Posted in Alzheimer's Disease, Etiology, Innovations in Neurophysiology & Neuropsychology, Pharmacotherapy and Cell Activity, tagged Alzheimer, Alzheimers Disease, Conditions and Diseases, MRI, Neurological Disorders, PET, TEDMED on September 29, 2012| 2 Comments »
Reporter: Aviva Lev-Ari, PhD, RN
Can new imaging techniques help determine who will develop Alzheimer’s before symptoms show? Sperling says early detection and prevention research is the best defense against a disease we discover too late to treat.
Posted in Imaging-based Cancer Patient Management, tagged biopsies, breast cancer, Cancer - General, cancer grade, cancer management, Clinical trial, Conditions and Diseases, costs of procedure, environment, FDA, Food and Drug Administration, health, Health care, medicine, mortality, Mortality rate, National Institutes of Health, New England Journal of Medicine, over-treatment, Proceedings of the National Academy of Sciences of the United States of America, prostat cancer screening, PSA, research, science, screening, transrectal, TRUS, United States on September 2, 2012| 12 Comments »
Author and Curator: Dror Nir, PhD
The management of men with prostate cancer is becoming one of the most challenging public health issues in the Western world. It is characterized by: over-diagnosis; over-treatment; low treatment efficacy; treatment related toxicity; escalating cost; and unsustainability [Bangma et al, 2007; Esserman et al, 2009]. How come? Well, everyone accepts that most prostate cancers are clinically insignificant. It is well known that all men above 65 harbor some sort of prostate cancer. Due to the current aggressive PSA-based screening, one in six men will be diagnosed with prostate cancer. Yet, the lifetime risk of dying of prostate cancer is only 3%. The problem is that, once diagnosed with prostate cancer, there is no accurate tool to identify those men that will die of the disease (in my previous post I mentioned 1:37). Currently, screening practices for prostate cancer are relying on the very unspecific prostate-specific-antigen (PSA) bio-marker test to determine which men are at higher risk of harboring prostate cancer and therefore need a biopsy. The existing diagnostic test is a transrectal ultrasound (TRUS) guided prostate biopsy aimed at extracting representative tissue from areas where cancer usually resides. This procedure suffers from several obvious faults:
1. Since the imaging tool used (B-mode ultrasound) is poor at detecting malignancies in the prostate, the probability of hitting a clinically significant cancer or missing a clinically insignificant cancer is subject to random error.
2. TRUS biopsy is also subjected to systematic error as it misses large parts of the prostate which might harbor cancer (e.g. apex and anterior zones). 
3. TRUS guided biopsies are often unrepresentative of the true burden of cancer as either the volume or grade of cancer can be underestimated.
In the last ten years I was leading the development of an innovative ultrasound-based technology, HistoScanningTM, aimed at improving the aforementioned faults;
Among the other most popular imaging modalities aimed at better prostate cancer detection in routine use are: MRI, Elastography, Contrast Enhanced Ultrasound etc…
In my future posts I will go into more detail on how these imaging modalities fit into routine workflow, how much they stay within budget constraints and what level of promise they bear for promoting personalized medicine. Stay tuned… Footnote: According to the final report by an advisory panel to the USA government: Doctors should no longer offer the PSA prostate cancer screening test to healthy men because they’re more likely to be harmed by the blood draw, and the chain of medical interventions that often follows than be helped; (http://www.usatoday.com/news/health/story/2012-05-21/prostate-cancer-screening-test-harmful/55118036/1) But then; what should be offered instead?
Prostate Cancers Plunged After USPSTF Guidance, Will It Happen Again?
New Prostate Cancer Screening Guidelines Face a Tough Sell, Study Suggests
ROLE OF VIRAL INFECTION IN PROSTATE CANCER
http://pharmaceuticalintelligence.com/2012/09/01/role-of-viral-infection-in-prostate-cancer/
Posted in CANCER BIOLOGY & Innovations in Cancer Therapy, Infectious Disease & New Antibiotic Targets, tagged Benign prostatic hyperplasia, Cancer - General, Conditions and Diseases, Doctor of Philosophy, Genitourinary, health, Prostate, Prostate cancer on September 1, 2012| 6 Comments »
Prostate cancer is the leading cause of cancer morbidity and the third greatest cause of cancer death among men in developed countries.
English: Two-panel drawing shows normal male reproductive and urinary anatomy and benign prostatic hyperplasia (BPH). Panel on the left shows the normal prostate and flow of urine from the bladder through the urethra. Panel on the right shows an enlarged prostate pressing on the bladder and urethra, blocking the flow of urine. (Photo credit: Wikipedia)
A major question in cancer research has been whether virus infection plays a role in cancers of the genitourinary tract.
Now there seem to be a new evidence suggesting human polyomavirus BK is involved in maintaining and enhancing an environment suitable for prostate cancer growth. The research results were published in the August Journal of Virology, and the authors hope that these findings could lead to preventive and/or therapeutic prostate cancer vaccines.
(G. Sais, S. Wyler, T. Hudolin, I. Banzola, C. Mengus, L. Bubendorf, P.J. Wild, H.H. Hirsch, T. Sulser, G.C. Spagnoli, and M. Provanzano, 2012. Differential patterns of large tumor antigen-specific immune responsiveness in patients with BK polyomavirus-positive prostate cancer or benign prostatic hyperplasia. J. Virol. 86:8461-8471.)
