What testosterone gene has to do with Hairy cell leukemia
What HLA has to do with Hairy cell leukemia (why the incidence in black is lower?)
Weight loss is linked to Cytokine discharges which interfere with Gluconeogenesis?
Organomegaly is linked to disturbances in the Catenins, protein mobility in the cells, or "cellular flagellation" ? but why?
Interesting this hairy cell, leads to hypocholesterolemia? what cytokine does this again? should it enter therapeutic trial?
Is it the Annexin A1, what TRAP has to do, BRAF-V600E (activity of Vemurafenib in Hairy cell)
what cytokine lead to collagen or reticulin expression in this disease?
High dose interferon works in this disease! Yes a Cytokine works (where is my Cytokine bank!)
The disease brings back a fundamental question, why susceptibility to infection, is it weakness in the mitochondria?is it the LYN gene, c-MYB or disturbance in the Ig.
Why vasculitis in this disease? disturbance of G-proteins?
Sunday, April 6, 2014
Friday, April 4, 2014
ALL STROKE PATIENTS UNDERGO A CYTOKIN STORM AND SHOULD EXPECT PTSD!
And once again we tremble to recognize that all stroke patients will suffer PTSD or post traumatic stress syndrome even though it is the basic principle and process that will and have happened
and will fluctuate based on our genetic heterogeneity, location in the brain, and intensity of cytokine. The reaction of cytokines could actually be predicted for each of us prior to event as we can test Macrophage reaction before hand! And knowing the genes,
and Early administration of MTOR inhibitor and interferon (or Sirtuins) like products could indeed dampen the Cytokine storm and minimize maximally the effect of a stroke! But we still wait to test what we know !
Here we stress the need to know our inflammatory index as age or status of our vascular status. we also stress the need for a camera deep in vessel to check our thrombus stratus and status. and report which thrombi are on the "brink" of collapse. Forget measuring by EEG, we are past Aspirin and plavix, the treatment of stroke is on the cytokine and the Macrophage! (what is Adenyl cyclase doing?) An "homocystein" and related gene system system will tell us if a thrombus somewhere is about to break! And gene activation (ie "cytokines or growth factor index") will tell physician how hard our blood vessel is! Are they ready to break?! Following blood pressure alone is not enough and has failed us! medicine of tomorrow is just genes! genes and genes! 25000 only and we can't read them despite all our computers! Lets go back to work!
(This article should be read by "scientists"only, or open minded person)
and will fluctuate based on our genetic heterogeneity, location in the brain, and intensity of cytokine. The reaction of cytokines could actually be predicted for each of us prior to event as we can test Macrophage reaction before hand! And knowing the genes,
and Early administration of MTOR inhibitor and interferon (or Sirtuins) like products could indeed dampen the Cytokine storm and minimize maximally the effect of a stroke! But we still wait to test what we know !
Here we stress the need to know our inflammatory index as age or status of our vascular status. we also stress the need for a camera deep in vessel to check our thrombus stratus and status. and report which thrombi are on the "brink" of collapse. Forget measuring by EEG, we are past Aspirin and plavix, the treatment of stroke is on the cytokine and the Macrophage! (what is Adenyl cyclase doing?) An "homocystein" and related gene system system will tell us if a thrombus somewhere is about to break! And gene activation (ie "cytokines or growth factor index") will tell physician how hard our blood vessel is! Are they ready to break?! Following blood pressure alone is not enough and has failed us! medicine of tomorrow is just genes! genes and genes! 25000 only and we can't read them despite all our computers! Lets go back to work!
(This article should be read by "scientists"only, or open minded person)
Thursday, April 3, 2014
New areas of investigation in cancer research
Can Cisplatin be used to stop recalcitrant Viral hepatitis load ?
or a combination of Cisplatin and Sunitinib or Imatinib
what is the relationship with RFX-1
" treatment with retinoic acid induces both MIBP1 and RFX1 protein, as well as their DNA-binding activity,"Z-Kaye et al. (Is there promotion of c-MYC in APL by retinoic Acid use)
Lubelsky"derepression of the RFX1 gene is only partially blocked by inhibiting Chk1, the DNA checkpoint kinase."...." Rfx1 binds and represses its own promoter. Furthermore, Rfx1 binding to its promoter is reduced upon induction of a DNA replication block by hydroxyurea," A dangerous gene by its ability to self promote and repress. Mutation here could have cataclysmic consequence, worth while checking number of this mutation in CML, and whether this would be a clone responding better to Hydrea?
how frequently Testicular cancer present with this Mutation
Is an indication that Hydrea could replace the bad, dangerous Bleomycin?
What is its (RFX1 mutation) presence in Thyroid cancer
Can Hydrea work there?
should Anaplastic thyroid cancer therapeutic combination include Hydrea when RFX-1 is over expressed?
Is RFX1 a biomarker for Hydrea activity? Can Cisplatin be associated to booster the effect?
==========================
do not confuse with NFX-1 implicated in Papilloma Virus but acting strangely the same as it come to penetrating the Nucleus? or may be they are both epigenetic, but this one linked to p109 according to the Seattle People!
To read more?
Go to: "
or a combination of Cisplatin and Sunitinib or Imatinib
what is the relationship with RFX-1
" treatment with retinoic acid induces both MIBP1 and RFX1 protein, as well as their DNA-binding activity,"Z-Kaye et al. (Is there promotion of c-MYC in APL by retinoic Acid use)
Lubelsky"derepression of the RFX1 gene is only partially blocked by inhibiting Chk1, the DNA checkpoint kinase."...." Rfx1 binds and represses its own promoter. Furthermore, Rfx1 binding to its promoter is reduced upon induction of a DNA replication block by hydroxyurea," A dangerous gene by its ability to self promote and repress. Mutation here could have cataclysmic consequence, worth while checking number of this mutation in CML, and whether this would be a clone responding better to Hydrea?
how frequently Testicular cancer present with this Mutation
Is an indication that Hydrea could replace the bad, dangerous Bleomycin?
What is its (RFX1 mutation) presence in Thyroid cancer
Can Hydrea work there?
should Anaplastic thyroid cancer therapeutic combination include Hydrea when RFX-1 is over expressed?
Is RFX1 a biomarker for Hydrea activity? Can Cisplatin be associated to booster the effect?
