*Since HAART, there has been a decrease of Lymphoma and CNS Lymphoma but not that much for Burkitt Lymphoma suggesting different pathology pathways in these various lymphoproliferative disorder in AIDS!
*3 factors impact Lymphoma occurrence inAIDS pt :
lack of HAART, age and low level of CD4
*The protective effect of HAART comes from the immune restoration following HAART.
*Incidence of CNS lymphoma, 5.6 /1000
*patient with HIV who developed Lymphoma had higher IL6, IL10, and expression of CD30. High serum free light chains was also observed!
*c-MYC is related to Plamablastic Lymphoma
whereas CCR5 has low risk for lymphoma
and stromal cell derived factor-1 Mutation has a higher risk of Lymphoma.
*Lymphoma can happen at any CD4 count and T cell count whereas Burkitt tend to occur at relatively high CD4 count where as Immunoblastic lymphoma and CNS lumphoma seem to prefer lower CD4 (around 50 or less).
*Plasmablastic Lymphoma involving mostly the Oral cavity is EBV related and characterized by CD138 and VS38s.
and Keratinization differ it from Oral Carcinoma!
*Hodgkin disease alone does not make it AIDS per CDC!
Wednesday, July 3, 2013
Tuesday, July 2, 2013
THE CRBCM
THE CRBCM
There are increasing signs the CRBCM will make it, and everyday that passes reaffirm this.
We are working on several projects, our Medicare payments are coming through finally and more and more contacts are generated. We have submitted more grant applications and we are feverishly looking for collaboration with good intention institutions, we know where we are headed and our consultation work in Indiana is still ongoing as we advance into the future.
Of course as we advance, some have elected to ignore us, some even have their knifes pulled waiting for an occasion to stab...but remember for those who are ready, no fears will stop us. We know where we are heading!
Our cause is just, come into our wagon or get out of the way, we will not back down because we feel we are righteous!
We come from Zero, so anything to us is a plus and everyday that passes is the sign of greatness awaiting. We keep advancing!
THE CRBCM our strength is build from a life full of fights, strong 16 years of Oncology practice full of memories and recognitions. It is not your isolate opinion that will shake us because we realize it is tainted with politics and no reality! We respond to higher good spirits!
The CRBCM, an original Coalition for the reversal of Mortality for all Cancers!
There are increasing signs the CRBCM will make it, and everyday that passes reaffirm this.
We are working on several projects, our Medicare payments are coming through finally and more and more contacts are generated. We have submitted more grant applications and we are feverishly looking for collaboration with good intention institutions, we know where we are headed and our consultation work in Indiana is still ongoing as we advance into the future.
Of course as we advance, some have elected to ignore us, some even have their knifes pulled waiting for an occasion to stab...but remember for those who are ready, no fears will stop us. We know where we are heading!
Our cause is just, come into our wagon or get out of the way, we will not back down because we feel we are righteous!
We come from Zero, so anything to us is a plus and everyday that passes is the sign of greatness awaiting. We keep advancing!
THE CRBCM our strength is build from a life full of fights, strong 16 years of Oncology practice full of memories and recognitions. It is not your isolate opinion that will shake us because we realize it is tainted with politics and no reality! We respond to higher good spirits!
The CRBCM, an original Coalition for the reversal of Mortality for all Cancers!
COLLABORATION, THE SAME SONG EVERYWHERE!
Every time I turn around, people are championing Collaboration in research, people embrace it as the way to go! People see it as a broader way to reach new opportunities and prove to the world. My experience in El Paso has been rather humbling and sad...People here find an invitation to collaborate as a shrewd way to get them, they see competition and threats!
The CRBCM has approached local universities with funded project, so far no result. I am told it is this kind of communities of researchers. Every one fight for survival ! We are now talking with University in Arizona. This is just pitiful!
===================================closes mind leads to a narrow world=========
07/02/2013.
"Team,
The CRBCM has approached local universities with funded project, so far no result. I am told it is this kind of communities of researchers. Every one fight for survival ! We are now talking with University in Arizona. This is just pitiful!
===================================closes mind leads to a narrow world=========
07/02/2013.
"Team,
As
we have discussed the new normal facing healthcare, we’ve talked about
the value of creating strategic partnerships not only to provide highly
coordinated care, but also as a way to meet the changing healthcare
needs in our community.
Today,
I want to tell you about a strategic partnership Inova has entered into
with Valley Health System. Our partnership provides for future
collaboration in the areas of clinical research, information technology,
population health, and clinical service delivery.
The
immediate impact of this partnership is Valley Health’s ability to
expand its IT capabilities through Inova’s EpicCare platform.
For more information about this partnership, please read the press release that is posted on Inova’s News page.
Thanks,
Mark"
-----------------------------THIS IS WHAT IS HAPPENING IN THE REAL WORLD------------PEOPLE EMBRACE COLLABORATION, AS IN UNITED WE STAND! ----------------------------------------------------------
CANCER RISK IN COMPLEX RENAL CYSTS
KIDNEY CYST
THE COMPLEX ONE ARE JUST A HEADACHE BUT BEAR A CANCER RISK
MELISSA HEUER ET AL HELPS!
THE COMPLEX ONE ARE JUST A HEADACHE BUT BEAR A CANCER RISK
MELISSA HEUER ET AL HELPS!
The risk that a complex kidney cyst is, or may become, a
kidney cancer depends on its appearance on radiographic imaging (CT
scan or MRI). A system to grade kidney cysts by their appearance on CAT
scan has been developed, which help doctors to predict which complex
kidney cysts are more likely to have kidney cancer inside. This system
is known as the Bosniak classification. The Bosniak classification
provides specific definitions to classify cysts by the risk of kidney
cancer.
Bosniak Categories of
Complex Kidney Cysts
| Category | Description | Risk of Kidney Cancer |
| Category I | A simple benign cyst with a hairline thin wall that does not contain septa, calcifications, or solid components. It measures as water density and does not enhance with contrast material. | 0% to < 2% |
| Category II | A cyst that might contain a few hairline thin septa. Fine calcifications might be present in the wall or septa. Uniformly high-attenuation (hyperdense) lesions of <3 cm that are well marginated and do not enhance. | 13.7% |
| Category IIF | These cysts might contain more hairline thin septa. No measurable enhancement of a hairline thin septum or wall can be seen. There can be minimal thickening of the septa or wall. The cyst might contain calcifications that are nodular and thick but there is no contrast enhancement. No enhancing soft tissue elements are seen. Totally intrarenal non-enhancing high-attenuation renal lesions equal to or greater than 3 cm are also included in this category. These lesions are generally well marginated. | 14.3% to 24% |
| Category III | These lesions are indeterminate cystic masses that have thickened irregular walls or septa in which enhancement can be measured. | 50.8% |
| Category IV | All of the criteria of category III along with enhancing soft-tissue components adjacent to, but independent of the wall or septum. These cysts are usually malignant cystic masses. | 90.1% |
The Bosniak
classification above, is designed to help your doctor predict the
chances that your complex renal cyst is associated with a kidney
cancer. This predictive ability is very important in helping you work
with your urologist to determine the best treatment strategy for you.
The risk that your kidney cyst harbors a kidney cancer must be balanced
with your overall health to so that a proper treatment strategy can be
created.
Bosniak category I complex
kidney cysts have a less than 2% chance of being associated with a
kidney cancer. Bosniak category II complex kidney cysts have an
approximately 14% chance of being associated with kidney cancer.
Bosniak category IIF lesions are complex kidney cysts that have more
irregularities and are typically larger than category II cysts. Also,
category IIF cysts do not have measurable enhancement on imaging and
therefore do not qualify as category III complex kidney cysts. The
“F” in the IIF designation is meant to suggest “Follow” or observe this
cyst rather than perform a procedure such as partial nephrectomy or
kidney cryoablation to treat the cyst. However, the category IIF
cysts have a higher rate of malignancy which is up to 24%, and
therefore it is important to discuss the merits of treatment versus
observation with your urologist. Bosniak catagory III and category IV
complex kidney cysts have a 50% and 90.1% chance respectively of being
kidney cancer and are often recommended for surgical removal or
treatment with cyst ablation."
FOR FULL INFO GO TO THE ARTICLE!
I have not finished speaking about osteonecrosis of the jaw, Medscape comes to the rescue!
Osteonecrosis of the Jaw Linked to Adjuvant Zoledronic Acid
Topic Alert
Receive an email from Medscape whenever new articles on this topic are available.
Drug & Reference Information
Adjuvant zoledronic acid (Zometa,
Novartis) used for bone strengthening in women with breast cancer was
associated with a 2.1% rate of osteonecrosis of the jaw (ONJ), in a
randomized controlled trial published online June 24 in the Journal of Clinical Oncology.
The study authors consider this rate of ONJ to be "encouragingly low," but an expert writing in an accompanying editorial say this rate is "not acceptable," because zoledronate did not improve disease-free survival or overall survival in the study population as a whole.
These latest findings on ONJ come from an analysis of the Adjuvant Zoledronic Acid to Reduce Recurrence (AZURE) trial, which was negative overall in that zoledronic acid (also known as zoledronate) did not reduce breast-cancer recurrence in the total study population, although a significant reduction was seen in a subset of postmenopausal women.
The AZURE trial involved 3360 women with stage II or III breast cancer randomized to receive standard adjuvant systemic therapy alone or with intensive zoledronate therapy (4 mg for 19 doses over 5 years). The investigators reported all potential cases of ONJ as serious adverse events (AEs), and these were reviewed centrally.
The current study focused on reports of osteonecrosis of the jaw and also on oral health, explain the authors, headed by Emma Rathbone, MD, from Weston Park Hospital, Sheffield, United Kingdom.