Download a copy of the article at: http://bit.ly/asm0812b
Posted in Bio Instrumentation in Experimental Life Sciences Research, Biomarkers & Medical Diagnostics, CANCER BIOLOGY & Innovations in Cancer Therapy, Cell Biology, Signaling & Cell Circuits, FDA Regulatory Affairs, Health Economics and Outcomes Research, HealthCare IT, Imaging-based Cancer Patient Management, International Global Work in Pharmaceutical, Medical Devices R&D Investment, Personalized and Precision Medicine & Genomic Research, Pharmaceutical R&D Investment, Population Health Management, Genetics & Pharmaceutical, Scientist: Career considerations, Statistical Methods for Research Evaluation, Technology Transfer: Biotech and Pharmaceutical, tagged breast cancer, breast cancer mortality, breast cancer screening, breast thermography, Cancer - General, Cancer screening, cancer tumours, Cardiac surgery, Chemotherapy, Clinical trial, Conditions and Diseases, costs of treatment, Diagnosis, early diagnosis, elastography, evidence based medicine, health, health economics, histoscanning, imaging based cancer detection, imaging ultrasound, innovations in cancer detection, Magnetic resonance imaging, mammography, medicine, National Institutes of Health, New England Journal of Medicine, new methods for cancer detection, Proceedings of the National Academy of Sciences of the United States of America, Prostate cancer, Prostate cancer screening, research, science, smart imaging, tissue characterisation, ultrasound based cancer detection, United States on August 27, 2012| 15 Comments »
Author and Curator: Dror Nir, PhD
It is generally agreed by radiologists and oncologists that in order to provide a comprehensive work-flow that complies with the principles of personalized medicine, future cancer patients’ management will heavily rely on “smart imaging” applications. These could be accompanied by highly sensitive and specific bio-markers, which are expected to be delivered by pharmaceutical companies in the upcoming decade. In the context of this post, smart imaging refers to imaging systems that are enhanced with tissue characterization and computerized image interpretation applications. It is expected that such systems will enable gathering of comprehensive clinical information on cancer tumors, such as location, size and rate of growth.
What is the main incentive for promoting cancer patients’ management based on smart imaging?
It promises to enable personalized cancer patient management by providing the medical practitioner with a non-invasive and non-destructive tool to detect, stage and follow up cancer tumors in a standardized and reproducible manner. Furthermore, applying smart imaging that provides valuable disease-related information throughout the management pathway of cancer patient will eventually result in reducing the growing burden of health-care costs related to cancer patients’ treatment.
Let’s briefly review the segments that are common to all cancer patients’ pathway: screening, treatment and costs.
Screening for cancer: It is well known that one of the important factors in cancer treatment success is the specific disease staging. Often this is dependent on when the patient is diagnosed as a cancer patient. In order to detect cancer as early as possible, i.e. before any symptoms appear, leaders in cancer patients’ management came up with the idea of screening. To date, two screening programs are the most spoken of: the “officially approved and budgeted” breast cancer screening; and the unofficial, but still extremely costly, prostate cancer screening. After 20 years of practice, both are causing serious controversies:
In trend analysis of WHO mortality data base [1], the authors, Autier P, Boniol M, Gavin A and Vatten LJ, argue that breast cancer mortality in neighboring European countries with different levels of screening but similar access to treatment is the same: “The contrast between the time differences in implementation of mammography screening and the similarity in reductions in mortality between the country pairs suggest that screening did not play a direct part in the reductions in breast cancer mortality”.
In prostate cancer mortality at 11 years of follow-up [2], the authors,Schröder FH et. al. argue regarding prostate cancer patients’ overdiagnosis and overtreatment: “To prevent one death from prostate cancer at 11 years of follow-up, 1055 men would need to be invited for screening and 37 cancers would need to be detected”.
The lobbying campaign (see picture below) that AdmeTech (http://www.admetech.org/) is conducting in order to raise the USA administration’s awareness and get funding to improve prostate cancer treatment is a tribute to patients’ and practitioners’ frustration.
Treatment: Current state of the art in oncology is characterized by a shift in the decision-making process from an evidence-based guidelines approach toward personalized medicine. Information gathered from large clinical trials with regard to individual biological cancer characteristics leads to a more comprehensive understanding of cancer.
Quoting from the National cancer institute (http://www.cancer.gov/) website: “Advances accrued over the past decade of cancer research have fundamentally changed the conversations that Americans can have about cancer. Although many still think of a single disease affecting different parts of the body, research tells us through new tools and technologies, massive computing power, and new insights from other fields that cancer is, in fact, a collection of many diseases whose ultimate number, causes, and treatment represent a challenging biomedical puzzle. Yet cancer’s complexity also provides a range of opportunities to confront its many incarnations”.
Personalized medicine, whether it uses cytostatics, hormones, growth inhibitors, monoclonal antibodies, and loco-regional medical devices, proves more efficient, less toxic, less expensive, and creates new opportunities for cancer patients and health care providers, including the medical industry.
To date, at least 50 types of systemic oncological treatments can be offered with much more quality and efficiency through patient selection and treatment outcome prediction.
