One of the nation's foremost vascular biologists, Dr. Timothy T. Hla, has been appointed as the new director of the Center for Vascular Biology and professor of pathology and laboratory medicine at Weill Cornell Medical College.
Founded in 1995, Weill Cornell's Center for Vascular Biology is dedicated to biomedical research into vascular disease -- specifically atherosclerosis and thrombosis -- and the contributing role of the vascular system in a wide range of diseases.
Previously leading the Center was its founding director, Dr. David P. Hajjar, executive vice provost and senior executive vice dean; dean of the Graduate School of Medical Sciences; and the Frank H.T. Rhodes Distinguished Professor of Cardiovascular Biology and Genetics and professor of biochemistry and pathology at Weill Cornell Medical College. After 15 years as director, Dr. Hajjar elected to step down in order to focus on comprehensive Medical College initiatives and responsibilities.
"Vascular biology is a tremendously fertile area for research. By better understanding the role of blood vessels in disease, we will improve our ability to develop new treatments for conditions from cancer to arthritis to heart disease," Dr. Hajjar says. "An accomplished researcher, administrator and teacher, Timothy Hla is uniquely qualified to lead this effort at Weill Cornell. Notably, he has made significant contributions to vascular biology across areas including the molecular basis of angiogenesis, the biology of the COX-2 pathway, sphingolipids as mediators in health and disease, and lipid mediators."
Dr. Hla's research into COX-2 has furthered scientific understanding of how this pathway is a molecular determinant of cancer progression and potentially a key component of the link between inflammation and cancer. He was the first to demonstrate exaggerated COX-2 expression in human chronic inflammatory disorders -- specifically rheumatoid arthritis. He subsequently discovered that COX-2 is over-expressed in human colorectal cancer tissues, and demonstrated that COX-2 over-expression in the mammary glands of transgenic mice results in invasive mammary cancer development.
As a postdoctoral fellow, Dr. Hla worked to clone mRNAs that arise during in vitro angiogenesis. During these efforts, he was able to clone the DNA for the orphan receptor EDG-1 (endothelial differentiation gene-1) -- the first-ever example of this kind of receptor in mammalian cell differentiation. And, in searching for EDG-1's binding site, he identified a platelet-derived lipid molecule called sphingosine-1-phosphate (S1P) -- a major discovery that brought together the fields of vascular biology and sphingolipid signaling. This research established S1P as an extracellular lipid mediator that acts in the extracellular environment to communicate between cells by binding to cell surface receptors. S1P receptor modulators are now in Phase III clinical trials to control inflammation in the treatment of multiple sclerosis.
Following the identification of the S1P receptor, Dr. Hla turned his attention to characterizing the signaling properties of S1P receptors and their actions on vascular cells, demonstrating the mechanisms behind formation of a stable vessel. He also showed that S1P signaling is important to tumor angiogenesis.
Dr. Hla's investigative studies have been well funded by the National Institutes of Health (NIH) and other granting agencies. Currently, Dr. Hla serves as principal investigator on two NIH-sponsored R01 awards. He was also granted a MERIT award from the NIH in 2006. In addition, his project grant was renewed by the NIH -- work that he will be continuing at Weill Cornell.
Dr. Hla has contributed significantly to a number of professional organizations and to the editorial boards of leading scientific journals. He has served on the council and as secretary-treasurer of the North American Vascular Biology Organization, and has served as a co-organizer of the 2003, 2005 and 2007 FASEB summer research conferences on lysophospholipids. He serves as editor-in-chief of the publications Prostaglandins and Other Lipid Mediators. He has also served as a member of the editorial boards of the Journal of Biological Chemistry, Vascular Pharmacology, The FASEB Journal, and Arthrosclerosis, Thrombosis and Vascular Biology.
Originally from Burma, Dr. Hla received his Ph.D. in biochemistry from George Washington University in 1988. Upon completion of a postdoctoral fellowship in the Laboratory of Molecular Biology at the American Red Cross, he was appointed Scientist I/assistant professor in the Department of Molecular Biology at George Washington University in 1991. He was promoted to Scientist II/associate professor in 1994. In 1996, Dr. Hla was recruited to the University of Connecticut School of Medicine, where he was appointed associate professor. Dr. Hla was appointed director of the Cell Biology Graduate Program in 1997, and director of the school's Center for Vascular Biology in 1998. He was promoted to professor of cell biology and of genetics and developmental biology in 2000.
"I very much look forward to collaborating with my new colleagues at Weill Cornell as we pursue a number of promising avenues for research," says Dr. Hla. "Specifically, we will be looking at the role of S1P signaling in regulating tumor development and the various ways by which COX-2 promotes cancer and angiogenesis. The longstanding strength in research areas of vascular biology, angiogenesis and hematology/oncology will allow us to branch into fruitful avenues in both basic and clinical research."