After completion of 5 years of study treatment, 486 participants were asked to complete the Oral Health Impact Profile-14 (OHIP-14) as a measure of oral quality of life (QOL). The investigators used multivariable linear regression to calculate mean scores and to identify independent prognostic factors.
Osteonecrosis and Oral-Health Findings
Median follow-up was 73.9 months (interquartile range, 60.7 – 84.2 months). Of 33 reports of possible ONJ during follow-up, all in patients treated with zoledronate, 26 were confirmed to be consistent with the diagnosis of ONJ. In the zoledronate group, cumulative incidence of ONJ was 2.1% (95% CI, 0.9% – 3.3%).
Among the 26 women with ONJ, 35% were said to be "completely recovered," 19% "improving," 12% "recovered with sequela," and in 31% ONJ was "present and unchanged" after treatment.
Based on 362 completed OHIP-14 questionnaires (74% response rate), participants given or not given zoledronate did not differ significantly in prevalence or severity of effects on oral QOL. Among 45 patients who reported 55 dental AEs, 84% were in the zoledronate group. Only 2 of these events were grade 3 (1 episode of jaw pain and 1 of loose teeth), and no grade 4 events were reported.
"Although the cumulative incidence of confirmed ONJ is encouragingly low at 2.1% after a median follow-up of 73.9 months and less than that associated with zoledronic-acid use in the setting of metastatic bone disease, it is higher than that observed in other trials of adjuvant zoledronate that have used a less intense schedule and fewer infusions (6 to 10 infusions) over 3 to 5 years," the study authors write. "There was also an apparent additional increase in reported dental-specific AEs, including jaw pain and dental infections, in the zoledronate arm."
Study Limitations and Clinical Implications
Limitations of this study include open-label design, which could have affected AE reporting; evaluation of oral QOL at a single time point at completion of 5 years of study; and reliance on retrospective patient evaluation of QOL at only 2 time points.
"Our data provide reassurance to clinicians and patients that zoledronate does not seem to significantly affect oral QOL," note the study authors. "The relationship between reporting of a dental AE during the study and worse oral QOL scores strongly suggests that the OHIP-14 is sensitive to oral-health events in patients with early breast cancer. The knowledge that there seems to be no demonstrable adverse impact on quality of life is encouraging, given the widespread use of zoledronate and the recent results in the adjuvant setting indicating that bisphosphonates may improve both disease-free survival (DFS) and overall survival (OS) in certain disease settings."
The problem of ONJ is not unique to zoledronate, as it has been reported with variable frequency in patients receiving intravenous or oral bisphosphonates, and it has also been reported with denosumab (Xgeva, Amgen), which is a RANK-ligand inhibitor.
The cumulative incidence of ONJ in patients receiving intravenous bisphosphonate as adjuvant cancer treatment ranges from 0.8% to 12%, according to an updated position paper from the American Association of Oral and Maxillofacial Surgeons. Significant potential risk factors include treatment potency and duration as well as dentoalveolar surgery.
In February 2004, on the basis of an awareness of these risk factors, the AZURE study protocol was amended to exclude patients with significant active dental problems or recent jaw surgery. All patients received dental-hygiene advice, and investigators received guidance on ONJ diagnosis, prevention, and treatment of ONJ based on emerging clinical guidelines. Exclusion of patients with risk factors for ONJ might have resulted in underestimation of ONJ prevalence, whereas increased vigilance by clinicians might have increased reports of possible ONJ, the authors comment.
"It seems unlikely that a bone-targeted agent will become available in the foreseeable future that is not associated with the development of ONJ," the study authors write. "We need to understand the potential genetic, oral-health, and treatment risk factors; incidence; and resolution of this uncommon problem somewhat better than we do at the present time."
In an accompanying editorial, Charles L. Shapiro, MD, from Wexner Medical Center and Comprehensive Cancer Center, Ohio State University, in Columbus, elaborates on unanswered questions regarding bisphosphonate-related ONJ (BONJ). These include specific underlying mechanism(s), why it is confined to the jaw, predisposing risk factors other than dental extractions, optimal treatments, outcomes, and health-related QOL.
The 2% total cumulative incidence of ONJ, although low, is clearly not acceptable.
Dr. Shapiro describes the AZURE findings as "an important
contribution" but points out an additional study limitation — namely,
the lack of clarity regarding whether a standard approach to case
ascertainment of ONJ was performed at every clinic visit. If not, there
could be potential bias of under- or overreporting suspected cases
of ONJ, he points out.
Furthermore, he notes that precise definitions were not given for
descriptors regarding ONJ outcomes, nor were the details of specific
treatments for ONJ.
"Overall, the AZURE trial results showed that IV zoledronic acid on an intensive schedule did not improve disease-free survival or overall survival, and therefore the 2% total cumulative incidence of ONJ, although low, is clearly not acceptable," Dr. Shapiro writes. "Whether there is a subpopulation of women with early-stage breast cancer as has been proposed — premenopausal receiving ovarian suppression or postmenopausal women — in which the therapeutic ratio favors using adjuvant zoledronic acid or clodronate vis-à-vis ONJ and other adverse effects remains to be verified in subsequent trials."
Novartis supported the study. Dr. Rathbone has reported no relevant financial relationships. Disclosures for the coauthors are listed in the article. Dr. Shapiro has reported no relevant financial relationships.
J Clin Oncol . Published online June 24, 2013. Abstract Editorial
The study authors consider this rate of ONJ to be "encouragingly low," but an expert writing in an accompanying editorial say this rate is "not acceptable," because zoledronate did not improve disease-free survival or overall survival in the study population as a whole.
These latest findings on ONJ come from an analysis of the Adjuvant Zoledronic Acid to Reduce Recurrence (AZURE) trial, which was negative overall in that zoledronic acid (also known as zoledronate) did not reduce breast-cancer recurrence in the total study population, although a significant reduction was seen in a subset of postmenopausal women.
The AZURE trial involved 3360 women with stage II or III breast cancer randomized to receive standard adjuvant systemic therapy alone or with intensive zoledronate therapy (4 mg for 19 doses over 5 years). The investigators reported all potential cases of ONJ as serious adverse events (AEs), and these were reviewed centrally.
The current study focused on reports of osteonecrosis of the jaw and also on oral health, explain the authors, headed by Emma Rathbone, MD, from Weston Park Hospital, Sheffield, United Kingdom.
After completion of 5 years of study treatment, 486 participants were asked to complete the Oral Health Impact Profile-14 (OHIP-14) as a measure of oral quality of life (QOL). The investigators used multivariable linear regression to calculate mean scores and to identify independent prognostic factors.
Osteonecrosis and Oral-Health Findings
Median follow-up was 73.9 months (interquartile range, 60.7 – 84.2 months). Of 33 reports of possible ONJ during follow-up, all in patients treated with zoledronate, 26 were confirmed to be consistent with the diagnosis of ONJ. In the zoledronate group, cumulative incidence of ONJ was 2.1% (95% CI, 0.9% – 3.3%).
Among the 26 women with ONJ, 35% were said to be "completely recovered," 19% "improving," 12% "recovered with sequela," and in 31% ONJ was "present and unchanged" after treatment.
Based on 362 completed OHIP-14 questionnaires (74% response rate), participants given or not given zoledronate did not differ significantly in prevalence or severity of effects on oral QOL. Among 45 patients who reported 55 dental AEs, 84% were in the zoledronate group. Only 2 of these events were grade 3 (1 episode of jaw pain and 1 of loose teeth), and no grade 4 events were reported.
"Although the cumulative incidence of confirmed ONJ is encouragingly low at 2.1% after a median follow-up of 73.9 months and less than that associated with zoledronic-acid use in the setting of metastatic bone disease, it is higher than that observed in other trials of adjuvant zoledronate that have used a less intense schedule and fewer infusions (6 to 10 infusions) over 3 to 5 years," the study authors write. "There was also an apparent additional increase in reported dental-specific AEs, including jaw pain and dental infections, in the zoledronate arm."
Study Limitations and Clinical Implications
Limitations of this study include open-label design, which could have affected AE reporting; evaluation of oral QOL at a single time point at completion of 5 years of study; and reliance on retrospective patient evaluation of QOL at only 2 time points.
"Our data provide reassurance to clinicians and patients that zoledronate does not seem to significantly affect oral QOL," note the study authors. "The relationship between reporting of a dental AE during the study and worse oral QOL scores strongly suggests that the OHIP-14 is sensitive to oral-health events in patients with early breast cancer. The knowledge that there seems to be no demonstrable adverse impact on quality of life is encouraging, given the widespread use of zoledronate and the recent results in the adjuvant setting indicating that bisphosphonates may improve both disease-free survival (DFS) and overall survival (OS) in certain disease settings."
The problem of ONJ is not unique to zoledronate, as it has been reported with variable frequency in patients receiving intravenous or oral bisphosphonates, and it has also been reported with denosumab (Xgeva, Amgen), which is a RANK-ligand inhibitor.
The cumulative incidence of ONJ in patients receiving intravenous bisphosphonate as adjuvant cancer treatment ranges from 0.8% to 12%, according to an updated position paper from the American Association of Oral and Maxillofacial Surgeons. Significant potential risk factors include treatment potency and duration as well as dentoalveolar surgery.
In February 2004, on the basis of an awareness of these risk factors, the AZURE study protocol was amended to exclude patients with significant active dental problems or recent jaw surgery. All patients received dental-hygiene advice, and investigators received guidance on ONJ diagnosis, prevention, and treatment of ONJ based on emerging clinical guidelines. Exclusion of patients with risk factors for ONJ might have resulted in underestimation of ONJ prevalence, whereas increased vigilance by clinicians might have increased reports of possible ONJ, the authors comment.
