we need his genes to see what is the most effective treatment, ACE inhibitors advised is to be taken with a grain of salt
Indeed they are hard to administer in a patient who has anxiety and undefined recurrent vomiting fully worked up by 2-3 Gastroenterologist. The patient vomiting with rising creatinine, the first thing the Nephrologist does is to stop the ACE inhibitor!
2.We are still on the move in El Paso:
"Hi Dr. Kankonde,
And Medical Assistants from Vista College tagging along to continue to learn how a complex practice works!
3. We are fascinated by our case of Endodermal Rabdomyosarcoma.
A 19 year old nice young man presented with a 7.5 cm Right Testicular mass of endodermal Rabdo. which eventually was resected, a PET scan revealed small uptake in the R groin and some in the lumbar region
MRI in this area revealed an Hemangioma in the Vertebrae.
The uptake in the R groin could be reactive small nodes, no other findings,
adjuvant chemotherapy is being given following Ewing Sarcoma protocol
and patient is on the 3rd cycle of Alternating chemotherapy drug. People in Boston offered 17 chemotherapy cycles to achieve a 80% control of disease, some offered chemotherapy for 2 years,
weigh in if you have different opinion. Folks in Radiation are still scratching their heads! When or if to give Radiation? You have an opinion, call 915-307-3354
915-307-3354, I want to hear your input!
At CRBCM, we are still after the genes involved in this disease!
4.We submitted a SBIR project in time and folks at NIH have contacted us for additional input, meaning we are still in play! The CRBCM is proud of this first step despite the fact that we remain optimistic, our feet are still on the ground. As a young enterprise, the CRBCM remains alert. Our submission with CPRIT, well it did not work!
"Dear Applicant,
CPRIT has considered your request for an extension of the submission deadline to complete your CPRIT Prevention Program application. This request was not approved.
You may consider submitting an application the next time this mechanism is offered. Thank you for your interest in CPRIT’s Prevention Program.
Sincerely,"
Talking about about a new CPRIT, tough guys over there, with a deadly portal making the submission a tough proposition for the little guy! Our proposal remains intact, Breast cancer Mortality is continuing while this is happening! Obstacles to improving the cure comes in all kinds of shapes! Be on the lookout folks! The CRBCM continues on its progress because we believe in the mission...
5. Participation in the Muscle Dystrophy activity this week, well that's just another challenge...! But be aware of this... and contribute!
THE CRBCM is still on the move....
new patients in the work
1. Patient with Polycystic Kidney, Hypertension, we need his genes to see what is the most effective treatment, ACE inhibitors advised is to be taken with a grain of salt
Indeed they are hard to administer in a patient who has anxiety and undefined recurrent vomiting fully worked up by 2-3 Gastroenterologist. The patient vomiting with rising creatinine, the first thing the Nephrologist does is to stop the ACE inhibitor!
2.We are still on the move in El Paso:
"Hi Dr. Kankonde,
I have everything booked for your assignment starting March 5th."
On a new contract, CRBCM continue its work! And Medical Assistants from Vista College tagging along to continue to learn how a complex practice works!
3. We are fascinated by our case of Endodermal Rabdomyosarcoma.
A 19 year old nice young man presented with a 7.5 cm Right Testicular mass of endodermal Rabdo. which eventually was resected, a PET scan revealed small uptake in the R groin and some in the lumbar region
MRI in this area revealed an Hemangioma in the Vertebrae.
The uptake in the R groin could be reactive small nodes, no other findings,
adjuvant chemotherapy is being given following Ewing Sarcoma protocol
and patient is on the 3rd cycle of Alternating chemotherapy drug. People in Boston offered 17 chemotherapy cycles to achieve a 80% control of disease, some offered chemotherapy for 2 years,
weigh in if you have different opinion. Folks in Radiation are still scratching their heads! When or if to give Radiation? You have an opinion, call 915-307-3354
915-307-3354, I want to hear your input!At CRBCM, we are still after the genes involved in this disease!
4.We submitted a SBIR project in time and folks at NIH have contacted us for additional input, meaning we are still in play! The CRBCM is proud of this first step despite the fact that we remain optimistic, our feet are still on the ground. As a young enterprise, the CRBCM remains alert. Our submission with CPRIT, well it did not work!
"Dear Applicant,
CPRIT has considered your request for an extension of the submission deadline to complete your CPRIT Prevention Program application. This request was not approved.
You may consider submitting an application the next time this mechanism is offered. Thank you for your interest in CPRIT’s Prevention Program.
Sincerely,"
Talking about about a new CPRIT, tough guys over there, with a deadly portal making the submission a tough proposition for the little guy! Our proposal remains intact, Breast cancer Mortality is continuing while this is happening! Obstacles to improving the cure comes in all kinds of shapes! Be on the lookout folks! The CRBCM continues on its progress because we believe in the mission...
5. Participation in the Muscle Dystrophy activity this week, well that's just another challenge...! But be aware of this... and contribute!
THE CRBCM is still on the move....
Friday, February 28, 2014
In our lung study! fascinating MDM-2 Mutation? (AT UTEP WITH DRS ZHANG AND CHOI)
The MDM2 amplification/Mutation was the highest finding and remain persistently present through the various stages of lung cancers making it the strongest predictor of the tested genes. We are now conducting studies to see its presence in nearby tissues or normal tissues of same patients in order to see if there is a baseline MDM2 amplification to be compared to levels of MDM2 in diseased tissues. I should also stress that among the tested tissues, some were from treated patients. Even treatment did not affect Much the MDM2 mutation/amplification expression. A follow-up study may indicate if this affect long term recurrence.
In the ERA of testing post adjuvant therapy, corollary question will be whether a treatment that affect the MDM2 should be included to improve the cure or whether fixing the MDM2 would be crucial in achieving cure or prolonging progression free survival. Could some of patients who achieve a cure, still display an MDM2 Mutation? what is the outcome and response rate on cancers with NO MDM-2 mutation. To what therapy they respond to....and therefore what therapy should be included in MDM-2 positive patients. Is there a P53 Mutation, These are relevent questions in this era of target therapy!
and when you think LIKE WIKIPEDIA
" Mdm2 achieves this repression by binding to and blocking the N-terminal trans-activation domain of p53. Mdm2 is a p53 responsive gene—that is, its transcription can be activated by p53. Thus when p53 is stabilized, the transcription of Mdm2 is also induced, resulting in higher Mdm2 protein levels." Mdm2 is capable of auto-polyubiquitination, and in complex with p300, a cooperating E3 ubiquitin ligase, is capable of polyubiquitinating p53. In this manner, Mdm2 and p53 are the members of a negative feedback control loop that keeps the level of p53 low in the absence of p53-stabilizing signals. This loop can be interfered with by kinases and genes like p14arf when p53 activation signals, including DNA damage, are high."