The Center for Vascular Biology
Under the direction of Dr. David P. Hajjar, the Center for Vascular Biology at Weill Cornell Medical College has made major contributions -- elucidating the biology of cells of the artery wall, the blood cells with which they interact, and the principal cellular and genetic changes that take place in arteries that predispose them to the formation of plaque and blood clots. Researchers at the Center have studied the interactions between blood cells and vessels, testing the hypothesis that mediators -- substances including nitrogen oxides, reactive oxygen species and growth factors -- regulate blood-vessel cell activity and plaque formation, and that atherosclerosis acts like a blood clot, forming a "response to injury."
Weill Cornell Medical College
Weill Cornell Medical College, Cornell University's medical school located in New York City, is committed to excellence in research, teaching, patient care and the advancement of the art and science of medicine, locally, nationally and globally. Physicians and scientists of Weill Cornell Medical College are engaged in cutting-edge research from bench to bedside, aimed at unlocking mysteries of the human body in health and sickness and toward developing new treatments and prevention strategies. In its commitment to global health and education, Weill Cornell has a strong presence in places such as Qatar, Tanzania, Haiti, Brazil, Austria and Turkey. Through the historic Weill Cornell Medical College in Qatar, the Medical College is the first in the U.S. to offer its M.D. degree overseas. Weill Cornell is the birthplace of many medical advances -- including the development of the Pap test for cervical cancer, the synthesis of penicillin, the first successful embryo-biopsy pregnancy and birth in the U.S., the first clinical trial of gene therapy for Parkinson's disease, and most recently, the world's first successful use of deep brain stimulation to treat a minimally conscious brain-injured patient. Weill Cornell Medical College is affiliated with NewYork-Presbyterian Hospital, where its faculty provides comprehensive patient care at NewYork-Presbyterian Hospital/Weill Cornell Medical Center. The Medical College is also affiliated with the Methodist Hospital in Houston, making Weill Cornell one of only two medical colleges in the country affiliated with two U.S. News Honor Roll hospitals.
Source: NewYork-Presbyterian Hospital
четверг, 26 мая 2011 г.
Cell Death Receptor Links Cancer Susceptibility And Inflammation
For over 10 years, Wafik S. El-Deiry, MD, PhD, Professor of Medicine, Genetics, and Pharmacology at the University of Pennsylvania School of Medicine, has been pursuing a cancer-targeting molecule called TRAIL and its molecular partners. TRAIL is normally produced by immune cells and curtails tumor spread by binding to a specialized receptor on a tumor's surface.
"However, in cancer patients who often have suppressed immunity, and for reasons we still don't understand, there isn't enough TRAIL being produced, so tumors are not suppressed," explains El-Deiry, who is also Co-Program Leader of the Radiation Biology Program for the Abramson Cancer Center at Penn.
Most recently, El-Deiry and colleagues demonstrated for the first time a link between TRAIL's receptor and cancer susceptibility, as reported online December 13, 2007 in the Journal of Clinical Investigation in advance of the January 2008 print issue. Unexpectedly, they also found a connection via Trail between inflammation and cancer susceptibility.
Mice engineered without the TRAIL receptor on their cells versus healthy controls developed larger and more tumors in their livers and other organs after being challenged with a chemical carcinogen or radiation. The team also bred TRAIL receptor knock-out mice with mice genetically engineered to get B-cell lymphomas that metastasize to the liver. Their offspring displayed more liver tumors compared to controls. "This is the first direct in vivo evidence that loss of the tumor death-inducing TRAIL receptor confers cancer susceptibility," says El-Deiry.
When intact, TRAIL and its receptor decrease the influx of inflammatory cells and molecules that can lead to cancer. New models of cancer have suggested a link between inflammation and cancer in the last five years, and El-Deiry is in the early stages of trying to understand this connection with respect to the TRAIL pathway.
For example, in this study, the mice without the TRAIL receptor that were irradiated developed chronic pneumonia, an inflammatory response, as well tumors, evidence pointing to the connection between cancer and inflammation via TRAIL. "One benefit of this work is that it provides a new and unanticipated model implicating a TRAIL pathway deficiency in the chronic toxicity of radiation therapy," he notes. Inflammation is a common late and serious side-effect of radiation treatment in people.
El-Deiry and his team are now looking within tumor tissue for inflammatory molecules as clues to how cancer and inflammation are coupled. "Our work with TRAIL and its receptor in mouse models represents a new way to look at cancer susceptibility and its potential therapy in humans as well as new ways to decrease debilitating radiation side-effects experienced by cancer patients," says El-Deiry.
Co-authors in addition to El-Deiry are Niklas Finnberg from Penn and Andres J.P. Klein-Szanto from Fox Chase Cancer Center, Philadelphia. This research was funded in part by the National Cancer Institute.
PENN Medicine is a $3.5 billion enterprise dedicated to the related missions of medical education, biomedical research, and excellence in patient care. PENN Medicine consists of the University of Pennsylvania School of Medicine (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System.