"It seems unlikely that a bone-targeted agent will become available in the foreseeable future that is not associated with the development of ONJ," the study authors write. "We need to understand the potential genetic, oral-health, and treatment risk factors; incidence; and resolution of this uncommon problem somewhat better than we do at the present time."
In an accompanying editorial, Charles L. Shapiro, MD, from Wexner Medical Center and Comprehensive Cancer Center, Ohio State University, in Columbus, elaborates on unanswered questions regarding bisphosphonate-related ONJ (BONJ). These include specific underlying mechanism(s), why it is confined to the jaw, predisposing risk factors other than dental extractions, optimal treatments, outcomes, and health-related QOL.
Paroxysmal nocturnal hemoglobinuria (PNH) can have severe health consequences for your patients
Patients with PNH are at increased risk for chronic kidney disease, thrombotic events, hypertension, and other serious health issues.
Patients with PNH are at increased risk for chronic kidney disease, thrombotic events, hypertension, and other serious health issues.
SOL-1572
Information from Industry
Information from Industry
"Overall, the AZURE trial results showed that IV zoledronic acid on an intensive schedule did not improve disease-free survival or overall survival, and therefore the 2% total cumulative incidence of ONJ, although low, is clearly not acceptable," Dr. Shapiro writes. "Whether there is a subpopulation of women with early-stage breast cancer as has been proposed — premenopausal receiving ovarian suppression or postmenopausal women — in which the therapeutic ratio favors using adjuvant zoledronic acid or clodronate vis-à-vis ONJ and other adverse effects remains to be verified in subsequent trials."
Novartis supported the study. Dr. Rathbone has reported no relevant financial relationships. Disclosures for the coauthors are listed in the article. Dr. Shapiro has reported no relevant financial relationships.
J Clin Oncol . Published online June 24, 2013. Abstract Editorial
ABNORMAL HOMEOSTASIS, STOP LOOKING AT IT! THAT IS IF YOU WANT A DIFFERENT OUTCOME.
HAVE HAPPEN TO WONDER WHY SOUTHERN CHINA HAS A FORM OF NASOPHARYNGEAL CANCER, IS IT LINKED TO A PARTICULAR CLASS II MAJOR HISTOCOMPATIBILITY ANTIGENS, OR A PARTICULAR VIRUS RESERVOIR LOCAL TO THE AREA,OR IS THIS LINKED TO LOCAL FOOD ?
Have you wonder why some people will develop Osteonecrosis of the jaw while on biphosphonate, and why the jaw in particular, and why sometime after traumatic intervention, is the shear stress necessary to the pathophysiology of the events, is TNF and the NF-kB involved?
have you wonder why some patient on Phenytoin will develop gum hyperplasia ?
Events at the gene level is your answer, and don't sit there on research fund, we boast that we know the genes but yet we don't don't know events of these very days! 50 years from now, medicine of today will be completely obsolete. We keep looking at a comprehensive chemical panel as our ways of monitoring, looking at potassium level in the blood without knowing the status of related genes ! You and I know that for a normal K (potassium) level hormonal events are in play, kidney function, oral intake and other many components are also in play to maintain Homeostasis!
But do remember there is a right homeostasis where all components leading to it are functioning normally, there is also bad, unstable homeostasis, the abnormal Homeostasis that requires certain component to overwork to achieve such an homeostasis! ie Hyperparathyroidism secondary to renal failure but with normal calcium level...there are consequences to the high hormone maintaining a normal level reuired by homeostasis. Why? because you realize that hormone is generated by a gene expression. that is the increased for hormone to be amplified, and gene is amplified. A gene to be amplified some genes are repressed some where, and gene repression can start start something Neoplastic some where! ie PTEN repression! Also Hormone are not fully specific to one receptor all the time, so there some unwarranted stimulation of some other pathways, and prolieration, evasion, and differentiation are triggered!
The point is we have 20% of people on dialysis dying every year for over a decade, and we are there sleeping at wheels! our current monitoring is clearly inadequate. We have no clue as to the status of the Notch and the Wnt in each individual, are we allowed to be surprise to observe a steady rate of sudden death in this population. And with their deaths, stops our observation...wake up people! fund research without politics!! put money where a difference will be made before other takes my message ! fund CRBCM! call 915-307-3354 and organizations such as us! Small but to the point! Remember when you fund a University, only 20% percent of your funding goes to the true research, the rest is waste and overhead! Check the budget of the MD Anderson, I am not kidding! fund CRBCM to get your money worth!
Have you wonder why some people will develop Osteonecrosis of the jaw while on biphosphonate, and why the jaw in particular, and why sometime after traumatic intervention, is the shear stress necessary to the pathophysiology of the events, is TNF and the NF-kB involved?
have you wonder why some patient on Phenytoin will develop gum hyperplasia ?
Events at the gene level is your answer, and don't sit there on research fund, we boast that we know the genes but yet we don't don't know events of these very days! 50 years from now, medicine of today will be completely obsolete. We keep looking at a comprehensive chemical panel as our ways of monitoring, looking at potassium level in the blood without knowing the status of related genes ! You and I know that for a normal K (potassium) level hormonal events are in play, kidney function, oral intake and other many components are also in play to maintain Homeostasis!
But do remember there is a right homeostasis where all components leading to it are functioning normally, there is also bad, unstable homeostasis, the abnormal Homeostasis that requires certain component to overwork to achieve such an homeostasis! ie Hyperparathyroidism secondary to renal failure but with normal calcium level...there are consequences to the high hormone maintaining a normal level reuired by homeostasis. Why? because you realize that hormone is generated by a gene expression. that is the increased for hormone to be amplified, and gene is amplified. A gene to be amplified some genes are repressed some where, and gene repression can start start something Neoplastic some where! ie PTEN repression! Also Hormone are not fully specific to one receptor all the time, so there some unwarranted stimulation of some other pathways, and prolieration, evasion, and differentiation are triggered!
The point is we have 20% of people on dialysis dying every year for over a decade, and we are there sleeping at wheels! our current monitoring is clearly inadequate. We have no clue as to the status of the Notch and the Wnt in each individual, are we allowed to be surprise to observe a steady rate of sudden death in this population. And with their deaths, stops our observation...wake up people! fund research without politics!! put money where a difference will be made before other takes my message ! fund CRBCM! call 915-307-3354 and organizations such as us! Small but to the point! Remember when you fund a University, only 20% percent of your funding goes to the true research, the rest is waste and overhead! Check the budget of the MD Anderson, I am not kidding! fund CRBCM to get your money worth!
FROM FDA BY MEDSCAPE
FDA Refuses Rivaroxaban Stent-Thrombosis Indication for Now
Topic Alert
Receive an email from Medscape whenever new articles on this topic are available.
RARITAN, New Jersey — The FDA has given a complete response letter (CRL) to one of the companies behind rivaroxaban
(Xarelto, Bayer Pharma/Janssen Pharmaceuticals) indicating that it
won't, for now, approve the oral factor Xa inhibitor for prevention of
stent thrombosis in patients with acute coronary syndromes [1].
As noted in a statement today from Janssen, approval for that
indication had been sought in a supplemental new drug application (sNDA)
based largely on the ATLAS ACS 2 TIMI 51
trial. The CRL, which signals that the FDA wants to see additional data
before it will further consider the sNDA, follows others that it sent
the companies regarding approval of rivaroxaban for patients with ACS, as reported by heartwire
. The drug is already approved for ACS secondary prevention in Europe.
"We remain confident in the results of the ATLAS ACS 2 TIMI 51 trial and are in ongoing discussions with the FDA regarding this sNDA," said a Janssen official in the company's press release on the stent-thrombosis CRL.
The agency has already approved rivaroxaban, an oral factor Xa inhibitor, for the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) and for preventing recurrences, for reducing the risk of DVT and PE after knee- or hip-replacement surgery, and for cutting the risk of stroke in nonvalvular atrial fibrillation.
This therapy has also been shown to improve bone mineral density after 24 months of treatment.
Information from Industry
"We remain confident in the results of the ATLAS ACS 2 TIMI 51 trial and are in ongoing discussions with the FDA regarding this sNDA," said a Janssen official in the company's press release on the stent-thrombosis CRL.
The agency has already approved rivaroxaban, an oral factor Xa inhibitor, for the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) and for preventing recurrences, for reducing the risk of DVT and PE after knee- or hip-replacement surgery, and for cutting the risk of stroke in nonvalvular atrial fibrillation.
Monday, July 1, 2013
METFORMIN SHOULD BE GIVEN WHENEVER ERLOTINIB IS GIVEN, TO SILENCE EGFR AND IGF CROSS-TALK
METFORMIN SHOULD BE GIVEN WHENEVER ERLOTINIB IS GIVEN, TO SILENCE EGFR AND IGF CROSS-TALK
==========================================================
WIKIPEDIA
Increased levels of the IGF-IR are expressed in the majority of primary and metastatic prostate cancer patient tumors.[6] Evidence suggests that IGF-IR signaling is required for survival and growth when prostate cancer cells progress to androgen independence.[7] In addition, when immortalized prostate cancer cells mimicking advanced disease are treated with the IGF-1R ligand, IGF-1, the cells become more motile.[8] Members of the IGF receptor family and their ligands also seem to be involved in the carcinogenesis of mammary tumors of dogs.[9][10]"
==============================================================
MOST OF OUR PATIENTS ARE OBESE, WE CAN EITHER MEASURE THE IGF OR ASSUME THAT OBESE PATIENT HAVE SOME INSULIN RECEPTOR RESISTANCE, AND THEREFORE MUST HAVE A RELATIVELY HIGH INSULIN, AND THEREFORE SOME METFORMIN WILL BE SAFE TO ADMINISTER.
