questions in basic medical sciences
1. Can new heat shock Proteins made to be recognized by the the endosomal immune system?
2. Can cancer cells express DNA motifs recognizable by the TLR9
3. Can cytokines (IL11, IL 17, GCSF,Interferon-beta, be used as reliable predictor markers of pulmonary fibrosis in patient treated with Bleomycin)
4. Can we electively silence MHC class I on cancer cell enough to trigger the "missing self Hypothesis".
(CD159,CD 158, CD 85)
5.Review the full role of Immunoglobulin-like transcription receptors
6.Harvesting Metastatic potential of cancer cell in their tagging with IgG susceptible to trigger FcyR NK cell-antibody dependent cell mediated cytotoxicity. (survey of cancer cell receptors).
7Quantifying heat shock proteins in normal Vs cancer cells as a way to detect cancer cells, targeting them for increased scusceptibilty to be detected by dendritic cells?
8. Silencing MHC class I gene in cancer cells could be a significant way to trigger NK cells
9. Can perturbation at the FAK, decrease of E-Cadherin be associated with antigenic triggering changes of memebrane phospholipids?
10. developement of small peptide susceptible to change MHC class I in cancer cells
11. pertubations of endonuclease in cancer cell as a way to induce changes in TCR
12. Is TAP (transporter in Antigen Processing) a valid target in cancer therapy?
Sunday, September 29, 2013
Saturday, September 28, 2013
OVEREXPRESSION OF TRIB3 AMD SUPPRESSION OF TIAF1,NEW TARGETS IN THERAPY!
Based on our current understanding most receptor failure will go on to induce the stress related pathways which ultimately will go on to produce epigenetic events which will include not only transcription factors production but also significant cytokines production. Some of these Cytokines includes growth factors which not only have the role of inducing growth of the cell, but also blocking Apoptosis.
The activation of NF-kB, one of our stress coping pathway, happens to induce TRIB3 but this elevation has a negative regulator effect on the NF-kB therefore decreasing the intensity of one of the most significant trigger (in chronic exposure to irritant stimuli) or amplifier of specific cancers, and driver of cytokine production. Activating this TRIB3 could have significant effect in autoimmune diseases and have a significant effect in supportive cancer treatment and maintenance settings.
TIAF1, however, needs to be suppressed because it is the mechanism by the TGF to block death of cells.
In diseases where growth factors are the drivers , block the hell out of this TIAF1 please. At CRBCM we are trying to see if these 2 interventions may help IL-2 effect in melanoma and Renal cancers. FUNDS are missing so please help if you can!
What we keep as a secret is the work on anti-granulin (because here Cyclin T is involved, and with it TRIB3)!(HIV is not far a target!)
"The protein encoded by this gene is a putative protein kinase that is induced by the transcription factor NF-kappaB. The encoded protein is a negative regulator of NF-kappaB, and can also sensitize cells to TNF- and TRAIL-induced apoptosis. In addition, this protein can negatively regulate the cell survival serine-threonine kinase AKT1.[3]
The activation of NF-kB, one of our stress coping pathway, happens to induce TRIB3 but this elevation has a negative regulator effect on the NF-kB therefore decreasing the intensity of one of the most significant trigger (in chronic exposure to irritant stimuli) or amplifier of specific cancers, and driver of cytokine production. Activating this TRIB3 could have significant effect in autoimmune diseases and have a significant effect in supportive cancer treatment and maintenance settings.
TIAF1, however, needs to be suppressed because it is the mechanism by the TGF to block death of cells.
In diseases where growth factors are the drivers , block the hell out of this TIAF1 please. At CRBCM we are trying to see if these 2 interventions may help IL-2 effect in melanoma and Renal cancers. FUNDS are missing so please help if you can!
What we keep as a secret is the work on anti-granulin (because here Cyclin T is involved, and with it TRIB3)!(HIV is not far a target!)
"The protein encoded by this gene is a putative protein kinase that is induced by the transcription factor NF-kappaB. The encoded protein is a negative regulator of NF-kappaB, and can also sensitize cells to TNF- and TRAIL-induced apoptosis. In addition, this protein can negatively regulate the cell survival serine-threonine kinase AKT1.[3]
Interactions
TRIB3 has been shown to interact with:- AKT1,[1]
- CSNK2B,[4]
- Fibronectin[4]
- MCM3AP,[5]
- RELA,[6]
- SIAH1,[4] and
- TIAF1.[4]"
- wikipedia
- ==================================================================
-
TGFB1-induced anti-apoptotic factor 1 is a protein that in humans is encoded by the TIAF1 gene.[1][2]
Interactions
TIAF1 has been shown to interact with Janus kinase 3[3] and TRIB3.[4]wikipedia
(watch this in Promyelocytic leukemia)
CRBCM is coming!
Friday, September 27, 2013
CPRIT NEW BOARD MEMBERS APPOINTED
THINGS ARE GETTING IN SHAPE AT CPRIT AS GOVERNOR RICK PERRY HAS NOMINATED NEW MEMBERS TO THE BOARD. THESE NOMINATIONS REPORTEDLY WERE MANDATED BY STATE LAW.
CPRIT IS STILL RESHAPING ITSELF AND WILL BE SOON BACK INTO OPERATION BEFORE THE END OF THE YEAR ACCORDING TO SEVERAL SOURCES... MANY STILL ARE HOPEFUL THIS TIME AROUND WILL BE LESS POLITICAL AND BIASED!
-----------------------------------------------------------------
CRBCM MEANWHILE HAS COMPLETED A MOVE AIMED AT HAVING A DIRECT FRONTAGE TO THE STREET. OUR PELLICANO LOCATION GIVES US DIRECT STREET EXPOSURE AS WE WELCOME WALK-INS.
-----------------------------------------------------------------------------
THE BEGINNING OF OCTOBER WILL MARK THE START OF THE FULL COLLABORATION WITH UTEP ON THE LUNG CANCER DETECTION EVALUATION. PER CONTRACTUAL AGREEMENT, THE PI WILL BE PROFESSOR JIANYING ZHANG and the University of Virginia is still providing the tissue SAMPLES. CRBCM is providing additional funding for the project !
CPRIT IS STILL RESHAPING ITSELF AND WILL BE SOON BACK INTO OPERATION BEFORE THE END OF THE YEAR ACCORDING TO SEVERAL SOURCES... MANY STILL ARE HOPEFUL THIS TIME AROUND WILL BE LESS POLITICAL AND BIASED!
-----------------------------------------------------------------
CRBCM MEANWHILE HAS COMPLETED A MOVE AIMED AT HAVING A DIRECT FRONTAGE TO THE STREET. OUR PELLICANO LOCATION GIVES US DIRECT STREET EXPOSURE AS WE WELCOME WALK-INS.
-----------------------------------------------------------------------------
THE BEGINNING OF OCTOBER WILL MARK THE START OF THE FULL COLLABORATION WITH UTEP ON THE LUNG CANCER DETECTION EVALUATION. PER CONTRACTUAL AGREEMENT, THE PI WILL BE PROFESSOR JIANYING ZHANG and the University of Virginia is still providing the tissue SAMPLES. CRBCM is providing additional funding for the project !
