Professor Thomas Chiles of the Biology Department, and colleagues at Boston University Medical Center, have been awarded a five-year, multimillion-dollar program project grant from the National Institutes of Allergy and Infectious Disease of the National Institutes of Health (NIH).
Their research will focus on understanding the growth and differentiation of a small subset of white blood cells called B-1a lymphocytes (B-1a cells). B-1a cells, which are found in the peritoneal cavity, and B-2 cells, which are located in the spleen and lymph nodes, help destroy pathogens that enter the body, and then help the body acquire immunity against those particular pathogens, protecting the body from future invasion. However, an over-production of B-1a cells can lead to autoimmune diseases and leukemias.
Thomas Chiles's group at Boston College, working with Dr. Thomas Rothstein of Boston University's Department of Medicine, previously demonstrated that the rules that govern cell cycle control and differentiation to immunoglobulin-secreting plasma cells are different in B-1a cells than in B-2 cells.
As part of the new NIH-funded program project, research carried out at Boston College will seek to better understand the molecular mechanisms that control when B-1a cells enter the cell cycle and proliferate. Insights from these studies will help us understand the molecular basis of several human lymphoproliferative disorders associated with B-1a cells, including a form of cancer called chronic lymphocytic leukemia.
Chronic lymphocytic leukemia, which involves overproduction of white blood cells by the bone marrow, is the most common type of leukemia in adults.
To learn more about research going on in the Chiles Laboratory, please visit:
bc/schools/cas/biology/facadmin/chiles/
BY JOHN P. ROCHE
Maintained: Biology Department
URL: bc/schools/cas/biology/news/chiles/
© 2004 The Trustees of Boston College
понедельник, 24 октября 2011 г.
пятница, 21 октября 2011 г.
New Book Uses ABCs To Teach Children Microbiology
A new children's book from ASM Press uses the familiar genre of the ABC book to introduce readers to the not-so-familiar world of microbes. The Invisible ABCs will delight readers of all ages with its colorful presentation and spectacular selection of illustrations. Intended for school-age children and younger, this unique new book will stimulate parents, teachers, librarians, and even older students to discover the fascinating world of microorganisms.
"We are immersed in microbes. They live in our bodies, in our food, and in everything that surrounds us; we cannot live without them. The Invisible ABCs presents answers to questions that we all have an interest in, such as 'Why can cows use grass for food but humans can't?' and 'Why do we get gas after we eat beans?'" says author Rodney Anderson, a microbiologist and professor at Ohio Northern University, who presents photos he has collected of microorganisms shaped like letters of the alphabet to illustrate the significant role microbes play in our daily lives.
This intriguing book contains a glossary of important terms, as well as endpapers illustrating the relative size of organisms from viruses to whales. Age-appropriate vocabulary and examples are used to communicate important scientific principles and concepts throughout the vibrant pages of The Invisible ABCs. A companion website provides deeper understanding for those who seek to learn more about microorganisms.
The Invisible ABCs can be purchased through ASM Press online at estore.asm/ or through other online retailers.
ASM Press is the book publishing arm of the American Society for Microbiology (ASM), the oldest and largest single life science membership organization in the world. The ASM's mission is to promote research in the microbiological sciences and to assist communication between scientists, policy makers, and the public to improve health and foster economic well-being.
Contact: Jim Sliwa
American Society for Microbiology
"We are immersed in microbes. They live in our bodies, in our food, and in everything that surrounds us; we cannot live without them. The Invisible ABCs presents answers to questions that we all have an interest in, such as 'Why can cows use grass for food but humans can't?' and 'Why do we get gas after we eat beans?'" says author Rodney Anderson, a microbiologist and professor at Ohio Northern University, who presents photos he has collected of microorganisms shaped like letters of the alphabet to illustrate the significant role microbes play in our daily lives.
This intriguing book contains a glossary of important terms, as well as endpapers illustrating the relative size of organisms from viruses to whales. Age-appropriate vocabulary and examples are used to communicate important scientific principles and concepts throughout the vibrant pages of The Invisible ABCs. A companion website provides deeper understanding for those who seek to learn more about microorganisms.
The Invisible ABCs can be purchased through ASM Press online at estore.asm/ or through other online retailers.
ASM Press is the book publishing arm of the American Society for Microbiology (ASM), the oldest and largest single life science membership organization in the world. The ASM's mission is to promote research in the microbiological sciences and to assist communication between scientists, policy makers, and the public to improve health and foster economic well-being.
Contact: Jim Sliwa
American Society for Microbiology
вторник, 18 октября 2011 г.
Worldwide Research Archive Doubles In Size Since 2004
The Protein Data Bank this month reached a significant milestone in its 37-year history as the 50,000th molecule structure was released into its archive, joining other structures vital to pharmacology, bioinformatics, and education.
With its origins in a handwritten petition circulated at a scientific meeting, the PDB is the single worldwide repository for the three-dimensional structures of large molecules and nucleic acids. This freely available online library allows biological researchers and students to study, store and share molecular information on a global scale. Officially founded in 1971 with seven structures at Brookhaven National Laboratory, the archive is currently managed by a consortium called the worldwide Protein Data Bank (wwPDB).
Today, the PDB archive receives approximately 25 new experimentally-determined structures from scientists each day - and more than 5 million files are downloaded from the PDB archive every month. Users include structural biologists, computational biologists, biochemists, and molecular biologists in academia, government, and industry as well as educators and students.
Notable examples include recent structures of the adrenergic receptor, which will revolutionize the discovery of drugs to fight heart disease, allergies, and numerous other diseases, and the many structures of enzymes from HIV, which have been pivotal in the design of new therapies to fight AIDS.
"Advances in science and technology have helped the archive grow by leaps and bounds in the last 10 years," said Dr. Helen M. Berman, director of the RCSB PDB and Board of Governors professor of chemistry and chemical biology, noting that the size of the PDB has doubled in just the last three-and-a-half years.
"We are estimating that the PDB will not only double, but triple to 150,000 structures by 2014," said Dr. Philip E. Bourne, Associate Director of the RCSB PDB and professor of pharmacology at the UCSD Skaggs School of Pharmacy and Pharmaceutical Sciences.
The RCSB PDB is based at Rutgers University in New Jersey, and the San Diego Supercomputer Center (SDSC) and Skaggs School of Pharmacy and Pharmaceutical Sciences at the University of California at San Diego. Bourne, a distinguished scientist with SDSC, has been leveraging the resources of the supercomputer center to create a highly uniform and robust process for archiving and providing access to the molecular structures.
The RCSB PDB is responsible for releasing PDB entries into the archive after they have been reviewed and annotated. At Rutgers, RCSB PDB members annotate structures and develop the sophisticated infrastructure needed to handle these complex data. The primary PDB FTP site is based at SDSC, which serves as the distribution point for PDB users. In addition to the SDSC site, there are failover sites at both the UCSD Skaggs School and Rutgers University to ensure constant access.