Figure taken from presentation given by Prof. Jaak Janssens at the INTERVENTIONAL ONCOLOGY SOCIETY meeting held in Brussels in October 2011
For oncologists, recent technological developments in medical imaging-guided tissue acquisition technology (biopsy) create opportunities to provide representative fresh biological materials in a large enough quantity for all kinds of diagnostic tests.
Health-care economics: We are living in an era where life expectancy is increasing while national treasuries are over their limits in supporting health care costs. In the USA, of the nation’s 10 most expensive medical conditions, cancer has the highest cost per person. The total cost of treating cancer in the U.S. rose from about $95.5 billion in 2000 to $124.6 billion in 2010, the National Cancer Institute (www.camcer.gov) estimates. The true sum is probably higher as this estimate is based on average costs from 2001-2006, before many expensive treatments came out; quoting from www.usatoday.com : “new drugs often cost $100,000 or more a year. Patients are being put on them sooner in the course of their illness and for a longer time, sometimes for the rest of their lives.”
With such high costs at stake, solutions to reduce the overall cost of cancer patients’ management should be considered. My experience is that introducing smart imaging applications into routine use could contribute to significant savings in the overall cost of cancer patients’ management, by enabling personalized treatment choice and timely monitoring of tumors’ response to treatment.
References
Posted in Biomarkers & Medical Diagnostics, Cell Biology, Signaling & Cell Circuits, Chemical Biology and its relations to Metabolic Disease, Chemical Genetics, Liver & Digestive Diseases Research, tagged Conditions and Diseases, Diabetes, Diabetes mellitus type 1, Diabetes mellitus type 2, Endocrine Disorders, Metabolomics, Pancreas on August 20, 2012| 3 Comments »
Reporter: Aviva Lev-Ari, PhD, RN
October 1-3, 2012
The Diabetes Drug Discovery and Beyond meeting will cover progress on promising pre-clinical and early clinical phase diabetes drug candidates. But this year, we will also highlight emerging therapeutic targets that probe how the underlying defects in metabolic diseases are connected. Some presentations will cover obesity, other metabolic disorders and cardiovascular disease in the context of diabetes and energy homeostasis.
TUESDAY, OCTOBER 2
1:30 pm Chairperson’s Remarks
Claire Steppan, Ph.D., Associate Research Fellow, Diabetes, Pfizer
| 1:40 FEATURED SPEAKER
Targeting Diabetes via Glucocorticoid Modulation: The Identification of Advanced 11b-HSD-1 Inhibitors
Preventing excess glucocorticoid tone in metabolically active tissues such as the liver and adipose may be beneficial in addressing glucose homeostasis and hyperglycemia in patients with type 2 diabetes. We have optimized a series of triazolopyridine based inhibitors resulting in the advancement of BMS-770767 to phase 2 clinical trials. The discovery of BMS-770767 will be presented as well as a description of its development properties, pharmacokinetics, and pre-clinical pharmacology profile. |
2:10 Dyslipidemia Targets and Diabetes
Rebecca Taub, M.D., CEO, Madrigal Pharmaceuticals
This talk will defining diabetic dyslipidemia and discuss how elevated VLDL, triglycerides and fatty liver might contribute to diabetic CV disease. Novel dyslipidemia mechanisms to treat diabetic dyslipidemia including THRbeta agonists will also be covered.
2:40 Effects of PF-04620110, a Novel Diacylglycerol Acyl-Transferase 1 (DGAT1) Inhibitor on Healthy-Obese Volunteers and Type 2 Diabetic Subjects
Claire Steppan, Ph.D., Associate Research Fellow, Diabetes, Pfizer
Inhibition of DGAT1, the terminal enzyme in the synthesis of triglycerides (TG), has been proposed for the treatment of type 2 diabetes (T2DM). We sought to examine the effects of a potent and selective DGAT1 inhibitor, PF-04620110, on vitamin A absorption, TG, glucose, insulin and total amide glucagon like peptide-1 (GLP-1) levels in both healthy-obese volunteers and Type 2 Diabetic subjects. The results of these studies will be presented.
3:10 Refreshment Break in the Exhibit Hall with Poster Viewing
3:45 Pharmacological Manipulation of Diacyl Glycerol Acyl Transferase 1 Using Pre-Clinical Models
Shirly Pinto, Ph.D., CVD – Atherosclerosis Team Lead, Merck Research Laboratories
4:15 Sponsored Presentations (Opportunities Available)
4:45 Beneficial and Adverse Effects of Glucokinase Activators on Glucose Metabolism in Rat Liver Cells
Gabriel Baverel, Ph.D., CEO and CSO, Metabolomics, Metabolys, Inc.
Using a metabolic flux approach, we show the potential beneficial and adverse effects of three gluco-kinase activator drug candidates for type2 diabetes. We report the gluco-kinase activators’ effects on glucose utilization and production, glycogen synthesis and degradation, lactic acid and triglyceride accumulation and on the citric acid cycle during glucose metabolism in rat liver cells. Our work illustrates the advantage of metabolic flux analysis for predicting early during the drug development process, both the efficacy and safety of very small amounts of antidiabetic drug candidates.