FOR POWER, WATCH THE COMPANY YOU KEEP! IBRUTINIB, A WONDER DRUG.
IBRUTINIB, A WONDER DRUG.
=========================
If there is a wonder drug, nothing comes close to Ibrutinib! This drug could be a wonder drug for sure because it affect not only powerful genes that cause malformations when they are mutated (a clear power of the gene) but also involve all mighty "wild genes" (those having multiple interactions).
Malformations involved by the Bruton (BTK) gene are particularly wide going from Agammaglobulinemia which kill children with multiple infections, to the Sturge-Weber syndrome which lead to mental Retardation and seizures, to the Albright syndrome! Even bone dysmorphy is in the wing.
wild genes involved include the Gerb2 through the GAB1, the LYN, PTPN1 etc...
The mere involvement of the Adenyl Cyclase remind us of some of the undesirable effect of powerful infection such as E.coli, Mycobacterium, and the Whooping cough! All these various pathways are affected broadening the impact of Ibrutinib to all white blood cell neoplastic process!
By affecting the GNAQ, Bruton's Inhibitor could work in Uveal Melanoma theoritically
And through inhibition of the GPCR family (S1PR1) Bruton inhibitor could act in Angiosarcoma and harmartomatous syndromes. Remember RIC8A and the Gs -ALPHA are affected!
Investors, if you have not jump on the wagon, it is not too late! Ibrutinib is a wild one with unlimited potential! IBRUTINIB IS POWERFUL BECAUSE OF THE GENE COMPANY IT KEEPS!
===========================================
the CRBCM has not invested in any drug to this point! But the science is behind this drug!
===========================================
WIKIPEDIA comes to the Rescue with scientific comments!
In preclinical studies on chronic lymphocytic leukemia (CLL) cells, ibrutinib has been reported to promote apoptosis, inhibit proliferation, and also prevent CLL cells from responding to survival stimuli provided by the microenvironment.[11] In this study, treatment of activated CLL cells with ibrutinib resulted in inhibition of Btk tyrosine phosphorylation and also effectively abrogated downstream survival pathways activated by this kinase including ERK1/2, PI3K, and NF-κB. Additionally, ibrutinib inhibited proliferation of CLL cells in vitro, effectively blocking survival signals provided externally to CLL cells from the microenvironment including soluble factors (CD40L, BAFF, IL-6, IL-4, and TNF-α), fibronectin engagement and stromal cell contact.
In early clinical studies, the activity of ibrutinib has been described to include a rapid reduction in lymphadenopathy accompanied by a transient lymphocytosis, suggesting that the drug might have direct effects on cell homing or migration to factors in tissue microenvironments.[12]
Ibrutinib has been reported to reduce CLL cell chemotaxis towards the chemokines CXCL12 and CXCL13, and inhibit cellular adhesion following stimulation at the B cell receptor.[13][14] Together, these data are consistent with a mechanistic model whereby ibrutinib blocks BCR signaling, which drives cells into apoptosis and/or disrupts cell migration and adherence to protective tumor microenvironments.
1.S1PR1 is one of the main responsible of vascular growth and development, at least during embryogenesis.[9] In vascular endothelial cells the binding of S1P to S1PR1 induces migration, proliferation, cell survival and morphogenesis into capillary-like structures.[10] Moreover, the binding of S1P to S1PR1 is implicated in the formation of cell-cell adherens junctions, therefore inhibiting paracellular permeability of solutes and macromolecules.[11][12] It was also shown in vivo that S1P synergizes with angiogenic factors such as FGF-2 and VEGF in inducing angiogenesis and vascular maturation through S1PR1.[12][13] showed that S1PR1-KO mice died during development due to a defect in vascular stabilization, suggesting that this receptor is essential for vascular development. In conclusion, several evidences confirm that S1P via S1PR1 is a potent regulator of vascular growth and development, at least during embryogenesis.[9]
2.RGS16. It inhibits signal transduction by increasing the GTPase activity of G protein alpha subunits.
3.GNAQ1 activity is terminated by:
Activation of GNAQ1 is terminated by a GTPase intrinsic to the G-alpha subunit. G-alpha-q is the alpha subunit of one of the heterotrimeric GTP-binding proteins that mediates stimulation of phospholipase C-beta (MIM 600230).[supplied by OMIM][2]
4. Bruton's tyrosine kinase (abbreviated Btk or BTK) is a type of kinase enzyme implicated in the primary immunodeficiency disease X-linked agammaglobulinemia (Bruton's agammaglobulinemia). Its exact mechanism of action remains unknown, but it plays a crucial role in B cell maturation as well as mast cell activation through the high-affinity IgE receptor. Patients with XLA have normal pre-B cell populations in their bone marrow but these cells fail to mature and enter the circulation. The Btk gene is located on the X chromosome.[1] At least 400 mutations of the Btk gene have been identified.WIKIPEDIA
=========================
If there is a wonder drug, nothing comes close to Ibrutinib! This drug could be a wonder drug for sure because it affect not only powerful genes that cause malformations when they are mutated (a clear power of the gene) but also involve all mighty "wild genes" (those having multiple interactions).
Malformations involved by the Bruton (BTK) gene are particularly wide going from Agammaglobulinemia which kill children with multiple infections, to the Sturge-Weber syndrome which lead to mental Retardation and seizures, to the Albright syndrome! Even bone dysmorphy is in the wing.
wild genes involved include the Gerb2 through the GAB1, the LYN, PTPN1 etc...
The mere involvement of the Adenyl Cyclase remind us of some of the undesirable effect of powerful infection such as E.coli, Mycobacterium, and the Whooping cough! All these various pathways are affected broadening the impact of Ibrutinib to all white blood cell neoplastic process!
By affecting the GNAQ, Bruton's Inhibitor could work in Uveal Melanoma theoritically
And through inhibition of the GPCR family (S1PR1) Bruton inhibitor could act in Angiosarcoma and harmartomatous syndromes. Remember RIC8A and the Gs -ALPHA are affected!
Investors, if you have not jump on the wagon, it is not too late! Ibrutinib is a wild one with unlimited potential! IBRUTINIB IS POWERFUL BECAUSE OF THE GENE COMPANY IT KEEPS!
===========================================
the CRBCM has not invested in any drug to this point! But the science is behind this drug!
===========================================
WIKIPEDIA comes to the Rescue with scientific comments!
In preclinical studies on chronic lymphocytic leukemia (CLL) cells, ibrutinib has been reported to promote apoptosis, inhibit proliferation, and also prevent CLL cells from responding to survival stimuli provided by the microenvironment.[11] In this study, treatment of activated CLL cells with ibrutinib resulted in inhibition of Btk tyrosine phosphorylation and also effectively abrogated downstream survival pathways activated by this kinase including ERK1/2, PI3K, and NF-κB. Additionally, ibrutinib inhibited proliferation of CLL cells in vitro, effectively blocking survival signals provided externally to CLL cells from the microenvironment including soluble factors (CD40L, BAFF, IL-6, IL-4, and TNF-α), fibronectin engagement and stromal cell contact.