WITH THE BROAD USE OF INSULIN, THE PERCEPTION IS THAT THIS WILL BE SAFE TO ADMINISTER. TOLERANCE OF ERLOTINIB AND SIDE EFFECT PROFILE MAY ALSO SUGGEST, THE COMBINATION MAY BE EASILY TOLERATED!
PROOF OF CONCEPT WILL BE HOWEVER ESTABLISH THAT REDUCING CROSS TALK MAY MAXIMIZE ERLOTINIB EFFECTIVENESS! REMEMBER METFORMIN HAS ITS OWN ANTIPROLIFERATIVE EFFECT! A WIN-WIN SITUATION THAT WILL PROVE SYNERGY!
CAUTION: SIDE EFFECTS ARE UNKNOWN UNTIL A FORMAL TRIAL-DON'T DO THIS ON YOUR OWN!
==================================================================
A GOOD TRIAL THOUGH SHOULD REPORT OR TRACK THE STATUS OF CAVEOLIN-1 THOUGH
==========================================================
WIKIPEDIA
"Role in cancer
The IGF-1R is implicated in several cancers,[4][5] including breast, prostate, and lung cancers. In some instances its anti-apoptotic properties allow cancerous cells to resist the cytotoxic properties of chemotherapeutic drugs or radiotherapy. In breast cancer, where EGFR inhibitors such as erlotinib are being used to inhibit the EGFR signaling pathway, IGF-1R confers resistance by forming one half of a heterodimer (see the description of EGFR signal transduction in the erlotinib page), allowing EGFR signaling to resume in the presence of a suitable inhibitor. This process is referred to as crosstalk between EGFR and IGF-1R. It is further implicated in breast cancer by increasing the metastatic potential of the original tumour by inferring the ability to promote vascularisation.Increased levels of the IGF-IR are expressed in the majority of primary and metastatic prostate cancer patient tumors.[6] Evidence suggests that IGF-IR signaling is required for survival and growth when prostate cancer cells progress to androgen independence.[7] In addition, when immortalized prostate cancer cells mimicking advanced disease are treated with the IGF-1R ligand, IGF-1, the cells become more motile.[8] Members of the IGF receptor family and their ligands also seem to be involved in the carcinogenesis of mammary tumors of dogs.[9][10]"
==============================================================
MOST OF OUR PATIENTS ARE OBESE, WE CAN EITHER MEASURE THE IGF OR ASSUME THAT OBESE PATIENT HAVE SOME INSULIN RECEPTOR RESISTANCE, AND THEREFORE MUST HAVE A RELATIVELY HIGH INSULIN, AND THEREFORE SOME METFORMIN WILL BE SAFE TO ADMINISTER.
WITH THE BROAD USE OF INSULIN, THE PERCEPTION IS THAT THIS WILL BE SAFE TO ADMINISTER. TOLERANCE OF ERLOTINIB AND SIDE EFFECT PROFILE MAY ALSO SUGGEST, THE COMBINATION MAY BE EASILY TOLERATED!
PROOF OF CONCEPT WILL BE HOWEVER ESTABLISH THAT REDUCING CROSS TALK MAY MAXIMIZE ERLOTINIB EFFECTIVENESS! REMEMBER METFORMIN HAS ITS OWN ANTIPROLIFERATIVE EFFECT! A WIN-WIN SITUATION THAT WILL PROVE SYNERGY!
CAUTION: SIDE EFFECTS ARE UNKNOWN UNTIL A FORMAL TRIAL-DON'T DO THIS ON YOUR OWN!
==================================================================
A GOOD TRIAL THOUGH SHOULD REPORT OR TRACK THE STATUS OF CAVEOLIN-1 THOUGH
Caveolin-1 is essential for metformin inhibitory effect on IGF1 action in non-small-cell lung cancer cells.
Salani B, Maffioli S, Hamoudane M, Parodi A, Ravera S, Passalacqua M, Alama A, Nhiri M, Cordera R, Maggi D.
Source
Department of Endocrinology and Medicine, University of Genoa, Genoa, Italy.Abstract
Metformin
causes an AMP/ATP ratio increase and AMP-activated protein kinase
(AMPK) activation. Since caveolin-1 (Cav-1) plays a role in AMPK
activation and energy balance, we investigated whether Cav-1 could
participate in metformin's inhibitory effect on IGF1 signaling. The
effect of metformin was studied in two non-small-cell lung cancer
(NSCLC) cell lines, Calu-1 and Calu-6, expressing higher and lower
amounts of Cav-1, respectively. In Calu-1, but not in Calu-6 cells,
metformin reduced phosphorylation of type 1 insulin-like growth factor
receptor (IGF-IR) substrates Akt and Forkhead transcription factor 3a
(FOXO3a), inhibited IGF1-dependent FOXO3a nuclear exit, and decreased
IGF1-dependent cell proliferation. Here, we show that sensitivity of
NSCLC cells to metformin was dependent on Cav-1 expression and that
metformin required Cav-1 to induce AMPK phosphorylation and AMP/ATP
ratio increase. Cav-1 silencing in Calu-1 and overexpression in Calu-6
reduced and improved, respectively, the inhibitory effect of metformin
on IGF1-dependent Akt phosphorylation. Prolonged metformin treatment in
Calu-6 cells induced a dose-dependent expression increase of Cav-1 and
OCT1, a metformin transporter. Cav-1 and OCT1 expression was associated
with the antiproliferative effect of metformin in Calu-6 cells
(IC(50)=18 mM). In summary, these data suggest that Cav-1 is required
for metformin action in NSCLC cells.
- PMID:
- 22038047
- [PubMed
Communications of Public Heath Importance
The
Indiana State Department of Health (ISDH), Indiana Board of Animal
Health (BOAH) and the Grant County Health Department are continuing the
investigation of cases of variant influenza A (H3N2v) associated with
the Grant County Fair.
ISDH has also been conducting statewide surveillance since other county
fairs are ongoing and others about to begin. ISDH has received samples
from another county within the state with reports of influenza-like
illness (ILI) among swine exhibitors. Laboratory
results are pending and are expected on Monday July 1st.
According
to BOAH, thirteen pigs at the Grant County fair tested positive for
H3N2. It is not uncommon for infected pigs to be asymptomatic. Pigs
that are ill with influenza typically recover within several days.
Symptoms of H3N2v in humans
include: fever, cough, sore throat, chills, headache, and muscle
aches. Diarrhea and nausea may occur in children. Symptoms usually
start about 1 to 4 days after being exposed and last 2 to 7 days.
Many
county fairs will open in the next few weeks, and the ISDH is
increasing surveillance for ILI. During the week of June 23-29, fairs
are scheduled in the following nine counties: Daviess, Hancock, Marion,
Miami, Rush, Spencer,
Vermillion, Washington, and Wayne. A list of dates and fairs is
available on the ISDH website at
http://bit.ly/1axgXqE.
The
ISDH strongly encourages influenza testing on patients presenting with
ILI, defined as a fever of 100 degrees F or greater and either cough or
sore throat. Nasopharyngeal swab specimens from symptomatic persons who
have attended
a fair or had contact with swine should be sent to the ISDH Laboratory
for polymerase chain reaction (PCR) testing. A negative rapid test does
not rule out H3N2v. For questions regarding specimen collection and
shipment, please contact Katie Masterson, ISDH
Virology/Preparedness Supervisor at 317-921-5843.
To
collect the specimen, insert swab into the nasopharynx until resistance
is felt, and place swab in the tube of viral transport medium. Break
the swab shaft at the scored mark before closing the screw cap tightly.
Label each tube
with the patient's name and the collection date. Transport the
specimen on cold packs for overnight delivery to ISDH Virology Lab. The
following video, available on the New England Journal of Medicine’s
website, is an excellent guide for collecting NP swabs:
http://content.nejm.org/cgi/content/full/NEJMe0903992/DC1
Health
care providers should contact Shawn Richards at 317-233-7740 for
specimen approval prior to submitting specimens to the ISDH Labs. Only
specimens with prior approval will be tested. Submit specimens via
LIMSnet, the ISDH lab's
electronic submission system, if possible. If you do not have an
account, please contact the LIMS Help Desk at 317-921-5506 or
888-535-0011, or e-mail at
LimsAppSupport@isdh.in.gov.
Before specimens are sent, please make sure that all sample tubes are
labeled with the patient's name and ship the specimens to:
Indiana State Department of Health Laboratories
Attn: Virology Lab
550 W. 16th St. Suite B
Indianapolis, IN 46202
When seeing patients with ILI,
please document exposure history for the four days prior to onset of
illness, including contact with animals, and information about friends
or family members with similar illness, including onset time and
dates. Contact your local health department about any patients
presenting with ILI.
Current recommendations from the Centers for Disease Control and Prevention (CDC) on antiviral treatment are located at
http://www.cdc.gov/flu/swineflu/h3n2v-clinician.htm and include:
- Antiviral treatment with oral
oseltamivir or inhaled zanamivir is recommended as soon as possible for
any hospitalized patient and those with evidence of severe complications
or progressive illness suspected to have influenza, including
H3N2v virus infection, without waiting for the results of laboratory
testing.
- Antiviral treatment with oral
oseltamivir or inhaled zanamivir is recommended as soon as possible for
outpatients suspected with influenza, including H3N2v virus infection,
if they are in a group considered to be at high risk for complications
from influenza, without waiting for the results of laboratory testing.
-
Antiviral treatment with oral oseltamivir or inhaled zanamivir is
encouraged as soon as possible for non high-risk outpatients without
underlying medical conditions and suspected to have H3N2v virus
infection, without waiting for the
results of laboratory testing. These persons may benefit from antiviral
treatment, if it can be started within 48 hours of illness onset.