In addition to a comprehensive website and database that lets users search, analyze, and visualize the structures of biological macromolecules and their relationships to sequence, function, and disease, the RCSB PDB features a Molecule of the Month series, which recently published its 100th installment. Proteins, one of the main building blocks for living organisms, come in a variety of shapes, with the form of a protein corresponding to its function. The structures housed in the PDB demonstrate great diversity in size, complexity, and function, including:
Insulin, the protein deficient in diabetic patients
p53 tumor suppressor, a protein often implicated in cancer
Anthrax toxin, the disease-causing protein made by anthrax
Amyloid peptide, a protein implicated in Alzheimer's disease
The RCSB PDB is supported by funds from the National Science Foundation, the National Institute of General Medical Sciences, the Office of Science, the Department of Energy, the National Library of Medicine, the National Cancer Institute, the National Center for Research Resources, the National Institute of Biomedical Imaging and Bioengineering, the National Institute of Neurological Disorders and Stroke, and the National Institute of Diabetes & Digestive & Kidney Diseases.
Source: Jan Zverina
University of California - San Diego
With its origins in a handwritten petition circulated at a scientific meeting, the PDB is the single worldwide repository for the three-dimensional structures of large molecules and nucleic acids. This freely available online library allows biological researchers and students to study, store and share molecular information on a global scale. Officially founded in 1971 with seven structures at Brookhaven National Laboratory, the archive is currently managed by a consortium called the worldwide Protein Data Bank (wwPDB).
Today, the PDB archive receives approximately 25 new experimentally-determined structures from scientists each day - and more than 5 million files are downloaded from the PDB archive every month. Users include structural biologists, computational biologists, biochemists, and molecular biologists in academia, government, and industry as well as educators and students.
Notable examples include recent structures of the adrenergic receptor, which will revolutionize the discovery of drugs to fight heart disease, allergies, and numerous other diseases, and the many structures of enzymes from HIV, which have been pivotal in the design of new therapies to fight AIDS.
"Advances in science and technology have helped the archive grow by leaps and bounds in the last 10 years," said Dr. Helen M. Berman, director of the RCSB PDB and Board of Governors professor of chemistry and chemical biology, noting that the size of the PDB has doubled in just the last three-and-a-half years.
"We are estimating that the PDB will not only double, but triple to 150,000 structures by 2014," said Dr. Philip E. Bourne, Associate Director of the RCSB PDB and professor of pharmacology at the UCSD Skaggs School of Pharmacy and Pharmaceutical Sciences.
The RCSB PDB is based at Rutgers University in New Jersey, and the San Diego Supercomputer Center (SDSC) and Skaggs School of Pharmacy and Pharmaceutical Sciences at the University of California at San Diego. Bourne, a distinguished scientist with SDSC, has been leveraging the resources of the supercomputer center to create a highly uniform and robust process for archiving and providing access to the molecular structures.
The RCSB PDB is responsible for releasing PDB entries into the archive after they have been reviewed and annotated. At Rutgers, RCSB PDB members annotate structures and develop the sophisticated infrastructure needed to handle these complex data. The primary PDB FTP site is based at SDSC, which serves as the distribution point for PDB users. In addition to the SDSC site, there are failover sites at both the UCSD Skaggs School and Rutgers University to ensure constant access.
In addition to a comprehensive website and database that lets users search, analyze, and visualize the structures of biological macromolecules and their relationships to sequence, function, and disease, the RCSB PDB features a Molecule of the Month series, which recently published its 100th installment. Proteins, one of the main building blocks for living organisms, come in a variety of shapes, with the form of a protein corresponding to its function. The structures housed in the PDB demonstrate great diversity in size, complexity, and function, including:
Insulin, the protein deficient in diabetic patients
p53 tumor suppressor, a protein often implicated in cancer
Anthrax toxin, the disease-causing protein made by anthrax
Amyloid peptide, a protein implicated in Alzheimer's disease
The RCSB PDB is supported by funds from the National Science Foundation, the National Institute of General Medical Sciences, the Office of Science, the Department of Energy, the National Library of Medicine, the National Cancer Institute, the National Center for Research Resources, the National Institute of Biomedical Imaging and Bioengineering, the National Institute of Neurological Disorders and Stroke, and the National Institute of Diabetes & Digestive & Kidney Diseases.
Source: Jan Zverina
University of California - San Diego
суббота, 15 октября 2011 г.
Study Identifies New Mechanism Linking Activation Of Key Heart Enzyme And Oxidative Stress
A study, led by University of Iowa researchers, reveals a new dimension for a key heart enzyme and sheds light on an important biological pathway involved in cell death in heart disease. The study, published in the May 2 issue of Cell, has implications for understanding, and potentially for diagnosing and treating, heart failure and arrhythmias.
The UI researchers and colleagues from Vanderbilt University in Nashville, Tenn., focused on calmodulin kinase II, or CaM kinase II, a well-studied enzyme critical to many fundamental processes including heartbeat and thought.
Scientists know that CaM kinase's activity is sustained by adding a phosphate group -- a process known as phosphorylation. The new study proves that oxidation -- adding oxygen -- also can sustain the enzyme's activity, and like phosphorylation, the mechanism can be reversed to inactivate the kinase.
"Our results suggest that oxidation of CaM kinase is a dynamic and reversible process that may direct cell signaling in health and disease," said Mark Anderson, M.D., Ph.D., UI professor of internal medicine and molecular physiology and biophysics and senior study author. "Because CaM kinase activity is involved in arrhythmias, hypertrophy and heart cell death, this work also provides new insights into a disease pathway in heart that may lead to development of new drugs to treat heart disease."
In patients with heart failure, the level of angiotensin II -- a signaling molecule that promotes oxidation and cell death -- is elevated. Using a specially created antibody, the researchers found that angiotensin II also increases the amount of oxidized CaM kinase.
In addition, by replacing the cell's normal CaM kinase with a CaM kinase unable to be oxidized, the scientists were able to block angiotensin-induced cell death. Scientists hope this discovery might lead to therapies that prevent cell death by blocking CaM kinase oxidation.
Currently, "angiotensin-blockers" are a mainstay for treating patients with sick hearts, but they work indirectly by targeting receptors on the cell surface. Anderson, who also is the Potter-Lambert Chair in Cardiology and director of the UI Division of Cardiovascular Medicine, suggested that by understanding the signaling mechanisms that occur inside the cell, it might be possible to inhibit the angiotensin pathway more directly. This approach may also preserve some of the good effects mediated by the cell surface receptor.
Using a wide range of scientific techniques and experimental methods, the team, led by Anderson and Jeffrey Erickson, Ph.D., a UI postdoctoral fellow, pinned down the details of the internal signaling mechanism.
Specifically, they showed that oxidation of two neighboring methionines -- sulfur-containing amino acids -- can sustain CaM kinase activity. Loss of these two methionines prevents activation by oxidation. They also found that they could return CaM kinase to its inactive state and inhibit heart cell death and dysfunction by using an enzyme called methionine sulfoxide reductase A (msrA), which reverses the methionine oxidation. Studies in worms, fruit flies and mice have shown that msrA increases lifespan, but, until now, the enzyme's targets in heart were unknown.