Penn's School of Medicine is currently ranked #3 in the nation in U.S. News & World Report's survey of top research-oriented medical schools; and, according to most recent data from the National Institutes of Health, received over $379 million in NIH research funds in the 2006 fiscal year. Supporting 1,400 fulltime faculty and 700 students, the School of Medicine is recognized worldwide for its superior education and training of the next generation of physician-scientists and leaders of academic medicine.
The University of Pennsylvania Health System includes three hospitals its flagship hospital, the Hospital of the University of Pennsylvania, rated one of the nation's "Honor Roll" hospitals by U.S. News & World Report; Pennsylvania Hospital, the nation's first hospital; and Penn Presbyterian Medical Center a faculty practice plan; a primary-care provider network; two multispecialty satellite facilities; and home care and hospice.
The Abramson Cancer Center (ACC) of the University of Pennsylvania is a national leader in cancer research, patient care, and education. The pre-eminent position of the Cancer Center is reflected in its continuous designation as a Comprehensive Cancer Center by the National Cancer Institute for 30 years, one of 39 such Centers in the United States. The ACC is dedicated to innovative and compassionate cancer care. The clinical program, comprised of a dedicated staff of physicians, nurse practitioners, nurses, social workers, physical therapists, nutritionists and patient support specialists, currently sees over 50,000 outpatient visits, 3400 inpatient admissions, and provides over 25,000 chemotherapy treatments, and more than 65,000 radiation treatments annually. Not only is the ACC dedicated to providing state-of-the-art cancer care, the latest forms of cancer prevention, diagnosis, and treatment are available to our patients through clinical themes that developed in the relentless pursuit to eliminate the pain and suffering from cancer. In addition, the ACC is home to the 300 research scientists who work relentlessly to determine the pathogenesis of cancer. Together, the faculty is committed to improving the prevention, diagnosis and treatment of cancer.
University of Pennsylvania School of Medicine
3600 Market St., Ste 240
Philadelphia, PA 19104
United States
med.upenn
"However, in cancer patients who often have suppressed immunity, and for reasons we still don't understand, there isn't enough TRAIL being produced, so tumors are not suppressed," explains El-Deiry, who is also Co-Program Leader of the Radiation Biology Program for the Abramson Cancer Center at Penn.
Most recently, El-Deiry and colleagues demonstrated for the first time a link between TRAIL's receptor and cancer susceptibility, as reported online December 13, 2007 in the Journal of Clinical Investigation in advance of the January 2008 print issue. Unexpectedly, they also found a connection via Trail between inflammation and cancer susceptibility.
Mice engineered without the TRAIL receptor on their cells versus healthy controls developed larger and more tumors in their livers and other organs after being challenged with a chemical carcinogen or radiation. The team also bred TRAIL receptor knock-out mice with mice genetically engineered to get B-cell lymphomas that metastasize to the liver. Their offspring displayed more liver tumors compared to controls. "This is the first direct in vivo evidence that loss of the tumor death-inducing TRAIL receptor confers cancer susceptibility," says El-Deiry.
When intact, TRAIL and its receptor decrease the influx of inflammatory cells and molecules that can lead to cancer. New models of cancer have suggested a link between inflammation and cancer in the last five years, and El-Deiry is in the early stages of trying to understand this connection with respect to the TRAIL pathway.
For example, in this study, the mice without the TRAIL receptor that were irradiated developed chronic pneumonia, an inflammatory response, as well tumors, evidence pointing to the connection between cancer and inflammation via TRAIL. "One benefit of this work is that it provides a new and unanticipated model implicating a TRAIL pathway deficiency in the chronic toxicity of radiation therapy," he notes. Inflammation is a common late and serious side-effect of radiation treatment in people.
El-Deiry and his team are now looking within tumor tissue for inflammatory molecules as clues to how cancer and inflammation are coupled. "Our work with TRAIL and its receptor in mouse models represents a new way to look at cancer susceptibility and its potential therapy in humans as well as new ways to decrease debilitating radiation side-effects experienced by cancer patients," says El-Deiry.
Co-authors in addition to El-Deiry are Niklas Finnberg from Penn and Andres J.P. Klein-Szanto from Fox Chase Cancer Center, Philadelphia. This research was funded in part by the National Cancer Institute.
PENN Medicine is a $3.5 billion enterprise dedicated to the related missions of medical education, biomedical research, and excellence in patient care. PENN Medicine consists of the University of Pennsylvania School of Medicine (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System.
Penn's School of Medicine is currently ranked #3 in the nation in U.S. News & World Report's survey of top research-oriented medical schools; and, according to most recent data from the National Institutes of Health, received over $379 million in NIH research funds in the 2006 fiscal year. Supporting 1,400 fulltime faculty and 700 students, the School of Medicine is recognized worldwide for its superior education and training of the next generation of physician-scientists and leaders of academic medicine.