IS THE MDM-2 A TRUE DRIVER MUTATION WHEN IT IS PRESENT GIVEN THE POSSIBILITY OF AUTO-UBUQUITINATION
WE THANK MDHONORS FOR THEIR SUPPORT!
In the ERA of testing post adjuvant therapy, corollary question will be whether a treatment that affect the MDM2 should be included to improve the cure or whether fixing the MDM2 would be crucial in achieving cure or prolonging progression free survival. Could some of patients who achieve a cure, still display an MDM2 Mutation? what is the outcome and response rate on cancers with NO MDM-2 mutation. To what therapy they respond to....and therefore what therapy should be included in MDM-2 positive patients. Is there a P53 Mutation, These are relevent questions in this era of target therapy!
and when you think LIKE WIKIPEDIA
" Mdm2 achieves this repression by binding to and blocking the N-terminal trans-activation domain of p53. Mdm2 is a p53 responsive gene—that is, its transcription can be activated by p53. Thus when p53 is stabilized, the transcription of Mdm2 is also induced, resulting in higher Mdm2 protein levels." Mdm2 is capable of auto-polyubiquitination, and in complex with p300, a cooperating E3 ubiquitin ligase, is capable of polyubiquitinating p53. In this manner, Mdm2 and p53 are the members of a negative feedback control loop that keeps the level of p53 low in the absence of p53-stabilizing signals. This loop can be interfered with by kinases and genes like p14arf when p53 activation signals, including DNA damage, are high."
IS THE MDM-2 A TRUE DRIVER MUTATION WHEN IT IS PRESENT GIVEN THE POSSIBILITY OF AUTO-UBUQUITINATION
WE THANK MDHONORS FOR THEIR SUPPORT!
Work still to be done in survivors
One of the aspect of cancer treatment that remains to be clearly categorized in most cancers including our focus:Breast cancers, is how to best monitor survivors and separate them early in high risk for recurrence versus those who should expect longer remission. So far we have concentrated purposely on monitoring recurrence by Xrays or checking bio-markers in the blood. But genetic work could also help predict recurrence and may be suggest target therapy to be envisioned early. ie OLOPADE et al: "A new model of ovarian cancer tumor progression implicates aberrant
FANCF promoter methylation that is associated with gene silencing and
disruption of the Fanconi-anemia-BRCA pathway. Disruption of the pathway
occurs de novo in ovarian cancers and may contribute to selective
sensitivity to platinum salts." (BRING BACK TO YOUR INTELLIGENCE THAT MANY DRUGS WORKS THROUGH EPIGENETIC EFFECTS AND NOT DNA CROSS-LINKING)
Although the disease can recur locally by increase of the original tumor size, most of the time the disease return in a metastatic fashion. And when this occurs, there are many implications to be drawn.
Neoplastic transformation assumes acquisition of new functions to the cell. One of the critical function is ability to metastasize, acquisition of MET1 amplification, activity at the Rho gene/RHOA/ROCK but also activity at Vimentin are important processes the cell has to go through to acquire these new functions. These are just some of the aspects.....
===============================================
Detection of cancer recurrence is as complex as the nature of the Neoplastic process itself!
1. There are activity at promoter genes, most of there activity are silencing of certain promoter genes through methylation. see implications of Methylation of such gene as TGF Beta, SMAD4 and even FBXO32, Cyclin D, 14.3.3. etc (Aberrant Methylation)
2. Suppression of E-Cadherin which for some poise the cell for Migration. If this occur through MSK1, it may also impact p38MAPK and restart tumor induced by the MAPK pathway amplification, and inducing VEGF induced migration of cells. This phenomena could be worse in these disease when Anti-VEGF is not usually used (since we use Anti-VEGF only in certain diseases--if we continue to use clinical trial as our basis foe adoption of a treatment)
3.Coming back to methylation, it has been stricking that certain genes are not remarkably expressed in certain cancer cells. ie. "
"DAB2 mRNA is expressed in normal ovarian epithelial cells but is down-regulated or absent from ovarian carcinoma cell lines."wikipedia This seems to involve somehow the SMAD
do remember "DAB2 has been shown to interact with C-src tyrosine kinase,[4] Cdk1,[5] Src,[4] LRP2,[6] DVL3,[7] PIN1,[5] MYO6,[8][9] DVL2,[7] DAB2IP,[10] Mothers against decapentaplegic homolog 3[11] and Mothers against decapentaplegic homolog 2.[11]" wikipedia
note many things please
attachment opportunity offered by C-Src
involvement of Cdk1 affecting cell proliferation and of course SMAD.... Terget therapy in mind!
ALSO
4. FOR RECURRENT DISEASE, PERSISTENCE OF CERTAIN INDUCERS (G-PROTEINS) PROPPING PUSH TO REESTABLISH A TUMOR PROCESS, OR LACK OF CERTAIN INHIBITORS TO GERB2 INVOLVEMENT SUCH AS SPRY-2. (MARKING AMPLIFICATION OF GERB2 IN SURVIVOR MONITORING!)
WILSON ET AL "HER-2 overexpression in the context of the mesenchymal MDA-MB-231 breast cell line potentiated the TGF-beta induced pro-invasive and pro-metastatic gene signature." MARKING THE IMPORTANCE OF TGF IN HER-2 POSITIVE CANCERS!
5.In BRCA-1 pt
we have already stress the importance of following PTPN2 as it impacts TGF, Paxillin, and mainly SHC1, the regulator of Apoptosis!
6. And if you are following Vimentin, weel check the AXL, decrease of RAB25, and the Integrin Beta subunit, these to gauge Epithelia-mesothelial transformation, an important step to acquisition of metastatic potential
well I stop here, survivors are deemed expensive because of this complexity and gene monitoring, weel we are not up to it yet, we chose head in the sand...And I am not talking yet about persistant of viral compounds that may also be important in metastatic potential in survivors. What we need is a better organization of pouring info coming to us ...."sparsely-disconnected" .
Although the disease can recur locally by increase of the original tumor size, most of the time the disease return in a metastatic fashion. And when this occurs, there are many implications to be drawn.
Neoplastic transformation assumes acquisition of new functions to the cell. One of the critical function is ability to metastasize, acquisition of MET1 amplification, activity at the Rho gene/RHOA/ROCK but also activity at Vimentin are important processes the cell has to go through to acquire these new functions. These are just some of the aspects.....
===============================================
Detection of cancer recurrence is as complex as the nature of the Neoplastic process itself!