The UI team compared mice without the msrA enzyme to normal mice when the animals underwent disease stresses, including excess angiotensin or induced heart attacks. The mice without msrA were more likely to die than normal mice under these circumstances, and the levels of oxidized CaM kinase were much higher in mice that lacked the enzyme.
Anderson speculated that the findings could implicate msrA as a susceptibility gene for patients - potentially, variations in the gene might help explain why some people do so badly after a heart attack where others do well.
The study demonstrates a direct link between CaM kinase activation and oxidative stress, two processes that are implicated in a wide variety of physiological and disease states. These findings will likely have broad implications and applications in basic research, diagnostics and new therapeutic approaches and represent an example of translation science of the type supported and encouraged by the new Institute for Clinical and Translational Science at the UI.
"This study also is a great example of collaborative science," added Anderson. "We had to apply expertise from several different labs to tackle this problem. So, the ease with which we can collaborate across disciplines at the UI and between institutions was enormously beneficial."
The work involved researchers from the UI Roy J. and Lucille A. Carver College of Medicine's Departments of Internal Medicine, Radiation Oncology and Biochemistry; and Vanderbilt University.
In addition to Anderson and Erickson, the UI researchers included Peter Mohler, Ph.D., assistant professor of internal medicine; Douglas Spitz, Ph.D., professor of radiation oncology in the Free Radical and Radiation Biology Graduate Program; Robert Weiss, M.D., professor of internal medicine; Madeline Shea, Ph.D., professor of biochemistry; Mei-ling Joiner, Xiaoqun Guan, Ph.D.; William Kutschke; Jinying Yang; John Lowe; Susan O'Donnell; Nukhet Aykin-Burns, Ph.D.; Matthew Zimmerman, Ph.D.; and Kathy Zimmerman.
The researchers from Vanderbilt University included, Carmine Oddis, M.D.; Ryan Bartlett, Ph.D.; Amy-Joan Ham, Ph.D.; and Roger Colbran, Ph.D.
The study was funded in part by the National Institutes of Health, the Pew Charitable Trust and the UI Research Foundation.
Source:
University of Iowa Health Science Relations, 5135 Westlawn, Iowa City, Iowa 52242-1178
Jennifer Brown
University of Iowa
The UI researchers and colleagues from Vanderbilt University in Nashville, Tenn., focused on calmodulin kinase II, or CaM kinase II, a well-studied enzyme critical to many fundamental processes including heartbeat and thought.
Scientists know that CaM kinase's activity is sustained by adding a phosphate group -- a process known as phosphorylation. The new study proves that oxidation -- adding oxygen -- also can sustain the enzyme's activity, and like phosphorylation, the mechanism can be reversed to inactivate the kinase.
"Our results suggest that oxidation of CaM kinase is a dynamic and reversible process that may direct cell signaling in health and disease," said Mark Anderson, M.D., Ph.D., UI professor of internal medicine and molecular physiology and biophysics and senior study author. "Because CaM kinase activity is involved in arrhythmias, hypertrophy and heart cell death, this work also provides new insights into a disease pathway in heart that may lead to development of new drugs to treat heart disease."
In patients with heart failure, the level of angiotensin II -- a signaling molecule that promotes oxidation and cell death -- is elevated. Using a specially created antibody, the researchers found that angiotensin II also increases the amount of oxidized CaM kinase.
In addition, by replacing the cell's normal CaM kinase with a CaM kinase unable to be oxidized, the scientists were able to block angiotensin-induced cell death. Scientists hope this discovery might lead to therapies that prevent cell death by blocking CaM kinase oxidation.
Currently, "angiotensin-blockers" are a mainstay for treating patients with sick hearts, but they work indirectly by targeting receptors on the cell surface. Anderson, who also is the Potter-Lambert Chair in Cardiology and director of the UI Division of Cardiovascular Medicine, suggested that by understanding the signaling mechanisms that occur inside the cell, it might be possible to inhibit the angiotensin pathway more directly. This approach may also preserve some of the good effects mediated by the cell surface receptor.
Using a wide range of scientific techniques and experimental methods, the team, led by Anderson and Jeffrey Erickson, Ph.D., a UI postdoctoral fellow, pinned down the details of the internal signaling mechanism.
Specifically, they showed that oxidation of two neighboring methionines -- sulfur-containing amino acids -- can sustain CaM kinase activity. Loss of these two methionines prevents activation by oxidation. They also found that they could return CaM kinase to its inactive state and inhibit heart cell death and dysfunction by using an enzyme called methionine sulfoxide reductase A (msrA), which reverses the methionine oxidation. Studies in worms, fruit flies and mice have shown that msrA increases lifespan, but, until now, the enzyme's targets in heart were unknown.
The UI team compared mice without the msrA enzyme to normal mice when the animals underwent disease stresses, including excess angiotensin or induced heart attacks. The mice without msrA were more likely to die than normal mice under these circumstances, and the levels of oxidized CaM kinase were much higher in mice that lacked the enzyme.
Anderson speculated that the findings could implicate msrA as a susceptibility gene for patients - potentially, variations in the gene might help explain why some people do so badly after a heart attack where others do well.
The study demonstrates a direct link between CaM kinase activation and oxidative stress, two processes that are implicated in a wide variety of physiological and disease states. These findings will likely have broad implications and applications in basic research, diagnostics and new therapeutic approaches and represent an example of translation science of the type supported and encouraged by the new Institute for Clinical and Translational Science at the UI.
"This study also is a great example of collaborative science," added Anderson. "We had to apply expertise from several different labs to tackle this problem. So, the ease with which we can collaborate across disciplines at the UI and between institutions was enormously beneficial."
The work involved researchers from the UI Roy J. and Lucille A. Carver College of Medicine's Departments of Internal Medicine, Radiation Oncology and Biochemistry; and Vanderbilt University.
In addition to Anderson and Erickson, the UI researchers included Peter Mohler, Ph.D., assistant professor of internal medicine; Douglas Spitz, Ph.D., professor of radiation oncology in the Free Radical and Radiation Biology Graduate Program; Robert Weiss, M.D., professor of internal medicine; Madeline Shea, Ph.D., professor of biochemistry; Mei-ling Joiner, Xiaoqun Guan, Ph.D.; William Kutschke; Jinying Yang; John Lowe; Susan O'Donnell; Nukhet Aykin-Burns, Ph.D.; Matthew Zimmerman, Ph.D.; and Kathy Zimmerman.
The researchers from Vanderbilt University included, Carmine Oddis, M.D.; Ryan Bartlett, Ph.D.; Amy-Joan Ham, Ph.D.; and Roger Colbran, Ph.D.
The study was funded in part by the National Institutes of Health, the Pew Charitable Trust and the UI Research Foundation.