The University of Pennsylvania Health System includes three hospitals its flagship hospital, the Hospital of the University of Pennsylvania, rated one of the nation's "Honor Roll" hospitals by U.S. News & World Report; Pennsylvania Hospital, the nation's first hospital; and Penn Presbyterian Medical Center a faculty practice plan; a primary-care provider network; two multispecialty satellite facilities; and home care and hospice.
The Abramson Cancer Center (ACC) of the University of Pennsylvania is a national leader in cancer research, patient care, and education. The pre-eminent position of the Cancer Center is reflected in its continuous designation as a Comprehensive Cancer Center by the National Cancer Institute for 30 years, one of 39 such Centers in the United States. The ACC is dedicated to innovative and compassionate cancer care. The clinical program, comprised of a dedicated staff of physicians, nurse practitioners, nurses, social workers, physical therapists, nutritionists and patient support specialists, currently sees over 50,000 outpatient visits, 3400 inpatient admissions, and provides over 25,000 chemotherapy treatments, and more than 65,000 radiation treatments annually. Not only is the ACC dedicated to providing state-of-the-art cancer care, the latest forms of cancer prevention, diagnosis, and treatment are available to our patients through clinical themes that developed in the relentless pursuit to eliminate the pain and suffering from cancer. In addition, the ACC is home to the 300 research scientists who work relentlessly to determine the pathogenesis of cancer. Together, the faculty is committed to improving the prevention, diagnosis and treatment of cancer.
University of Pennsylvania School of Medicine
3600 Market St., Ste 240
Philadelphia, PA 19104
United States
med.upenn
B-Cell Development And Yin And Yang 1
A new paper in Genes & Development reveals how a protein called Yin Yang 1 regulates early B cell development.
B cells are the antibody-producing cells of the body, which form the basis for the body's recognition of foreign pathogens. B cells undergo a multi-staged maturation process, whereby variable segments of their genome are recombined in various different ways to produce the diversity of antigen recognition that underlies the immune system.
In their upcoming paper, Dr. Yang Shi (Harvard Medical School) and colleagues demonstrate that Yin Yang 1 (YY1) plays a crucial role in regulating VH to DHJH recombination, an essential event for the differentiation of pro-B cell to pre-B cell.
"VHDHJH recombination is a fascinating, but incompletely understood process, which is initiated with the movement of the IgH locus from the periphery to the center of the nucleus where the locus undergoes contraction and recombination. YY1 represents the second transcription factor demonstrated to control IgH locus contraction, thus offering a unique opportunity to investigate molecular mechanisms that control this important process," explains Dr. Shi.
Contact: Heather Cosel
Cold Spring Harbor Laboratory
B cells are the antibody-producing cells of the body, which form the basis for the body's recognition of foreign pathogens. B cells undergo a multi-staged maturation process, whereby variable segments of their genome are recombined in various different ways to produce the diversity of antigen recognition that underlies the immune system.
In their upcoming paper, Dr. Yang Shi (Harvard Medical School) and colleagues demonstrate that Yin Yang 1 (YY1) plays a crucial role in regulating VH to DHJH recombination, an essential event for the differentiation of pro-B cell to pre-B cell.
"VHDHJH recombination is a fascinating, but incompletely understood process, which is initiated with the movement of the IgH locus from the periphery to the center of the nucleus where the locus undergoes contraction and recombination. YY1 represents the second transcription factor demonstrated to control IgH locus contraction, thus offering a unique opportunity to investigate molecular mechanisms that control this important process," explains Dr. Shi.
Contact: Heather Cosel
Cold Spring Harbor Laboratory
A Potential Sugar Fix For Tumors
Researchers at the Duke School of Medicine apparently have solved the riddle of why cancer cells like sugar so much, and it may be a mechanism that could lead to better cancer treatments.
Jonathan Coloff, a graduate student in Assistant Professor Jeffrey Rathmell's laboratory in the Duke Department of Pharmacology and Cancer Biology, has found that the tumor cells use glucose sugar as a way to avoid programmed cell death. They make use of a protein called Akt, which promotes glucose metabolism, which in turn regulates a family of proteins critical for cell survival, the researchers shared during an April 15 presentation at the American Association of Cancer Research Annual Meeting in San Diego.
In normal cells, growth factors regulate metabolism and cell survival. Removing these factors leads to loss of glucose uptake and metabolism and cell death. Cancer cells, however, maintain glucose metabolism and resist cell death, even when deprived of growth factors.
To study how Akt might affect these processes, Coloff and colleagues introduced a cancer-causing form of Akt called myrAkt, into cells that depend on growth factor to survive. The mutant form of Akt allowed cells to maintain glucose usage and survive even when no growth factors were present, allowing them to bypass a normal safeguard used by cells to prevent cancer development.