For additional questions, please contact Shawn Richards, ISDH Respiratory Epidemiologist, at 317-233-7740 or
srichard@isdh.in.gov. For after-hours calls, please contact the ISDH Duty Officer at 317-233-1325.
_______________________________________________
Physicians mailing list
Physicians@lists.in.gov
http://lists.in.gov/mailman/listinfo/physicians
Sunday, June 30, 2013
GENETIC MELI-MELO IN BREAST CANCER MEDICINE
There are now no questions that autoimmune syndromes are closely linked to cancer development
Inflammatory breast cancer-IBC is really linked to Inflammatory processes as 80 percent of IBC have under-expression (or repression) of genes under significant interferon gamma and TNF influence. INTERFERON ALPHA which is amplified in autoimmune diseases. Indeed abnormality at WISP3 id found in 60-80% of IBC!
Interferon negative effect on CTGF depent on an intact expression of JAK-2.
chemotactic activity of WISP3 but not CYR61 was mediated through integrin ανß5.(schuze et al)
(recombinant angiopoeitin2 could boost Avastin role in diabetic retinopathy)
There are now no questions that autoimmune syndromes are closely linked to cancer development
Inflammatory breast cancer-IBC is really linked to Inflammatory processes as 80 percent of IBC have under-expression (or repression) of genes under significant interferon gamma and TNF influence. INTERFERON ALPHA which is amplified in autoimmune diseases. Indeed abnormality at WISP3 id found in 60-80% of IBC!
Interferon negative effect on CTGF depent on an intact expression of JAK-2.
chemotactic activity of WISP3 but not CYR61 was mediated through integrin ανß5.(schuze et al)
(recombinant angiopoeitin2 could boost Avastin role in diabetic retinopathy)
Saturday, June 29, 2013
Genes in breast cancer from wikipedia!
CDH1 gene
It is CD324 (cluster of differentiation 324). It is a tumor suppressor gene
The encoded protein is a calcium-dependent cell-cell adhesion glycoprotein composed of five extracellular cadherin repeats, a transmembrane region, and a highly conserved cytoplasmic tail. Mutations in this gene are correlated with gastric, breast, colorectal, thyroid, and ovarian cancers. Loss of function is thought to contribute to progression in cancer by increasing proliferation, invasion, and/or metastasis.
Through
Proto-oncogene tyrosine-protein kinase Fyn is an enzyme that in humans is encoded by the FYN gene.[1]
This gene is a member of the protein-tyrosine kinase oncogene family. It encodes a membrane-associated tyrosine kinase that has been implicated in the control of cell growth. The protein associates with the p85 subunit of phosphatidylinositol 3-kinase and interacts with the fyn-binding protein. Alternatively spliced transcript variants encoding distinct isoforms exist.[2]
Through
Ras GTPase-activating-like protein IQGAP1 (IQGAP1) also known as p195 is a ubiquitously expressed protein that in humans is encoded by the IQGAP1 gene.[1][2][3] IQGAP1 is a scaffold protein involved in regulating various cellular processes ranging from organization of the actin cytoskeleton, transcription, and cellular adhesion to regulating the cell cycle.
through
Histone deacetylase 1 is an enzyme that in humans is encoded by the HDAC1 gene.[1]
Histone acetylation and deacetylation, catalyzed by multisubunit complexes, play a key role in the regulation of eukaryotic gene expression. The protein encoded by this gene belongs to the histone deacetylase/acuc/apha family and is a component of the histone deacetylase complex. It also interacts with retinoblastoma tumor-suppressor protein and this complex is a key element in the control of cell proliferation and differentiation. Together with metastasis-associated protein-2 MTA2, it deacetylates p53 and modulates its effect on cell growth and apoptosis.[2]
The protein encoded by this gene is a member of the protein tyrosine phosphatase (PTP) family. PTPs are known to be signaling molecules that regulate a variety of cellular processes including cell growth, differentiation, mitotic cycle, and oncogenic transformation. PTPrho has been proposed to function during development of the nervous system and as a tumor suppressor in cancer.
c-Met (MET or MNNG HOS Transforming gene) is a proto-oncogene that encodes a protein known as hepatocyte growth factor receptor (HGFR).[1][2] The hepatocyte growth factor receptor protein possesses tyrosine-kinase activity.[3] The primary single chain precursor protein is post-translationally cleaved to produce the alpha and beta subunits, which are disulfide linked to form the mature receptor.
MET is a membrane receptor that is essential for embryonic development and wound healing. Hepatocyte growth factor (HGF) is the only known ligand of the MET receptor. MET is normally expressed by cells of epithelial origin, while expression of HGF is restricted to cells of mesenchymal origin. Upon HGF stimulation, MET induces several biological responses that collectively give rise to a program known as invasive growth.
Abnormal MET activation in cancer correlates with poor prognosis, where aberrantly active MET triggers tumor growth, formation of new blood vessels (angiogenesis) that supply the tumor with nutrients, and cancer spread to other organs (metastasis). MET is deregulated in many types of human malignancies, including cancers of kidney, liver, stomach, breast, and brain. Normally, only stem cells and progenitor cells express MET, which allows these cells to grow invasively in order to generate new tissues in an embryo or regenerate damaged tissues in an adult. However, cancer stem cells are thought to hijack the ability of normal stem cells to express MET, and thus become the cause of cancer persistence and spread to other sites in the body.
thrpogh HDAC1
Sp1 has been used as a control protein to compare with when studying the increase or decrease of the aryl hydrocarbon receptor and/or the estrogen receptor, since it binds to both and generally remains at a relatively constant level.[2] Withaferin A, a sterodial lactone from Withania Somnifera plant is known to inhibit Sp1 Transcription factor[33]. etoposide resistance
========================================================
Rhoc gene
RhoC can activate formins such as mDia1 and FMNL2 to remodel the cytoskelton.[3]
It is prenylated at its C-terminus, and localizes to the cytoplasm and plasma membrane. It is thought to be important in cell locomotion. Overexpression of this gene is associated with tumor cell invasion and metastasis. RhoC-deficient mice can still develop tumors but these fail to metastasize, arguing that RhoC is essential for metastasis.[4]
WNT1-inducible-signaling pathway protein 3[1][2] (WISP3, also named CCN6) is a matricellular protein that in humans is encoded by the WISP3 gene.
Loss of WISP3 expression is associated with aggressive inflammatory breast cancer and breast cancer with axillary lymph node metastasis, suggesting that WISP3/CCN6 may function as a suppressor of breast cancer growth and metastasis.[2]
=================
palb2 gene
This gene encodes a protein that functions in genome maintenance (double strand break repair). This protein binds to and colocalizes with the breast cancer 2 early onset protein (BRCA2) in nuclear foci and likely permits the stable intranuclear localization and accumulation of BRCA2.[1] PALB2 binds the single strand DNA and directly interacts with the recombinase RAD51 to stimulates strand invasion a vital step of homologous recombination.[4] PALB2 can function synergistically with a BRCA2 chimera (termed piccolo, or piBRCA2) to further promote strand invasion.[4]
CDH1 gene
It is CD324 (cluster of differentiation 324). It is a tumor suppressor gene
The encoded protein is a calcium-dependent cell-cell adhesion glycoprotein composed of five extracellular cadherin repeats, a transmembrane region, and a highly conserved cytoplasmic tail. Mutations in this gene are correlated with gastric, breast, colorectal, thyroid, and ovarian cancers. Loss of function is thought to contribute to progression in cancer by increasing proliferation, invasion, and/or metastasis.
Through
Proto-oncogene tyrosine-protein kinase Fyn is an enzyme that in humans is encoded by the FYN gene.[1]
This gene is a member of the protein-tyrosine kinase oncogene family. It encodes a membrane-associated tyrosine kinase that has been implicated in the control of cell growth. The protein associates with the p85 subunit of phosphatidylinositol 3-kinase and interacts with the fyn-binding protein. Alternatively spliced transcript variants encoding distinct isoforms exist.[2]
Through
Ras GTPase-activating-like protein IQGAP1 (IQGAP1) also known as p195 is a ubiquitously expressed protein that in humans is encoded by the IQGAP1 gene.[1][2][3] IQGAP1 is a scaffold protein involved in regulating various cellular processes ranging from organization of the actin cytoskeleton, transcription, and cellular adhesion to regulating the cell cycle.
through
Histone deacetylase 1 is an enzyme that in humans is encoded by the HDAC1 gene.[1]
Histone acetylation and deacetylation, catalyzed by multisubunit complexes, play a key role in the regulation of eukaryotic gene expression. The protein encoded by this gene belongs to the histone deacetylase/acuc/apha family and is a component of the histone deacetylase complex. It also interacts with retinoblastoma tumor-suppressor protein and this complex is a key element in the control of cell proliferation and differentiation. Together with metastasis-associated protein-2 MTA2, it deacetylates p53 and modulates its effect on cell growth and apoptosis.[2]
The protein encoded by this gene is a member of the protein tyrosine phosphatase (PTP) family. PTPs are known to be signaling molecules that regulate a variety of cellular processes including cell growth, differentiation, mitotic cycle, and oncogenic transformation. PTPrho has been proposed to function during development of the nervous system and as a tumor suppressor in cancer.
c-Met (MET or MNNG HOS Transforming gene) is a proto-oncogene that encodes a protein known as hepatocyte growth factor receptor (HGFR).[1][2] The hepatocyte growth factor receptor protein possesses tyrosine-kinase activity.[3] The primary single chain precursor protein is post-translationally cleaved to produce the alpha and beta subunits, which are disulfide linked to form the mature receptor.