5:15 Connecting Mitochondrial Dysfunction and Diabetes
James Dykens, CEO, Eyecyte Therapeutics
Mitochondrial dysfunction contributes via bioenergetic and oxidative mechanisms to a host of degenerative and metabolic diseases, including diabetes. Mitochondrial Ca2+ dynamics alter insulin release, while production of free radicals yields dysregulation of glycolysis. Importantly, xenobiotic therapies for diabetes, e.g., biguanides and thiazolidinediones, directly undermine mitochondrial function thereby lowering blood glucose, albeit via an untoward mechanism. The latter results from cell culture conditions that model diabetes and anaerobic poise, not normal aerobic physiology.
5:45 End of Day
WEDNESDAY, OCTOBER 3
| 8:00 am Interactive Breakfast Breakout Discussion Groups
Targeting GPCRs Moderator: Peter Cornelius, Ph.D., Director of Metabolic Diseases, SystaMedic Inc.
Cardiovascular Challenges Moderator: Rebecca Taub, CEO, Madrigal Pharmaceuticals
Better Diabetes Models and Markers Moderator: Jerome J. Schentag, PharmD, Professor of Pharmaceutical Sciences, University at Buffalo
|
9:05 Chairperson’s Remarks
Peter Cornelius, Ph.D., Director of Metabolic Diseases, SystaMedic Inc.
| 9:10 FEATURED PRESENTATION
Discovery of Ertugliflozin: An Anti-Diabetic Agent from a New Class of SGLT2 Inhibitors
Inhibition of sodium-dependent glucose co-transporter 2 (SGLT2), located in the kidney, promotes reduction of plasma glucose concentration. The medicinal and synthetic organic chemistry rationale that led to the rapid identification of Ertugliflozin (PF-04971729), an anti-diabetic agent currently in development and belonging to a new class of SGLT2 inhibitors bearing a dioxa-bicyclo[3.2.1]octane bridged ketal motif, will be presented. |
9:40 Targeting FGF21 for Type 2 Diabetes
Andrew C. Adams, Ph.D., Post-Doctoral Research Fellow, Diabetes Research, Lilly Research Laboratories
10:10 Coffee Break in the Exhibit Hall with Poster Viewing
10:55 Update on the Clinical Candidate ARRY-981: A GPR119 Agonist
Brad Fell, Senior Research Investigator, Medicinal Chemistry, Array BioPharma
GPR119 is a promising new target for the treatment of type 2 diabetes. Agonists of this GPCR, which promote insulin secretion from pancreatic ß-cells and GLP-1 release from enteroendocrine L-cells, provide a unique opportunity for a single drug to elicit insulin secretion via two distinct pathways. However, several GPR119 agonists have recently demonstrated poor clinical efficacy. We will discuss our novel GPR119 clinical candidate, ARRY-981, that has shown meaningful and durable glucose control in preclinical models of diabetes.
11:25 Inflammation, Obesity and Diabetes: Pre-Clinical Investigations of a CCR2 Antagonist
Dana Johnson, Ph.D., Senior Scientific Director, Drug Discovery, Janssen Pharmaceuticals, Johnson & Johnson
With the growing idea of insulin resistance due, in part, to low grade systemic inflammation, mechanistic investigations aimed at altering inflammatory tone have been undertaken by us as well as others. Recruitment of the macrophage and continued activity in the adipose tissue appears to drive insulin resistance, in part, via the secretion of Moncocyte Chemoattractant Protein 1 (MCP-1) and its cognate receptor C-C Chemokine Receptor-2 (CCR2). Our efforts in disrupting the macrophage recruitment via the use of CCR2 antagonists will be presented.
11:55 Monoclonal Antibody Antagonists of the Glucagon Receptor as Therapeutic Agents
Bernard B. Allan, Ph.D., Scientist, Department of Molecular Biology, Genentech, Inc.
Excess glucagon signaling plays a key role in the development of hyperglycemia in type 1 and type 2 diabetic patients. We have generated potent anti-glucagon receptor antagonist antibodies and will present the mechanisms underlying their anti-diabetic activities in pre-clinical models, including their direct effects on hepatic glucose metabolism and indirect effects on beta-cell mass.
12:25 pm Sponsored Presentation (Opportunity Available)
12:40 Luncheon Workshop (Sponsorship Opportunity Available) or Lunch on Your Own
1:55 Chairperson’s Remarks
Jesper Gromada, Ph.D., Executive Director, Cardiovascular and Metabolic Diseases, Novartis Institutes for BioMedical Research
2:00 XMetA, an Allosteric Agonist Antibody to the Insulin Receptor that Selectively Activates Insulin Receptor Metabolic Signaling and Restores Glycemic Control in Mouse Models of Diabetes
John Corbin, Ph.D., Associate Director, Molecular Interactions and Biophysics, Preclinical Research, XOMA
The XMetA antibody represents novel drug class for the treatment of diabetes. XMetA has unique properties including selective partial agonism of insulin receptor metabolic signaling resulting in improvements in the disease state of both hyperinsulinemic insulin resistant and insulinopenic diabetic animals. The in vitro and in vivo data to be presented for XMetA will provide a clear demonstration of how allosteric modulation of the insulin receptor with a monoclonal antibody can translate to improvements in disease.