1. There are activity at promoter genes, most of there activity are silencing of certain promoter genes through methylation. see implications of Methylation of such gene as TGF Beta, SMAD4 and even FBXO32, Cyclin D, 14.3.3. etc (Aberrant Methylation)
2. Suppression of E-Cadherin which for some poise the cell for Migration. If this occur through MSK1, it may also impact p38MAPK and restart tumor induced by the MAPK pathway amplification, and inducing VEGF induced migration of cells. This phenomena could be worse in these disease when Anti-VEGF is not usually used (since we use Anti-VEGF only in certain diseases--if we continue to use clinical trial as our basis foe adoption of a treatment)
3.Coming back to methylation, it has been stricking that certain genes are not remarkably expressed in certain cancer cells. ie. "
"DAB2 mRNA is expressed in normal ovarian epithelial cells but is down-regulated or absent from ovarian carcinoma cell lines."wikipedia This seems to involve somehow the SMAD
do remember "DAB2 has been shown to interact with C-src tyrosine kinase,[4] Cdk1,[5] Src,[4] LRP2,[6] DVL3,[7] PIN1,[5] MYO6,[8][9] DVL2,[7] DAB2IP,[10] Mothers against decapentaplegic homolog 3[11] and Mothers against decapentaplegic homolog 2.[11]" wikipedia
note many things please
attachment opportunity offered by C-Src
involvement of Cdk1 affecting cell proliferation and of course SMAD.... Terget therapy in mind!
ALSO
Decreased expression of 14-3-3 sigma is associated with advanced disease in human epithelial ovarian cancer: its correlation with aberrant DNA methylation.
Akahira J1, Sugihashi Y (READ THE ARTICLE)4. FOR RECURRENT DISEASE, PERSISTENCE OF CERTAIN INDUCERS (G-PROTEINS) PROPPING PUSH TO REESTABLISH A TUMOR PROCESS, OR LACK OF CERTAIN INHIBITORS TO GERB2 INVOLVEMENT SUCH AS SPRY-2. (MARKING AMPLIFICATION OF GERB2 IN SURVIVOR MONITORING!)
WILSON ET AL "HER-2 overexpression in the context of the mesenchymal MDA-MB-231 breast cell line potentiated the TGF-beta induced pro-invasive and pro-metastatic gene signature." MARKING THE IMPORTANCE OF TGF IN HER-2 POSITIVE CANCERS!
5.In BRCA-1 pt
we have already stress the importance of following PTPN2 as it impacts TGF, Paxillin, and mainly SHC1, the regulator of Apoptosis!
6. And if you are following Vimentin, weel check the AXL, decrease of RAB25, and the Integrin Beta subunit, these to gauge Epithelia-mesothelial transformation, an important step to acquisition of metastatic potential
well I stop here, survivors are deemed expensive because of this complexity and gene monitoring, weel we are not up to it yet, we chose head in the sand...And I am not talking yet about persistant of viral compounds that may also be important in metastatic potential in survivors. What we need is a better organization of pouring info coming to us ...."sparsely-disconnected" .
Wednesday, February 26, 2014
AND IT KEEPS HAPPENING FOR THE" WONDER" DRUG
FROM MEDSCAPE:
"The FDA has given accelerated approval to ibrutinib (Imbruvica) for treating CLL in patients who have undergone at least 1 previous therapy. Approval was granted based on the findings of a clinical study of 48 previously treated patients who were diagnosed with CLL, on average, 6.7 years before the study. The patients had an overall response rate of nearly 58%, with a duration of response from 5.6 to 24.2 months. The most common adverse effects observed in the study included thrombocytopenia, diarrhea, bruising, neutropenia, anemia, and upper respiratory tract infection. Ibrutinib was also approved for treating mantle cell lymphoma in 2013."
================================THIS DRUG IS JUST WONDERFUL, ATTESTING TO THE STRENGTH AND IMPORTANCE OF THIS RECEPTOR IN LYMPHOCYTE RELATED PROLIFERATIONS.....=================
"The FDA has given accelerated approval to ibrutinib (Imbruvica) for treating CLL in patients who have undergone at least 1 previous therapy. Approval was granted based on the findings of a clinical study of 48 previously treated patients who were diagnosed with CLL, on average, 6.7 years before the study. The patients had an overall response rate of nearly 58%, with a duration of response from 5.6 to 24.2 months. The most common adverse effects observed in the study included thrombocytopenia, diarrhea, bruising, neutropenia, anemia, and upper respiratory tract infection. Ibrutinib was also approved for treating mantle cell lymphoma in 2013."
================================THIS DRUG IS JUST WONDERFUL, ATTESTING TO THE STRENGTH AND IMPORTANCE OF THIS RECEPTOR IN LYMPHOCYTE RELATED PROLIFERATIONS.....=================
CAN YOU PLEASE GET ME TO MELBOURNE, SCIENCE WILL ACTUALLY OCCUR THERE!
"The
2014 meeting of the International Cytokine and Interferon Society is to
be held in Melbourne, Australia, during October 26-29, at the
state-of-the-art Melbourne Convention Centre. The meeting will provide
an outstanding forum for basic science and clinical researchers to
present their latest data and exchange ideas relating to the broad role
of cytokines and interferons in human disease, and applications to
therapies." FROM THEIR SITE!
DO YOU WANT ME TO REPORT TO YOU OR WHAT!?
CYTOKINE IS THE ANSWER, FROM TRAUMATIC BRAIN INJURY TO DIABETES
BUT YOU STILL NEED THE CRBCM ANGLE !? HOW CAN WE GET THERE?...CALL 915-307-3354 IF YOU COME UP WITH SOMETHING!
DO YOU WANT ME TO REPORT TO YOU OR WHAT!?
CYTOKINE IS THE ANSWER, FROM TRAUMATIC BRAIN INJURY TO DIABETES
BUT YOU STILL NEED THE CRBCM ANGLE !? HOW CAN WE GET THERE?...CALL 915-307-3354 IF YOU COME UP WITH SOMETHING!
INSTEAD OF TORTURING PATIENT WITH NODE DISSECTION, HOW ABOUT SIMPLY TESTING FOR VGEF-D
IN BREAST CANCER, AND MELANOMA
OBTAINING SENTINEL NODE HAS BECOME A PREOCUPATION
UNLESS WE REALLY NEED TO (SUCH AS CHECKING FOR MORE ABNORMAL GENE) can we just check VGEF D.
