Experimental Biology Meeting
Experimental Biology 2008**
April 5 – 9, 2008
San Diego, CA
AFMR-Translational Medical Research Development Workshop*
Saturday, April 5, 2008 – 4:00 pm to 7:00 pm – Room 25A
Strategies for Innovation and Interdisciplinary Translational Research:
Research and Career Benefits and Barriers
Deborah Zucker, MD, PhD, Chair
Tufts Medical Center
http://www.afmr.org/Translational-Symposia-08.cgi
Symposia I*
Monday, April 7, 2008 - 10:30 am to 12:30 pm - Ballroom 20A
Acute Lung Injury and the Acute Respiratory Distress Syndrome (ALI/ARDS): Therapeutics on the Horizon
Timothy M. Moore, M.D. and Brian William Fouty, M.D., Chairs
University of South Alabama College of Medicine
307 University BLVD MSB 3340; Center for Lung Biology
Telephone: (251) 460-6790
Fax: (251) 460-7452
E-Mail: bfouty@jaguar1.usouthal.edu or tmoore@jaguar1.usouthal.edu
Abstract: In 1967, Ashbaugh et al. described 12 patients exhibiting a condition of acute hypoxemic respiratory failure which they called the adult respiratory distress syndrome (Acute respiratory distress in adults. Lancet. 1967 Aug 12;2(7511):319-23). Since then, the clinical syndromes of acute lung injury (ALI) and its more severe manifestation, the acute respiratory distress syndrome (ARDS), have been recognized as important clinical problems affecting patients in all subspecialties; it is no longer a disease of interest only to pulmonologists and critical care physicians at academic centers. Using the consensus definition for ALI/ARDS established in 1994, the most recent United States population-based studies estimate 190,000 cases of ALI/ARDS occur annually with 74,000 deaths each year (a mortality rate of 35% - 40%).
Acute lung injury remains a syndrome without a well-defined etiology. Reduction in mortality has resulted primarily from improved supportive care. At a recent “state-of -the-art” pulmonary research conference (Aspen Lung Conference, 2007) where findings from the NHLBI ARDS Network clinical trials were summarized, decreasing mechanical ventilation tidal volumes and implementing restrictive fluid management policies were highlighted as the only proven measures to reduce overall mortality. Emerging from this conference, however, was the hope that new pharmacologic, biologic, and genetic approaches to understanding and treating ALI would improve outcomes in the ensuing decade. We are submitting this symposium proposal to highlight the current recommendations for treating ALI/ARDS and to inform clinicians and scientists about current research which will hopefully be translated into clinical practice within the next 10 years.
Our symposium offers an evaluation of current clinical practice for treating ALI/ARDS, but emphasizes ongoing basic and clinical research that will hopefully reduce the morbidity and mortality of ALI/ARDS in the future. In keeping with the mission of the AFMR, speakers have been selected who are emerging as leaders in basic and translational research relating to acute lung injury. The invited speakers work at established NIH-funded centers and have been recommended by senior investigators. We believe that these individuals’ highly collaborative work represents a cross-section of the overall direction in which ALI/ARDS research and clinical practice is headed in the early 21st century.
At the symposium’s conclusion, attendees will be familiar with the evidence used to support the current recommendations for the treatment of patients with ALI/ARDS. More importantly they will be introduced to the basic and translational research that will likely alter therapy for this disease within the next several years.
Presenters/Discussants:
Lorraine Ware, MD
“Current evidence-based practices in managing ALI/ARDS”
Timothy M. Moore, MD, PhD
“Translational approaches to studying ALI/ARDS”
Jeffrey R. Jacobson, MD
“Pharmacologic therapies on the horizon for treating ALI/ARDS”
Diego F. Alvarez, MD, PhD
“Cell-based therapies on the horizon for treating ALI/ARDS”
James P. Maloney, MD
“Genetic factors impacting therapies in ALI/ARDS”
Symposia II*
Monday, April 7, 2008 - 3:15 to 5:15 pm - Ballroom 20A
Focus on the Fibroblast: Therapeutic Target for the Failing Heart?
Carlin S. Long, M.D., Chair
University of Colorado
Denver Health Medical Center
777 Bannock St, Box 0960
Denver, CO 80204
Telephone: 303-436-5498
Fax: 303-436-7739
E-Mail: clong@dhha.org
Abstract: Cardiac fibroblasts play a central role in the maintenance of extracellular matrix in the normal heart and as mediators of inflammatory and fibrotic myocardial remodeling in the injured and failing heart. The contribution of cardiac fibrosis as an independent risk factor in the outcome of heart failure is well known. Less well known however is the concept that some of the well accepted drug therapies in heart failure may, in fact, derive at least some of their benefit from actions on cardiac fibroblasts, including inhibitors of renin-angiotensin-aldosterone systems, endothelin receptor antagonists, statins, anti-cytokine therapies, matrix metalloproteinase inhibitors, and novel antifibrotic/anti-inflammatory agents. These observations point the way to future challenges in cardiac fibroblast biology and suggest that the fibroblast may be a therapeutic target in heart disease. This symposium will focus on new developments in the field of cardiac fibroblast biology as it relates to the development and maintenance of the failing heart.