2:30 Phenotype-Driven Approaches towards Novel Beta-Cell Proliferative and Protective Therapies
Bryan Laffitte, Ph.D., Associate Director, Genomics Institute of the Novartis Research Foundation
Type 1 and type 2 diabetes are characterized by a loss of beta cell mass. However, therapeutic options aimed at preservation or restoration of endogenous beta cell mass, are not currently available. We used phenotypic screening approaches for both small molecule and biologic agents to identify regulators of beta cell survival and beta cell proliferation. We report on several series of small molecules that induce beta cell proliferation and/or protect beta cells from various forms of stress and have potential as therapeutic options for both type 1 and type 2 diabetes.
3:00 Refreshment Break in the Exhibit Hall with Poster Viewing
3:40 Gastric Bypass in Mice as a Model for Target Identification
Vincent Aguirre, M.D., Ph.D., Assistant Professor, Internal Medicine, University of Texas Southwestern Medical Center
We will discuss a mouse model of gastric bypass, which recapitulates effects of this procedure on body weight, body composition, glucose homeostasis, and stool energy observed in humans. The reproducibility of this model allows high-resolution comparison of effects of gastric bypass across genetic models using advanced methodologies, such as MRS metabolic flux, proteo metabolomics, and deep sequencing. As such, it enables targeted investigation of bypass-induced biological pathways and refined identification of novel pharmaceutical targets capable of mimicking beneficial effects of bariatric surgery.
4:10 Cell-Based Therapies to Treat Diabetes
Norma Kenyon, Ph.D., Professor of Surgery, Microbiology and Immunology and Biomedical Engineering; Executive Director of the Wallace H. Coulter Center for Translational Research; School of Medicine, University of Miami
This presentation will focus on the role of stem cell-based therapies to treat diabetes, highlighting the therapeutic potential of mesenchymal stem cells in diabetes. Our research group’s focus is on ways to transplant islet cells without the need for anti-rejection drugs, including the incorporation of stem cells into transplant protocols.
4:40 Discovery of Lorcaserin: A Selective 5-HT2C Agonist for Weight Management
Graeme Semple, Ph.D., Vice President, Discovery Chemistry, Arena Pharmaceuticals, Inc.
Compelling evidence suggests that drugs which activate the 5-HT2C receptor cause weight loss and thus have potential for use as weight management agents. Because serotonin elicits a number of biological responses through modulation of other 5HTrelated proteins, selectivity was a critical challenge particularly with respect to the closely related 5-HT2A and 5-HT2B receptors. This presentation outlines some of events, challenges and achievements that led to the discovery and development of lorcaserin.
Posted in Bio Instrumentation in Experimental Life Sciences Research, Chemical Biology and its relations to Metabolic Disease, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Genomic Testing: Methodology for Diagnosis, Health Economics and Outcomes Research, Human Immune System in Health and in Disease, Infectious Disease & New Antibiotic Targets, Liver & Digestive Diseases Research, tagged Blood sugar, Blood vessel, Conditions and Diseases, health, Pancreas, University of Pennsylvania on August 20, 2012| 1 Comment »
Reporter: Aviva Lev-Ari, PhD, RN
Technion researchers have built pancreatic tissue with insulin-secreting cells, surrounded by a three-dimensional network of blood vessels. The engineered tissue could pave the way for improved tissue transplants to treat diabetes.
The tissue created by Professor Shulamit Levenberg of the Technion-Israel Institute of Technology and her colleagues has some significant advantages over traditional transplant material that has been harvested from healthy pancreatic tissue.
 |
| Prof. Shulamit Levenberg |
The insulin-producing cells survive longer in the engineered tissue, and produce more insulin and other essential hormones, Levenberg and colleagues said. When they transplanted the tissue into diabetic mice, the cells began functioning well enough to lower blood sugar levels in the mice.
Transplantation of islets, the pancreatic tissue that contains hormone-producing cells, is one therapy considered for people with type 1 diabetes, who produce little or no insulin because their islets are destroyed by their own immune systems. But as with many tissue and organ transplants, donors are scarce, and there is a strong possibility that the transplantation will fail.
The well-developed blood vessel network built into the engineered tissue is key to its success, the researchers concluded. The blood vessels encourage cell-to-cell communication, by secreting growth hormones and other molecules, that significantly improve the odds that transplanted tissue will survive and function normally.
The findings confirm that the blood vessel network “provides key survival signals to pancreatic, hormone-producing cells even in the absence of blood flow,” Levenberg and colleagues concluded in their study published in the journal PLoS One.
One reason transplants fail, Levenberg said, “is that the islets are usually transplanted without any accompanying blood vessels.” Until the islets begin to connect with a person’s own vascular system, they are vulnerable to starvation.
The 3-D system developed by the Technion researchers tackled this challenge by bringing together several different cell types to form a new transplantable tissue. Using a porous plastic material as the scaffold for the new tissue, the scientists seeded the scaffold with mouse islets, tiny blood vessel cells taken from human umbilical veins, and human foreskin cells that encouraged the blood vessels to develop a tube-like structure.
“The advantages provided by this type of environment are really profound,” said Xunrong Luo, an islet transplantation specialist at the Northwestern University Feinberg School of Medicine. She noted that the number of islets used to lower blood sugar levels in the mice was nearly half the number used in a typical islet transplant.
Islets grown in these rich, multicellular environments lived three times as long on average as islets grown by themselves, Levenberg and colleagues found.
The technology “is still far from tests in humans,” Levenberg said, but she noted that she and her colleagues are beginning to test the 3-D tissue scaffolds using human instead of mouse islets.