(rattling the cage at CRBCM)
can't make up this stuff:
"
Tumor metastasis to lymph nodes:
Lymph node metastasis is very often associated with several types of human malignancies. Cancer cells’ journey to lymph node takes place largely through lymphatic tunnel located in and around of primary tumor. VEGF-D’s interactions with VEGFR-3 predominantly expressed in lymphatic vessels plays a key role in restructuring lymphatic channel and, hence, able to alter its functions related to fluid and cell transport along the conduits. VEGF-D has been established to be over-expressed in both tumor tissues and patients’ serum samples in several types of human cancer. In addition, VEGF-D expression has been implicated with increased incidence of regional lymph node metastasis. In experimental mice study, genetically modified tumor cell that was forced to produce VEGF-D protein have been established to boost up regional lymph nodes metastases.[2]" wikipedia
and instead of the c-FOS, dose the FIGF,
INSTED OF .....DON'T LET ME STARTED NOW, GO WITH WHAT YOU KNOW!
OBTAINING SENTINEL NODE HAS BECOME A PREOCUPATION
UNLESS WE REALLY NEED TO (SUCH AS CHECKING FOR MORE ABNORMAL GENE) can we just check VGEF D.
(rattling the cage at CRBCM)
can't make up this stuff:
"
Tumor metastasis to lymph nodes:
Lymph node metastasis is very often associated with several types of human malignancies. Cancer cells’ journey to lymph node takes place largely through lymphatic tunnel located in and around of primary tumor. VEGF-D’s interactions with VEGFR-3 predominantly expressed in lymphatic vessels plays a key role in restructuring lymphatic channel and, hence, able to alter its functions related to fluid and cell transport along the conduits. VEGF-D has been established to be over-expressed in both tumor tissues and patients’ serum samples in several types of human cancer. In addition, VEGF-D expression has been implicated with increased incidence of regional lymph node metastasis. In experimental mice study, genetically modified tumor cell that was forced to produce VEGF-D protein have been established to boost up regional lymph nodes metastases.[2]" wikipedia
and instead of the c-FOS, dose the FIGF,
INSTED OF .....DON'T LET ME STARTED NOW, GO WITH WHAT YOU KNOW!
CSK random phosphorylation/related clinical questions
FYN
LCK
LYN
YES-1
HCK
Src
FRG
BLK
FRK
1.ATRA combined to Geevec as a way to break gleevec resistance?
2.disease with PDGF with STATs amplification could benefit from Gleevec if inhibition of Src is promoted
3.Could ATRA or the Piperazines (Gleevec) disrupt enough deployment of signal pathways to slow down a Cytokine storm (and TBI).
4.Could dampening of CRKL be used as a marker in CML
5.can ADAMs 17 be a biomarker of CML response or Myeloma response
6"PDGFR-beta is a key marker of hepatic stellate cell activation in the process of fibrogenesis."wikipedia
level of PDGFR in hepatoma?or Glioblastoma/ Nexavar activity linked to effect on PDGFR?
JUST WATCH OUT WITH THESE Random PHOSPHORYLATION, IT IS HOW CASEIN INDUCES TRIPLE NEGATIVE
BREAST CANCERS.
JUST REMEMBER Src INFLUENCES PDGF INDUCED PHOSPHORYLATION OF STATs.
LCK
LYN
YES-1
HCK
Src
FRG
BLK
FRK
1.ATRA combined to Geevec as a way to break gleevec resistance?
2.disease with PDGF with STATs amplification could benefit from Gleevec if inhibition of Src is promoted
3.Could ATRA or the Piperazines (Gleevec) disrupt enough deployment of signal pathways to slow down a Cytokine storm (and TBI).
4.Could dampening of CRKL be used as a marker in CML
5.can ADAMs 17 be a biomarker of CML response or Myeloma response
6"PDGFR-beta is a key marker of hepatic stellate cell activation in the process of fibrogenesis."wikipedia
level of PDGFR in hepatoma?or Glioblastoma/ Nexavar activity linked to effect on PDGFR?
JUST WATCH OUT WITH THESE Random PHOSPHORYLATION, IT IS HOW CASEIN INDUCES TRIPLE NEGATIVE
BREAST CANCERS.
JUST REMEMBER Src INFLUENCES PDGF INDUCED PHOSPHORYLATION OF STATs.
vain attempt but we keep dancing!
Dear Peggy;
You have been successfully registered for the following training event.
------------------------------
Title: SBA Lending Fair
Location: 9050 Viscount Blvd. , ASC "A" Bldg. (Auditorium), El Paso, TX 79925
Date(s): 2/27/2014
Time(s): 5:30pm to 7:30pm
Description:
Instructions:
------------------------------
Thank you for your participation!
Best regards,
C.G.
El Paso Community College SBDC
You have been successfully registered for the following training event.
------------------------------
Title: SBA Lending Fair
Location: 9050 Viscount Blvd. , ASC "A" Bldg. (Auditorium), El Paso, TX 79925
Date(s): 2/27/2014
Time(s): 5:30pm to 7:30pm
Description:
Instructions:
------------------------------
Thank you for your participation!
Best regards,
C.G.
El Paso Community College SBDC
Good News at CRBCM
It is official,
DR kankonde became Iterim Director of El Paso 4 Griffols/Talecris Plasma Center starting 03/01/2014.
He is also the full time Center Medical Director of El Paso 2 since 8/15/2013.
we keep progressing slowly but surely!
DR kankonde became Iterim Director of El Paso 4 Griffols/Talecris Plasma Center starting 03/01/2014.
He is also the full time Center Medical Director of El Paso 2 since 8/15/2013.
we keep progressing slowly but surely!
Pick into the cure!
Cytokines that can induce cellular stress, may also exacerbate P53 induced apoptosis through release of its regulators. Indeed P53 regulators include
Tomasini et al
" that TP53INP1s, in association with HIPK2, regulate p53 transcriptional activity on p21, mdm2, pig3, and bax promoters. Furthermore, TP53INP1s overexpression induces G1 arrest and increases p53-mediated apoptosis. Although a TP53INP1s and HIPK2 additive effect was observed on apoptosis, G1 arrest was weaker when HIPK2 was transfected together with TP53INP1. These results indicate that TP53INP1s and HIPK2 could be partners in regulating p53 activity."
the role of TGF on these regulators needs further scrutiny since it it such an important growth factor in breast cancer
could blockage of the Cutlins help?
Blocking these regulator could decrease cancer dependance on rescue measure and restore the effectiveness of Hypoxic apoptosis?
GO TO ARTICLE!
Tomasini et al
" that TP53INP1s, in association with HIPK2, regulate p53 transcriptional activity on p21, mdm2, pig3, and bax promoters. Furthermore, TP53INP1s overexpression induces G1 arrest and increases p53-mediated apoptosis. Although a TP53INP1s and HIPK2 additive effect was observed on apoptosis, G1 arrest was weaker when HIPK2 was transfected together with TP53INP1. These results indicate that TP53INP1s and HIPK2 could be partners in regulating p53 activity."
the role of TGF on these regulators needs further scrutiny since it it such an important growth factor in breast cancer
could blockage of the Cutlins help?