Presenters/Discussants:
Carlin S. Long, MD
“Cytokine modulation of cardiac fibroblast migration”
Francisco Villarreal, MD, PhD
“Role of cAMP-EPAC signaling in modulating cardiac fibroblast collagen synthesis”
Barry Greenberg, MD
“Angiotensin receptor signaling in the cardiac fibroblast”
Robert S. Ross, MD
“Integrins, focal adhesions and the cardiac fibroblast”
Symposia III*
Tuesday, April 8, 2008, 3:15 to 5:15 pm - Room 23
Inhibiting Cyclooxygenase with Coxibs and NSAIDs: Efficacy vs. Cardiovascular Risk
Allison B. Reiss, M.D., Co-chair
Winthrop University Hospital
222 Station Plaza North, Suite 511-A
Mineola, NY 11501
Telephone: 516-663-3455
Fax: 516-663-4710
E-Mail: AReiss@winthrop.org
Edwin S.L. Chan, M.D., Co-chair
New York University School of Medicine
550 First Avenue, Room NB16N1
New York, NY 10016
Telephone: 212-263-6275
Fax: 212-263-1048
E-Mail: chane01@nyu.edu
Abstract: Nonsteroidal anti-inflammatory drugs (NSAIDs), and selective inhibitors of cyclooxygenase-2 (COX-2) are highly effective anti-inflammatory and analgesic drugs that exert their action by preventing the formation of prostanoids. Non-selective NSAIDs are widely used in both over-the-counter and prescription settings. Inhibition of prostaglandins by NSAIDs may result in untoward cardiorenal effects, including hypertension, fluid and electrolyte abnormalities, congestive heart failure, acute renal failure, and nephrotic syndrome. The association of NSAIDs, including COX-2 inhibitors, with elevated risk of myocardial infarction and stroke is a major public health concern. The worldwide withdrawal of rofecoxib because of adverse cardiovascular events has complicated clinical decision making for the physician treating patients with pain and inflammation. Whether the benefits of COX-2 inhibitors ("coxibs") and NSAIDs outweigh their cardiovascular risks is an ongoing debate. The mechanisms by which these drugs might predispose individuals to heart disease and stroke are not completely understood.
This session will focus on the latest progress in NSAIDs research including clinical trial results, proposed mechanisms, prescribing recommendations and guidelines and promising new drugs in development. It will explore the underlying biochemical processes that confer cardiovascular hazard.
This topic is of great interest because physicians in multiple specialties have had no choice but to change their prescribing habits for patients who were getting good pain relief on previous regimens. Doctors must calculate with their patients the risks and benefits of the available drug options. Many are concerned that this may translate into undertreated pain. There is also concern that in a general backlash against this class of drugs, researchers will shy away from experimenting with new treatments that utilize their anti-inflammatory properties.
Presenters/Discussants:
Tilo Grosser, MD
“Biological basis for the cardiovascular consequences of COX inhibition“
Michael H. Pillinger, MD
“Prostaglandins as Anti-inflammatory Agents”
David J. Graham, MD, MPH
“Regulatory Perspective on COX-2 Inhibitors: The Safety Issue“
Symposia IV*
Wednesday, April 9, 2008, 10:30 am to 12:30 pm - Room 22
Cardiac Hormones: For the Treatment of Acute Myocardial Infarctions, Congestive Heart Failure, Acute Renal Failure and Cancer
David L. Vesely, M.D., Chair
University of South Florida Health Sciences Center
13000 Bruce B. Downs Blvd. (VAR 151)
Tampa, FL 33612
Telephone: (813) 972-7624
Fax: (813) 972-7623
E-Mail: david.vesely@va.gov
Abstract: This is an exciting time for the translational research of cardiac hormones in the treatment of human disease. In the last few months cardiac hormones (i.e. atrial natriuretic peptides) have been shown for the first time to decrease the size of infarcts after acute myocardial infarctions and to cure 80% of human pancreatic cancers and two-thirds of human breast cancers in athymic mice without any surgery. Even the human pancreatic cancers that were not cured had their volume decreased to less than 10% with each of four cardiac hormones and with vessel dilator to less than 2% compared to untreated animals. None of the treated human pancreatic cancer animals died of cancer – they lived a normal lifespan and died of old age. Human pancreatic cancer is the worst of the common cancers with only a four month survival and this four month survival is for patients treated with surgery, current chemotherapy, and radiation which together extend the life of human pancreatic cancer patients by one to two months. In the past year the mechanism of how cardiac hormones cure cancer(s) has been largely elucidated in cancer cells: They target the RAS/RAF-MEK 1/2-ERK 1/2 kinase cascade by inhibiting up to 98% of the activation (phosphorylation) of both MEK 1/2 and ERK 1/2 and block completely the stimulation of ERK by mitogens such as epideral growth factor resulting in decreased DNA synthesis within the nucleus of the cancer cell.