In early clinical studies, the activity of ibrutinib has been described to include a rapid reduction in lymphadenopathy accompanied by a transient lymphocytosis, suggesting that the drug might have direct effects on cell homing or migration to factors in tissue microenvironments.[12]
Ibrutinib has been reported to reduce CLL cell chemotaxis towards the chemokines CXCL12 and CXCL13, and inhibit cellular adhesion following stimulation at the B cell receptor.[13][14] Together, these data are consistent with a mechanistic model whereby ibrutinib blocks BCR signaling, which drives cells into apoptosis and/or disrupts cell migration and adherence to protective tumor microenvironments.
1.S1PR1 is one of the main responsible of vascular growth and development, at least during embryogenesis.[9] In vascular endothelial cells the binding of S1P to S1PR1 induces migration, proliferation, cell survival and morphogenesis into capillary-like structures.[10] Moreover, the binding of S1P to S1PR1 is implicated in the formation of cell-cell adherens junctions, therefore inhibiting paracellular permeability of solutes and macromolecules.[11][12] It was also shown in vivo that S1P synergizes with angiogenic factors such as FGF-2 and VEGF in inducing angiogenesis and vascular maturation through S1PR1.[12][13] showed that S1PR1-KO mice died during development due to a defect in vascular stabilization, suggesting that this receptor is essential for vascular development. In conclusion, several evidences confirm that S1P via S1PR1 is a potent regulator of vascular growth and development, at least during embryogenesis.[9]
2.RGS16. It inhibits signal transduction by increasing the GTPase activity of G protein alpha subunits.
3.GNAQ1 activity is terminated by:
Activation of GNAQ1 is terminated by a GTPase intrinsic to the G-alpha subunit. G-alpha-q is the alpha subunit of one of the heterotrimeric GTP-binding proteins that mediates stimulation of phospholipase C-beta (MIM 600230).[supplied by OMIM][2]
4. Bruton's tyrosine kinase (abbreviated Btk or BTK) is a type of kinase enzyme implicated in the primary immunodeficiency disease X-linked agammaglobulinemia (Bruton's agammaglobulinemia). Its exact mechanism of action remains unknown, but it plays a crucial role in B cell maturation as well as mast cell activation through the high-affinity IgE receptor. Patients with XLA have normal pre-B cell populations in their bone marrow but these cells fail to mature and enter the circulation. The Btk gene is located on the X chromosome.[1] At least 400 mutations of the Btk gene have been identified.WIKIPEDIA
ROLE OF GLYCOPEPTIDE (receptor) ALTERATION IN THE MALIGNANT TRANSFORMATION
One of the function of the Glycan coverage of protein receptor is not only to be a an integral part of the Glycopeptide nature of the receptor as it is recognized, but to also induce Antigenic like recognition by the immune system when the cell is altered as it occurs during a neoplastic transformation of the cell. During such a transformation, it is believed that cyclines and altered FAK abnormally produced may cause membrane alterations which include alterations at cellular receptors that will dampen cellular induction of chemokines that could be naturally induced. This effect will reduce normal recognition of cellular abnormality, and dampen caspase 3 stimulation as well as allowing the changed cell to escape immune recognition. There is indeed a cascade of maneuvers that allow the cell to survive a neoplastic transformation. Aside for an uncontrolled DNA duplication and cellular proliferation, gene alterations and mistakes must be tolerated through suppression of control genetic mechanisms, gen repair must fail, BRCA genes and the like of them must be "mutated" and Breaks such as P53 must be 'MUTATED" to let the neoplastic process advance. Suppressor gene such as Rb1 must be silenced! Receptors under the attack of cytokines, will have their Glycan portion altered. the Receptor consequently become resistant to its stimulant growth factor, a fact which under normal considition will stimulate further growth factor to try to conquer the resistance, this increase will stimulate intact secondary factor and dampen some pathway genes (PTEN) an break to the PI3K pathway. further stressful action will start the HSP family of Heat stroke Protein and cause the c-JUN/c-fos, increasing further epigenetic events....Again glycopeptide alteration is a critical step in cellular tolerance of malignant transformed cell (IT IS BELIEVED)
Thursday, September 26, 2013
NEW! Market Research
Clinical Trial Detail
◄ Back to SearchStudies on Tumors of the Thyroid
See this on ClinicalTrials.gov
| Trial Phase N/A |
Enrollment Quota 99999999 |
Specialty: Endocrinology,Internal Medicine,Oncology Subspecialty: Endocrine Oncology,Thyroid/Parathyroid,Endocrinology,Hematology/Oncology,Endocrine Oncology Sponsor: National Institutes of Health Clinical Center (CC) |
Estimated Completion Date: Not specified
Interventions
No interventions citedInclusion criteria
- Adults and children with known or suspected thyroid neoplasm will be considered for participation. Enrollment will be capped accordingly:
- Patients with thyroid nodules requiring evaluation and possible biopsy (no more than 30 per year)
- Patients with recent diagnosis of thyroid cancer requiring consultation and counseling about therapeutic options (no more than 10 per year)
- Patients with established thyroid cancer requiring specialized studies such as (131)I dosimetry (no more than 5 per year)
- Enrollment of high risk, non-iodine avid, inoperable thyroid cancer only for purposes of screening for eligibility for other specific thyroid cancer protocols
Exclusion criteria
- Serious underlying medical conditions that restrict diagnostic testing or therapy such as renal failure, congestive cardiac failure or active coexisting non-thyroid carcinoma
- Patients unable or unwilling to give informed consent
Study Locations And Contact Information
-
National Institutes of Health Clinical Center, 9000 Rockville Pike, Bethesda Maryland
Contact: For more information at the NIH Clinical Center contact Patient Recruitment and Public Liaison Office (PRPL) 800-411-1222 prpl@mail.cc.nih.gov
Description:
Participants in this study will be patients diagnosed with or suspected to have a thyroid nodule or thyroid cancer. The main purpose of this study is to further understand the methods for the diagnosis and treatment of thyroid nodules and thyroid cancer. Many of the test performed are in the context of standard medical care that is offered to all patients with thyroid nodules or thyroid cancer. Other tests are performed for research purposes. In addition, blood and tissue samples will be taken for research and genetic studies.See this on ClinicalTrials.gov
1
General practitioner involvement in follow-up of childhood cancer survivors: A systematic review
Pediatric Blood & Cancer, July 8, 2013
Evidence Based Medicine
Review Article
2
Cancer incidence and survival among adolescents in Israel during the years 1998 to 2009
Pediatric Blood & Cancer, July 8, 2013
Clinical Article
3
PAX8 is expressed in Anaplastic Thyroid Carcinoma diagnosed by
fine needle aspiration. A study of three cases with histological
correlates
European Journal of Endocrinology, July 1, 2013
4
Targeting mTOR in RET mutant medullary and differentiated thyroid cancer cells
Endocrine-Related Cancer, July 8, 2013
Review Article
5
Thyroid carcinoma in children and adolescents: diagnostic implications of analysis of the tumor genome
Current Opinion in Pediatrics, July 19, 2013
Review Article
Sponsor
Just an annoucement from the "District"
"Evaluation
of the recent cases of perinatal HIV infection and/or exposure shows
that some of our HIV-infected District residents need more support,
ranging from medication adherence and medical appointment compliance to
more social issues such as inadequate housing and food insecurity. As
such, the HIV/AIDS, Hepatitis, STD and TB Administration has made
pregnancy in HIV-infected women a reportable condition. This change was
made so that we can ensure the health of pregnant women, prevent the
transmission of a communicable disease and offer medical and/or social
services they may require.