==========================
do not confuse with NFX-1 implicated in Papilloma Virus but acting strangely the same as it come to penetrating the Nucleus? or may be they are both epigenetic, but this one linked to p109 according to the Seattle People!
To read more?
Go to: "
Study of FoxA Pioneer Factor at Silent Genes Reveals Rfx-Repressed Enhancer at Cdx2 and a Potential Indicator of Esophageal Adenocarcinoma Development
Wednesday, April 2, 2014
Questions in Diabetes
Importance of measuring residual Insulin by weight, how that affect control of DM type2
how does the level insulin affect the need for Insulin supply to patient
Is there level of insulin predictive of the need for insulin
how to you gauge vascular age in DM
how do you gauge Neurologic age in DM
Is it necessary to obtain G-protein profile at diagnosis, plasminogen activator inhibitors
can Mitochondrial data help predict the course of therapy
IMPORTANCE OF LISTING ALL ENDOCRINOPATHY, AUTOIMMUNE DISEASES AT ONSET!
GLUCOKINASES, with the highest glucose output (heterogenity in HNF-1-alpha) can it predict Insulin use/need.
rate of lipolysis?
rate of Hepatic glucose production
impact of free fatty acid ?are they predictive or prognosis
role of presence of Antibody to Insulin receptor, clinical use?
GLUT1,4 gene expression, TCF7L2,PPAR-gamma,calpain, Beta-adrenergic receptors,secretion of insulin ,amylin level, leptin, adiponectin
deficiency in glucogen synthesis
does level of cortisol impact prognosis in DM-2
TNF level
resistin
TGF
how does the level insulin affect the need for Insulin supply to patient
Is there level of insulin predictive of the need for insulin
how to you gauge vascular age in DM
how do you gauge Neurologic age in DM
Is it necessary to obtain G-protein profile at diagnosis, plasminogen activator inhibitors
can Mitochondrial data help predict the course of therapy
IMPORTANCE OF LISTING ALL ENDOCRINOPATHY, AUTOIMMUNE DISEASES AT ONSET!
GLUCOKINASES, with the highest glucose output (heterogenity in HNF-1-alpha) can it predict Insulin use/need.
rate of lipolysis?
rate of Hepatic glucose production
impact of free fatty acid ?are they predictive or prognosis
role of presence of Antibody to Insulin receptor, clinical use?
GLUT1,4 gene expression, TCF7L2,PPAR-gamma,calpain, Beta-adrenergic receptors,secretion of insulin ,amylin level, leptin, adiponectin
deficiency in glucogen synthesis
does level of cortisol impact prognosis in DM-2
TNF level
resistin
TGF
few questions on Sarcoidosis?
What's wrong with Macrophages in sarcoidosis?
why cells are so incited to become multinucleated (epithelioid)giant cells?
Could blocking of any of the cytokine stops the process
is it mandatory an intervention
and how to monitor this activity
can persistent low Vit D suggests activity of the disease
or Urine calcium level
Can Anergy suggests disease activity?
can frequent SPE be biomarker to test
should we test KatG protein in every case, BTLN2, ANXA11
how do you follow pulmonary hypertension in these patient
does ACE affects Blood Pressure in these patients
?serial EKGs
FEV
response to inhalers
why cells are so incited to become multinucleated (epithelioid)giant cells?
Could blocking of any of the cytokine stops the process
is it mandatory an intervention
and how to monitor this activity
can persistent low Vit D suggests activity of the disease
or Urine calcium level
Can Anergy suggests disease activity?
can frequent SPE be biomarker to test
should we test KatG protein in every case, BTLN2, ANXA11
how do you follow pulmonary hypertension in these patient
does ACE affects Blood Pressure in these patients
?serial EKGs
FEV
response to inhalers
Tuesday, April 1, 2014
With every case, some twists (Seminoma)
At CRBCM,
A 40 year old prisoner was referred to us after an Orchiectomy.
there is still a residual 10.6 cm retroperitoneal mass now know encasing the Aorta and major blood vessel
and invading the L4, L5. Threatening the spine stability in this area. The pain ihere is controlled with Medication. HCG 159. PET obtained show extension of the mass laterally, Nephrostomy bilaterally in place. Hct 27%, Hx of HTN
===========================================
some of the considerations and consulted Published notes follow:
will admit for the 1st Cycle of BEP
please contact us with questions;
1.how much we will reduce Cisplatin?
2.should attempt to resection be proposed?
3.or do you think RT after 4 cycles of BEP should do?
4.Is this patient at higher risk for secondary AML?
5.do we need a MRI of the brain?
===========================
"Urology was consulted and recommended induction chemotherapy and consideration of surgical consolidation after chemotherapy. The case was discussed extensively at tumor board. The consensus was that cisplatin-based chemotherapy is an essential component of potentially curative treatment, so the planned treatment included reduced-dose etoposide and cisplatin with aggressive IV hydration along with renally dosed allopurinol given the bulk of the tumor."
Tim McCarthy.
BEP
Regimen 1 (5-day schedule)
Bleomycin 30 U or 30 mg iv bolus d1, 8, 15 or d2, 9, 16
Etoposide (VP-16) 100 mg/m2/d iv over 1 h d1-5
Cisplatin (CDDP) 20 mg/m2/d iv over 1 h d1-5
Q3w x 3-4 cycles
Culine S et al. Randomized trial comparing bleomycin/etoposide/cisplatin with alternating cisplatin/cyclophosphamide/doxorubicin and vinblastine/bleomycin regimens of chemotherapy for patients with intermediate- and poor-risk metastatic nonseminomatous germ cell tumors: Genito-Urinary Group of the French Federation of Cancer Centers Trial T93MP. J Clin Oncol 2008; 26:421 (link to the article).
de Wit R et al. Equivalence of three or four cycles of bleomycin, etoposide, and cisplatin chemotherapy and of 3- or 5-day schedule in good-prognosis germ cell tumor: a randomized study of the European Organization for Research and Treatment of Cancer Genitourinary Tract Cancer Cooperative Group and the Medical Research Council. J Clin Oncol 2001; 19:1629 (link to the article).
Nichols CR et al. Randomized comparison of cisplatin and etoposide and either bleomycin or ifosfamide in treatment of advanced disseminated germ cell tumors: an Eastern Cooperative Oncology Group, Southwest Oncology Group, and Cancer and Leukemia Group B study. J Clin Oncol 1998; 16:1287 (link to the article).