Source:
University of Iowa Health Science Relations, 5135 Westlawn, Iowa City, Iowa 52242-1178
Jennifer Brown
University of Iowa
среда, 12 октября 2011 г.
Identification Of Stem Cells That Repair Injured Muscles Has Important Implications For Muscular Dystrophy
A University of Colorado at Boulder research team has identified a type of skeletal muscle stem cell that contributes to the repair of damaged muscles in mice, which could have important implications in the treatment of injured, diseased or aging muscle tissue in humans, including the ravages of muscular dystrophy.
The newly identified stem cells are found within populations of satellite cells located between muscle fibers and the surrounding connective tissue that are responsible for the repair and maintenance of skeletal muscles, said Professor Bradley Olwin of CU-Boulder's molecular, cellular and developmental biology department.
When muscle fibers are stressed or traumatized, satellite cells divide to make more specialized muscle cells and repair the muscle, said Olwin. The stem cell population identified by the CU team within the satellite cells -- dubbed "satellite-SP" cells -- were shown to renew the satellite cell population after injection into injured muscle cells, contributing to recovery of muscle tissue in the laboratory mice.
"This research shows how satellite cells can maintain their populations within injured tissues," said Olwin. "The hope is this new method will allow us to repair damaged or diseased skeletal muscle tissue."
A paper on the subject was published in the March 5 issue of the journal Cell Stem Cell. Co-authors on the study included the MCD biology department's Kathleen Tanaka, John Hall and Andrew Troy, as well as Dawn Cornelison from the University of Missouri and Susan Majka from the University of Colorado Denver.
Stem cells are distinguished by their ability to renew themselves through cell division and differentiate into specialized cell types. In healthy skeletal muscle tissue, the population of satellite cells is constantly maintained, leading the CU-Boulder team to believe that at least some of the satellite cell population in the mouse study included stem cells.
For the study, the researchers injected 2,500 satellite-SP cells into a population of satellite cells within injured mouse muscle tissue. They found that 75 percent of the satellite cells that reproduced were derived from the previous satellite-SP cells injected into the tissue. The results demonstrated the injected satellite-SP cells were renewing the satellite cell pool, Olwin said.
"The key point here is we are not just repairing the tissue," said Olwin. "We injected a permanent, self-renewing population of stem cells. One advantage of using this technology is that we can use a relatively small number of stem cells and do the job with a small number of injections -- in this case, only one."
The research has implications for a number of human diseases, he said. In muscular dystrophy, the loss of a protein called dystrophin causes the muscle to literally tear itself apart, a process that cannot be repaired without cell-based intervention. Although injected cells will repair the muscle fibers, maintaining the muscle fibers requires additional cell injections.
The research was funded in part by the National Institutes of Health and the Muscular Dystrophy Association. Olwin is now collaborating with a group at the University of Washington and the Fred Hutchinson Cancer Research Center in Seattle to extend the research.
Source: Bradley Olwin
University of Colorado at Boulder
The newly identified stem cells are found within populations of satellite cells located between muscle fibers and the surrounding connective tissue that are responsible for the repair and maintenance of skeletal muscles, said Professor Bradley Olwin of CU-Boulder's molecular, cellular and developmental biology department.
When muscle fibers are stressed or traumatized, satellite cells divide to make more specialized muscle cells and repair the muscle, said Olwin. The stem cell population identified by the CU team within the satellite cells -- dubbed "satellite-SP" cells -- were shown to renew the satellite cell population after injection into injured muscle cells, contributing to recovery of muscle tissue in the laboratory mice.
"This research shows how satellite cells can maintain their populations within injured tissues," said Olwin. "The hope is this new method will allow us to repair damaged or diseased skeletal muscle tissue."
A paper on the subject was published in the March 5 issue of the journal Cell Stem Cell. Co-authors on the study included the MCD biology department's Kathleen Tanaka, John Hall and Andrew Troy, as well as Dawn Cornelison from the University of Missouri and Susan Majka from the University of Colorado Denver.
Stem cells are distinguished by their ability to renew themselves through cell division and differentiate into specialized cell types. In healthy skeletal muscle tissue, the population of satellite cells is constantly maintained, leading the CU-Boulder team to believe that at least some of the satellite cell population in the mouse study included stem cells.
For the study, the researchers injected 2,500 satellite-SP cells into a population of satellite cells within injured mouse muscle tissue. They found that 75 percent of the satellite cells that reproduced were derived from the previous satellite-SP cells injected into the tissue. The results demonstrated the injected satellite-SP cells were renewing the satellite cell pool, Olwin said.
"The key point here is we are not just repairing the tissue," said Olwin. "We injected a permanent, self-renewing population of stem cells. One advantage of using this technology is that we can use a relatively small number of stem cells and do the job with a small number of injections -- in this case, only one."
The research has implications for a number of human diseases, he said. In muscular dystrophy, the loss of a protein called dystrophin causes the muscle to literally tear itself apart, a process that cannot be repaired without cell-based intervention. Although injected cells will repair the muscle fibers, maintaining the muscle fibers requires additional cell injections.
The research was funded in part by the National Institutes of Health and the Muscular Dystrophy Association. Olwin is now collaborating with a group at the University of Washington and the Fred Hutchinson Cancer Research Center in Seattle to extend the research.
Source: Bradley Olwin
University of Colorado at Boulder
воскресенье, 9 октября 2011 г.
Deadly Fungus Decimating Bat Populations Cannot Be Controlled By Culling
Culling will not stop the spread of a deadly fungus that is threatening to wipe out hibernating bats in North America, according to a new mathematical model.
White-nose syndrome, which is estimated to have killed over a million bats in a three year period, is probably caused by a newly discovered cold-adapted fungus, Geomyces destructans. The new model examines how WNS is passed from bat to bat and concludes that culling would not work because of the complexity of bat life history and because the fungal pathogen occurs in the caves and mines where the bats live.
"Because the disease is highly virulent, our model results support the hypothesis that transmission occurs in all contact areas," write the paper's authors, Tom Hallam and Gary McCracken, both of the University of Tennessee. "Our simulations indicated culling will not control WNS in bats primarily because contact rates are high among colonial bats, contact occurs in multiple arenas, and periodic movement between arenas occurs."
Ground work on the model was initiated in a 2009 modeling workshop on white-nose syndrome held at the National Institute for Mathematical and Biological Synthesis (NIMBioS) in Knoxville, Tennessee. At the interdisciplinary workshop, experts in the fields of bat physiology, fungal ecology, ecotoxicology, and epidemiology discussed ways in which mathematical modeling could be applied to predict and control the spread of WNS.
"NIMBioS' support for the workshop that initiated this project was crucial in helping formulate models that could be useful in looking at white-nose syndrome," Hallam said.
Culling of bats in areas where the disease is present is one of several options that have been considered by state and federal agencies as a way to control the disease. However, a review of management options for controlling WNS in the paper indicates that culling is ineffective for disease control in wild animals and in some cases, can exacerbate the spread.