Blocking these regulator could decrease cancer dependance on rescue measure and restore the effectiveness of Hypoxic apoptosis?
GO TO ARTICLE!
TP53INP1s and Homeodomain-interacting Protein Kinase-2 (HIPK2) Are Partners in Regulating p53 Activity*
Richard Tomasiniठet al!Tuesday, February 25, 2014
new NF1 case stumbled upon!
As if things were not enough today a case of metastatic Head and neck cancer with vertebral involvement showed up, the interest in abnormality in G-proteins and may be the SProuty2 may be growing.
what does the NF-1 gene has to do with these propensity to Neoplasm. The patient had severe bipolar syndrome!
Its mutation release cell control through removal of RAS regulation, growth becomes uncontrolled.
Its ATPase shape affects deeply activity of the G-proteins.
Mutation in NF1 seems to be a trigger to EGFR expression (and erbB2) and may contribute to mass formation, in other words, recuperation of some embryonal fucntion is at the basis of tumor formation
?those with NF-1 Mutation becomes sensitive to anti-EGFR inhibition?
NF-1 mutation is also cause for over expression of Insulin Growth Factor Receptor and associated EMA/GLUT-1, and CD34 particularly on Fibroblasts, and S-100. (identifying several bio-markers and detection, may be prognosis in several research pertaining to NF-1)
other genes involved
Snx5
MIB-1
Neur2
Zath1
E2, DPK and DIP
Delta and the Notch
reference
====================================
and into the details of negative activity
all these identify new targets?
what does the NF-1 gene has to do with these propensity to Neoplasm. The patient had severe bipolar syndrome!
Its mutation release cell control through removal of RAS regulation, growth becomes uncontrolled.
Its ATPase shape affects deeply activity of the G-proteins.
Mutation in NF1 seems to be a trigger to EGFR expression (and erbB2) and may contribute to mass formation, in other words, recuperation of some embryonal fucntion is at the basis of tumor formation
?those with NF-1 Mutation becomes sensitive to anti-EGFR inhibition?
NF-1 mutation is also cause for over expression of Insulin Growth Factor Receptor and associated EMA/GLUT-1, and CD34 particularly on Fibroblasts, and S-100. (identifying several bio-markers and detection, may be prognosis in several research pertaining to NF-1)
other genes involved
Snx5
MIB-1
Neur2
Zath1
E2, DPK and DIP
Delta and the Notch
reference
Mind Bomb Is a Ubiquitin Ligase that Is Essential for Efficient Activation of Notch Signaling by Delta
Motoyuki Itoh1, Ch====================================
and into the details of negative activity
The mechanism of growth-inhibitory effect of DOC-2/DAB2 in prostate cancer. Characterization of a novel GTPase-activating protein associated with N-terminal domain of DOC-2/DAB2.
Wang Z1,all these identify new targets?
And now it comes
In sarcoma particularly GIST
people seems to try Pazopanib added to Gleevec!
and Panobinostat seems the selected HDAC inhibitor of choice!
"
Panobinostat (LBH-589) is an experimental drug developed by Novartis for the treatment of various cancers. It is a hydroxamic acid[1] and acts as a non-selective histone deacetylase inhibitor (HDAC inhibitor)." wikipedia
In Gist, a sudden interest in the SRC gene! more work for CRBCM, will look into this!
people seems to try Pazopanib added to Gleevec!
and Panobinostat seems the selected HDAC inhibitor of choice!
"
Panobinostat (LBH-589) is an experimental drug developed by Novartis for the treatment of various cancers. It is a hydroxamic acid[1] and acts as a non-selective histone deacetylase inhibitor (HDAC inhibitor)." wikipedia
In Gist, a sudden interest in the SRC gene! more work for CRBCM, will look into this!
and questions keep ringing the deep senses!
Does random phosphorylation induced by Casein and related decrease of AP-1 critical to Breast cancer (TNBC) development
can we equate or parallel depression of PTEN under HIF influence to Casein phosphorylation induced depression of AP-1 in inducing cancers?
The same phosphorylation affect the RELA causing cross talking of the NOTCH and Catenins
all this putting center epigenetic phenomena to Neoplastic transformation
does this justify the cancer preventive force of certain anti-inflamatory drugs
can the effect of neoplastic prevention be linked to expression of c-fos
how does BCL-2 expression linked to c-fos
As easy at it sound, only certain facts leads to c-Fos expression...suggestion is overexpression of c-fos indicates that certain condition in the cell have been satisfied!
Are we in the belly of the beast when it comes to Breast and Pancreatic cancers, Are we at the bottom of the GTX combination used in Pancreatic cancer ?(the founders was talking of enzyme limiting activities and saturation?
check it out!
can we equate or parallel depression of PTEN under HIF influence to Casein phosphorylation induced depression of AP-1 in inducing cancers?
The same phosphorylation affect the RELA causing cross talking of the NOTCH and Catenins
all this putting center epigenetic phenomena to Neoplastic transformation
does this justify the cancer preventive force of certain anti-inflamatory drugs
can the effect of neoplastic prevention be linked to expression of c-fos
how does BCL-2 expression linked to c-fos
As easy at it sound, only certain facts leads to c-Fos expression...suggestion is overexpression of c-fos indicates that certain condition in the cell have been satisfied!
Are we in the belly of the beast when it comes to Breast and Pancreatic cancers, Are we at the bottom of the GTX combination used in Pancreatic cancer ?(the founders was talking of enzyme limiting activities and saturation?
check it out!
Casein kinase II is a negative regulator of c-Jun DNA binding and AP-1 activity
Monday, February 24, 2014
Role of the RELA gene in Triple negative Breast cancer
Is it the best biomarker
Is it the gene at play?
Is it the sign of Involvement of the epigenetic Zone
Is it a sign of Etoposide activity
Is it at play in hair discoloration
Is RELA sufficiently connected to be an adaptor gene, a wild gene? could it be a driver gene through autophosphorylation?
Pivotal role of the RELA in Breast Cancer though cross talking with the NOTCH, the steroidsand the Catenins?
Is RELA's role underestimated in Breast Cancer (TNBC)?
These are just some of the questions that the RELA gene raises !
Is it the gene at play?
Is it the sign of Involvement of the epigenetic Zone
Is it a sign of Etoposide activity
Is it at play in hair discoloration
Is RELA sufficiently connected to be an adaptor gene, a wild gene? could it be a driver gene through autophosphorylation?
Pivotal role of the RELA in Breast Cancer though cross talking with the NOTCH, the steroidsand the Catenins?
Is RELA's role underestimated in Breast Cancer (TNBC)?