Williams, SD et al. Treatment of disseminated germ-cell tumors with cisplatin, bleomycin, and either vinblastine or etoposide. N Engl J Med 1987; 316:1435 (link to the article).
===================================
R.Miller et al! Cisplatin induced Nephrotoxicity!
==================================
1.Acute Renal failure
2.Hypomagnesemia
3.Hypocalcemia
4.Fanconi like Syndrome
5.Distal RTA
6.Renal salt wasting
7.Renal Concentration defect
8.Hyperuricemia
9.Erythropoietin deficiency
10Thrombotic Micro-angiopathy
11.Chronic Renal Failure
what is in store
----------------------
" Testicular Cancer
Initial chemotherapy
Salvage chemotherapy
Initial chemotherapy
Carboplatin (for stage I seminoma)
Carboplatin (Paraplatin) AUC 7 x 1 dose
Oliver RT et al. Radiotherapy versus carboplatin for stage I seminoma: updated analysis of the MRC/EORTC randomized trial (ISRCTN27163214). 2008 ASCO annual meeting. Abstract 1 (link to the abstract).
Oliver RT et al. Radiotherapy versus single-dose carboplatin in adjuvant treatment of stage I seminoma: a randomized trial. Lancet 2005; 366:293 (link to the article).
BEP
Regimen 1 (5-day schedule)
Bleomycin 30 U or 30 mg iv bolus d1, 8, 15 or d2, 9, 16
Etoposide (VP-16) 100 mg/m2/d iv over 1 h d1-5
Cisplatin (CDDP) 20 mg/m2/d iv over 1 h d1-5
Q3w x 3-4 cycles
Culine S et al. Randomized trial comparing bleomycin/etoposide/cisplatin with alternating cisplatin/cyclophosphamide/doxorubicin and vinblastine/bleomycin regimens of chemotherapy for patients with intermediate- and poor-risk metastatic nonseminomatous germ cell tumors: Genito-Urinary Group of the French Federation of Cancer Centers Trial T93MP. J Clin Oncol 2008; 26:421 (link to the article).
de Wit R et al. Equivalence of three or four cycles of bleomycin, etoposide, and cisplatin chemotherapy and of 3- or 5-day schedule in good-prognosis germ cell tumor: a randomized study of the European Organization for Research and Treatment of Cancer Genitourinary Tract Cancer Cooperative Group and the Medical Research Council. J Clin Oncol 2001; 19:1629 (link to the article).
Nichols CR et al. Randomized comparison of cisplatin and etoposide and either bleomycin or ifosfamide in treatment of advanced disseminated germ cell tumors: an Eastern Cooperative Oncology Group, Southwest Oncology Group, and Cancer and Leukemia Group B study. J Clin Oncol 1998; 16:1287 (link to the article).
Williams, SD et al. Treatment of disseminated germ-cell tumors with cisplatin, bleomycin, and either vinblastine or etoposide. N Engl J Med 1987; 316:1435 (link to the article).
Regimen 2 (3-day schedule)
Bleomycin 30 U or 30 mg iv bolus d1, 8, 15
Etoposide (VP-16) 165 mg/m2/d iv d1-3
Cisplatin (CDDP) 50 mg/m2/d iv d1-2
Q3w x 3-4 cycles
de Wit R et al. Equivalence of three or four cycles of bleomycin, etoposide, and cisplatin chemotherapy and of 3- or 5-day schedule in good-prognosis germ cell tumor: a randomized study of the European Organization for Research and Treatment of Cancer Genitourinary Tract Cancer Cooperative Group and the Medical Research Council. J Clin Oncol 2001; 19:1629 (link to the article).
EP
Etoposide (VP-16) 100 mg/m2/d iv over 1 h d1-5
Cisplatin (CDDP) 20 mg/m2/d iv over 1 h d1-5
Q3w x 4 cycles
Kondagunta, GV et al. Etoposide and Cisplatin chemotherapy for metastatic good-risk germ cell tumors. J Clin Oncol 2005; 23:9290 (link to the article).
VIP (for patients with underlying lung disease)
Etoposide (VP-16) 75 mg/m2/d iv over 1 h d1-5
Ifosfamide 1.2 g/m2/d iv d1-5
Cisplatin (CDDP) 20 mg/m2/d iv over 1 h d1-5
Mesna 120 mg/m2 iv bolus d1 before ifosfamide, followed by 1.2 g/m2/d civi d1-5
Filgrastim (Neupogen) 5 mcg/kg sc qd d7-16
Q3w x 4 cycles
Nichols, CR et al. Randomized comparison of cisplatin and etoposide and either bleomycin or ifosfamide in treatment of advanced disseminated germ cell tumors: an Eastern Cooperative Oncology Group, Southwest Oncology Group, and Cancer and Leukemia Group B study. J Clin Oncol 1998; 16:1287 (link to the article).
Hinton, S et al. Cisplatin, etoposide and either bleomycin or ifosfamide in the treatment of disseminated germ cell tumors: final analysis of an intergroup trial. Cancer 2003; 97:1869 (link to the article).
Salvage chemotherapy (back to top)
VIP
Etoposide (VP-16) 75 mg/m2/d iv over 1 h d1-5
Ifosfamide 1.2 g/m2/d iv d1-5
Cisplatin (CDDP) 20 mg/m2/d iv over 1 h d1-5
Mesna 120 mg/m2 iv bolus d1 before ifosfamide, followed by 1.2 g/m2/d civi d1-5
Filgrastim (Neupogen) 5 mcg/kg sc qd d7-16
Q3w x 4 cycles
Loehrer, PJ Sr et al. Salvage therapy in recurrent germ cell cancer: ifosfamide and cisplatin plus either vinblastine or etoposide. Ann Intern Med 1988; 109:540 (link to the article).
McCaffrey, JA et al. Ifosfamide- and cisplatin-containing chemotherapy as first-line salvage therapy in germ cell tumors: response and survival. J Clin Oncol 1997; 15:2559 (link to the article).
VeIP (for patients who received prior etoposide)
Vinblastine 0.11 mg/kg/d iv over 1 h d1-2
Ifosfamide 1.2 g/m2/d iv d1-5
Cisplatin (CDDP) 20 mg/m2/d iv over 1 h d1-5
Mesna 400 mg/m2 iv 15 min before first ifosfamide dose, followed by 1.2 g/m2/d civi d1-5
Q3w x 4 cycles
Loehrer, PJ Sr et al. Salvage therapy in recurrent germ cell cancer: ifosfamide and cisplatin plus either vinblastine or etoposide. Ann Intern Med 1988; 109:540 (link to the article).