The death of normal cells after growth factors are removed is partly accomplished by two proteins called Mcl-1 and Puma. But the cancer-causing version of Akt prevents these two proteins from accomplishing their tasks, allowing the cell to survive when it shouldn't.
Once glucose was withdrawn from the environment, however, Akt was no longer able to maintain regulation of the key targeted proteins Mcl-1 and Puma, and the cells died.
"Akt's dependence on glucose to provide an anti-cell-death signal could be a sign of metabolic addiction to glucose in cancer cells, and could give us a new avenue for a metabolic treatment of cancer," said Dr. Rathmell.
Source: Mary Jane Gore
Duke University Medical Center
Jonathan Coloff, a graduate student in Assistant Professor Jeffrey Rathmell's laboratory in the Duke Department of Pharmacology and Cancer Biology, has found that the tumor cells use glucose sugar as a way to avoid programmed cell death. They make use of a protein called Akt, which promotes glucose metabolism, which in turn regulates a family of proteins critical for cell survival, the researchers shared during an April 15 presentation at the American Association of Cancer Research Annual Meeting in San Diego.
In normal cells, growth factors regulate metabolism and cell survival. Removing these factors leads to loss of glucose uptake and metabolism and cell death. Cancer cells, however, maintain glucose metabolism and resist cell death, even when deprived of growth factors.
To study how Akt might affect these processes, Coloff and colleagues introduced a cancer-causing form of Akt called myrAkt, into cells that depend on growth factor to survive. The mutant form of Akt allowed cells to maintain glucose usage and survive even when no growth factors were present, allowing them to bypass a normal safeguard used by cells to prevent cancer development.
The death of normal cells after growth factors are removed is partly accomplished by two proteins called Mcl-1 and Puma. But the cancer-causing version of Akt prevents these two proteins from accomplishing their tasks, allowing the cell to survive when it shouldn't.
Once glucose was withdrawn from the environment, however, Akt was no longer able to maintain regulation of the key targeted proteins Mcl-1 and Puma, and the cells died.
"Akt's dependence on glucose to provide an anti-cell-death signal could be a sign of metabolic addiction to glucose in cancer cells, and could give us a new avenue for a metabolic treatment of cancer," said Dr. Rathmell.
Source: Mary Jane Gore
Duke University Medical Center
Study Findings Have Implications For Development Of Pain Relieving Drugs
Morphine and other opioids are widely used to treat both acute and chronic pain yet their benefits are often limited because some people experience side effects or do not respond to them efficiently.
Now, new research from the University of North Carolina at Chapel Hill's Center for Neurosensory Disorders, based within the School of Dentistry, has identified genetic variants that offer insight into individual responses to morphine. Researchers said long-term implications of the findings may include the development of drugs with greater pain-relieving effects and fewer side effects, as well as the development of genetic tests predicting individual responses to these medications.
Up to one-third of people treated with opioids develop substantial side effects, said Luda Diatchenko, M.D., Ph.D., an associate professor in the center and the study's co-senior author. In addition, there is more than a 10-fold difference in the responses some patients show a very good response and others show a very poor response to the same amount.
The study, which appeared in the March 15, 2009, issue of the journal Human Molecular Genetics, identifies new variations in the gene that produces the OPRM1 receptor, the primary biological target for opioid analgesics such as morphine. The research also provides evidence that the receptor carries many more genetic variations than previously thought.
"Genetic variations in this receptor play a crucial role in individual responsiveness to these drugs, but we currently have very little understanding of its genetic structures and molecular and cellular mechanisms," Diatchenko said.
She added that collaboration with the National Institutes of Health's National Center for Biotechnology Information had provided crucial insights into these mechanisms. Bioinformatics is an emerging field combining information technology and biology.
"Bioinformatics has become one of the driving forces of modern biomedical science," said Svetlana Shabalina, Ph.D., a senior scientist at the National Center for Biotechnology Information and the other study co-senior author. "Bioinformatic tools are indispensable for the identification of underlying genetic causes in complex disorders. We expect many important discoveries in this field."
"The outcomes of these studies are very exciting and are likely to lead to new diagnostic tests that will permit clinicians to predict a patient's risk for inadequate or adverse responses to opioids," said William Maixner, D.D.S., Ph.D., co-author of the study, director of the Center for Neurosensory Disorders and professor of endodontics and pharmacology in the UNC schools of dentistry and medicine, respectively. "The outcomes may also enable the development of a new class of opioids that are safer and more effective than those currently available," he said.
The study was funded by grants from the National Institutes of Health.