These are just some of the questions that the RELA gene raises !
Sunday, February 23, 2014
An interesting clinical case, A CLASSIC CASE OF GENE INTERFERENCE
a 49 year hispanic woman passed out while taking a shower, she was taken to the ER, further work-up revealed a 6.4 mass in the in her stomach which passed the physical wall of the and into the peritoneal wall. The mass turned up to be A GIST (Gastrointestinal stromal Tumor). An interesting finding by itself since it twist positively the prognosis and raise considerable interest for surgical Intervention.
The internet and the American cancer society suggest "
from the same sources
"
What makes this case even more interesting are 2 additional informations (and believe me I would not bring forth this case if there are no more twists), few months back the dermatologist had seen the same patient for Neurofibromatosis. Indeed she has disseminated on her skin "NEVI" like lesions typical of this disease. NOT ONLY SHE HAS THE NF-1 RELATED GENE, BUT SHE ALSO HAVE "CAFE AU LAIT " SPOTS
--------------------------------------------------------------------------------------------------
RAISING THE POSSIBILITY :" Mutations in the NF1 gene have been linked to NF-1, Juvenile myelomonocytic leukemia and Watson syndrome. A condition with a separate gene mutation but similar Café au lait spots is Legius syndrome which has a mutation on the SPRED1 gene.Patients without Neurofibromin 1 or SPRED1 mutations may have SPRED2, SPRED3 or SPRY1, SPRY2, SPRY3 or SPRY4 mutations.[5]...." WIKIPEDIA
and
(raising the possibility of anti-EFR in this disease)
AND A NEW CULPRIT IS BORN: ANDERSON ET AL.
"
Sprouty (Spry) proteins modulate the actions of receptor tyrosine kinases during development and tumorigenesis. Decreases in cellular levels of Spry, especially Sprouty2 (Spry2), have been implicated in the growth and progression of tumors of the breast, prostate, lung, and liver. During development and tumor growth, cells experience hypoxia. Therefore, we investigated how hypoxia modulates the levels of Spry proteins. Hypoxia elevated the levels of all four expressed Spry isoforms in HeLa cells."
PLEASE INTERFERE WITH SPROUTY ABSOLUTELY......
AND THIS INCREASES THE ROLE OF THE RAS AMPLIFICATION IN THIS DISEASE, AND MAKES ANTI-MEK EVEN MORE IMPRORTANT....AS A POTENTIAL AMPLIFIER DOWNSTREAM!
CAN SPROUTY EXPRESSION BE A BIOMARKER IN THIS DISEASE?
====================================================
Just as you start to get comfortable with the case
let me bring up yet another twist to this genetic rich case,
as I examine the patient, I find out quickly she has been unable to raise her hands for years and has been told to be ANA antibody positive....Now if you have been a careful reader, you may have noted that Juvenile Myelomonocytic Leukemia is part of this syndrome, pointing to a potential disruption of Monocyte which are incriminated in autoimmune diseases. Polymyositis came to mind as I examine the woman
" Another important event in the pathogenesis of Polymyositis is the increased expression of MHC proteins by m/s cells. Auto-Ag is presented in association with MHC-I molecules on the surface of Myocytes and is recognized by CD8 cytotoxic T cells that subsequently initiate m/s destruction."wikipedia
Pachman et al!
" It is our premise that JDMS is a distinct disease entity and that the increase in HLA-B8 and -DR3 in JDMS places this disease in the company of other immunopathic disorders. There are conflicting data concerning immunological abnormalities in JDMS , but there appears to be impairment of natural killing and evidence of complement activation. The frequent positive ANA in JDMS raises the speculation of its relationship to the antinuclear antibody, Jo-1, found in some adults with PM, which has specificity for tRNAHis. Most newly diagnosed JDMS patients have antibodies to Coxsackie B which may be related to the pathogenesis of this disease. Specific pathological findings of endothelial cells containing reticulotubular inclusions are associated with vessel occlusion, subsequent obliteration and increased Factor VIII levels in clinically active disease."
SHOULD I TEST FOR COXSACKIE, WHO IS GOING TO PAY!
THE LADY WAS FOUND WITH A PULMONARY EMBOLUS
AND COULD NOT BE ANTICOAGULATED AND A FILTER WAS PLACED
SHE HAS AN HARDENED RIGHT THIGH
AND TO CONCLUDE, HER FATHER DIED OF PANCREATIC CANCER
AND SHE HAS AN INQUISITIVE DAUGHTER WHOM I MAY BE FORCED TO TEST ALSO AS TO HER PREDISPOSITION TO THIS CALAMITY SYNDROME!
The internet and the American cancer society suggest "
"Based on people treated between 1992 and
2000, the overall relative 5-year survival rate of people diagnosed with
a malignant GIST was estimated to be about 45%.
- If the tumor was confined to the organ where it started, the 5-year relative survival was 64%.
- If it had grown into nearby tissue when it was first diagnosed, the 5-year relative survival was around 30%.
- If it had spread to distant sites when it was first diagnosed, the 5-year relative survival was 13%. "
from the same sources
"
A few families have gastrointestinal stromal
tumors (GISTs) caused by a DNA mutation passed down from parent to
child. But most DNA mutations related to GISTs are not inherited. These
changes occur for no apparent reason, and are called acquired or sporadic.
The cancer cells of most patients with GIST have a change in an oncogene called c-kit. The c-kit
gene is found in all cells of the body. It directs the cell to make a
protein called KIT, which causes the cell to grow and divide. Usually
the c-kit gene is inactive. It is only active if there is a need for more interstitial cells of Cajal (ICCs). In most GISTs the c-kit
gene is mutated and is always active. This may explain why the cancer
forms. The cells are always growing and dividing. In some families that
have many members with GISTs, doctors have found inherited mutations of
the c-kit gene.
In about 5% to 10% of GISTs, the cancer cells have mutation in a different gene called PDGFRA,
which causes the cell to make too much of a different protein (also
called PDGFRA). This has the same effect on the cell as does KIT.
Most GISTs have changes in either the c-kit or the PDGFRA
gene, but not both. A small number of GISTs do not have changes in
either of these genes. Researchers are still trying to determine what
gene changes lead to these cancers."
Most of these stromal tumors stained positively for CD34 (Miettinen et al 1995). The KIT protein is a transmembrane receptor for stem cell factor. The
intracytoplasmic portion of this receptor functions as a tyrosine
kinase. The availability of the immunohistochemical marker, CD117, to
the KIT protein, has revolutionized the diagnosis of GIST, by
identifying a treatment target. Approximately 95% of GISTs stain
positive for CD117, making it a very useful marker for diagnosis (Miettinen and Lasota 2001). This has led to the development of the targeted therapy imatinib mesylate (STI-571; Glivec®,
Novartis, Basel, Switzerland). This drug inhibits several tyrosine
kinase receptors with varying affinity, including KIT, the BCR-ABL
fusion protein, and the platelet derived growth factor receptor (PDGFR) (Heinrich et al 2000, De Giorgi and Verweij 2005). DIN et al
The surgeon have discussed the case and referred the case for Neoadjuvant Gleevec.