Loehrer PJ, Sr et al. Vinblastine plus ifosfamide plus cisplatin as initial salvage therapy in recurrent germ cell tumor. J Clin Oncol 1998; 16:2500 (link to the article).
TIP
Paclitaxel (Taxol) 250 mg/m2 iv over 24 hrs d1
Ifosfamide 1.5 g/m2/d iv over 1 h d2-5
Cisplatin (CDDP) 25 mg/m2/d iv over 30 min d2-5
Mesna 500 mg/m2 iv before ifosfamide, and at 4 and 8 hrs after ifosfamide daily, d2-5
Filgrastim (Neupogen) 5 mcg/kg sc qd d7-18
Q3w x 4 cycles
Kondagunta, GV et al. Combination of paclitaxel, ifosfamide, and cisplatin is an effective second-line therapy for patients with relapsed testicular germ cell tumors. J Clin Oncol 2005; 23:6549 (link to the article).
Cisplatin + Epirubicin
Cisplatin (CDDP) 20 mg/m2/d iv d1-5
Epirubicin 90 mg/m2 iv over 15-30 min d1
Filgrastim (Neupogen) 5 mcg/kg sc qd d7-16, or pegfilgrastim 6 mg sc d7
Q3w x 4 cycles
Bedano P et al. Phase II study of cisplatin plus epirubicin salvage chemotherapy in refractory germ cell tumors. J Clin Oncol 2006; 24:5403 (link to the article).
Paclitaxel + Gemcitabine (for platinum-refractory disease)
Paclitaxel (Taxol) 100-110 mg/m2 iv over 1 h d1, 8, 15
Gemcitabine (Gemzar) 1000 mg/m2 iv over 30 min d1, 8, 15
Q4w x 6 cycles
Einhorn LH et al. Phase II study of paclitaxel plus gemcitabine salvage chemotherapy for germ cell tumors after progression following high-dose chemotherapy with tandem transplant. J Clin Oncol 2007; 25:513 (link to the article).
Hinton, S et al. Phase II study of paclitaxel plus gemcitabine in refractory germ cell tumors (E9897): a trial of the Eastern Cooperative Oncology Group. J Clin Oncol 2002; 20:1859 (link to the article)."
A 40 year old prisoner was referred to us after an Orchiectomy.
there is still a residual 10.6 cm retroperitoneal mass now know encasing the Aorta and major blood vessel
and invading the L4, L5. Threatening the spine stability in this area. The pain ihere is controlled with Medication. HCG 159. PET obtained show extension of the mass laterally, Nephrostomy bilaterally in place. Hct 27%, Hx of HTN
===========================================
some of the considerations and consulted Published notes follow:
will admit for the 1st Cycle of BEP
please contact us with questions;
1.how much we will reduce Cisplatin?
2.should attempt to resection be proposed?
3.or do you think RT after 4 cycles of BEP should do?
4.Is this patient at higher risk for secondary AML?
5.do we need a MRI of the brain?
===========================
"Urology was consulted and recommended induction chemotherapy and consideration of surgical consolidation after chemotherapy. The case was discussed extensively at tumor board. The consensus was that cisplatin-based chemotherapy is an essential component of potentially curative treatment, so the planned treatment included reduced-dose etoposide and cisplatin with aggressive IV hydration along with renally dosed allopurinol given the bulk of the tumor."
Tim McCarthy.
A randomized trial of cisplatin, etoposide and bleomycin (PEB) versus carboplatin, etoposide and bleomycin (CEB) for patients with 'good-risk' metastatic non-seminomatous germ cell tumors.
Bokemeyer C1, Köhrmann O, Tischler J, Weissbach L, Räth U, Haupt A, Schöffski P, Harstrick A, Schmoll HJ.
Abstract
BACKGROUND:
Cisplatin-based combination chemotherapy will cure 70% to 80% of patients with metastatic non-seminomatous germ cell tumors but is associated with the possibility of severe neuro-, oto- and nephro-toxicities. Carboplatin, a cisplatin analogue, is an active drug in testicular cancer with a more favourable spectrum of side effects. In a randomized trial, the German Testicular Cancer Study Group compared a combination regimen of carboplatin, etoposide and bleomycin (CEB) to standard cisplatin, etoposide and bleomycin (PEB) chemotherapy for patients with 'minimal-' and moderate-disease' non-seminomatous germ cell tumors, according to the Indiana University classification.PATIENTS AND METHODS:
PEB was given for three cycles at standard doses (given days 1-5), and the CEB regimen consisted of carboplatin (target AUC of 5 mg/ml x min) on day 1, etoposide 120 mg/m2 on days 1 to 3 and bleomycin 30 mg on days 1, 8 and 15. Four cycles of CEB were given, with the omission of bleomycin in the fourth cycle. Thus, the cumulative doses of etoposide and bleomycin applied in the two treatment arms were comparable. Fifty-four patients were entered on the trial, 29 were treated with PEB and 25 with CEB chemotherapy. Patients were stratified according to disease extent (minimal versus moderate) and the degree of tumor marker elevation. Thirty-two patients (59%) belonged to the group with minimal disease and low markers.RESULTS:
No significant difference in response to chemotherapy was seen between the two arms, with CR rates of 81% for the PEB arm and 76% for CEB treatment. However, more patients treated with CEB (32% versus 13%) have relapsed after therapy, and 4 patients (16%) have died of disease progression after CEP in contrast to 1 (3%) after PEB therapy. The first interim analysis of negative events (relapse, vital tumor at secondary resection, death from disease and therapy-associated death) showed a significantly higher rate after CEB than after PEB therapy, and the trial was terminated early. After a median follow-up of 33 months for all patients, the calculation of negative events is still significantly in favour of PEB-treated patient, particularly since three late relapses > 2 years have been observed in the CEB arm (P = 0.03).CONCLUSION:
This randomized trial demonstrates that even with the use of adequate doses of etoposide and full-dose bleomycin, carboplatin cannot altogether replace cisplatin in patients with testicular cancer. Treatment with the PEB regimen remains the standard approach in patients with 'good-risk' non-seminomatous germ cell tumors.BEP
Regimen 1 (5-day schedule)
Bleomycin 30 U or 30 mg iv bolus d1, 8, 15 or d2, 9, 16
Etoposide (VP-16) 100 mg/m2/d iv over 1 h d1-5
Cisplatin (CDDP) 20 mg/m2/d iv over 1 h d1-5
Q3w x 3-4 cycles
Culine S et al. Randomized trial comparing bleomycin/etoposide/cisplatin with alternating cisplatin/cyclophosphamide/doxorubicin and vinblastine/bleomycin regimens of chemotherapy for patients with intermediate- and poor-risk metastatic nonseminomatous germ cell tumors: Genito-Urinary Group of the French Federation of Cancer Centers Trial T93MP. J Clin Oncol 2008; 26:421 (link to the article).