Other study authors from the UNC School of Dentistry are Pavel Gris, Ph.D.; Josee Gauthier and Inna E. Tchivileva, M.D. Additional study authors are Dmitri V. Zaykin, Ph.D., and Kyoko Shibata, Ph.D., of the National Institute of Environmental Health Sciences; Aleksey Y. Ogurtsov, Ph.D., of the National Center for Biotechnology Information; Inna Belfer, M.D., Ph.D., of the National Institute of Dental and Craniofacial Research, the National Institute on Alcohol Abuse and Alcoholism and the University of Pittsburgh; Bikashkumar Mishra, M.D., and Carly Kiselycznyk, Ph.D. of the NIDCR and NIAAA; Margaret R. Wallace, Ph.D., of the University of Florida College of Medicine; Roland Staud, M.D., and Roger B. Fillingim, Ph.D., of the University of Florida College of Dentistry; Nikolay A. Spiridonov, Ph.D., of the U.S. Food and Drug Administration; Mitchell B. Max, M.D., Ph.D., of the NIDCR and University of Pittsburgh; and David Goldman, M.D., of the NIAAA.
Source: University of North Carolina at Chapel Hill
Now, new research from the University of North Carolina at Chapel Hill's Center for Neurosensory Disorders, based within the School of Dentistry, has identified genetic variants that offer insight into individual responses to morphine. Researchers said long-term implications of the findings may include the development of drugs with greater pain-relieving effects and fewer side effects, as well as the development of genetic tests predicting individual responses to these medications.
Up to one-third of people treated with opioids develop substantial side effects, said Luda Diatchenko, M.D., Ph.D., an associate professor in the center and the study's co-senior author. In addition, there is more than a 10-fold difference in the responses some patients show a very good response and others show a very poor response to the same amount.
The study, which appeared in the March 15, 2009, issue of the journal Human Molecular Genetics, identifies new variations in the gene that produces the OPRM1 receptor, the primary biological target for opioid analgesics such as morphine. The research also provides evidence that the receptor carries many more genetic variations than previously thought.
"Genetic variations in this receptor play a crucial role in individual responsiveness to these drugs, but we currently have very little understanding of its genetic structures and molecular and cellular mechanisms," Diatchenko said.
She added that collaboration with the National Institutes of Health's National Center for Biotechnology Information had provided crucial insights into these mechanisms. Bioinformatics is an emerging field combining information technology and biology.
"Bioinformatics has become one of the driving forces of modern biomedical science," said Svetlana Shabalina, Ph.D., a senior scientist at the National Center for Biotechnology Information and the other study co-senior author. "Bioinformatic tools are indispensable for the identification of underlying genetic causes in complex disorders. We expect many important discoveries in this field."
"The outcomes of these studies are very exciting and are likely to lead to new diagnostic tests that will permit clinicians to predict a patient's risk for inadequate or adverse responses to opioids," said William Maixner, D.D.S., Ph.D., co-author of the study, director of the Center for Neurosensory Disorders and professor of endodontics and pharmacology in the UNC schools of dentistry and medicine, respectively. "The outcomes may also enable the development of a new class of opioids that are safer and more effective than those currently available," he said.
The study was funded by grants from the National Institutes of Health.
Other study authors from the UNC School of Dentistry are Pavel Gris, Ph.D.; Josee Gauthier and Inna E. Tchivileva, M.D. Additional study authors are Dmitri V. Zaykin, Ph.D., and Kyoko Shibata, Ph.D., of the National Institute of Environmental Health Sciences; Aleksey Y. Ogurtsov, Ph.D., of the National Center for Biotechnology Information; Inna Belfer, M.D., Ph.D., of the National Institute of Dental and Craniofacial Research, the National Institute on Alcohol Abuse and Alcoholism and the University of Pittsburgh; Bikashkumar Mishra, M.D., and Carly Kiselycznyk, Ph.D. of the NIDCR and NIAAA; Margaret R. Wallace, Ph.D., of the University of Florida College of Medicine; Roland Staud, M.D., and Roger B. Fillingim, Ph.D., of the University of Florida College of Dentistry; Nikolay A. Spiridonov, Ph.D., of the U.S. Food and Drug Administration; Mitchell B. Max, M.D., Ph.D., of the NIDCR and University of Pittsburgh; and David Goldman, M.D., of the NIAAA.
Source: University of North Carolina at Chapel Hill
Memory Impairment Common In People With A History Of Cancer
People with a history of cancer have a 40 percent greater likelihood of experiencing memory problems that interfere with daily functioning, compared with those who have not had cancer, according to results of a new, large study.
The findings, believed to be one of the first culled from a nationwide sample of people diagnosed with different cancers, mirror findings of cancer-related memory impairment in smaller studies of certain cancers, such as breast and prostate cancer. Results were presented at the Third AACR Conference on The Science of Cancer Health Disparities.
"The findings show that memory impairment in cancer patients is a national problem that we must pay special attention to," said Pascal Jean-Pierre, Ph.D., M.P.H., assistant professor at the University of Miami Miller School of Medicine, department of pediatrics, and the Sylvester Comprehensive Cancer Center.
He added that while there is no curative treatment yet for memory impairment ongoing studies are testing therapies physicians can still help these patients.