The report form is available at the DOH website (http://doh.dc.gov/page/doh-applications-and-forms).
It is also attached to this announcement. For additional details there
is an attached “Dear Colleague” letter that was agreed to by our local
American Academy of Pediatrics and local American College of
Obstetricians and Gynecologists chapters. There is also a Frequently
Asked Questions document.
New, expanded library hours start
Oct. 1. More hours for story time. More hours for
community meetings. More hours to use free computers. Check out the
library's new hours at dclibrary.org/newhours."
Be aware of PAX8
What is the normal function of the PAX8 gene?
The PAX8 gene belongs to a family of
genes that plays a critical role in the formation of tissues and organs
during embryonic development. The PAX gene family is also important for
maintaining the normal function of certain cells after birth. To carry
out these roles, the PAX genes provide instructions for making proteins
that attach to specific areas of DNA. By attaching to critical DNA
regions, these proteins help control the activity of particular genes
(gene expression). On the basis of this action, PAX proteins are called
transcription factors.
During embryonic development, the PAX8 protein is thought to activate genes involved in the formation of the kidney and the thyroid gland. The thyroid gland is a butterfly-shaped tissue in the lower neck. It releases hormones that play an important role in regulating growth, brain development, and the rate of chemical reactions in the body (metabolism). Following birth, the PAX8 protein regulates several genes involved in the production of thyroid hormones.(fromGenetics home reference)
=======================================
It is now used a biomarker:
"PAX8 is expressed in Anaplastic Thyroid Carcinoma diagnosed by
fine needle aspiration. A study of three cases with histological
correlates
"
===========================
"
During embryonic development, the PAX8 protein is thought to activate genes involved in the formation of the kidney and the thyroid gland. The thyroid gland is a butterfly-shaped tissue in the lower neck. It releases hormones that play an important role in regulating growth, brain development, and the rate of chemical reactions in the body (metabolism). Following birth, the PAX8 protein regulates several genes involved in the production of thyroid hormones.(fromGenetics home reference)
=======================================
It is now used a biomarker:
"PAX8 is expressed in Anaplastic Thyroid Carcinoma diagnosed by
fine needle aspiration. A study of three cases with histological
correlates
"
European Journal of Endocrinology, 07/01/2013
Bellevicine C et al. – The aim of this study was to evaluate
whether PAX8 could identify anaplastic thyroid carcinoma (ATC) also on
cytology. PAX8 immunocytochemistry can help the cytopathologist to
diagnose ATC.
"
Wednesday, September 25, 2013
just in now!
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Developed under the direction and sponsorship of Bristol-Myers Squibb. |
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Genetic going deeper in the Obesity research!
Going deep into Obesity issues and tumor induced cachexia, we stumble upon RIP 140, Sp1, and believe or not E2F1(a wild gene).
"RIP140 is part of the chain by which tumors can cause cachexia.[15][16]
Levels of RIP140 expression in various tissues varies during aging in mice, suggesting changes in metabolic function.[17] RIP140 is implicated in certain human disease processes. In morbid obesity, RIP140 levels are down-regulated in visceral adipose tissue.[18] In breast cancer, RIP140 is involved in regulation of E2F1, an oncogene which discriminates between luminal and basal types of tumours. RIP140 has an influence upon cancer phenotype and prognosis.[19] In addition, RIP140 has a role in inflammation, since it acts as a coactivator for NFkappaB/RelA-dependent cytokine gene expression. Lack of RIP140 leads to an inhibition of proinflammatory pathways in macrophages."
wikipedia
It seems that this is where Obesity becomes a disease by its state of high inflammatory state. The diease process in Obesity is defined or determined by a relatively high level of Growth factor and Cytokines inducing major deleterious consequences on the muscle skeletal system through the activated NF-KB. The RIP 140 (also known as NRIP1) is hard at work. Remember it interacts with DAX1 which involves the COPS2 (nothing to do with the police!),SREBF1 (the bone modulator) and SF1 ("feminization" of the obese individual).
It is clearly important that the understanding and measurement of the obese by clear new biomarkers allow us to establish new guidelines for monitoring. Following BMI, lipid profile and pushing diet is clearly insufficient. Blocking the central Nervous system to force mental rejection of food is not the only answer ...remember RIP-140 modulation is part of cachexia induced by Tumors.
(remember the rule, if it can induce a malformation, it is an important gene (check out DAX1 and SREBF1)
Othre gene in the link TRERF1, CREB-binding protein,EP 300.
Get to work! At CRBCM...the race is on!
"RIP140 is part of the chain by which tumors can cause cachexia.[15][16]
Levels of RIP140 expression in various tissues varies during aging in mice, suggesting changes in metabolic function.[17] RIP140 is implicated in certain human disease processes. In morbid obesity, RIP140 levels are down-regulated in visceral adipose tissue.[18] In breast cancer, RIP140 is involved in regulation of E2F1, an oncogene which discriminates between luminal and basal types of tumours. RIP140 has an influence upon cancer phenotype and prognosis.[19] In addition, RIP140 has a role in inflammation, since it acts as a coactivator for NFkappaB/RelA-dependent cytokine gene expression. Lack of RIP140 leads to an inhibition of proinflammatory pathways in macrophages."
wikipedia
It seems that this is where Obesity becomes a disease by its state of high inflammatory state. The diease process in Obesity is defined or determined by a relatively high level of Growth factor and Cytokines inducing major deleterious consequences on the muscle skeletal system through the activated NF-KB. The RIP 140 (also known as NRIP1) is hard at work. Remember it interacts with DAX1 which involves the COPS2 (nothing to do with the police!),SREBF1 (the bone modulator) and SF1 ("feminization" of the obese individual).
It is clearly important that the understanding and measurement of the obese by clear new biomarkers allow us to establish new guidelines for monitoring. Following BMI, lipid profile and pushing diet is clearly insufficient. Blocking the central Nervous system to force mental rejection of food is not the only answer ...remember RIP-140 modulation is part of cachexia induced by Tumors.
(remember the rule, if it can induce a malformation, it is an important gene (check out DAX1 and SREBF1)
Othre gene in the link TRERF1, CREB-binding protein,EP 300.
Get to work! At CRBCM...the race is on!
Tuesday, September 24, 2013
Breakthrough!