According to Northwestern’s Luo, the 3-D model demonstrated in the study “will have important and rapid clinical implications” if the same results can be replicated with human cells. “This model system also provides a good platform to study the details and mechanisms that underlie successful transplantation.”
The Technion-Israel Institute of Technology is a major source of the innovation and brainpower that drives the Israeli economy, and a key to Israel’s renown as the world’s “Start-Up Nation.” Its three Nobel Prize winners exemplify academic excellence. Technion people, ideas and inventions make immeasurable contributions to the world including life-saving medicine, sustainable energy, computer science, water conservation and nanotechnology.
American Technion Society (ATS) donors provide critical support for the Technion—more than $1.7 billion since its inception in 1940. Based in New York City, the ATS and its network of chapters across the U.S. provide funds for scholarships, fellowships, faculty recruitment and chairs, research, buildings, laboratories, classrooms and dormitories, and more.
http://www.ats.org/site/News2?page=NewsArticle&id=7567&news_iv_ctrl=1161
Posted in Biomarkers & Medical Diagnostics, Cell Biology, Signaling & Cell Circuits, Chemical Biology and its relations to Metabolic Disease, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Health Economics and Outcomes Research, Human Immune System in Health and in Disease, Metabolomics, Nutrition, Population Health Management, Nutrition and Phytochemistry, tagged Conditions and Diseases, Diabetes, Diabetes mellitus type 2, Endocrine Disorders, GLP-1, Glucagon-like peptide-1, health, Impaired glucose tolerance on August 17, 2012| Leave a Comment »
Reporter: Aviva Lev-Ari, PhD, RN
By Mark Abrahams, MD
Reviewed by Loren Wissner Greene, MD, MA (Bioethics), Clinical Associate Professor of Medicine, NYU School of Medicine, New York, NY
Published: 05/23/2012
For many years, it has been well known that causes of type 2 diabetes include: decreased ability of pancreatic beta cells to produce insulin, insulin resistance, and increased production of glucose by the liver.1,2 More recently, the role of the incretin hormones, GLP-1 (glucagon-like peptide 1) and GIP (glucose-dependent insulinotropic polypeptide) has been elucidated. This article reviews the pathophysiology of GLP-1 and the impaired incretin effect observed in type 2 diabetes.
The significant reduction in the “incretin effect” observed in patients with type 2 diabetes offers strong evidence as to the importance of GLP-1. The incretin effect refers to the observation that, when challenged by glucose delivered via an oral route (as would occur with ingestion of a meal), the resulting increase in insulin levels is higher than that seen when glucose is delivered intravenously.3 The impaired ability of patients with type 2 diabetes to mount such a postprandial incretin effect appears to be due primarily to decreased circulating levels of GLP-1. This may be secondary to either decreased secretion by the gut or increased elimination of GLP-1 (elimination occurs most notably via enzymatic degradation by DPP-4 [dipeptidyl peptidase-4]).4
Despite the impaired incretin effect seen in patients with type 2 diabetes, the ability of GLP-1, when present, to elicit the secretion of insulin by pancreatic beta cells appears to be preserved.4Furthermore, it has also been shown that the ability of GLP-1 to slow gastric emptying and decrease glucagon secretion remains intact in these patients.4 This implies that the impaired incretin effect appears to be largely a function of decreased circulating levels of incretin hormones, rather than a decreased ability of target tissues to respond appropriately.
At present, it is not known if the decreased incretin effect seen in patients with type 2 diabetes is a cause or effect of the disease. While it may be intuitive to think about pathophysiology as preceding clinical disease, at least two studies suggest otherwise. In one study in patients with chronic pancreatitis, the investigators leveraged the assumption that these patients eventually develop diabetes.5 This study compared patients with chronic pancreatitis and secondary diabetes to patients with chronic pancreatitis and normal glucose tolerance. In the patients with secondary diabetes, the incretin effect was significantly impaired—but not so in patients with normal glucose tolerance. The authors concluded that clinical diabetes is more likely a cause of an impaired incretin effect rather than a consequence. In another study comparing identical twins, one with type 2 diabetes and one without, impaired secretion of GLP-1 was seen only in the siblings with diabetes—also suggesting that clinical disease may precede deficits in GLP-1 secretion.6Regardless, this subject remains controversial.
The relationship between obesity and the incretin effect is an area of active exploration as well. In one study investigating the impact of obesity on the incretin effect, a proportional relationship was observed between severity of obesity and degree of impairment of incretin effect. The authors concluded that obesity was an independent cause of diminished incretin effect.7
In summary, decreased levels of circulating GLP-1 and GIP appear to be primarily responsible for the impaired ability of the type 2 diabetes patient to mount an effective postprandial insulin response—while tissue sensitivity to hormone, when present, remains intact. Obesity is believed to contribute to the development of such an impaired incretin effect, and the question of incretin effect as either causing, or resulting from, clinical disease remains controversial.
References:
Consequences of Elevated HbA1c in Type 2 Diabetes
05/22/2012
Elevated HbA1c leads to multiple complications via cellular toxicity and resulting end-organ damage.
Physiology of GLP-1 in Post-prandial Glucose Homeostasis
05/22/2012
A review of GLP-1 secretion, degradation, and the importance of the incretin effect in healthy individuals.