"One of the most important parts of cancer treatment is management of symptoms, such as impairments in attention, memory and fatigue, in order to improve a patient's quality of life. This study suggests these memory issues are more common than had been recognized before, and should be assessed in all patients with a history of cancer," Jean-Pierre said.
Jean-Pierre and colleagues used data from the National Health and Nutrition Examination Survey (NHANES), a population-based survey sponsored by the U.S. Centers for Disease Control and Prevention designed to collect information on the health and nutrition in U.S. households. Their sample included 9,819 people, aged 40 years and older, from diverse educational and racial-ethnic backgrounds. Within that group, 1,305 participants reported they had cancer or a history of cancer.
All participants had a physical exam and responded to a survey, which included the question: "Are you limited in any way because of difficulty remembering or because you experience periods of confusion?"
Fourteen percent of participants who had cancer reported memory impairment compared to 8 percent of participants who did not have cancer. Those with cancer were 40 percent more likely to have memory issues than other participants impairments that interfered with daily functioning.
"The findings indicate that cancer is, therefore, a key independent predictor of memory problems in the sample studied," said Jean-Pierre.
He calls the condition "cancer related cognitive dysfunction," suggesting that it goes beyond the "chemobrain" label that has been attached primarily to women treated with chemotherapy for their breast cancer who reported problems in cognitive function (e.g., attention and memory).
"These memory issues can be related to treatment, such as chemotherapy, radiation, and hormone therapies, or to the tumor biology itself, which could change brain chemistry and neurobehavioral function," said Jean-Pierre.
Source: American Association for Cancer Research (AACR)
The findings, believed to be one of the first culled from a nationwide sample of people diagnosed with different cancers, mirror findings of cancer-related memory impairment in smaller studies of certain cancers, such as breast and prostate cancer. Results were presented at the Third AACR Conference on The Science of Cancer Health Disparities.
"The findings show that memory impairment in cancer patients is a national problem that we must pay special attention to," said Pascal Jean-Pierre, Ph.D., M.P.H., assistant professor at the University of Miami Miller School of Medicine, department of pediatrics, and the Sylvester Comprehensive Cancer Center.
He added that while there is no curative treatment yet for memory impairment ongoing studies are testing therapies physicians can still help these patients.
"One of the most important parts of cancer treatment is management of symptoms, such as impairments in attention, memory and fatigue, in order to improve a patient's quality of life. This study suggests these memory issues are more common than had been recognized before, and should be assessed in all patients with a history of cancer," Jean-Pierre said.
Jean-Pierre and colleagues used data from the National Health and Nutrition Examination Survey (NHANES), a population-based survey sponsored by the U.S. Centers for Disease Control and Prevention designed to collect information on the health and nutrition in U.S. households. Their sample included 9,819 people, aged 40 years and older, from diverse educational and racial-ethnic backgrounds. Within that group, 1,305 participants reported they had cancer or a history of cancer.
All participants had a physical exam and responded to a survey, which included the question: "Are you limited in any way because of difficulty remembering or because you experience periods of confusion?"
Fourteen percent of participants who had cancer reported memory impairment compared to 8 percent of participants who did not have cancer. Those with cancer were 40 percent more likely to have memory issues than other participants impairments that interfered with daily functioning.
"The findings indicate that cancer is, therefore, a key independent predictor of memory problems in the sample studied," said Jean-Pierre.
He calls the condition "cancer related cognitive dysfunction," suggesting that it goes beyond the "chemobrain" label that has been attached primarily to women treated with chemotherapy for their breast cancer who reported problems in cognitive function (e.g., attention and memory).
"These memory issues can be related to treatment, such as chemotherapy, radiation, and hormone therapies, or to the tumor biology itself, which could change brain chemistry and neurobehavioral function," said Jean-Pierre.
Source: American Association for Cancer Research (AACR)
Bone Implicated As Therapeutic Target For Type 2 Diabetes
Bones are typically thought of as calcified, inert structures, but researchers at Columbia University Medical Center have now identified a surprising and critically important novel function of the skeleton. They've shown for the first time that the skeleton is an endocrine organ that helps control our sugar metabolism and weight and, as such, is a major determinant of the development of type 2 diabetes.
The research, published in Cell, demonstrates that bone cells release a hormone called osteocalcin, which controls the regulation of blood sugar (glucose) and fat deposition through synergistic mechanisms previously not recognized. Usually, an increase in insulin secretion is accompanied by a decrease in insulin sensitivity. Osteocalcin, however, increases both the secretion and sensitivity of insulin, in addition to boosting the number of insulin-producing cells and reducing stores of fat.
In this published research, authors show that an increase in osteocalcin activity prevents the development of type 2 diabetes and obesity in mice. This discovery potentially opens the door for novel therapeutic avenues for the prevention and treatment of type 2 diabetes.