"The U.S. Food and Drug
Administration has granted breakthrough therapy designation to
volasertib for the treatment of patients with previously untreated acute
myeloid leukemia who are ineligible for intensive remission induction
therapy, and who are 65 or older. Volasertib is an investigational
inhibitor of polo-like kinase (Plk)." from Oncology time. go to full article
*Kathy Miller from Indiana University suggests that the best adjuvant chemotherapy in relevent Breast cancer patient is AC Q3weeks followed by weekly Paclitaxel as it has comparative efficacy and better tolerance of the weekly Taxol part!
*Kathy Miller from Indiana University suggests that the best adjuvant chemotherapy in relevent Breast cancer patient is AC Q3weeks followed by weekly Paclitaxel as it has comparative efficacy and better tolerance of the weekly Taxol part!
How long you can live: Determination through the genes! DO YOU KNOW YOUR FOXO3 VARIANT?
Many patients that I meet these days stress during my interview with them that their own parents died of "old age". Meaning that there seems to be a certain finality to life of humans. There will be a time when despite good care and prevention, human life will end. Patients deny their parents died of heart failure, stroke or any other cause but "old age" as if at some point we are doomed to a programmed death. Inquisition into people who live longer (more then a hundred years) point to the existence of a gene, a particular variant FOXO3 (see below). DO YOU KNOW YOUR FOXO3 VARIANT?
Evidence abounds now that how long we shall live is encrypted in our genes, but no one seems to rush to offer this option of an approach to care because it is not as simple as that! But I still believe that for proper "advance directives" preparation of this information should be included as we gauge our sens of survival! At the individual cellular level, basically this FOXO3,4,6 upregulates BIM and PUMA (wild animal in us keeping us alive!) and downregulates (FLIP) to slow programmed cellular death (Apoptosis). The interesting thing is this FOX ability to work is very tightly linked to energy! Yes, when you touch the FOXO, Galactose and Insulin metabolisms come right at you! As if telling you if you monitor me closely (as in Biomarkers) you may know what FOXY is doing. In other words, the GALT gene is a good Biomarker of FOXO3. And may tell you the status of cancer cells! (think carefully) during and after treatments!"
A variant of FOXO3 has been shown to be associated with longevity in humans. It is found in most centenarians across a variety of ethnic groups around the world.[7][8] The homologous genes daf-16 in the nematode C. elegans and dFOXO in the fruit fly are also associated with longevity in those organisms."
DAF-16 is the sole ortholog of the FOXO family of transcription factors in the nematode Caenorhabditis elegans.[1] DAF-16 is notable for being the primary transcription factor required for the profound lifespan extension observed upon mutation of the insulin-like receptor daf-2.[2] Moreover, the tractability of C. elegans as a model and interest in teasing out this conserved aging-associated genetic pathway allowed the intricacies of Insulin and Insulin-like growth factor (IGF) Signaling (IIS) to be thoroughly characterized primarily through studies using this model organism.[3]wikipedia
"The expression of GALT is controlled by the actions of the FOXO3 gene. The absence of this enzyme results in classic galactosemia in humans and can be fatal in the newborn period if lactose is not removed from the diet. The pathophysiology of galactosemia has not been clearly defined.[1]wikipedia"
Evidence abounds now that how long we shall live is encrypted in our genes, but no one seems to rush to offer this option of an approach to care because it is not as simple as that! But I still believe that for proper "advance directives" preparation of this information should be included as we gauge our sens of survival! At the individual cellular level, basically this FOXO3,4,6 upregulates BIM and PUMA (wild animal in us keeping us alive!) and downregulates (FLIP) to slow programmed cellular death (Apoptosis). The interesting thing is this FOX ability to work is very tightly linked to energy! Yes, when you touch the FOXO, Galactose and Insulin metabolisms come right at you! As if telling you if you monitor me closely (as in Biomarkers) you may know what FOXY is doing. In other words, the GALT gene is a good Biomarker of FOXO3. And may tell you the status of cancer cells! (think carefully) during and after treatments!"
A variant of FOXO3 has been shown to be associated with longevity in humans. It is found in most centenarians across a variety of ethnic groups around the world.[7][8] The homologous genes daf-16 in the nematode C. elegans and dFOXO in the fruit fly are also associated with longevity in those organisms."
DAF-16 is the sole ortholog of the FOXO family of transcription factors in the nematode Caenorhabditis elegans.[1] DAF-16 is notable for being the primary transcription factor required for the profound lifespan extension observed upon mutation of the insulin-like receptor daf-2.[2] Moreover, the tractability of C. elegans as a model and interest in teasing out this conserved aging-associated genetic pathway allowed the intricacies of Insulin and Insulin-like growth factor (IGF) Signaling (IIS) to be thoroughly characterized primarily through studies using this model organism.[3]wikipedia
"The expression of GALT is controlled by the actions of the FOXO3 gene. The absence of this enzyme results in classic galactosemia in humans and can be fatal in the newborn period if lactose is not removed from the diet. The pathophysiology of galactosemia has not been clearly defined.[1]wikipedia"
Monday, September 23, 2013
Major implication of the Gli-1
I. The Gli-1 gene
affects the following other genes
---PDGFR in mesenchymal tissue
---FOXM1
---Sufu
---SP1, USF1
---Twist1
---CyclinD2
---Plakoglobulin
---Shh
II. PTCH1: Act as a receptor to the Hedgehog ---the contact releases the SMO
Revant Info-Vismodegib
"The substance acts as a cyclopamine-competitive antagonist of the smoothened receptor (SMO) which is part of the hedgehog signaling pathway.[2] SMO inhibition causes the transcription factors GLI1 and GLI2 to remain inactive, which prevents the expression of tumor mediating genes within the hedgehog pathway.[4] This pathway is pathogenetically relevant in more than 90% of basal-cell carcinomas.[5]"wikipedia
link to chondrosarcoma is most puzzling
role in bladder cancer still to be explored, mostly I guess in the squamous type?
in Medulloblastoma?
affects the following other genes
---PDGFR in mesenchymal tissue
---FOXM1
---Sufu
---SP1, USF1
---Twist1
---CyclinD2
---Plakoglobulin
---Shh
II. PTCH1: Act as a receptor to the Hedgehog ---the contact releases the SMO
Revant Info-Vismodegib
"The substance acts as a cyclopamine-competitive antagonist of the smoothened receptor (SMO) which is part of the hedgehog signaling pathway.[2] SMO inhibition causes the transcription factors GLI1 and GLI2 to remain inactive, which prevents the expression of tumor mediating genes within the hedgehog pathway.[4] This pathway is pathogenetically relevant in more than 90% of basal-cell carcinomas.[5]"wikipedia
link to chondrosarcoma is most puzzling
role in bladder cancer still to be explored, mostly I guess in the squamous type?
in Medulloblastoma?