MET is a membrane receptor that is essential for embryonic development and wound healing. Hepatocyte growth factor (HGF) is the only known ligand of the MET receptor. MET is normally expressed by cells of epithelial origin, while expression of HGF is restricted to cells of mesenchymal origin. Upon HGF stimulation, MET induces several biological responses that collectively give rise to a program known as invasive growth.
Abnormal MET activation in cancer correlates with poor prognosis, where aberrantly active MET triggers tumor growth, formation of new blood vessels (angiogenesis) that supply the tumor with nutrients, and cancer spread to other organs (metastasis). MET is deregulated in many types of human malignancies, including cancers of kidney, liver, stomach, breast, and brain. Normally, only stem cells and progenitor cells express MET, which allows these cells to grow invasively in order to generate new tissues in an embryo or regenerate damaged tissues in an adult. However, cancer stem cells are thought to hijack the ability of normal stem cells to express MET, and thus become the cause of cancer persistence and spread to other sites in the body.
thrpogh HDAC1
Sp1 has been used as a control protein to compare with when studying the increase or decrease of the aryl hydrocarbon receptor and/or the estrogen receptor, since it binds to both and generally remains at a relatively constant level.[2] Withaferin A, a sterodial lactone from Withania Somnifera plant is known to inhibit Sp1 Transcription factor[33]. etoposide resistance
========================================================
Rhoc gene
RhoC can activate formins such as mDia1 and FMNL2 to remodel the cytoskelton.[3]
It is prenylated at its C-terminus, and localizes to the cytoplasm and plasma membrane. It is thought to be important in cell locomotion. Overexpression of this gene is associated with tumor cell invasion and metastasis. RhoC-deficient mice can still develop tumors but these fail to metastasize, arguing that RhoC is essential for metastasis.[4]
WNT1-inducible-signaling pathway protein 3
From Wikipedia, the free encyclopedia
| WNT1 inducible signaling pathway protein 3 | |||||
|---|---|---|---|---|---|
| Identifiers | |||||
| Symbols | WISP3; CCN6; LIBC; PPAC; PPD | ||||
| External IDs | OMIM: 603400 HomoloGene: 77038 GeneCards: WISP3 Gene | ||||
|
|||||
| RNA expression pattern | |||||
 |
|||||
| More reference expression data | |||||
| Orthologs | |||||
| Species | Human | Mouse | |||
| Entrez | 8838 | 327743 | |||
| Ensembl | ENSG00000112761 | ENSMUSG00000062074 | |||
| UniProt | O95389 | D3Z5L9 | |||
| RefSeq (mRNA) | NM_003880 | NM_001127376 | |||
| RefSeq (protein) | NP_003871 | NP_001120848 | |||
| Location (UCSC) | Chr 6: 112.38 – 112.39 Mb |
Chr 10: 39.15 – 39.16 Mb |
|||
| PubMed search | [1] | [2] | |||
Contents |
Structure
It is a member of the CCN family (CCN intercellular signaling protein) of secreted, extracellular matrix (ECM)-associated signaling matricellular proteins. The CCN acronym is derived from the first three members of the family identified, namely CYR61 (CCN1), CTGF (connective tissue growth factor, or CCN2), and NOV. These proteins, together with WISP1 (CCN4), and WISP2 (CCN5) comprise the six-member CCN family in vertebrates. CCN proteins characteristically contain an N-terminal secretory signal peptide followed by four structurally distinct domains with homologies to insulin-like growth factor binding protein (IGFBP), von Willebrand type C repeats (vWC), thrombospondin type 1 repeat (TSR), and a cysteine knot motif within the C-terminal (CT) domain.Loss of WISP3 expression is associated with aggressive inflammatory breast cancer and breast cancer with axillary lymph node metastasis, suggesting that WISP3/CCN6 may function as a suppressor of breast cancer growth and metastasis.[2]
=================
palb2 gene
This gene encodes a protein that functions in genome maintenance (double strand break repair). This protein binds to and colocalizes with the breast cancer 2 early onset protein (BRCA2) in nuclear foci and likely permits the stable intranuclear localization and accumulation of BRCA2.[1] PALB2 binds the single strand DNA and directly interacts with the recombinase RAD51 to stimulates strand invasion a vital step of homologous recombination.[4] PALB2 can function synergistically with a BRCA2 chimera (termed piccolo, or piBRCA2) to further promote strand invasion.[4]
Clinical significance
Variants in the PALB2 gene are associated with an increased risk of developing breast cancer [5] and PALB2-deficient cells are sensitive to PARP inhibitors. [4]
ISSUES IN BREAST CANCER
FOR MEN
There is an increased risk
-with BRAC2 Mutation
-Klinefelter syndrome
-Obesity and Cirrhosis (E/T ratio)
-undescended testicles or testicular trauma.
*When testing in a family, the youngest woman with the disease should be the one to undergo testing!
*In Male, the risk of developing breast cancer by age 80 with BRCA2 is 7%.
*Invasive Lobular carcinoma associated with family hx of diffuse gastric cancer occur with Mutation of E-Cadherin-CDH-1 gene.
*Hormone replacement therapy has not been associated with DCIS.
*If oral contraceptive use increased your risk of Breast Cancer, you have the BRCA Mutation!
*Involution of terminal duct lobule is linked to a lower incidence of Breast cancer.
*larger waist circumfernce is linked to ER Negative breast cancer risk.
FOR MEN
There is an increased risk
-with BRAC2 Mutation
-Klinefelter syndrome
-Obesity and Cirrhosis (E/T ratio)
-undescended testicles or testicular trauma.
*When testing in a family, the youngest woman with the disease should be the one to undergo testing!
*In Male, the risk of developing breast cancer by age 80 with BRCA2 is 7%.
*Invasive Lobular carcinoma associated with family hx of diffuse gastric cancer occur with Mutation of E-Cadherin-CDH-1 gene.
*Hormone replacement therapy has not been associated with DCIS.
*If oral contraceptive use increased your risk of Breast Cancer, you have the BRCA Mutation!
*Involution of terminal duct lobule is linked to a lower incidence of Breast cancer.
*larger waist circumfernce is linked to ER Negative breast cancer risk.
Friday, June 28, 2013
DISCUSSION OF NEW ANTI-HYPERTENSIVE APPROACHES TARGETING GENES
*Pseudo-Bartter’s syndrome has been seen in cystic fibrosis,[12] as well as in excessive use of laxatives.[13] WIKIPEDIA
*IN CYSTIC FIBROSIS IT IS THE :
"(MSD1 and MSD2) that form the chloride ion channel"WHICH PART OF THE CFTR MOLECULE,
iN CYSTIC FIBROSIS (CFM1), a modifier gene located on chromosome 19, may determine MI susceptibility.
( U.S. Department of Energy (DOE) Human Genome Project Information Web site.)
*Pseudo-Bartter’s syndrome has been seen in cystic fibrosis,[12] as well as in excessive use of laxatives.[13] WIKIPEDIA
*IN CYSTIC FIBROSIS IT IS THE :
"(MSD1 and MSD2) that form the chloride ion channel"WHICH PART OF THE CFTR MOLECULE,
iN CYSTIC FIBROSIS (CFM1), a modifier gene located on chromosome 19, may determine MI susceptibility.
( U.S. Department of Energy (DOE) Human Genome Project Information Web site.)
NEW STRATEGIES TO FIGHT HYPERTENSION AT GENETIC LEVEL
WATCH BARTER'S AND GITELMAN'S SYNDROMES! (SEE WIKIPEDIA)
IN THIS DISEASE, HYPERTENSION DOES NOT OCCUR! THE ONLY DANGER IS OF COURSE DEAFNESS SO KEEP AWAY FROM CLCNK A and B (CIC-kB), ALL OTHER ARE TARGETABLE, OF COURSE DO NOT REPRODUCE THE FULL DISEASE, CHALLENGES AHEAD BUT DON'T RULE IT OUT JUST YET!
Bartter and Gitelman syndromes can be divided into different subtypes based on the genes involved:[5]
WATCH BARTER'S AND GITELMAN'S SYNDROMES! (SEE WIKIPEDIA)
IN THIS DISEASE, HYPERTENSION DOES NOT OCCUR! THE ONLY DANGER IS OF COURSE DEAFNESS SO KEEP AWAY FROM CLCNK A and B (CIC-kB), ALL OTHER ARE TARGETABLE, OF COURSE DO NOT REPRODUCE THE FULL DISEASE, CHALLENGES AHEAD BUT DON'T RULE IT OUT JUST YET!
Bartter and Gitelman syndromes can be divided into different subtypes based on the genes involved:[5]
| Name | Bartter type | Associated gene mutations | Defect | ||||
| neonatal Bartter's syndrome | type 1 | SLC12A2 (NKCC2) | Na-K-2Cl symporter | ||||
| neonatal Bartter's syndrome | type 2 | ROMK/KCNJ1 | thick ascending limb K+ channel | ||||
| classic Bartter's syndrome | type 3 | CLCNKB | Cl- channel | ||||
| Bartter's syndrome with sensorineural deafness | type 4 | BSND[6] | Cl- channel accessory subunit | ||||
| Bartter's syndrome associated with autosomal dominant hypocalcemia | type 5 | CASR[7] | activating mutation of the calcium-sensing receptor | ||||
| Gitelman's syndrome | - | SLC12A3 (NCCT) | Sodium-chloride symporter |
WILL JOIN THIS ACTIVITY WHILE IN DC!
INOVA FAIRFAX HOSPITAL DEPARTMENT OF MEDICINE
MEDICAL GRAND ROUNDS
"Anal Cancer and AIN: Is It Inevitable?”