"The discovery that our bones are responsible for regulating blood sugar in ways that were not known before completely changes our understanding of the function of the skeleton and uncovers a crucial aspect of energy metabolism," said Gerard Karsenty, M.D., Ph.D., chair of the department of Genetics and Development at Columbia University Medical Center, Paul Marks Professor in the Basic Sciences, and senior author of the paper. "These results uncover an important aspect of endocrinology that was unappreciated until now."
Karsenty and his colleagues had previously shown that leptin, a hormone released by fat cells, acts upon and ultimately controls bone mass. They reasoned that bones must in turn communicate with fat, so they searched bone-forming cells for molecules that could potentially send signals back to fat cells.
The researchers found that osteocalcin, a protein made only by bone-forming cells (osteoblasts), was not a mere structural protein, but rather a hormone with totally unanticipated and crucial functions. Osteocalcin directs the pancreas' beta cells, which produce the body's supply of insulin, to produce more insulin. At the same time, osteocalcin directs fat cells to release a hormone called adiponectin, which improves insulin sensitivity. This discovery showed for the first time that one hormone has a synergistic function in regulating insulin secretion and insulin sensitivity, and that this coordinating signal comes from the skeleton. Additionally, osteocalcin enhances the production of insulin-producing beta cells, which is considered one of the best, but currently unattainable, strategies to treat diabetes.
People with type 2 diabetes have been shown to have low osteocalcin levels, suggesting that altering the activity of this molecule could be an effective therapy. That hypothesis is supported by the Columbia research, which showed that mice with high levels of osteocalcin activity were prevented from gaining weight or becoming diabetic even when they ate a high fat diet. Analysis of mice lacking the osteocalcin protein showed that they had type 2 diabetes, increased fat mass, a decrease in insulin and adiponectin expression, and decreased beta-cell proliferation.
This research was supported by the National Institutes of Health, the American Diabetes Association, the Japan Society for the Promotion of Science, and the Pennsylvania Department of Health.
The researchers are now examining the role of osteocalcin in the regulation of blood sugar in humans and are continuing investigations into the relationship between osteocalcin and the appearance of type 2 diabetes and obesity.
Source: Susan Craig
Columbia University Medical Center
The research, published in Cell, demonstrates that bone cells release a hormone called osteocalcin, which controls the regulation of blood sugar (glucose) and fat deposition through synergistic mechanisms previously not recognized. Usually, an increase in insulin secretion is accompanied by a decrease in insulin sensitivity. Osteocalcin, however, increases both the secretion and sensitivity of insulin, in addition to boosting the number of insulin-producing cells and reducing stores of fat.
In this published research, authors show that an increase in osteocalcin activity prevents the development of type 2 diabetes and obesity in mice. This discovery potentially opens the door for novel therapeutic avenues for the prevention and treatment of type 2 diabetes.
"The discovery that our bones are responsible for regulating blood sugar in ways that were not known before completely changes our understanding of the function of the skeleton and uncovers a crucial aspect of energy metabolism," said Gerard Karsenty, M.D., Ph.D., chair of the department of Genetics and Development at Columbia University Medical Center, Paul Marks Professor in the Basic Sciences, and senior author of the paper. "These results uncover an important aspect of endocrinology that was unappreciated until now."
Karsenty and his colleagues had previously shown that leptin, a hormone released by fat cells, acts upon and ultimately controls bone mass. They reasoned that bones must in turn communicate with fat, so they searched bone-forming cells for molecules that could potentially send signals back to fat cells.
The researchers found that osteocalcin, a protein made only by bone-forming cells (osteoblasts), was not a mere structural protein, but rather a hormone with totally unanticipated and crucial functions. Osteocalcin directs the pancreas' beta cells, which produce the body's supply of insulin, to produce more insulin. At the same time, osteocalcin directs fat cells to release a hormone called adiponectin, which improves insulin sensitivity. This discovery showed for the first time that one hormone has a synergistic function in regulating insulin secretion and insulin sensitivity, and that this coordinating signal comes from the skeleton. Additionally, osteocalcin enhances the production of insulin-producing beta cells, which is considered one of the best, but currently unattainable, strategies to treat diabetes.
People with type 2 diabetes have been shown to have low osteocalcin levels, suggesting that altering the activity of this molecule could be an effective therapy. That hypothesis is supported by the Columbia research, which showed that mice with high levels of osteocalcin activity were prevented from gaining weight or becoming diabetic even when they ate a high fat diet. Analysis of mice lacking the osteocalcin protein showed that they had type 2 diabetes, increased fat mass, a decrease in insulin and adiponectin expression, and decreased beta-cell proliferation.
This research was supported by the National Institutes of Health, the American Diabetes Association, the Japan Society for the Promotion of Science, and the Pennsylvania Department of Health.
The researchers are now examining the role of osteocalcin in the regulation of blood sugar in humans and are continuing investigations into the relationship between osteocalcin and the appearance of type 2 diabetes and obesity.
Source: Susan Craig
Columbia University Medical Center
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