de Wit R et al. Equivalence of three or four cycles of bleomycin, etoposide, and cisplatin chemotherapy and of 3- or 5-day schedule in good-prognosis germ cell tumor: a randomized study of the European Organization for Research and Treatment of Cancer Genitourinary Tract Cancer Cooperative Group and the Medical Research Council. J Clin Oncol 2001; 19:1629 (link to the article).
Nichols CR et al. Randomized comparison of cisplatin and etoposide and either bleomycin or ifosfamide in treatment of advanced disseminated germ cell tumors: an Eastern Cooperative Oncology Group, Southwest Oncology Group, and Cancer and Leukemia Group B study. J Clin Oncol 1998; 16:1287 (link to the article).
Williams, SD et al. Treatment of disseminated germ-cell tumors with cisplatin, bleomycin, and either vinblastine or etoposide. N Engl J Med 1987; 316:1435 (link to the article).
===================================
R.Miller et al! Cisplatin induced Nephrotoxicity!
==================================
1.Acute Renal failure
2.Hypomagnesemia
3.Hypocalcemia
4.Fanconi like Syndrome
5.Distal RTA
6.Renal salt wasting
7.Renal Concentration defect
8.Hyperuricemia
9.Erythropoietin deficiency
10Thrombotic Micro-angiopathy
11.Chronic Renal Failure
what is in store
----------------------
" Testicular Cancer
Initial chemotherapy
Salvage chemotherapy
Initial chemotherapy
Carboplatin (for stage I seminoma)
Carboplatin (Paraplatin) AUC 7 x 1 dose
Oliver RT et al. Radiotherapy versus carboplatin for stage I seminoma: updated analysis of the MRC/EORTC randomized trial (ISRCTN27163214). 2008 ASCO annual meeting. Abstract 1 (link to the abstract).
Oliver RT et al. Radiotherapy versus single-dose carboplatin in adjuvant treatment of stage I seminoma: a randomized trial. Lancet 2005; 366:293 (link to the article).
BEP
Regimen 1 (5-day schedule)
Bleomycin 30 U or 30 mg iv bolus d1, 8, 15 or d2, 9, 16
Etoposide (VP-16) 100 mg/m2/d iv over 1 h d1-5
Cisplatin (CDDP) 20 mg/m2/d iv over 1 h d1-5
Q3w x 3-4 cycles
Culine S et al. Randomized trial comparing bleomycin/etoposide/cisplatin with alternating cisplatin/cyclophosphamide/doxorubicin and vinblastine/bleomycin regimens of chemotherapy for patients with intermediate- and poor-risk metastatic nonseminomatous germ cell tumors: Genito-Urinary Group of the French Federation of Cancer Centers Trial T93MP. J Clin Oncol 2008; 26:421 (link to the article).
de Wit R et al. Equivalence of three or four cycles of bleomycin, etoposide, and cisplatin chemotherapy and of 3- or 5-day schedule in good-prognosis germ cell tumor: a randomized study of the European Organization for Research and Treatment of Cancer Genitourinary Tract Cancer Cooperative Group and the Medical Research Council. J Clin Oncol 2001; 19:1629 (link to the article).
Nichols CR et al. Randomized comparison of cisplatin and etoposide and either bleomycin or ifosfamide in treatment of advanced disseminated germ cell tumors: an Eastern Cooperative Oncology Group, Southwest Oncology Group, and Cancer and Leukemia Group B study. J Clin Oncol 1998; 16:1287 (link to the article).
Williams, SD et al. Treatment of disseminated germ-cell tumors with cisplatin, bleomycin, and either vinblastine or etoposide. N Engl J Med 1987; 316:1435 (link to the article).
Regimen 2 (3-day schedule)
Bleomycin 30 U or 30 mg iv bolus d1, 8, 15
Etoposide (VP-16) 165 mg/m2/d iv d1-3
Cisplatin (CDDP) 50 mg/m2/d iv d1-2
Q3w x 3-4 cycles
de Wit R et al. Equivalence of three or four cycles of bleomycin, etoposide, and cisplatin chemotherapy and of 3- or 5-day schedule in good-prognosis germ cell tumor: a randomized study of the European Organization for Research and Treatment of Cancer Genitourinary Tract Cancer Cooperative Group and the Medical Research Council. J Clin Oncol 2001; 19:1629 (link to the article).
EP
Etoposide (VP-16) 100 mg/m2/d iv over 1 h d1-5
Cisplatin (CDDP) 20 mg/m2/d iv over 1 h d1-5
Q3w x 4 cycles
Kondagunta, GV et al. Etoposide and Cisplatin chemotherapy for metastatic good-risk germ cell tumors. J Clin Oncol 2005; 23:9290 (link to the article).
VIP (for patients with underlying lung disease)
Etoposide (VP-16) 75 mg/m2/d iv over 1 h d1-5
Ifosfamide 1.2 g/m2/d iv d1-5
Cisplatin (CDDP) 20 mg/m2/d iv over 1 h d1-5
Mesna 120 mg/m2 iv bolus d1 before ifosfamide, followed by 1.2 g/m2/d civi d1-5
Filgrastim (Neupogen) 5 mcg/kg sc qd d7-16
Q3w x 4 cycles
Nichols, CR et al. Randomized comparison of cisplatin and etoposide and either bleomycin or ifosfamide in treatment of advanced disseminated germ cell tumors: an Eastern Cooperative Oncology Group, Southwest Oncology Group, and Cancer and Leukemia Group B study. J Clin Oncol 1998; 16:1287 (link to the article).
Hinton, S et al. Cisplatin, etoposide and either bleomycin or ifosfamide in the treatment of disseminated germ cell tumors: final analysis of an intergroup trial. Cancer 2003; 97:1869 (link to the article).