Cardiac hormones (i.e. atrial natriuretic peptides) consist of a family of peptides which are synthesized and then stored as three different prohormones, i.e., 126 amino acid (a.a.) atrial natriuretic peptide (ANP), 108 a.a. brain natriuretic peptide (BNP) and 103 a.a. C-natriuretic peptide (CNP) prohormones. Within the 126 a.a. ANP prohormone are four peptide hormones i.e. ANP, long acting natriuretic peptide (LANP), vessel dilator, and kaliuretic peptide with blood pressure lowering, natriuretic, diuretic and/or kaliuretic (i.e., potassium excreting) properties. Brain natriuretic peptide (BNP), so named because of its initial isolation from porcine brain, has subsequently been shown to be 10-fold more abundant in the heart than in the brain. Brain natriuretic peptide (BNP) has remarkable sequence homology to ANP with only four amino acids being different in the 17 a.a. ring structure common to both peptides. Brain natriuretic peptide is now utilized in many of the hospitals in the United States and Europe for the diagnosis and treatment of congestive heart failure (CHF) under the trade name Nesiritide or Natrecor. There is, however, considerable controversy as to which of the natriuretic peptides are best for the diagnosis and treatment of CHF and renal failure. This controversy will be addressed in the present symposia. Natrecor, since the last symposia, has been found to worsen renal function and cause almost 2-fold increase in death within 30 days of its infusion to treat CHF compared to placebo-treated patients. This will be discussed. The specific questions that this symposia will address are 1) “Which of the natriuretic peptides are beneficial and safe for the diagnosis and treatment of congestive heart failure, acute myocardial infarction, renal failure and cancer?”, and 2) “What is the evidence that the basic science findings can be translated to the treatment of congestive heart failure, acute myocardial infarction, renal failure and cancer in humans?”
This symposium will concentrate on: 1) The physiology and gene expression of the natriuretic peptides (Dr. Aldolfo de Bold), 2) The translation of basic science knowledge to the treatment of acute myocardial infarction with ANP and BNP (Dr. Burnett), 3) The translation of basic science knowledge to treatment of renal failure and these peptides circulating levels as a guide to hemodialysis (Dr. Hörl), and 4) The new data that cardiac hormones can eliminate human cancers (Dr. Vesely).
Presentation of the molecular biology, physiology and the potential clinical applications of the atrial natriuretic peptides in one symposium should generate wide interest among the attendees of EB2008. Completely new this year is data that ANP and BNP can reduce the size of infarction of the heart in animals. Dr. Burnett has begun a large study in humans with acute myocardial infarction, funded by the NIH, where persons have BNP infused for 8 hours when a patient presents with acute myocardial infarction. Results of this trial should be available for the 2008 EB meeting
Seven natriuretic peptides having been found to decrease up to 97% of human colon, ovarian, breast, prostate and pancreatic adenocarcinomas, melanomas of skin, glioblastoma of brain as well as small-cell and squamous carcinoma cells of the lung within 24 hours in vitro. New unpublished information from Dr. Vesely’s laboratory demonstrates that the four natriuretic peptides synthesized by the ANP gene eliminate up to 80% of human pancreatic adenocarcinomas growing in athymic mice. This new information will be presented at this symposia. The plan would be to utilize the four/five suggested speakers so the symposium would be two hours with each speaker’s presentation limited to 30 minutes including time for audience’s questions. The deBolds (husband and wife) team presentation will be limited to a total of 30 minutes for their combined presentation.
This session will offer to the audience the latest knowledge on cardiac hormones with respect to their physiology, biochemistry and clinical application(s). Future directions will be presented so the audience will know where these areas of investigation are headed in the future. One would expect that this will be an extremely well attended session as it will be very multidisciplinary from basic science to clinical application(s) presented by the investigators who have made major contributions to this knowledge.
Presenters/Discussants:
Adolfo J. de Bold, OC, PhD, FRSC
Mercedes de Bold, PhD
John C. Burnett, Jr., MD
“Natriuretic Peptides: Novel therapeutic agents for acute myocardial infarction”
Walter H. Hörl, MD, PhD, FRCP
“Natriuretic peptides in acute and chronic kidney disease and during renal replacement therapy”
*This symposium is supported by a grant from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH) and its contents are solely the responsibility of the authors and do not necessarily represent the official view of NCRR or NIH.
 Prior EB Symposia
2007
2006
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