White-nose syndrome first appeared in a cave in upstate New York in 2006, and has since spread to 14 states and as far north as Canada. Regional extinctions of the most common bat species, the little brown bat, are predicted within two decades due to WNS.
Eating up to two-thirds of their body weight in insects every night, bats help suppress insect populations ultimately reducing crop damage and the quantities of insecticides used on crops. Bats also play an important ecological role in plant pollination and seed dissemination.
Citations: Hallam TG, McCracken GF. 2011. Management of the panzootic white-nose syndrome through culling of bats. Conservation Biology 25(1): 189-194.
Source:
Catherine Crawley
National Institute for Mathematical and Biological Synthesis (NIMBioS)
White-nose syndrome, which is estimated to have killed over a million bats in a three year period, is probably caused by a newly discovered cold-adapted fungus, Geomyces destructans. The new model examines how WNS is passed from bat to bat and concludes that culling would not work because of the complexity of bat life history and because the fungal pathogen occurs in the caves and mines where the bats live.
"Because the disease is highly virulent, our model results support the hypothesis that transmission occurs in all contact areas," write the paper's authors, Tom Hallam and Gary McCracken, both of the University of Tennessee. "Our simulations indicated culling will not control WNS in bats primarily because contact rates are high among colonial bats, contact occurs in multiple arenas, and periodic movement between arenas occurs."
Ground work on the model was initiated in a 2009 modeling workshop on white-nose syndrome held at the National Institute for Mathematical and Biological Synthesis (NIMBioS) in Knoxville, Tennessee. At the interdisciplinary workshop, experts in the fields of bat physiology, fungal ecology, ecotoxicology, and epidemiology discussed ways in which mathematical modeling could be applied to predict and control the spread of WNS.
"NIMBioS' support for the workshop that initiated this project was crucial in helping formulate models that could be useful in looking at white-nose syndrome," Hallam said.
Culling of bats in areas where the disease is present is one of several options that have been considered by state and federal agencies as a way to control the disease. However, a review of management options for controlling WNS in the paper indicates that culling is ineffective for disease control in wild animals and in some cases, can exacerbate the spread.
White-nose syndrome first appeared in a cave in upstate New York in 2006, and has since spread to 14 states and as far north as Canada. Regional extinctions of the most common bat species, the little brown bat, are predicted within two decades due to WNS.
Eating up to two-thirds of their body weight in insects every night, bats help suppress insect populations ultimately reducing crop damage and the quantities of insecticides used on crops. Bats also play an important ecological role in plant pollination and seed dissemination.
Citations: Hallam TG, McCracken GF. 2011. Management of the panzootic white-nose syndrome through culling of bats. Conservation Biology 25(1): 189-194.
Source:
Catherine Crawley
National Institute for Mathematical and Biological Synthesis (NIMBioS)
четверг, 6 октября 2011 г.
New $1.16 Million Study Investigates How Dietary Iron Is Used By Cells
A four-year study on iron metabolism within cells, an essential process that impacts both iron deficiency and iron toxicity, conditions responsible for a multitude of human diseases, is underway at the University at Buffalo funded by a $1.16 million grant from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK).
Daniel Kosman, Ph.D., professor of biochemistry in the UB School of Medicine and Biomedical Sciences, is lead researcher on the study.
"The concern about how iron is managed in our cells has never been more acute," said Kosman. "The reasons for this are three-fold. First is the endemic problem of iron deficiency that the World Health Organization estimates afflicts 80 percent of the world's population, or more than 5 billion people.
"Iron deficiency is not confined to developing nations. In the U.S., 5 percent of newborns and 7 percent of new mothers have clinical symptoms of iron deficiency. Reducing the incidence of this nutritional deficit is one of the objectives of the U.S. Department of Health and Human Services' Healthy People 2010 program.
"Second is the broad recognition that the 'corrosive chemistry' associated with iron and oxygen interactions is a major factor in a multitude of human diseases."
Too much iron in tissues, called iron-loading, is thought to increase the risk of tumor development, infection, cardiomyopathy, joint disorders and several endocrine and neurodegenerative disorders.
"And third, we now have an increasingly sophisticated knowledge and understanding of iron metabolic pathways, the proteins involved in these pathways and how these pathways are regulated in all organisms, making this issue ripe for investigation," he said.
Kosman proposes that a general mechanism of cellular iron metabolism requires that iron-handling proteins involved in sequential steps in the pathway must be "architecturally arranged" contiguously in the cell's membranes, at the interfaces between membranes and soluble compartments or within soluble compartments.
The researchers will test this form-function model of ionic iron metabolism by focusing on three steps critical to maintaining the proper balance of iron in cells: 1) the reduction of ferric to ferrous iron and the subsequent transport of ferrous iron into a cell; 2) the "hand-off" of this ferrous iron from a membrane protein to iron chaperones in the cell's cytoplasm; and 3) the utilization of this ionic iron for the activation of essential iron-containing enzymes.
"These three components of cellular iron metabolism are relatively under-investigated," said Kosman, "yet they represent the essence of cell iron metabolism in all organisms."
Understanding the intermediary metabolism of iron is one of the primary objectives of a program announcement from NIH titled "Metals In Medicine," he noted. This announcement encourages studies that lead to the "identification and characterization of the macromolecular players and vesicular compartments involved in metal ion homeostasis and metal trafficking."
Arvinder Singh, Ph.D., a post-doctoral research associate in Kosman's lab; and William E. Wiltsie, a doctoral candidate in biochemistry, also will be involved in the research.
The University at Buffalo is a premier research-intensive public university, the largest and most comprehensive campus in the State University of New York. The School of Medicine and Biomedical Sciences is one of five schools that constitute UB's Academic Health Center. UB's more than 27,000 students pursue their academic interests through more than 300 undergraduate, graduate and professional degree programs.
Contact: Lois Baker
University at Buffalo
Daniel Kosman, Ph.D., professor of biochemistry in the UB School of Medicine and Biomedical Sciences, is lead researcher on the study.
"The concern about how iron is managed in our cells has never been more acute," said Kosman. "The reasons for this are three-fold. First is the endemic problem of iron deficiency that the World Health Organization estimates afflicts 80 percent of the world's population, or more than 5 billion people.
"Iron deficiency is not confined to developing nations. In the U.S., 5 percent of newborns and 7 percent of new mothers have clinical symptoms of iron deficiency. Reducing the incidence of this nutritional deficit is one of the objectives of the U.S. Department of Health and Human Services' Healthy People 2010 program.
"Second is the broad recognition that the 'corrosive chemistry' associated with iron and oxygen interactions is a major factor in a multitude of human diseases."
Too much iron in tissues, called iron-loading, is thought to increase the risk of tumor development, infection, cardiomyopathy, joint disorders and several endocrine and neurodegenerative disorders.
"And third, we now have an increasingly sophisticated knowledge and understanding of iron metabolic pathways, the proteins involved in these pathways and how these pathways are regulated in all organisms, making this issue ripe for investigation," he said.