Salvage chemotherapy (back to top)
VIP
Etoposide (VP-16) 75 mg/m2/d iv over 1 h d1-5
Ifosfamide 1.2 g/m2/d iv d1-5
Cisplatin (CDDP) 20 mg/m2/d iv over 1 h d1-5
Mesna 120 mg/m2 iv bolus d1 before ifosfamide, followed by 1.2 g/m2/d civi d1-5
Filgrastim (Neupogen) 5 mcg/kg sc qd d7-16
Q3w x 4 cycles
Loehrer, PJ Sr et al. Salvage therapy in recurrent germ cell cancer: ifosfamide and cisplatin plus either vinblastine or etoposide. Ann Intern Med 1988; 109:540 (link to the article).
McCaffrey, JA et al. Ifosfamide- and cisplatin-containing chemotherapy as first-line salvage therapy in germ cell tumors: response and survival. J Clin Oncol 1997; 15:2559 (link to the article).
VeIP (for patients who received prior etoposide)
Vinblastine 0.11 mg/kg/d iv over 1 h d1-2
Ifosfamide 1.2 g/m2/d iv d1-5
Cisplatin (CDDP) 20 mg/m2/d iv over 1 h d1-5
Mesna 400 mg/m2 iv 15 min before first ifosfamide dose, followed by 1.2 g/m2/d civi d1-5
Q3w x 4 cycles
Loehrer, PJ Sr et al. Salvage therapy in recurrent germ cell cancer: ifosfamide and cisplatin plus either vinblastine or etoposide. Ann Intern Med 1988; 109:540 (link to the article).
Loehrer PJ, Sr et al. Vinblastine plus ifosfamide plus cisplatin as initial salvage therapy in recurrent germ cell tumor. J Clin Oncol 1998; 16:2500 (link to the article).
TIP
Paclitaxel (Taxol) 250 mg/m2 iv over 24 hrs d1
Ifosfamide 1.5 g/m2/d iv over 1 h d2-5
Cisplatin (CDDP) 25 mg/m2/d iv over 30 min d2-5
Mesna 500 mg/m2 iv before ifosfamide, and at 4 and 8 hrs after ifosfamide daily, d2-5
Filgrastim (Neupogen) 5 mcg/kg sc qd d7-18
Q3w x 4 cycles
Kondagunta, GV et al. Combination of paclitaxel, ifosfamide, and cisplatin is an effective second-line therapy for patients with relapsed testicular germ cell tumors. J Clin Oncol 2005; 23:6549 (link to the article).
Cisplatin + Epirubicin
Cisplatin (CDDP) 20 mg/m2/d iv d1-5
Epirubicin 90 mg/m2 iv over 15-30 min d1
Filgrastim (Neupogen) 5 mcg/kg sc qd d7-16, or pegfilgrastim 6 mg sc d7
Q3w x 4 cycles
Bedano P et al. Phase II study of cisplatin plus epirubicin salvage chemotherapy in refractory germ cell tumors. J Clin Oncol 2006; 24:5403 (link to the article).
Paclitaxel + Gemcitabine (for platinum-refractory disease)
Paclitaxel (Taxol) 100-110 mg/m2 iv over 1 h d1, 8, 15
Gemcitabine (Gemzar) 1000 mg/m2 iv over 30 min d1, 8, 15
Q4w x 6 cycles
Einhorn LH et al. Phase II study of paclitaxel plus gemcitabine salvage chemotherapy for germ cell tumors after progression following high-dose chemotherapy with tandem transplant. J Clin Oncol 2007; 25:513 (link to the article).
Hinton, S et al. Phase II study of paclitaxel plus gemcitabine in refractory germ cell tumors (E9897): a trial of the Eastern Cooperative Oncology Group. J Clin Oncol 2002; 20:1859 (link to the article)."
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Sunday, March 30, 2014
LOOKING DEEPER INTO THIS
IS IT THE CYTOKINES AGAIN?
how to detect vascular health?
objective 130/80
biomarkers for detecting risk of stroke, A-fib, ESRD,peripheral
and how that correlate with BMI and age, and level of HTN
how to detect vascular health?
objective 130/80
biomarkers for detecting risk of stroke, A-fib, ESRD,peripheral
and how that correlate with BMI and age, and level of HTN
Cytokine Bank!
Nothing will produce such a bounce in medicine
there no parallel in progress in medicine
but constitution of a cytokine bank will have the most benefit both financially and medically without precedent! Its touch will be wide, unprecedent and a marvel in science. With genetic know how of current days, an amplification of minimally present cytokine could have unpredictable effect. A cytokine storm kill the host, there is no increment or change in our cells that is more likely cytokine driven, it leads to scar and every major complicated syndrome includes somewhere cytokine release or activity. From PTSD to diarrhea, from treatment of cancers (IL-2 for renal cell cancer including the rare cures in this disease come from IL-2), from lung fibrosis to why CD4 drops in HIV, you name you got it in medicine, from being young to becoming old, all phenomena are affected by Cytokines. We know this and the cytokines know they exist, but we keep our heads in the sand. But I know this, medicine of the next century will be made by how much a condition needs in term of cytokine to be treated.
We got to start a cytokine Bank Now!
HOW CAN WE GO WRONG?
WIKIPIDEA FOR EXAMPLE:
"
AND THIS IS JUST A START!
there no parallel in progress in medicine
but constitution of a cytokine bank will have the most benefit both financially and medically without precedent! Its touch will be wide, unprecedent and a marvel in science. With genetic know how of current days, an amplification of minimally present cytokine could have unpredictable effect. A cytokine storm kill the host, there is no increment or change in our cells that is more likely cytokine driven, it leads to scar and every major complicated syndrome includes somewhere cytokine release or activity. From PTSD to diarrhea, from treatment of cancers (IL-2 for renal cell cancer including the rare cures in this disease come from IL-2), from lung fibrosis to why CD4 drops in HIV, you name you got it in medicine, from being young to becoming old, all phenomena are affected by Cytokines. We know this and the cytokines know they exist, but we keep our heads in the sand. But I know this, medicine of the next century will be made by how much a condition needs in term of cytokine to be treated.
We got to start a cytokine Bank Now!
HOW CAN WE GO WRONG?