Lynn Dougherty, MD, FACS, FASCRS
Fairfax Colon and Rectal Surgery, PC
Medical Director, Division of Colon and Rectal Surgery,
Inova Fairfax Hospital
Staff Surgeon, Inova Fairfax, Fair Oaks, and Alexandria Hospitals
Part-time Assistant Professor, VCU School of Medicine
Caroline Sanchez, MD
Fairfax Colon and Rectal Surgery, PC
Staff Surgeon, Inova Fairfax, Fair Oaks, and Alexandria Hospitals
July 2, 2013
12:30PM
Cyrus Vesuna Auditorium
(Lunch will be served at 12:00PM outside the auditorium)
MEDICAL GRAND ROUNDS
"Anal Cancer and AIN: Is It Inevitable?”
Lynn Dougherty, MD, FACS, FASCRS
Fairfax Colon and Rectal Surgery, PC
Medical Director, Division of Colon and Rectal Surgery,
Inova Fairfax Hospital
Staff Surgeon, Inova Fairfax, Fair Oaks, and Alexandria Hospitals
Part-time Assistant Professor, VCU School of Medicine
Caroline Sanchez, MD
Fairfax Colon and Rectal Surgery, PC
Staff Surgeon, Inova Fairfax, Fair Oaks, and Alexandria Hospitals
July 2, 2013
12:30PM
Cyrus Vesuna Auditorium
(Lunch will be served at 12:00PM outside the auditorium)
GENOME AND THE FUTURE IN CANCER MEDICINE.
SOME OF THE BARRIERS TO GENOME INTEGRATION INTO PATIENT CHARTS!
(Excerpt of our preliminary work)
As we advance in Medicine, and particularly in cancer Medicine, it is increasingly recognized that Medical patho-physiology find its source and implications tightly linked to sets of genes. There are genes that initiate the pathophysiology, but also pathway genes that once activated by the initiating gene(s), squarely drive the subsequent events, or amplify them as if it release the breaks with devastating consequences.
Genes can be in all kind of states. They can be amplified or repressed, or the can be full blown expressed and participating, or they can be silenced! Their expression can be forced or deliberate. They are forced when in a linkage situation or in an abnormal fusion, or deliberately expressing themselves when they have something to say or do due to their intrinsic nature! Of significant interest is the aspect that gene expression can be dependent on our age, gender, race and place !
AGE:
Although we inherit the same from birth, if you believe that at any given point, the genes expressed in you as an embryo, and subsequent ages, are the same, think again. Life is in a constant flux, nothing is still in a living being! And life is purposeful. AND SURVIVAL IS THE OBJECTIVE! Everything our cells do is to keep surviving. and so does cancer cells to our own surprise and demise! The first years are destined to growth and we gobble up things (unfortunately we don't know when to stop, realize you just have reached the lifetime external Carbohydrates needed!), by age 3, we stop having ability to have a fever induced seizure! in our twenties, we stop growing in height! well age has something to say through our GENES!
GENDER:
We know that one of the X Chromosome and its genes may be silenced!
But the strongest evidence of gender influence on gene expression is on Major Histocompatibility antigens (class I antigen). Women during their reproductive years get ready to carry a foreign body (baby)inside them without fighting it! They have got to dampen their Class I (UNO or ONE) Antigens ability. It is this very reason that Inflammatory bowel disease and autoimmune diseases are most fulminant (or simply more active, but I love the fulminant word) during these reproductive years. (Lupus 15 to 45 years of age range!). It is hypothesized that pattern of gene Methylation leads to silencing of some of the HLA-A, and B mostly!
Race
Disparity in incidence, frequency and mortality among races are the strongest evidence of this relationship between Gene expression and the races! class II MHC Antigen are linked to various Autoimmune and Metabolic diseases (DM). Even high blood pressure pathophysioplogy varies among the races.
For CRBCM, it is that flagrant case of Triple Negative Breast cancer that we are struggling with (struggling to link to the races, the class II Antigens and to PSROS-1 gene!-Go figure!)
Place!
Or better Environment! It is incredible to realize our environmental influences affect our genes. Cancer rates are known to increase in immigrants to match the locals over time! Immigrants share in joy but also in subsequent pains at gene levels!
BARRIERS ....STILL TO COME !
SOME OF THE BARRIERS TO GENOME INTEGRATION INTO PATIENT CHARTS!
(Excerpt of our preliminary work)
As we advance in Medicine, and particularly in cancer Medicine, it is increasingly recognized that Medical patho-physiology find its source and implications tightly linked to sets of genes. There are genes that initiate the pathophysiology, but also pathway genes that once activated by the initiating gene(s), squarely drive the subsequent events, or amplify them as if it release the breaks with devastating consequences.
Genes can be in all kind of states. They can be amplified or repressed, or the can be full blown expressed and participating, or they can be silenced! Their expression can be forced or deliberate. They are forced when in a linkage situation or in an abnormal fusion, or deliberately expressing themselves when they have something to say or do due to their intrinsic nature! Of significant interest is the aspect that gene expression can be dependent on our age, gender, race and place !
AGE:
Although we inherit the same from birth, if you believe that at any given point, the genes expressed in you as an embryo, and subsequent ages, are the same, think again. Life is in a constant flux, nothing is still in a living being! And life is purposeful. AND SURVIVAL IS THE OBJECTIVE! Everything our cells do is to keep surviving. and so does cancer cells to our own surprise and demise! The first years are destined to growth and we gobble up things (unfortunately we don't know when to stop, realize you just have reached the lifetime external Carbohydrates needed!), by age 3, we stop having ability to have a fever induced seizure! in our twenties, we stop growing in height! well age has something to say through our GENES!
GENDER:
We know that one of the X Chromosome and its genes may be silenced!
But the strongest evidence of gender influence on gene expression is on Major Histocompatibility antigens (class I antigen). Women during their reproductive years get ready to carry a foreign body (baby)inside them without fighting it! They have got to dampen their Class I (UNO or ONE) Antigens ability. It is this very reason that Inflammatory bowel disease and autoimmune diseases are most fulminant (or simply more active, but I love the fulminant word) during these reproductive years. (Lupus 15 to 45 years of age range!). It is hypothesized that pattern of gene Methylation leads to silencing of some of the HLA-A, and B mostly!
Race
Disparity in incidence, frequency and mortality among races are the strongest evidence of this relationship between Gene expression and the races! class II MHC Antigen are linked to various Autoimmune and Metabolic diseases (DM). Even high blood pressure pathophysioplogy varies among the races.
For CRBCM, it is that flagrant case of Triple Negative Breast cancer that we are struggling with (struggling to link to the races, the class II Antigens and to PSROS-1 gene!-Go figure!)
Place!
Or better Environment! It is incredible to realize our environmental influences affect our genes. Cancer rates are known to increase in immigrants to match the locals over time! Immigrants share in joy but also in subsequent pains at gene levels!
BARRIERS ....STILL TO COME !
DOING OUR BEST AT CRBCM!
TH ANSWER TO THE MPIN FINALLY CAME AS WE COMPLAINED BITTERLY TO THE GOVERNMENT. THE DEADLINE FOR SUBMISSION IS HOWEVER PAST, WE BELIEVE THEY WILL REOPEN THIS RFA BECAUSE THEY WILL MISS US (WISHFUL THINKING!) BUT WITH A SLEW OF UNANSWERED QUESTIONS IN CANCER MEDICINE SOMEONE SOMEWHERE WILL BE INTERESTED IN WHAT WE HAVE TO SAY. AND PLEASE DON'T BE SHY, REACH OVER TO CRBCM AND TALK TO US. OUR DOOR IS ALWAYS OPEN, OUR MIND RECEPTIVE AND ALWAYS READY TO LEARN...
CALL US AT 915-307-3354!
TH ANSWER TO THE MPIN FINALLY CAME AS WE COMPLAINED BITTERLY TO THE GOVERNMENT. THE DEADLINE FOR SUBMISSION IS HOWEVER PAST, WE BELIEVE THEY WILL REOPEN THIS RFA BECAUSE THEY WILL MISS US (WISHFUL THINKING!) BUT WITH A SLEW OF UNANSWERED QUESTIONS IN CANCER MEDICINE SOMEONE SOMEWHERE WILL BE INTERESTED IN WHAT WE HAVE TO SAY. AND PLEASE DON'T BE SHY, REACH OVER TO CRBCM AND TALK TO US. OUR DOOR IS ALWAYS OPEN, OUR MIND RECEPTIVE AND ALWAYS READY TO LEARN...
CALL US AT 915-307-3354!
Thursday, June 27, 2013
NIH/GOVERNMENT STRATEGY TO KEEP MINORITY AWAY FROM PARTICIPATING !
It is clear that in a so called free society, one of the fundamental principle is to allow everyone to participate, enter a competition for government services. But to believe that free participation is true in these United States you better think again. Especially if your name is clearly of African origin!
When you have a medical practice, reimbursement for service rendered is a particular challenge. 8 months after starting to see Medicare patients, We are still waiting for the first penny from the Obama administration. Every time we call them, their computer has a glitch! "wait another 60 days!". It seems that the government that made the internet has other computer experts sleeping at the wheels or full of nerds who
can't figure out their own doing! They have hired an Intermediary called:
It is clear that in a so called free society, one of the fundamental principle is to allow everyone to participate, enter a competition for government services. But to believe that free participation is true in these United States you better think again. Especially if your name is clearly of African origin!
When you have a medical practice, reimbursement for service rendered is a particular challenge. 8 months after starting to see Medicare patients, We are still waiting for the first penny from the Obama administration. Every time we call them, their computer has a glitch! "wait another 60 days!". It seems that the government that made the internet has other computer experts sleeping at the wheels or full of nerds who
can't figure out their own doing! They have hired an Intermediary called:
[Novitas Solutions
which sounds like new solution to government no-solvency. these guys amuse themselves with messages like "
JH Part A Provider Outreach and Education(POE) Advisory Group (AG) Meeting Minutes - May 22, 2013
The JH Provider Outreach and Education (POE)
Advisory Group (AG) meeting minutes from May 22, 2013 are now available
for your reading pleasure. Enjoy!"
while we are not paid!