Focus on Peroxisome
Peroxisomes IPA: [pɛɜˈɹɒksɪˌsoʊmz][1] (also called microbodies) are organelles found in virtually all eukaryotic cells.[2] They are involved in the catabolism of very long chain fatty acids, branched chain fatty acids, D-amino acids, polyamines, and biosynthesis of plasmalogens, i.e. ether phospholipids critical for the normal function of mammalian brains and lungs.[3] They also contain approximately 10% of the total activity of two enzymes in the pentose phosphate pathway, which is important for energy metabolism.[3] It is vigorously debated if peroxisomes are involved in isoprenoid and cholesterol synthesis in animals.[3] Other known peroxisomal functions include the glyoxylate cycle in germinating seeds ("glyoxysomes"), photorespiration in leaves,[4] glycolysis in trypanosomes ("glycosomes"), and methanol and/or amine oxidation and assimilation in some yeasts.(Wikipedia)
============================================
with our discussion on the PEX26 and Sufu, we are working on opportunities of interventions through the peroxisome!
============================================
with our discussion on the PEX26 and Sufu, we are working on opportunities of interventions through the peroxisome!
Sunday, September 22, 2013
"Bigger is better"
New York
— Memorial Sloan-Kettering Cancer Center has launched a transformative
initiative to improve the quality of cancer care and the lives of cancer
patients. Hartford HealthCare, a multi-hospital health care system in
Connecticut, was selected as a pioneering member of the newly formed
Memorial Sloan-Kettering Cancer Alliance.
The MSK Cancer Alliance is designed to enable an ongoing, living, breathing dynamic partnership between the comprehensive cancer center and community oncology providers, in order to bring the newest knowledge into the community setting.
The critical need for such an Alliance can be found in a report recently issued by the Institute of Medicine (IOM) that described the challenge of delivering high-quality cancer care as a national “crisis” and noted advances in treatment may be unavailable to patients who lack access to sophisticated genetic tests or clinical trials.
The MSK Cancer Alliance is designed to enable an ongoing, living, breathing dynamic partnership between the comprehensive cancer center and community oncology providers, in order to bring the newest knowledge into the community setting.
The critical need for such an Alliance can be found in a report recently issued by the Institute of Medicine (IOM) that described the challenge of delivering high-quality cancer care as a national “crisis” and noted advances in treatment may be unavailable to patients who lack access to sophisticated genetic tests or clinical trials.
“Currently,
the vast majority of cancer care in the United States is delivered by
community oncologists, but cancer advances can take years to be adopted
in a community setting,” said José Baselga, MD, Physician-in-Chief of
Memorial Sloan-Kettering, who notes that ongoing, interactive real-time
relationships are needed to effectively close this gap. “We want to
rapidly accelerate the pace of integrating the latest advances of cancer
care into a community setting. This unprecedented approach will
demonstrate real value to both organizations and most importantly will
improve the lives of cancer patients,” he added.
=======================================================
BUT HERE AT THE CRBCM WE BELIEVE :
THE MORE VERSATILE, COST EFFICIENT SMALLER CLINIC IS THE ANSWER FOR BETTER STREAMLINING OF CANCER RESEARCH AND APPLICATION OF NEW KNOWLEDGE. THE PROBLEM IS NOT THE COMMUNITY ONCOLOGIST'S LACK OF WILLINGNESS TO LEARN, BUT INDEED THE MEANS OF COMMUNICATION WITH RESEARCHERS IN THE FIELD.
Researchers are taking over main Oncology publications by publishing non readily useable information while support for conferences is dwindling. It is amazing how many Oncologists do not read Blood or JCO because the immediate relevancy of information/articles are perceived as relevant to day to day practice. Among oncologists, FDA approval and whether a randomized phase III trial has demonstrated benefits, seems to be the overwhelming standard for adoption of new therapeutics. Of course the input from trusted authors and opinions from their local referral center also drives the practice.
Larger Institutions could serve a purpose of streamlining referrals if carefully orchestrated, however something may be lost in quality of care (may be because staff there lose a bit of compassion) and money and administrative weight increase dramatically to impair the quick delivery of care they mean to better!
The weight of overheads, the number of meetings, size of committees and political infighting, tends to slow the process by the nature of the beast! These larger institutions attract more research money for a relatively poor output. The CPRIT experience proves this case. Over half of the money given to date went to large institutions in Texas, we are still waiting for the return on investment, and communities overall have still to see lingering effects.
At the CRBCM we like the idea of smaller, more versatile organizations with more effect and efficiency. We believe that science does not belong to any particular institution, and that we can not lead from behind and that we absolutely need to create new paths. This is driving how we perceive new scientific progress results, and most of all how readers will note that our interpretation of facts may be at odds, but that is deliberate and ready to open new approaches! And at least open the debate! If we have not progressed as fast as wished, it is because of political elephants in the room!
Friday, September 20, 2013
The Crux of Tumorgenesis
The secret of cancer proliferation and persistence lays in phenomena at the membrane, where the NOTCH, Wnt and Hedgehog are located. These functions of the membrane start and drive the cancer with help from the ABCG2, MRp1, Pgp gene; it gives it resistance to powerful medications (Adriamycin, CPT11), with SuFu/PEX it reaches a gene capable of inducing malformation, with FOXM1, proliferation is guaranteed, through GLI1, Cyclin D2 is reached. Differentiation is reached though the MEK and failure of control is assured by dysregulation at the FAK. The Cancer's mind set is driven by the FOXM1 for sure. Other genes involve the NANOG, the PTCH1, The SOX and the OCT, CDH1, Shh,Twist, Plakoglobulin...
Profiling through at the CRBCM!
At the CRBCM something is coming through:
1. Deterioration at membrane receptor by lack of stimulation or "false or abnormal stimulation" could not only alter the nature of the "glycan" covering the protein portion of the receptor, but also induce stress like molecules.(HSP)
2. As a result of receptor failure new cytokines and TGFs are secreted which unfortunately fail at the initial receptor, but induce other receptors, amplifying standard pathways like RAS or PIK
3. Certains TGFs have an intrinsic power to maintain life of cells no matter what and induce metastasis.
4. Certain genes have an auto-phosphorylation or self-limiting mechanism that can easily go wrong (RAS, FAK) driving to neoplastic process
5. FAK plays a larger role in aggressive prostate cancer than it has been recognized!
6. FAK has a closer relation to Androgen than recognized
7. NOTCH has closer relation with MEK and "stem cell potential" than recognized.
8. FAK disturbance prominence in cancer explains its sensitivity to Taxanes! That is on top of Microtubule disturbances induced by the drug!
9. Metalloproteases are the ultimate Biomarkers of membrane events !
10. Epigenetic methylation and its patterns are one of the largest mystery still to be elucidated!
1. Deterioration at membrane receptor by lack of stimulation or "false or abnormal stimulation" could not only alter the nature of the "glycan" covering the protein portion of the receptor, but also induce stress like molecules.(HSP)
2. As a result of receptor failure new cytokines and TGFs are secreted which unfortunately fail at the initial receptor, but induce other receptors, amplifying standard pathways like RAS or PIK
3. Certains TGFs have an intrinsic power to maintain life of cells no matter what and induce metastasis.
4. Certain genes have an auto-phosphorylation or self-limiting mechanism that can easily go wrong (RAS, FAK) driving to neoplastic process
5. FAK plays a larger role in aggressive prostate cancer than it has been recognized!
6. FAK has a closer relation to Androgen than recognized
7. NOTCH has closer relation with MEK and "stem cell potential" than recognized.
8. FAK disturbance prominence in cancer explains its sensitivity to Taxanes! That is on top of Microtubule disturbances induced by the drug!