WIKIPIDEA FOR EXAMPLE:
"
- Immunoglobulin (Ig) superfamily, which are ubiquitously present throughout several cells and tissues of the vertebrate body, and share structural homology with immunoglobulins (antibodies), cell adhesion molecules, and even some cytokines. Examples: IL-1 receptor types.
- Hemopoietic Growth Factor (type 1) family, whose members have certain conserved motifs in their extracellular amino-acid domain. The IL-2 receptor belongs to this chain, whose γ-chain (common to several other cytokines) deficiency is directly responsible for the x-linked form of Severe Combined Immunodeficiency (X-SCID).
- Interferon (type 2) family, whose members are receptors for IFN β and γ.
- Tumor necrosis factors (TNF) (type 3) family, whose members share a cysteine-rich common extracellular binding domain, and includes several other non-cytokine ligands like CD40, CD27 and CD30, besides the ligands on which the family is named (TNF).
- Seven transmembrane helix family, the ubiquitous receptor type of the animal kingdom. All G protein-coupled receptors (for hormones and neurotransmitters) belong to this family. Chemokine receptors, two of which act as binding proteins for HIV (CD4 and CCR5), also belong to this family.[citation needed]
- Interleukin-17 receptor (IL-17R) family, which shows little homology with any other cytokine receptor family. Structural motifs conserved between members of this family include: an extracellular fibronectin III-like domain, a transmembrane domain and a cytoplasmic SERIF domain. The known members of this family are as follows: IL-17RA, IL-17RB, IL-17RC, IL17RD and IL-17RE.[12]
- Interleukin-12 (IL-12), secreted by macrophages and act on TH0 (T-helper cell 0) and convert into TH1 (T-helper cell 1)which produce IFN γ. IFN γ activates macrophages, thus starting cell mediated immune response."
AND THIS IS JUST A START!
Thursday, March 27, 2014
ZERO-ING ON MEMBRANE PHENOMENA
*Metastatic processes are facilitated with depression of E-Cadherin
but are PKP2 also depressed or overexpressed
does the processes of metastatic diseases different than base line natural cellular displacement in terms of Vimentin, plakoglobin, and desmoplakin expression. Or are these proteins behaving the same way no matter the cellular process.
*Can these parameters translate well the activity of Taxotere.
*Can level of methylated Vimentin coincide with Taxotere resistance or susceptibility, or level of side effects in the patient being treated.
*Can these genes reliably predict Adriamycin toxicity!
*can tightening Microtubule -Vimentin interaction by Antibody slow down cancer metastatic potentials?
*Is Tuberin/Hamartin more easily evaluated in the peripheral sera
*
NOW DOES LEVEL OF TUBERIN REFLECT LEVEL OF ACTIVITY OF E6, TRANSFORMATION IN CERVICAL CANCER, OR RESPONSE TO PLATIN BASED CHEMOTHERAPY, OR SIDE EFFECT LINKED TO INVOLVEMENT OF INSULIN, CNS DISEASES OR SIDE EFFECTS
but are PKP2 also depressed or overexpressed
does the processes of metastatic diseases different than base line natural cellular displacement in terms of Vimentin, plakoglobin, and desmoplakin expression. Or are these proteins behaving the same way no matter the cellular process.
*Can these parameters translate well the activity of Taxotere.
*Can level of methylated Vimentin coincide with Taxotere resistance or susceptibility, or level of side effects in the patient being treated.
*Can these genes reliably predict Adriamycin toxicity!
*can tightening Microtubule -Vimentin interaction by Antibody slow down cancer metastatic potentials?
*Is Tuberin/Hamartin more easily evaluated in the peripheral sera
*
Human Papillomavirus 16 E6 Oncoprotein Interferences with Insulin Signaling Pathway by Binding to Tuberin
Zheming Lu ET AL!NOW DOES LEVEL OF TUBERIN REFLECT LEVEL OF ACTIVITY OF E6, TRANSFORMATION IN CERVICAL CANCER, OR RESPONSE TO PLATIN BASED CHEMOTHERAPY, OR SIDE EFFECT LINKED TO INVOLVEMENT OF INSULIN, CNS DISEASES OR SIDE EFFECTS
Wednesday, March 26, 2014
looking into new targets
Casolaro et al
" Recently Polo-Like Kinase 1 (PLK1) has emerged as a new candidate drug target in AML."
but evidence is imposing PLGC1 because of its critical interactions with Gerb2 and DVL1, the FLT
and may be more importantly with ETS.
*Anti-NHE1/CHP could have a larger impact in resistant Thyroid cancers theoritically, or diseases where the Calcineurin/NFAT have a stronger role?
" Recently Polo-Like Kinase 1 (PLK1) has emerged as a new candidate drug target in AML."
but evidence is imposing PLGC1 because of its critical interactions with Gerb2 and DVL1, the FLT
and may be more importantly with ETS.
*Anti-NHE1/CHP could have a larger impact in resistant Thyroid cancers theoritically, or diseases where the Calcineurin/NFAT have a stronger role?
Sunday, March 23, 2014
from those who know the regulators of major pathways!
"Nde1, Lis1, and Brap regulates the dynamic MAPK signaling threshold in a spatially dependent fashion. Brap, a mitogen-activated protein kinase (MAPK) signaling threshold modulator,"
what more, we need to find out!
what more, we need to find out!
Careful what you read
In cancer reading, one should be careful because so much remains unknown
most of the time, the reader is exposed to the writer interpretation of facts.
One may suggest that a gene amplification, mutation or repression is bad for the cancer as if that gene presentation is notoriously bad for the patient. The statement tends to suggest the presence of this gene variation from the norm to be either predictive or prognosis. But little is said on whether that gene happens to be bad because the use of the current therapy ensure a poor response! What is bad is not the gene presence, it is the use of a poor therapy that worsen the situation. This is why target therapy is warranted! Now it is true that at current time, we don't know it all, but one thing is for sure, as we progress with medicine, and as we know more, our therapy is improving sharply...our patient are noticing the difference. Our Colon cancer patients have ripped the benefit...and so do those with Multiple Myeloma.
But there are recalcitrant cancers such as the Gliomas in which we are still struggling! But so we intensify our research...