Kosman proposes that a general mechanism of cellular iron metabolism requires that iron-handling proteins involved in sequential steps in the pathway must be "architecturally arranged" contiguously in the cell's membranes, at the interfaces between membranes and soluble compartments or within soluble compartments.
The researchers will test this form-function model of ionic iron metabolism by focusing on three steps critical to maintaining the proper balance of iron in cells: 1) the reduction of ferric to ferrous iron and the subsequent transport of ferrous iron into a cell; 2) the "hand-off" of this ferrous iron from a membrane protein to iron chaperones in the cell's cytoplasm; and 3) the utilization of this ionic iron for the activation of essential iron-containing enzymes.
"These three components of cellular iron metabolism are relatively under-investigated," said Kosman, "yet they represent the essence of cell iron metabolism in all organisms."
Understanding the intermediary metabolism of iron is one of the primary objectives of a program announcement from NIH titled "Metals In Medicine," he noted. This announcement encourages studies that lead to the "identification and characterization of the macromolecular players and vesicular compartments involved in metal ion homeostasis and metal trafficking."
Arvinder Singh, Ph.D., a post-doctoral research associate in Kosman's lab; and William E. Wiltsie, a doctoral candidate in biochemistry, also will be involved in the research.
The University at Buffalo is a premier research-intensive public university, the largest and most comprehensive campus in the State University of New York. The School of Medicine and Biomedical Sciences is one of five schools that constitute UB's Academic Health Center. UB's more than 27,000 students pursue their academic interests through more than 300 undergraduate, graduate and professional degree programs.
Contact: Lois Baker
University at Buffalo
понедельник, 3 октября 2011 г.
Minor Genetic Differences Between Individuals Change The Effect Of A Common Medication, Study Shows
Medicine has moved a little bit closer to the era of tailor-made treatments, based on the unique genetic profiles of individual patients, according to recent research conducted by Dr Rima Rozen of the Research Institute of the McGill University Health Centre (RI MUHC) at the Montreal Children's Hospital and McGill University. Her study, published June 18 in the journal Pharmacogenetics and Genomics, shows how minor genetic differences between individuals alter the way a common drug affects the body.
Rozen has measured the impact of Methotrexate -- a drug that inhibits the metabolism of folate -- on mice with an altered MTHFR gene, which is a gene crucial for folate metabolism. The results were striking: after treatment with Methotrexate, mice with the altered gene had approximately 20 per cent less hemoglobin and red blood cells than their counterparts with non-altered genes. The altered mice also showed increased susceptibility to liver and kidney damage following treatment.
"We know that these results are applicable to humans because a parallel mutation in the human MTHFR gene affects human folate metabolism similarly. The results demonstrate that medication affects subjects differently according to individual genetic traits," Dr. Rozen explained. "And tests exist to detect this mutation." Genetic testing would allow physicians the modify treatment based on each patient's personal genetic makeup, limiting potential side effects.
In earlier studies, Rozen's laboratory cloned the MTHFR gene and identified the common variant which interferes in folate metabolism in human populations. Between 10 and 15 per cent of the total caucasian population have two copies of the variant in MTHFR. Folate, a form of water-soluble Vitamin B2, is essential to the production of red blood cells and provides protection against spina bifida, other birth defects, and heart disease. Patients with cancer or auto-immune diseases are often treated with medications that affect folate metabolism, but physicians are not trained to verify how patients naturally metabolize folate, even though this could be an important factor in effective treatment.
"This is a first step towards personalized medicine that is based not only on symptoms but also on the patient's own genetic 'baggage,'" Rozen said. "This trend definitely represents the medicine of the future."
This release is available in French.
Dr. Rima Rozen is a Scientist in the Medical Genetics and Genomics Axis of the RI MUHC at the Montreal Children's Hospital. At McGill University, she holds the positions of Associate Vice-Principal (Research and International Relations) and Professor in the Human Genetics, Pediatrics and Biology Departments.
This study was funded by the Canadian Institutes of Health Research (CIHR) and the U.S. National Institutes of Health (NIH). Students working on Dr. Rozen's study also received scholarships, such as a Turkish Higher Education Council-Hacettepe University Hospital scholarship, a Cole Foundation Award, and a Studentship Award from the Montreal Children's Hospital Research Institute.
The Montreal Children's Hospital (MCH) is the pediatric teaching hospital of the McGill University Health Centre (MUHC) and is affiliated with McGill University. The MCH is a leader in providing a broad spectrum of highly specialized care to newborns, children, and adolescents from across Quebec. Our areas of medical expertise include programs in brain development/behaviour, cardiovascular sciences, critical care, medical genetics and oncology, tertiary medical and surgical services, and trauma care. Fully bilingual, the hospital also promotes multiculturalism and serves an increasingly diverse community in more than 50 languages. The Montreal Children's Hospital sets itself apart with its team approach to innovative patient care. Our health professionals and staff are dedicated to ensuring children and their families receive exceptional health care in a friendly and supportive environment.
The Research Institute of the McGill University Health Centre (RI MUHC) is a world-renowned biomedical and health-care hospital research centre. Located in Montreal, Quebec, the institute is the research arm of the MUHC, the university health center affiliated with the Faculty of Medicine at McGill University. The institute supports over 600 researchers, nearly 1200 graduate and post-doctoral students and operates more than 300 laboratories devoted to a broad spectrum of fundamental and clinical research. The Research Institute operates at the forefront of knowledge, innovation and technology and is inextricably linked to the clinical programs of the MUHC, ensuring that patients benefit directly from the latest research-based knowledge.
The Research Institute of the MUHC is supported in part by the Fonds de la recherche en santГ© du QuГ©bec.
For further details visit: muhc.ca/research.
Source: Isabelle Kling
McGill University Health Centre
Rozen has measured the impact of Methotrexate -- a drug that inhibits the metabolism of folate -- on mice with an altered MTHFR gene, which is a gene crucial for folate metabolism. The results were striking: after treatment with Methotrexate, mice with the altered gene had approximately 20 per cent less hemoglobin and red blood cells than their counterparts with non-altered genes. The altered mice also showed increased susceptibility to liver and kidney damage following treatment.
"We know that these results are applicable to humans because a parallel mutation in the human MTHFR gene affects human folate metabolism similarly. The results demonstrate that medication affects subjects differently according to individual genetic traits," Dr. Rozen explained. "And tests exist to detect this mutation." Genetic testing would allow physicians the modify treatment based on each patient's personal genetic makeup, limiting potential side effects.
In earlier studies, Rozen's laboratory cloned the MTHFR gene and identified the common variant which interferes in folate metabolism in human populations. Between 10 and 15 per cent of the total caucasian population have two copies of the variant in MTHFR. Folate, a form of water-soluble Vitamin B2, is essential to the production of red blood cells and provides protection against spina bifida, other birth defects, and heart disease. Patients with cancer or auto-immune diseases are often treated with medications that affect folate metabolism, but physicians are not trained to verify how patients naturally metabolize folate, even though this could be an important factor in effective treatment.