-------------------------------------------------------------------------------------------------------------------
"As imatinib targets the ATP (adenosine triphosphate) binding site of the KIT receptor (encoded by exon 11), tumors with exon 11 mutations treated with imatinib have a significantly better partial response rate, event free and overall survival compared to exon 9 or no detectable mutation. A partial response rate of up to 83% has been achieved, showing how sensitive these tumors can be (Heinrich et al 2003a; Corless et al 2004; Debiec-Rychter et al 2006)."DIN
(DO PATIENT NEEDS TO REDUCE ATP PRODUCING MOLECULES IN THIS DISEASE ?)
(HOW DOES CAJAL CELL ACTIVITY LINKED TO TUMOR PROGRESSION/PRODUCTION)
(IS IT CRITICAL TO KNOW WHICH GENE IS AFFECTED IN AN INDIVIDUAL PATIENT)
DON'T GET EXCITED WE KNOW THE ROLE OF EXON 11.
and like any good thing, Gleevec comes with a word of caution per DIN et al:
--------------------------------------------------------------------------------------------------------
" The main circulating metabolite is an N-demethylated piperazine derivative which accounts for 16% of the AUC (area under the curve) for imatinib. This, with imatinib accounts for most of the activity, but there are a number of smaller metabolites. CYP3A4 is the major cytochrome P450 involved in imatinib metabolism. Thus, drugs that are co-administered may alter the pharmacokinetics. Erythromycin, fluconazole, and rifampicin have shown inhibition of imatinib metabolism. Imatinib increases exposure to simvastatin. Alprazolam, caffeine, clindamycin, clonazepam, cortisol, ethinyl oestradiol, and verapamil may cause toxic effects when given with imatinib. St. John’s wort increases imatinib clearance by 43%. Patients should avoid excessive amounts of paracetamol as both are metabolized by CYP3A4 (D’Amato et al 2005; Novartis 2005).
-------------------------------------------------------------------------------------------------------------------
"As imatinib targets the ATP (adenosine triphosphate) binding site of the KIT receptor (encoded by exon 11), tumors with exon 11 mutations treated with imatinib have a significantly better partial response rate, event free and overall survival compared to exon 9 or no detectable mutation. A partial response rate of up to 83% has been achieved, showing how sensitive these tumors can be (Heinrich et al 2003a; Corless et al 2004; Debiec-Rychter et al 2006)."DIN
(DO PATIENT NEEDS TO REDUCE ATP PRODUCING MOLECULES IN THIS DISEASE ?)
(HOW DOES CAJAL CELL ACTIVITY LINKED TO TUMOR PROGRESSION/PRODUCTION)
(IS IT CRITICAL TO KNOW WHICH GENE IS AFFECTED IN AN INDIVIDUAL PATIENT)
DON'T GET EXCITED WE KNOW THE ROLE OF EXON 11.
and like any good thing, Gleevec comes with a word of caution per DIN et al:
--------------------------------------------------------------------------------------------------------
" The main circulating metabolite is an N-demethylated piperazine derivative which accounts for 16% of the AUC (area under the curve) for imatinib. This, with imatinib accounts for most of the activity, but there are a number of smaller metabolites. CYP3A4 is the major cytochrome P450 involved in imatinib metabolism. Thus, drugs that are co-administered may alter the pharmacokinetics. Erythromycin, fluconazole, and rifampicin have shown inhibition of imatinib metabolism. Imatinib increases exposure to simvastatin. Alprazolam, caffeine, clindamycin, clonazepam, cortisol, ethinyl oestradiol, and verapamil may cause toxic effects when given with imatinib. St. John’s wort increases imatinib clearance by 43%. Patients should avoid excessive amounts of paracetamol as both are metabolized by CYP3A4 (D’Amato et al 2005; Novartis 2005).
What makes this case even more interesting are 2 additional informations (and believe me I would not bring forth this case if there are no more twists), few months back the dermatologist had seen the same patient for Neurofibromatosis. Indeed she has disseminated on her skin "NEVI" like lesions typical of this disease. NOT ONLY SHE HAS THE NF-1 RELATED GENE, BUT SHE ALSO HAVE "CAFE AU LAIT " SPOTS
--------------------------------------------------------------------------------------------------
RAISING THE POSSIBILITY :" Mutations in the NF1 gene have been linked to NF-1, Juvenile myelomonocytic leukemia and Watson syndrome. A condition with a separate gene mutation but similar Café au lait spots is Legius syndrome which has a mutation on the SPRED1 gene.Patients without Neurofibromin 1 or SPRED1 mutations may have SPRED2, SPRED3 or SPRY1, SPRY2, SPRY3 or SPRY4 mutations.[5]...." WIKIPEDIA
and
Sprouty2 acts at the Cbl/CIN85 interface to inhibit epidermal growth factor receptor downregulation
Kaisa Haglund,"(raising the possibility of anti-EFR in this disease)
AND A NEW CULPRIT IS BORN: ANDERSON ET AL.
"
Sprouty (Spry) proteins modulate the actions of receptor tyrosine kinases during development and tumorigenesis. Decreases in cellular levels of Spry, especially Sprouty2 (Spry2), have been implicated in the growth and progression of tumors of the breast, prostate, lung, and liver. During development and tumor growth, cells experience hypoxia. Therefore, we investigated how hypoxia modulates the levels of Spry proteins. Hypoxia elevated the levels of all four expressed Spry isoforms in HeLa cells."
PLEASE INTERFERE WITH SPROUTY ABSOLUTELY......
AND THIS INCREASES THE ROLE OF THE RAS AMPLIFICATION IN THIS DISEASE, AND MAKES ANTI-MEK EVEN MORE IMPRORTANT....AS A POTENTIAL AMPLIFIER DOWNSTREAM!
CAN SPROUTY EXPRESSION BE A BIOMARKER IN THIS DISEASE?
====================================================
Just as you start to get comfortable with the case
let me bring up yet another twist to this genetic rich case,
as I examine the patient, I find out quickly she has been unable to raise her hands for years and has been told to be ANA antibody positive....Now if you have been a careful reader, you may have noted that Juvenile Myelomonocytic Leukemia is part of this syndrome, pointing to a potential disruption of Monocyte which are incriminated in autoimmune diseases. Polymyositis came to mind as I examine the woman
" Another important event in the pathogenesis of Polymyositis is the increased expression of MHC proteins by m/s cells. Auto-Ag is presented in association with MHC-I molecules on the surface of Myocytes and is recognized by CD8 cytotoxic T cells that subsequently initiate m/s destruction."wikipedia
Pachman et al!