SOURCE:
Posted in Frontiers in Cardiology and Cardiovascular Disorders, HTN, Medical Devices R&D and Inventions, Origins of Cardiovascular Disease, Pharmacotherapy of Cardiovascular Disease, Scientist: Career considerations, Technology Transfer: Biotech and Pharmaceutical, tagged Cardiovascular Disorders, Conditions and Diseases, Heart disease, medicine, New England Journal of Medicine on August 16, 2012| 2 Comments »
http://nejm200.nejm.org/news-and-events/dialogues-in-medicine/?panel=4
Reporter: Aviva Lev-Ari, PhD, RN
Moderator:
Joseph Loscalzo
Panelists:
Emelia Benjamin
Eugene Braunwald
Desmond Jordan
Thomas Luscher
Craig Smith
Click on the Live Link Above, then click on the arrow to watch a 1:35 minutes VIDEO on Heart Disease
Posted in Biomarkers & Medical Diagnostics, Cardiovascular Pharmacogenomics, Cell Biology, Signaling & Cell Circuits, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Genome Biology, Genomic Testing: Methodology for Diagnosis, Human Immune System in Health and in Disease, Infectious Disease & New Antibiotic Targets, Innovations in Neurophysiology & Neuropsychology, Nitric Oxide in Health and Disease, Pharmacotherapy of Cardiovascular Disease, tagged cell fragments, Conditions and Diseases, Dr. Venkat S. Karra, health, Hematology, hemolytic uremic syndrome, Idiopathic thrombocytopenic purpura, ITP, Platelet, platelet count, SUNY Downstate Medical Center, Thrombus, Von Willebrand disease, Von Willebrand factor on August 16, 2012| 13 Comments »
Author: Dr. Venkat S. Karra, Ph.D.
Platelets are a natural source of growth factors and they circulate in the blood. They are involved in hemostasis, leading to the formation of blood clots. Platelets, otherwise known as thrombocytes, are small, irregularly shaped clear cell fragments derived from fragmentation of precursor megakaryocytes. The average lifespan of a platelet is 5 to 9 days. An abnormality or disease of the platelets leads to a condition called thrombocytopathy.
For example:
1. If the number of platelets is too low (called thrombocytopenia), excessive bleeding can occur.
Disorders leading to a reduced platelet count are:
Thrombocytopenia
Idiopathic thrombocytopenic purpura – also known as immune thrombocytopenic purpura (ITP)
Thrombotic thrombocytopenic purpura
Drug-induced thrombocytopenic purpura (for example heparin-induced thrombocytopenia (HIT))
Gaucher’s disease
Aplastic anemia
Onyalai
Alloimmune disorders
Fetomaternal alloimmune thrombocytopenia
2. If the number of platelets is too high (called thrombocytosis), blood clots (thrombosis) can form. Such clots in the blood may obstruct blood vessels and result in events like stroke, myocardial infarction, pulmonary embolism or the blockage of blood vessels to other parts of the body (e.g., arms, legs).
Disorders featuring an elevated count are:
Thrombocytosis, including essential thrombocytosis (elevated counts, either reactive or as an expression of myeloproliferative disease).
3. Thrombasthenia is a condition in which a decrease in function of platelets is observed.
Disorders leading to platelet dysfunction or reduced count are:
HELLP syndrome
Hemolytic-uremic syndrome
Chemotherapy
Dengue
Platelets play a significant role in the repair and regeneration of connective tissues. They release a multitude of growth factors, which have been used as an adjunct to wound healing, include:
Platelet-derived growth factor (PDGF), a potent chemotactic agent,
TGF beta, which stimulates the deposition of extracellular matrix.
Fibroblast growth factor,
Insulin-like growth factor 1,
Platelet-derived epidermal growth factor,
Vascular endothelial growth factor.
As said earlier, the function of platelets is the maintenance of hemostasis (the opposite of hemostasis is hemorrhage). This is achieved primarily by the formation of thrombi. When a damage to the endothelium of blood vessels occurs, the endothelial cells stop secretion of coagulation and aggregation inhibitors and instead secrete von Willebrand factor which initiate the maintenance of hemostasis after injury.
Hemostasis has three major steps: 1) vasoconstriction, 2) temporary blockage of a break by a platelet plug, and 3) blood coagulation, or formation of a clot that seals the hole until tissues are repaired.
The platelets get activated when a damage occurs to the blood vessel and the platelets clump at the site of blood vessel injury as a protective mechanism – a process that precedes the formation of a blood clot. This is the case if there is a damage to the endothelium otherwise thrombus formation should be considered seriously and must be inhibited immediately.
Vascular spasm is the first response as the blood vessels constrict to allow less blood to be lost during the injury to the blood vessel. In the second step – platelet plug formation – platelets stick together to form a temporary seal to cover the break in the vessel wall. The third and last step is called coagulation or blood clotting. Coagulation reinforces the platelet plug with fibrin threads that act as a “molecular glue”
Disorders of platelet adhesion or aggregation are:
Bernard-Soulier syndrome
Glanzmann’s thrombasthenia
Scott’s syndrome
von Willebrand disease
Hermansky-Pudlak Syndrome
Gray platelet syndrome
In normal hemostasis a thin layer of endothelial cells, that are lined with the inner surface of blood vessels, act to inhibit platelet activation by producing nitric oxide, endothelial-ADPase (which clears away the platelet activator, ADP – this activator otherwise can be blocked by the famous blockbuster clopidogrel), and PGI2 (also known as prostacyclin or eicosanoids, like PGD2, PGI2 is an inflammatory product that inhibits the aggregation of platelets). Intact blood vessels are central to moderating blood’s tendency to clot because the endothelial cells of intact vessels prevent blood clotting with a heparin-like molecule and thrombomodulin and prevent platelet aggregation with
1. Nitric oxide (NO), and
2. Prostacyclin (PGI2) – a member of eicosanoids family.
In this post, nitric oxide role in inhibiting platelet aggregation will be presented. Similarly Interaction of NO and prostacyclin (PGI2) in vascular endothelium will be presented as a separate post.