One other area of caution is the weight loss in our cancer patients. We like the idea that there is associated production of cytokine or growth factors that accompany cancers and causes the cachexia or marked weight loss in these diseases. Cachectins and other cytokines have been thrown at our faces as a reason for the phenomena. We fail to recognize that deep in the belly of genes draining the cancers, these unique perturbations of genes actually directly affect other genes compromising the Glucolysis or Glucogenesis. ie TPI genes (G3P combination to DHAP). And that may be supplying the end result to this combination to these patient should be a therapeutic intervention to be incorporated in the therapeutic strategy (if the failure is diagnosed). We could use Giardia infection as a sign this is actually happening! wake up folks we see this all the time!
(to be continued)
most of the time, the reader is exposed to the writer interpretation of facts.
One may suggest that a gene amplification, mutation or repression is bad for the cancer as if that gene presentation is notoriously bad for the patient. The statement tends to suggest the presence of this gene variation from the norm to be either predictive or prognosis. But little is said on whether that gene happens to be bad because the use of the current therapy ensure a poor response! What is bad is not the gene presence, it is the use of a poor therapy that worsen the situation. This is why target therapy is warranted! Now it is true that at current time, we don't know it all, but one thing is for sure, as we progress with medicine, and as we know more, our therapy is improving sharply...our patient are noticing the difference. Our Colon cancer patients have ripped the benefit...and so do those with Multiple Myeloma.
But there are recalcitrant cancers such as the Gliomas in which we are still struggling! But so we intensify our research...
One other area of caution is the weight loss in our cancer patients. We like the idea that there is associated production of cytokine or growth factors that accompany cancers and causes the cachexia or marked weight loss in these diseases. Cachectins and other cytokines have been thrown at our faces as a reason for the phenomena. We fail to recognize that deep in the belly of genes draining the cancers, these unique perturbations of genes actually directly affect other genes compromising the Glucolysis or Glucogenesis. ie TPI genes (G3P combination to DHAP). And that may be supplying the end result to this combination to these patient should be a therapeutic intervention to be incorporated in the therapeutic strategy (if the failure is diagnosed). We could use Giardia infection as a sign this is actually happening! wake up folks we see this all the time!
(to be continued)
looking into cancer resistance and the autoimmune syndromes
-Does chronic exposure to autoimmune diseases or antigen stimulate
a new set of genes
-does these gene include genes from cellular growth
or cellular growth in autoimmune diseases is limited by consequence of energy consumption
does blocking energy consumption a valid intervention in cancer cure
-is vitamin D deficiency linked to consumption or repression of this gene or lack of absorption
-what are the cytokines liberated during an autoimmune disease
-how does decrease of proliferation rate linked to resistance to apoptosis
-how necrosis, senescence, autophagy (type II programmed cell death) and mitotic disruptions can be brought to bear in cancer resistance
-detections of inhibitors to main pathways,
-does inhibition represent a valid option to cancer cure
-does inhibitions of pump/ion receptor a potential way of wining resistance to cancer therapy
-can amplifying c-MYC be a major therapeutic intervention given its effect on Bcl-2
-According to the ASCPB:"DNA methylation is established by DNA methyltransferase (DMT) enzymes that transfer a methyl group from S-adenosyl Met to the fifth carbon of cytosine. Depending on whether the recognition site is already methylated or not, these enzymes can largely be subdivided into maintenance and de novo DMTs. Maintenance DMTs conserve the methylation status of symmetrical (palindromic) sites after DNA replication by recognizing the hemimethylated locus and methylating the newly synthesized strand. Candaele et al. (pp. 1350–1364)"
dosing this Methylation may be a significant intervention in cancer resistance particularly in cancer that use the subterfuge of migrating at distant levels to recur (glioblastoma)
-does combining
-does Pomalidomide or vectibix increase the effect of Temozolimide
-or is it Panobinostat (hydroxamic acid) the next enhancer of Temolomide!
-or is it Erivedge the next big thing?
-what is the the cytokines involved or is there any?
a new set of genes
-does these gene include genes from cellular growth
or cellular growth in autoimmune diseases is limited by consequence of energy consumption
does blocking energy consumption a valid intervention in cancer cure
-is vitamin D deficiency linked to consumption or repression of this gene or lack of absorption
-what are the cytokines liberated during an autoimmune disease
-how does decrease of proliferation rate linked to resistance to apoptosis
-how necrosis, senescence, autophagy (type II programmed cell death) and mitotic disruptions can be brought to bear in cancer resistance
-detections of inhibitors to main pathways,
-does inhibition represent a valid option to cancer cure
-does inhibitions of pump/ion receptor a potential way of wining resistance to cancer therapy
-can amplifying c-MYC be a major therapeutic intervention given its effect on Bcl-2
-According to the ASCPB:"DNA methylation is established by DNA methyltransferase (DMT) enzymes that transfer a methyl group from S-adenosyl Met to the fifth carbon of cytosine. Depending on whether the recognition site is already methylated or not, these enzymes can largely be subdivided into maintenance and de novo DMTs. Maintenance DMTs conserve the methylation status of symmetrical (palindromic) sites after DNA replication by recognizing the hemimethylated locus and methylating the newly synthesized strand. Candaele et al. (pp. 1350–1364)"
dosing this Methylation may be a significant intervention in cancer resistance particularly in cancer that use the subterfuge of migrating at distant levels to recur (glioblastoma)
-does combining
-does Pomalidomide or vectibix increase the effect of Temozolimide
-or is it Panobinostat (hydroxamic acid) the next enhancer of Temolomide!
-or is it Erivedge the next big thing?
-what is the the cytokines involved or is there any?
Saturday, March 22, 2014
Another Local hospital will accept our patients
It was long awaited
another Large local hospital will start accepting greater east cancer center patients
another Large local hospital will start accepting greater east cancer center patients
Del Sol Medical Center, has approved privileges to crbcm
we are happy, and look forward to admitting our patients there! Progress is slow but certain. We will greatly use their infusion center capabilities and their radiology dept. It is great that most of the inherited patients have been asking about this affiliation since they are used to use this facility for their care. They will be happy to learn that crbcm can assure them a continuation of care with this large facility in El Paso!
In the mean time our work at Griffols/Talecris Plasma centers (El Paso 2& 4) continue...
and we saw one patient with familial Rosacea, we are glad to report that a combination of metronidazole cream and Acid Azelaic gel is performing wonderfully! A closer look on Familial Rosacea is warranted (genetic base!)in our future blog! crbcm has a wide panel of patients!
Thursday, March 20, 2014
Evidences increase that FOXO3 (HYPOTHESIS)
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!
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!
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!
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