You just have to wonder who hired these guys and to what purpose? what are their connections?
========================================
1 week after we had trouble with the MPIN, we still don't know who gives you a MPIN number and no government institution we spoke to knows what entity of the government gives you a MPIN, and without it we can't submit a response to an RFA. These strategies are used stupidly to keep Minority institutions away! It is believed that if you multiply the road blocks, folks will quit asking!
========================================
1 week after we had trouble with the MPIN, we still don't know who gives you a MPIN number and no government institution we spoke to knows what entity of the government gives you a MPIN, and without it we can't submit a response to an RFA. These strategies are used stupidly to keep Minority institutions away! It is believed that if you multiply the road blocks, folks will quit asking!
Wednesday, June 26, 2013
THE UNIVERSITY OF PENNSYLVANIA HAS LAUNCHED THE CD19 TRIAL
"ADOPTIVE IMMUNOTHERAPY FOR CHEMOTHERAPY RESISTANT OR REFRACTORY CD19+ LEUKEMIA AND LYMPHOMA"
THEY ARE STUDYING CTL-O19, "AN AGENT COMPRISED OF AUTOLOGOUS T CELLS ENGINEERED TO EXPRESS AN ANTIBODY AGAINST CD19"
CALL DR NOELLE FREY AND DAVID PORTER AT 215-662-2867 TO REFER PATIENTS!
"ADOPTIVE IMMUNOTHERAPY FOR CHEMOTHERAPY RESISTANT OR REFRACTORY CD19+ LEUKEMIA AND LYMPHOMA"
THEY ARE STUDYING CTL-O19, "AN AGENT COMPRISED OF AUTOLOGOUS T CELLS ENGINEERED TO EXPRESS AN ANTIBODY AGAINST CD19"
CALL DR NOELLE FREY AND DAVID PORTER AT 215-662-2867 TO REFER PATIENTS!
1.ABCC1 GENE (WIKIPEDIA)
Multidrug resistance-associated protein 1 is a protein that in humans is encoded by the ABCC1 gene.[1][2]
The protein encoded by this gene is a member of the superfamily of ATP-binding cassette (ABC) transporters. ABC proteins transport various molecules across extra-and intra-cellular membranes. ABC genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, White). This full transporter is a member of the MRP subfamily which is involved in multi-drug resistance. This protein functions as a multispecific organic anion transporter, with oxidized glutathione, cysteinyl leukotrienes, and activated aflatoxin B1 as substrates. This protein also transports glucuronides and sulfate conjugates of steroid hormones and bile salts. Alternative splicing by exon deletion results in several splice variants but maintains the original open reading frame in all forms.[3]
=====================================================ATP IS REQUIRED FOR THE FUNCTION OF ION CHANNELS BUT THE PRIMARY DYSFUNCTION APPEARS TO INVOLVE CYTOKINES AND GROWTH FACTOR. ITS EXISTENCE SEEMS TO CONFER RESISTANCE TO DRUGS.
======================================================================
ALSO READ
2
============================================================IS GATA 2 A VIABLE TARGET TO REDUCE DRUG RESISTANCE AND SURVIVAL OF MYELOID LEUKEMIA.
ARE LUNA AND MIEP INDICATIONS OF ROLE OF AZACITIDINE!
3.
4.SPINK GENE
INVOLVED IN CELIAC DISEASE
WIKI"The structure of the Kazal repeat includes a large quantity of extended chain, 2 short alpha-helices and a 3-stranded anti-parallel beta sheet.[2] The inhibitor makes 11 contacts with its enzyme substrate: unusually, 8 of these important residues are hypervariable.[3] Altering the enzyme-contact residues, and especially that of the active site bond, affects the strength of inhibition and specificity of the inhibitor for particular serine proteases.[3][4] The presence of this Pfam domain is usually indicative of serine protease inhibitors, however, Kazal-like domains are also seen in the extracellular part of agrins which are not known to be proteinase inhibitors.
WITH THEM A SLEW OF GENES COME TO YOUR ATTENTION:
Human genes encoding proteins containing Kazal-type domains include:
Multidrug resistance-associated protein 1 is a protein that in humans is encoded by the ABCC1 gene.[1][2]
The protein encoded by this gene is a member of the superfamily of ATP-binding cassette (ABC) transporters. ABC proteins transport various molecules across extra-and intra-cellular membranes. ABC genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, White). This full transporter is a member of the MRP subfamily which is involved in multi-drug resistance. This protein functions as a multispecific organic anion transporter, with oxidized glutathione, cysteinyl leukotrienes, and activated aflatoxin B1 as substrates. This protein also transports glucuronides and sulfate conjugates of steroid hormones and bile salts. Alternative splicing by exon deletion results in several splice variants but maintains the original open reading frame in all forms.[3]
=====================================================ATP IS REQUIRED FOR THE FUNCTION OF ION CHANNELS BUT THE PRIMARY DYSFUNCTION APPEARS TO INVOLVE CYTOKINES AND GROWTH FACTOR. ITS EXISTENCE SEEMS TO CONFER RESISTANCE TO DRUGS.
======================================================================
ALSO READ
- study found a cytomegalovirus UL138-mediated loss of cell surface MRP1 and reduction of substrate export by MRP1; cytomegalovirus latency-associated loss of MRP1 and accumulation of vincristine, an MRP1 substrate, depleted virus from naturally latent progenitors all of which are in vivo sites of latency
- This is the first study showing significant associations of a higher MRP1 protein expression with less accelerated FEV1 decline in COPD patients using long-term therapy with inhaled corticosteroids
- Expression of ABCC1 by HRS cells in CHL patients predicts a higher risk of treatment failure and is marginally associated with poorer failure-free survival using standard frontline chemotherapy regimens.
- A review of recent advances in understanding the role and mechanism of MRP1/ABCC1 polymorphisms in drug resistance, disease susceptibility and severity, and prognosis prediction.
- collagen/beta1 integrin/ERK signaling up-regulates the expression and function of ABCC1
- Substitution of two of these residues with alternative amino acids has allowed us to produce an almost cysless form of DeltaMRP1 that traffics to the plasma membrane
- CK2alpha and MRP1 interact physically, and recombinant CK2 phosphorylates MRP1-derived peptide in vitro in a Thr249-dependent manner.
- ABCB1 expression is limited to endothelial cells, whereas ABCC1 expression could mark a minority of tumor cells approaching a stem-like status.
- ABCB1 and ABCC1 expression correlates with different prognostic factors in pediatric patients with acute leukemia.
- We have demonstrated that vincristine resistance mediated by CD40 activation was induced by an increased expression of MRP1 by AKT signaling in human multiple myeloma cell lines.
2
The myeloid transcription factor GATA-2 regulates the viral UL144 gene during human cytomegalovirus latency in an isolate-specific manner.
Poole E============================================================IS GATA 2 A VIABLE TARGET TO REDUCE DRUG RESISTANCE AND SURVIVAL OF MYELOID LEUKEMIA.
ARE LUNA AND MIEP INDICATIONS OF ROLE OF AZACITIDINE!
3.
A novel selective LSD1/KDM1A inhibitor epigenetically blocks herpes simplex virus lytic replication and reactivation from latency.
Liang Y, Quenelle D,4.SPINK GENE
INVOLVED IN CELIAC DISEASE
WIKI"The structure of the Kazal repeat includes a large quantity of extended chain, 2 short alpha-helices and a 3-stranded anti-parallel beta sheet.[2] The inhibitor makes 11 contacts with its enzyme substrate: unusually, 8 of these important residues are hypervariable.[3] Altering the enzyme-contact residues, and especially that of the active site bond, affects the strength of inhibition and specificity of the inhibitor for particular serine proteases.[3][4] The presence of this Pfam domain is usually indicative of serine protease inhibitors, however, Kazal-like domains are also seen in the extracellular part of agrins which are not known to be proteinase inhibitors.
Kazal_2
This domain is usually indicative of serine protease inhibitors that belong to Merops inhibitor families: I1, I2, I17 and I31. However, kazal-like domains are also seen in the extracellular part of agrins, which are not known to be protease inhibitors. Kazal domains often occur in tandem arrays and have a central alpha-helix, a short two-stranded antiparallel beta-sheet and several disulphide bonds.[5][6][7] The amino terminal segment of this domain binds to the active site of its target proteases, thus inhibiting their function."WITH THEM A SLEW OF GENES COME TO YOUR ATTENTION:
Human genes encoding proteins containing Kazal-type domains include:
Kazal_1
- AGRIN, CPAMD8
- FST, FSTL3, FSTL4, FSTL5
- IGFBPL1
- SMOC1, SPARC, SPARCL1, SPINK1, SPINK2, SPINK4, SPINK5, SPINK5L2, SPINK5L3, SPINK6, SPINK7, SPINK9
- TMEFF1, TMEFF2
Kazal_2
- C6, CFI
- FSTL1, FSTL3
- HTRA1, HTRA3, HTRA4
- IGFBP7, KAZALD1, LST3, RECK
- SLC21A8, SLCO1A2, SLCO1B1, SLCO1B3, SLCO1C1, SLCO2A1, SLCO3A1, SLCO4A1, SLCO4C1, SLCO5A1, SLCO6A1, SMOC2, SPINK5, SPOCK1, SPOCK2, SPOCK3
- WFIKKN1, WFIKKN2
- LET'S GO TO WORK!
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