"This is a first step towards personalized medicine that is based not only on symptoms but also on the patient's own genetic 'baggage,'" Rozen said. "This trend definitely represents the medicine of the future."
This release is available in French.
Dr. Rima Rozen is a Scientist in the Medical Genetics and Genomics Axis of the RI MUHC at the Montreal Children's Hospital. At McGill University, she holds the positions of Associate Vice-Principal (Research and International Relations) and Professor in the Human Genetics, Pediatrics and Biology Departments.
This study was funded by the Canadian Institutes of Health Research (CIHR) and the U.S. National Institutes of Health (NIH). Students working on Dr. Rozen's study also received scholarships, such as a Turkish Higher Education Council-Hacettepe University Hospital scholarship, a Cole Foundation Award, and a Studentship Award from the Montreal Children's Hospital Research Institute.
The Montreal Children's Hospital (MCH) is the pediatric teaching hospital of the McGill University Health Centre (MUHC) and is affiliated with McGill University. The MCH is a leader in providing a broad spectrum of highly specialized care to newborns, children, and adolescents from across Quebec. Our areas of medical expertise include programs in brain development/behaviour, cardiovascular sciences, critical care, medical genetics and oncology, tertiary medical and surgical services, and trauma care. Fully bilingual, the hospital also promotes multiculturalism and serves an increasingly diverse community in more than 50 languages. The Montreal Children's Hospital sets itself apart with its team approach to innovative patient care. Our health professionals and staff are dedicated to ensuring children and their families receive exceptional health care in a friendly and supportive environment.
The Research Institute of the McGill University Health Centre (RI MUHC) is a world-renowned biomedical and health-care hospital research centre. Located in Montreal, Quebec, the institute is the research arm of the MUHC, the university health center affiliated with the Faculty of Medicine at McGill University. The institute supports over 600 researchers, nearly 1200 graduate and post-doctoral students and operates more than 300 laboratories devoted to a broad spectrum of fundamental and clinical research. The Research Institute operates at the forefront of knowledge, innovation and technology and is inextricably linked to the clinical programs of the MUHC, ensuring that patients benefit directly from the latest research-based knowledge.
The Research Institute of the MUHC is supported in part by the Fonds de la recherche en santГ© du QuГ©bec.
For further details visit: muhc.ca/research.
Source: Isabelle Kling
McGill University Health Centre
пятница, 30 сентября 2011 г.
First Compound That Specifically Kills Cancer Stem Cells Found
The cancer stem cells that drive tumor growth and resist chemotherapies and radiation treatments that kill other cancer cells aren't invincible after all. Researchers reporting online on August 13th in the journal Cell, a Cell Press publication, have discovered the first compound that targets those cancer stem cells directly.
"It wasn't clear it would be possible to find compounds that selectively kill cancer stem cells," said Piyush Gupta of the Massachusetts Institute of Technology (MIT) and the Broad Institute. "We've shown it can be done."
The team including MIT's Robert Weinberg and the Broad Institute's Eric Lander developed a new high-throughput screening method that makes it possible for the first time to systematically look for agents that kill cancer stem cells. That ability had previously eluded researchers due to the rarity of those cells within tumor cell populations and their relative instability in laboratory culture.
In the new study, the researchers manipulated cultured breast cancer cells to greatly enrich for those with the stem-like properties, including increased resistance to standard cancer drugs. They then screened a library of 16,000 natural and commercial chemical compounds for their ability to kill those stem-like cells and not other cancer cells. That screen turned up 32 contenders.
The researchers narrowed that list down to a handful of chemicals that they could readily get in sufficient quantities for further testing on normal cancer stem cells. Of those, one called salinomycin was the clear winner.
Salinomycin reduced the proportion of breast cancer stem cells by more than 100-fold compared to a commonly used chemotherapeutic drug for breast cancer called paclitaxel (aka Taxol™). Salinomycin-treated cells were less able than paclitaxel-treated ones to seed tumors when injected into mice, they report. Salinomycin treatment also slowed the growth of the animals' tumors.
Studies of salinomycin-treated human breast tumors also showed a loss in the activity of genes associated with cancer stem cells.
Exactly how salinomycin's works against cancer stem cells, the researchers don't yet know. As its name suggests, the chemical has antibiotic properties that likely aren't relevant to its newfound cancer stem cell-killing ability. It also disturbs cells' potassium balance.
It remains unclear whether salinomycin itself might find its way to the clinic, Gupta said, since many pharmaceutical steps are involved in the drug discovery process. Nevertheless, the chemical does serve as an immediate tool for manipulating cancer stem cell numbers and observing the effects on cancer's spread and progression.
The findings also highlight a new avenue for the development of cancer therapies, the researchers say.
" To date, rational cancer therapies have been designed to target specific genetic alterations present within tumors," they wrote. "The findings here indicate that a second approach may also prove useful - namely, searching for agents that target specific states of cancer cell differentiation. Accordingly, future therapies could offer greater possibilities for individualized treatment by considering both the genetic alterations and differentiation states present within the cancer cells of a tumor at the time of diagnosis."
They envision a future in which combination therapies might couple more traditional cancer drugs with those designed to hit the cancer stem cells that would otherwise get left behind.
The researchers include Piyush B. Gupta, Massachusetts Institute of Technology, Cambridge, MA, Broad Institute of MIT and Harvard, Cambridge, MA; Tamer T. Onder, Massachusetts Institute of Technology, Cambridge, MA, Whitehead Institute for Biomedical Research, Cambridge, MA; Guozhi Jiang, Massachusetts Institute of Technology, Cambridge, MA, Broad Institute of MIT and Harvard, Cambridge, MA; Kai Tao, Tufts Medical Center, Boston, MA; Charlotte Kuperwasser, Tufts Medical Center, Boston, MA; Robert A. Weinberg, Massachusetts Institute of Technology, Cambridge, MA, Whitehead Institute for Biomedical Research, Cambridge, MA, MIT Ludwig Center for Molecular Oncology, Cambridge, MA; and Eric S. Lander, Massachusetts Institute of Technology, Cambridge, MA, Whitehead Institute for Biomedical Research, Cambridge, MA, Broad Institute of MIT and Harvard, Cambridge, MA, Harvard Medical School, Boston, MA.
Source:
Cathleen Genova
Cell Press
View drug information on Taxol.
"It wasn't clear it would be possible to find compounds that selectively kill cancer stem cells," said Piyush Gupta of the Massachusetts Institute of Technology (MIT) and the Broad Institute. "We've shown it can be done."
The team including MIT's Robert Weinberg and the Broad Institute's Eric Lander developed a new high-throughput screening method that makes it possible for the first time to systematically look for agents that kill cancer stem cells. That ability had previously eluded researchers due to the rarity of those cells within tumor cell populations and their relative instability in laboratory culture.