9. Metalloproteases are the ultimate Biomarkers of membrane events !
10. Epigenetic methylation and its patterns are one of the largest mystery still to be elucidated!
Thursday, September 19, 2013
QUESTIONS IN PROSTATE CANCER
1. INDOLENT Vs AGGRESSIVE CANCER
2. Belief that the older you get, the less important to detect the disease yet 2/3 of deaths is in patients older than 75 years of age.
3.Aggressiveness of this disease in the black race mimick exposure to different inducer (the dutasteride experience)
4.does sensitivity to androgen increase FAK, NOTCH, Wnt
2. Belief that the older you get, the less important to detect the disease yet 2/3 of deaths is in patients older than 75 years of age.
3.Aggressiveness of this disease in the black race mimick exposure to different inducer (the dutasteride experience)
4.does sensitivity to androgen increase FAK, NOTCH, Wnt
surprise, surprise! AND THE NOTCH DANCE CONTINUA!
Arsenic trioxide inhibits the proliferation of myeloma cell line through notch signaling pathway
wonders of the NOTCH
Aberrant Activation of Notch Signaling in Human Breast Cancer
"Notch signaling prevents induction of the p53 target genes Puma and Noxa following mitoxantrone treatment. Western blot analysis for JNK activation, Thr81 phosphorylation of p53, Puma, Noxa, and cleaved caspase-3 levels in parental (lane 1), vector control (lane 2), MCF 10A/RBP-Jκ (lane 3), and MCF 10A/NICD (lane 4) cells treated with mitoxantrone for 16 hours. Activation of JNK and Thr81 phosphorylation of p53, leading to the up-regulation of Puma and Noxa and cleavage of caspase-3, were observed in parental and vector control cells but not in cells stably expressing RBP-Jκ/VP16 or NICD. Puma, Noxa, and cleaved caspase-3 were undetectable in untreated cells.
=====================================================
THAT'S HOW THE NOTCH ENSURE CELLS DO NOT DIE!
====================================================
Crosstalk Between Vascular Endothelial Growth Factor, Notch, and Transforming Growth Factor-β in Vascular Morphogenesis
- Matthew T. Holderfield,
- Christopher C.W. Hughes
- "
The formation of a new capillary involves endothelial cell activation, migration, alignment, proliferation, tube formation, branching, anastomosis, and maturation of intercellular junctions and the surrounding basement membrane. Each of these stages is either known or suspected to fall under the influence of the vascular endothelial growth factor, notch, and transforming growth factor-β/bone morphogenetic protein signaling pathways. Vascular endothelial growth factor is essential for initiation of angiogenic sprouting, and also regulates migration of capillary tip cells, proliferation of trunk cells, and gene expression in both." - ===========================================
- NO NEW BLOOD VESSELS WITHOUT THE NOTCH!
- SEE IMPLICATIONS FOR STROKE AND TUMOR METASTASIS========
- ========================================
- " The Jagged/Notch signaling pathways control cell fate determination and differentiation, and their dysfunction is associated with human pathologies involving cardiovascular abnormalities."(LINDNER ET AL!)
- ===================================ARRHYTHMIA AND SUDDEN DEATH IS AN AREA WHERE THE NOTCH IS IMPORTANT (OF COURSE DON'T FORGET THE DYSTROPHIES, CHANNELOPATHIES AND VARIOUS MITOCHONDRIAL DISTURBANCES (MCARDLE DISEASES)
WHERE NOTCH PLAYS, THE Wnt /cADHERIN IS NOT VERY FAR
===================================================
FOR ANY ACTIVE MOLECULE, THERE IS ONE THAT TAMPERS IT, SLOW IT DOWN...FOR THE NOTCH IT IS THE "NUMB" MOLECULE THAT "COOLS" IT!
Wednesday, September 18, 2013
so you know!
 |
 |
SUBJECT: Risks associated with the use of XGEVA® (denosumab 120 mg)
August 27, 2013
Dear Health Care Professional,
This
letter is issued to notify healthcare providers about risks associated
with
Severe symptomatic hypocalcemia, including fatal casesthe use of Xgeva; severe symptomatic hypocalcemia, including fatal cases, and hypersensitivity, including anaphylactic reactions. Xgeva is indicated for the prevention of skeletal-related events in patients with bone metastases from solid tumors and for the treatment of adults and skeletally mature adolescents with giant cell tumor of bone that is unresectable or where surgical resection is likely to result in severe morbidity. Xgeva is not indicated for the prevention of skeletal-related events in patients with multiple myeloma.
In
the postmarketing setting, in patients with cancer receiving Xgeva for
prevention of skeletal-related events, severe symptomatic hypocalcemia, including fatal cases, has been reported. Signs and symptoms of these cases include altered mental status, tetany, seizures and QTc prolongation, which were temporally associated with Xgeva use and decreased serum calcium levels. The calculated reporting rate of severe symptomatic hypocalcemia suggests that the incidence in the postmarketing setting is similar to the rate observed in clinical trials. During clinical trials, severe hypocalcemia (corrected serum calcium < 7 mg/dL or < 1.75 mmol/L) occurred in 3.1% of patients receiving treatment with Xgeva and 1.4% of patients had hypocalcemia reported as a serious adverse event.
Action being taken by Amgen
To communicate this important safety information, changes have been madeto the US prescribing information (USPI) as described below:
The risk of severe symptomatic hypocalcemia among patients receiving Xgeva can be minimized by the following:
In the postmarketing setting, two spontaneously reported cases of anaphylactic reactions were identified and were considered causally related to Xgeva. The calculated reporting rate of anaphylactic reaction is 5.4 per 100,000 patient-years, which classifies anaphylactic reaction as a very rare event. Action being taken by Amgen To communicate this important safety information, changes have been made to the US prescribing information (USPI) as described below:
Patients with clinically significant hypersensitivity to Xgeva should not receive Xgeva. Further Information These are not the only risks associated with the use of this product. Please see the full prescribing information for more information about the risks associated with the use of this product. This information is also available at www.xgeva.com. Contact details for adverse event reporting or to request further information Any suspected adverse reactions should be reported to FDA’s MedWatch Adverse Event Reporting Program:
use of Xgeva, please contact Amgen’s Medical Information Department at 1-800-77-AMGEN. Sincerely,  Michael Severino, MD Senior Vice President, Global Development, and Chief Medical Officer Amgen
Amgen, Inc. | PO Box 681308 | Indianapolis, IN 46268
74864-R1-V1 |
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Multiple Sclerosis would fit
Multiple sclerosis would fit the model of pathology prompted by failure at the receptor of Interleukins
with resulting increase of Cytokines. In this model the initial insult will be destruction of Glycans at the IL-2,7 receptor resulting in the increase of these cytokines. Although they will fail at the receptors, they will still attract T cell and other relevant inflammatory cell. This is confirmed by the scenario of Traumatic brain injury in which lack of post-synaptic stimulation also result in post synaptic neuron destruction. Failure at the receptors stays the most dangerous cellular event. The triple negative Breast cancer is another example.