" It is our premise that JDMS is a distinct disease entity and that the increase in HLA-B8 and -DR3 in JDMS places this disease in the company of other immunopathic disorders. There are conflicting data concerning immunological abnormalities in JDMS , but there appears to be impairment of natural killing and evidence of complement activation. The frequent positive ANA in JDMS raises the speculation of its relationship to the antinuclear antibody, Jo-1, found in some adults with PM, which has specificity for tRNAHis. Most newly diagnosed JDMS patients have antibodies to Coxsackie B which may be related to the pathogenesis of this disease. Specific pathological findings of endothelial cells containing reticulotubular inclusions are associated with vessel occlusion, subsequent obliteration and increased Factor VIII levels in clinically active disease."
SHOULD I TEST FOR COXSACKIE, WHO IS GOING TO PAY!
THE LADY WAS FOUND WITH A PULMONARY EMBOLUS
AND COULD NOT BE ANTICOAGULATED AND A FILTER WAS PLACED
SHE HAS AN HARDENED RIGHT THIGH
AND TO CONCLUDE, HER FATHER DIED OF PANCREATIC CANCER
AND SHE HAS AN INQUISITIVE DAUGHTER WHOM I MAY BE FORCED TO TEST ALSO AS TO HER PREDISPOSITION TO THIS CALAMITY SYNDROME!
Friday, February 21, 2014
Side effects at the cellular level
The development of unintended consequences is one of the most significant events full of duplicity. It leads to unplanned events that could unravel the whole experiment. The cell knows it is not perfect and has prepared itself to a world of various stimulants that scientists around the world and nature keep creating. The cell keeps its options open, ready to adapt. Its flexibility to conversion expands its potential to undergo unplanned events or side effects. Some of the side effects are favorable, other neutral, but still some have deleterious effects.
1. One such example are Reuptake inhibitors:
----------------------------------------------
Whether it is a serotonin or Dopamine, inhibitor or reuptake, it results in increased extracellular concentrations of the targeted compound. Now it is always of use to remind ourselves that not all compounds are target specific and that certain compounds can stimulate several receptors, therefore raising the possibility of creating unintended consequences that we can call "side effects".
2.Co-stimulation of several Receptors Versus Co-binding of several Receptors.
----------------------------------------------------------------------------------
Multikinases have the advantage of blocking several of their targets, and may shutdown or activate several pathways. Generally, this is a positive thing. Side effects come along when some receptors blocked in the process lead to obligatory vital pathways or processes that are also shutdown or impacted, leading to miserable consequences. One of the things most researchers fear is the distant presence of an unplanned receptor in the Brain! You give a medication planned to act on a Muscle or a white cell, and you get a significant seizure side effect (real case).
Some Multikinases are so effective that they shut down the effect of other therapeutic interventions (don't try anti-VEGF and M-TOR inhibitor concurrently until you are sure of your purpose).
3.Adaptor genes:
---------------------
The cell is a master of giving directions to cellular reactions. To achieve this it put stogether "Core Binding Factors" (term used here loosely to make a point) or a congregate of various molecules that may come together to master, interact and shape sometimes one molecule (give this molecule a specific post-translational modification) into a new molecule that will achieve a specific purpose...like a factory would! ie. check the prognosis of CBF presence in Leukemias!
Certain genes, however, orient squarely a molecule to some clear purpose, if a molecule A attaches to the LYN gene Vs Gerb2, consequences are drastically different....Whether a solid tumor or a hematologic disease results could be a matter of which Adaptor gene was used!
4. Co-binding of Receptor
5. Lack of Inhibitors
6. Non specificity, sing the common pathways and possibility of saturation
7. Secondary liberation and release of "second messenger"
8. Unique localization of certain common receptors
9. Susceptibilty of certain Heterogeneic genes
10. The G proteins
etc.; all these could be expanded to justify why side effects develop, like it or not, in cellular life...No wonder we have to give "consents" for clinical trials....
AND GUESS HOW LONG THIS ARTICLE COULD BECOME IF MEATS AND BONES WERE ADDED! A BOOK WOULD NOT CUT IT!
1. One such example are Reuptake inhibitors:
----------------------------------------------
Whether it is a serotonin or Dopamine, inhibitor or reuptake, it results in increased extracellular concentrations of the targeted compound. Now it is always of use to remind ourselves that not all compounds are target specific and that certain compounds can stimulate several receptors, therefore raising the possibility of creating unintended consequences that we can call "side effects".
2.Co-stimulation of several Receptors Versus Co-binding of several Receptors.
----------------------------------------------------------------------------------
Multikinases have the advantage of blocking several of their targets, and may shutdown or activate several pathways. Generally, this is a positive thing. Side effects come along when some receptors blocked in the process lead to obligatory vital pathways or processes that are also shutdown or impacted, leading to miserable consequences. One of the things most researchers fear is the distant presence of an unplanned receptor in the Brain! You give a medication planned to act on a Muscle or a white cell, and you get a significant seizure side effect (real case).
Some Multikinases are so effective that they shut down the effect of other therapeutic interventions (don't try anti-VEGF and M-TOR inhibitor concurrently until you are sure of your purpose).
3.Adaptor genes:
---------------------
The cell is a master of giving directions to cellular reactions. To achieve this it put stogether "Core Binding Factors" (term used here loosely to make a point) or a congregate of various molecules that may come together to master, interact and shape sometimes one molecule (give this molecule a specific post-translational modification) into a new molecule that will achieve a specific purpose...like a factory would! ie. check the prognosis of CBF presence in Leukemias!
Certain genes, however, orient squarely a molecule to some clear purpose, if a molecule A attaches to the LYN gene Vs Gerb2, consequences are drastically different....Whether a solid tumor or a hematologic disease results could be a matter of which Adaptor gene was used!
4. Co-binding of Receptor
5. Lack of Inhibitors
6. Non specificity, sing the common pathways and possibility of saturation
7. Secondary liberation and release of "second messenger"
8. Unique localization of certain common receptors
9. Susceptibilty of certain Heterogeneic genes
10. The G proteins
etc.; all these could be expanded to justify why side effects develop, like it or not, in cellular life...No wonder we have to give "consents" for clinical trials....
AND GUESS HOW LONG THIS ARTICLE COULD BECOME IF MEATS AND BONES WERE ADDED! A BOOK WOULD NOT CUT IT!
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