Nitric oxide (NO) and its role in inhibiting platelet aggregation:
Nitric oxide (NO) is known as the ‘endothelium-derived relaxing factor’, or ‘EDRF’. The endothelium (inner lining) of blood vessels uses NO to signal the surrounding smooth muscle to relax, thus resulting in vasodilation and increasing blood flow. NO is biosynthesized endogenously from L-arginine, oxygen and NADPH by various nitric oxide synthase (NOS) enzymes. Nitric oxide is highly reactive and yet diffuses freely across membranes that makes it ideal for a transient paracrine (between adjacent cells) and autocrine (within a single cell) signaling molecule.
This is an important cellular signaling molecule involved in many physiological and pathological processes. It is a powerful vasodilator with a short half-life of a few seconds in the blood. Low levels of nitric oxide production are important in protecting organs such as the liver from ischemic damage. Nitric oxide is considered an antianginal drug as it causes vasodilation, which can help with ischemic pain, known as angina, by decreasing the cardiac workload. By dilating the veins, nitric oxide lowers arterial pressure and left ventricular filling pressure. This vasodilation does not decrease the volume of blood the heart pumps, but rather it decreases the force the heart muscle must exert to pump the same volume of blood.
Chronic expression of NO is associated with various carcinomas and inflammatory conditions including Type-1 diabetes, multiple sclerosis, arthritis and ulcerative colitis.
Endothelium-derived relaxing factor (EDRF), the best-characterized is nitric oxide (NO), is produced and released by the endothelium to promote smooth muscle relaxation. EDRF was discovered and characterized by Robert F. Furchgott, a winner of the Nobel Prize in Medicine in 1998 with his co-researchers Louis J. Ignarro and Ferid Murad.
According to Furchgott’s website at SUNY Downstate Medical Center, “…we are investigating whether the endothelium-derived relaxing factor (EDRF) is simply nitric oxide or a mixture of substances”.
Although there is strong evidence that nitric oxide elicits vasodilation, there is some evidence tying this effect to neuronal rather than endothelial reactions. http://www.nature.com/jhh/journal/v15/n4/abs/1001165a.html.
The article says that “The possibility that neuronal rather than endothelial production of NO might play a significant role in the aetiology of essential hypertension is a promising area for future human research”.
Mechanism of Platelet Aggregation:
Platelets aggregate, or clump together, using fibrinogen and von Willebrand factor (vWF) as a connecting agent. The most abundant platelet aggregation receptor is glycoprotein IIb/IIIa (gpIIb/IIIa) which is a calcium-dependent receptor for fibrinogen, fibronectin, vitronectin, thrombospondin, and vWF. Other receptors include GPIb-V-IX complex (vWF) and GPVI (collagen).
Activated platelets will adhere, via glycoprotein (GP) Ia, to the collagen that is exposed by endothelial damage. Aggregation and adhesion act together to form the platelet plug. Myosin and actin filaments in platelets are stimulated to contract during aggregation, further reinforcing the plug. Platelet aggregation is stimulated by ADP, thromboxane, and α2 receptor-activation, and further enhanced by exogenous administration of anabolic steroids.
In an injury to the blood vessel, once the blood clot takes control of the bleeding, the aggregated platelets help the healing process by secreting chemicals that promote the invasion of fibroblasts from surrounding connective tissue into the wounded area to completely heal the wound or form a scar. The obstructing clot is slowly dissolved by the fibrinolytic enzyme, plasmin, and the platelets are cleared by phagocytosis.
Possible usefulness of measuring GP IIb-IIIa content as a marker of increased platelet reactivity is discussed in the following very recent (2011) reveiw article: “Glycoprotein IIb-IIIa content and platelet aggregation in healthy volunteers and patients with acute coronary syndrome”. http://www.ncbi.nlm.nih.gov/pubmed/21329420
Further readings:
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3134593/?tool=pubmed
http://www.ncbi.nlm.nih.gov/pubmed/2620689
http://pharmaceuticalintelligence.com/2012/07/25/nitric-oxide-production-in-systemic-sclerosis/
http://pharmaceuticalintelligence.com/2012/08/10/nitric-oxide-chemistry-and-function/
http://pharmaceuticalintelligence.com/2012/08/05/nitric-oxide-a-short-historic-perspective-7/
http://pharmaceuticalintelligence.com/2012/07/16/nitric-oxide-in-bone-metabolism/
http://pharmaceuticalintelligence.com/2012/06/22/bone-remodelling-in-a-nutshell/
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2717403/?tool=pubmed
http://www.ncbi.nlm.nih.gov/pubmed/7605019
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