The effect of Interferon as a therapeutic intervention confirms that increase of Interleukins is the most significant driving event in the disease! It is driving even the coexisting gliosis found in the disease...
with resulting increase of Cytokines. In this model the initial insult will be destruction of Glycans at the IL-2,7 receptor resulting in the increase of these cytokines. Although they will fail at the receptors, they will still attract T cell and other relevant inflammatory cell. This is confirmed by the scenario of Traumatic brain injury in which lack of post-synaptic stimulation also result in post synaptic neuron destruction. Failure at the receptors stays the most dangerous cellular event. The triple negative Breast cancer is another example.
The effect of Interferon as a therapeutic intervention confirms that increase of Interleukins is the most significant driving event in the disease! It is driving even the coexisting gliosis found in the disease...
Tuesday, September 17, 2013
ANTI-EGFR, what is the inside story (full story)
Could anti-EGFR effect be simply an intra-tumoral Vasculitis blocking vascular Oxygenation? Can ANCA be a significant Biomarker particularly in those with Dermatitis? Is FAK and Metalloproteases be better biomarkers
text to follow!
"The fact is that anti-EGFR activity is associated with a significant dermatitis. And the dermatitis is associated or has been linked to drug activity. Indeed the more severe the rash, the more the activity of the drug. At skin level, we know as a result of the drug, toxic chemical are liberated to induce the reaction.
Myeloperoxidase (MPO) is a peroxidase enzyme that in humans is encoded by the MPO gene.[2] Myeloperoxidase is most abundantly expressed in neutrophil granulocytes (a subtype of white blood cells).[3] It is a lysosomal protein stored in azurophilic granules of the neutrophil. MPO has a heme pigment, which causes its green color in secretions rich in neutrophils, such as pus and some forms of mucus.
As part of the respiratory burst that neutrophils use to kill bacteria, myeloperoxidase converts hydrogen peroxide (H2O2) into hypochlorous acid (HOCl). HOCl is the most potent oxidant generated by neutrophils, and can cause significant tissue damage during inflammation. Dapsone arrests myeloperoxidase in an inactive intermediate form, reversibly inhibiting the enzyme. This prevents accumulation of hypochlorous acid, and reduces tissue damage during inflammation" wikipedia
Antibody " against MPO have been implicated in various types of vasculitis, most prominently crescentic glomerulonephritis and Churg-Strauss syndrome. They are detected as perinuclear ANCAs (p-ANCAs), as opposed to the cytoplasmic ANCAs (c-ANCAs) against proteinase-3 (PR3), which are strongly associated with Wegener's granulomatosis. Recent studies have reported an association between myeloperoxidase levels and the severity of coronary artery disease.[8] It has been suggested that myeloperoxidase plays a significant role in the development of the atherosclerotic lesion and rendering plaques unstable."wikipedia
The above discussion bring to mind that dermatitis seen with use of Drugs aiming at epithelial covering of blood vessel could indeed lead to secretion of molecules such as Cyclo-oxygenease (target of NSAID), MPO such as in this case Dapsone but Anti EGFR dose liberate from other affected cells cytokines of similar products that induced rash as a secondary effect. Should study confirms that MPO is our guy, then ANCA would be a legitimate candidate Bio-Marker.
Certainly during the activity of anti-EGFR, there is significant mambranes activity in terms of shedding proteins/Cytokines, FAK will be over express as a function of this activity and high FAK will be expected, liberations of Metalloproteases and the ADAMS such as 12 will follow the same logic and could join biomarkers of EGFR activity. Elevated stress at the membrane could be associated with HSP 90 amplification...let's go get them in a trial!
text to follow!
"The fact is that anti-EGFR activity is associated with a significant dermatitis. And the dermatitis is associated or has been linked to drug activity. Indeed the more severe the rash, the more the activity of the drug. At skin level, we know as a result of the drug, toxic chemical are liberated to induce the reaction.
Myeloperoxidase (MPO) is a peroxidase enzyme that in humans is encoded by the MPO gene.[2] Myeloperoxidase is most abundantly expressed in neutrophil granulocytes (a subtype of white blood cells).[3] It is a lysosomal protein stored in azurophilic granules of the neutrophil. MPO has a heme pigment, which causes its green color in secretions rich in neutrophils, such as pus and some forms of mucus.
As part of the respiratory burst that neutrophils use to kill bacteria, myeloperoxidase converts hydrogen peroxide (H2O2) into hypochlorous acid (HOCl). HOCl is the most potent oxidant generated by neutrophils, and can cause significant tissue damage during inflammation. Dapsone arrests myeloperoxidase in an inactive intermediate form, reversibly inhibiting the enzyme. This prevents accumulation of hypochlorous acid, and reduces tissue damage during inflammation" wikipedia
Antibody " against MPO have been implicated in various types of vasculitis, most prominently crescentic glomerulonephritis and Churg-Strauss syndrome. They are detected as perinuclear ANCAs (p-ANCAs), as opposed to the cytoplasmic ANCAs (c-ANCAs) against proteinase-3 (PR3), which are strongly associated with Wegener's granulomatosis. Recent studies have reported an association between myeloperoxidase levels and the severity of coronary artery disease.[8] It has been suggested that myeloperoxidase plays a significant role in the development of the atherosclerotic lesion and rendering plaques unstable."wikipedia
The above discussion bring to mind that dermatitis seen with use of Drugs aiming at epithelial covering of blood vessel could indeed lead to secretion of molecules such as Cyclo-oxygenease (target of NSAID), MPO such as in this case Dapsone but Anti EGFR dose liberate from other affected cells cytokines of similar products that induced rash as a secondary effect. Should study confirms that MPO is our guy, then ANCA would be a legitimate candidate Bio-Marker.
Certainly during the activity of anti-EGFR, there is significant mambranes activity in terms of shedding proteins/Cytokines, FAK will be over express as a function of this activity and high FAK will be expected, liberations of Metalloproteases and the ADAMS such as 12 will follow the same logic and could join biomarkers of EGFR activity. Elevated stress at the membrane could be associated with HSP 90 amplification...let's go get them in a trial!
SRC-3Delta4 mediates the interaction of EGFR with FAK to promote cell migration.
Source
Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030 USA.Abstract
EGF induces signal transduction between EGFR and FAK, and FAK is required for EGF-induced cell migration. It is unknown, however, what factor mediates the interaction between EGFR and FAK and leads to EGF-induced FAK phosphorylation. Here, we identify SRC-3Delta4, a splicing isoform of the SRC-3 oncogene, as a signaling adaptor that links EGFR and FAK and promotes EGF-induced phosphorylations of FAK and c-Src.
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