In the new study, the researchers manipulated cultured breast cancer cells to greatly enrich for those with the stem-like properties, including increased resistance to standard cancer drugs. They then screened a library of 16,000 natural and commercial chemical compounds for their ability to kill those stem-like cells and not other cancer cells. That screen turned up 32 contenders.
The researchers narrowed that list down to a handful of chemicals that they could readily get in sufficient quantities for further testing on normal cancer stem cells. Of those, one called salinomycin was the clear winner.
Salinomycin reduced the proportion of breast cancer stem cells by more than 100-fold compared to a commonly used chemotherapeutic drug for breast cancer called paclitaxel (aka Taxol™). Salinomycin-treated cells were less able than paclitaxel-treated ones to seed tumors when injected into mice, they report. Salinomycin treatment also slowed the growth of the animals' tumors.
Studies of salinomycin-treated human breast tumors also showed a loss in the activity of genes associated with cancer stem cells.
Exactly how salinomycin's works against cancer stem cells, the researchers don't yet know. As its name suggests, the chemical has antibiotic properties that likely aren't relevant to its newfound cancer stem cell-killing ability. It also disturbs cells' potassium balance.
It remains unclear whether salinomycin itself might find its way to the clinic, Gupta said, since many pharmaceutical steps are involved in the drug discovery process. Nevertheless, the chemical does serve as an immediate tool for manipulating cancer stem cell numbers and observing the effects on cancer's spread and progression.
The findings also highlight a new avenue for the development of cancer therapies, the researchers say.
" To date, rational cancer therapies have been designed to target specific genetic alterations present within tumors," they wrote. "The findings here indicate that a second approach may also prove useful - namely, searching for agents that target specific states of cancer cell differentiation. Accordingly, future therapies could offer greater possibilities for individualized treatment by considering both the genetic alterations and differentiation states present within the cancer cells of a tumor at the time of diagnosis."
They envision a future in which combination therapies might couple more traditional cancer drugs with those designed to hit the cancer stem cells that would otherwise get left behind.
The researchers include Piyush B. Gupta, Massachusetts Institute of Technology, Cambridge, MA, Broad Institute of MIT and Harvard, Cambridge, MA; Tamer T. Onder, Massachusetts Institute of Technology, Cambridge, MA, Whitehead Institute for Biomedical Research, Cambridge, MA; Guozhi Jiang, Massachusetts Institute of Technology, Cambridge, MA, Broad Institute of MIT and Harvard, Cambridge, MA; Kai Tao, Tufts Medical Center, Boston, MA; Charlotte Kuperwasser, Tufts Medical Center, Boston, MA; Robert A. Weinberg, Massachusetts Institute of Technology, Cambridge, MA, Whitehead Institute for Biomedical Research, Cambridge, MA, MIT Ludwig Center for Molecular Oncology, Cambridge, MA; and Eric S. Lander, Massachusetts Institute of Technology, Cambridge, MA, Whitehead Institute for Biomedical Research, Cambridge, MA, Broad Institute of MIT and Harvard, Cambridge, MA, Harvard Medical School, Boston, MA.
Source:
Cathleen Genova
Cell Press
View drug information on Taxol.
вторник, 27 сентября 2011 г.
Paradoxical Protein Might Prevent Cancer
One difficulty with fighting cancer cells is that they are similar in many respects to the body's stem cells. By focusing on the differences, researchers at Karolinska Institutet have found a new way of tackling colon cancer. The study is presented in the prestigious journal Cell.
Molecular signal pathways that stimulate the division of stem cells are generally the same as those active in tumour growth. This limits the possibility of treating cancer as the drugs that kill cancer cells also often adversely affect the body's healthy cells, particularly stem cells. A new study from Karolinska Institutet, conducted in collaboration with an international team of scientists led by Professor Jonas FrisГ©n, is now focusing on an exception that can make it possible to treat a form of colon cancer.
The results concern a group of signal proteins called EphB receptors. These proteins stimulate the division of stem cells in the intestine and can contribute to the formation of adenoma (polyps), which are known to carry a risk of cancer. Paradoxically, these same proteins also prevent the adenoma from growing unchecked and becoming cancerous.
The new results show that EphB controls two separate signal pathways, one of which stimulates cell division and the other that curbs the cells' ability to become cancerous. Using this knowledge, the scientists have identified a drug substance called imatinib, which can inhibit the first signal pathway without affecting the other, protective, pathway.
"Imatinib or a similar substance could possibly be used for preventing the development of cancer in people who are in the risk zone for colon cancer instead of intestinal resection," says Maria Genander, one of the researchers involved in the study.
Imatinib has so far proved to inhibit cell division in intestinal tumour cells in vitro and in mice. The substance is a component of the drug Glivec, which is used, amongst other things, in the treatment of certain forms of leukaemia. Whether it can also be used against adenoma and colon cancer in humans remains to be seen. The company that manufactures the drug did not fund the study.
Publication:
Maria Genander, Michael M. Halford, Nan-Jie Xu, Malin Eriksson, Zuoren Yu, Zhaozhu Qiu, Anna Martling, Gedas Greicius, Sonal Thakar, Timothy Catchpole, Michael J. Chumley, Sofia Zdunek, Chenguang Wang, Torbjörn Holm, Stephen P. Goff, Sven Pettersson, Richard G. Pestell, Mark Henkemeyer & Jonas Frisén
Dissociation of EphB2 Signaling Pathways Mediating Progenitor Cell Proliferation and Tumor Suppression
Cell, print issue, 13 Nov 2009
Source: Press Officer Katarina Sternudd
Karolinska Institutet
Molecular signal pathways that stimulate the division of stem cells are generally the same as those active in tumour growth. This limits the possibility of treating cancer as the drugs that kill cancer cells also often adversely affect the body's healthy cells, particularly stem cells. A new study from Karolinska Institutet, conducted in collaboration with an international team of scientists led by Professor Jonas FrisГ©n, is now focusing on an exception that can make it possible to treat a form of colon cancer.
The results concern a group of signal proteins called EphB receptors. These proteins stimulate the division of stem cells in the intestine and can contribute to the formation of adenoma (polyps), which are known to carry a risk of cancer. Paradoxically, these same proteins also prevent the adenoma from growing unchecked and becoming cancerous.
The new results show that EphB controls two separate signal pathways, one of which stimulates cell division and the other that curbs the cells' ability to become cancerous. Using this knowledge, the scientists have identified a drug substance called imatinib, which can inhibit the first signal pathway without affecting the other, protective, pathway.
"Imatinib or a similar substance could possibly be used for preventing the development of cancer in people who are in the risk zone for colon cancer instead of intestinal resection," says Maria Genander, one of the researchers involved in the study.
Imatinib has so far proved to inhibit cell division in intestinal tumour cells in vitro and in mice. The substance is a component of the drug Glivec, which is used, amongst other things, in the treatment of certain forms of leukaemia. Whether it can also be used against adenoma and colon cancer in humans remains to be seen. The company that manufactures the drug did not fund the study.
Publication:
Maria Genander, Michael M. Halford, Nan-Jie Xu, Malin Eriksson, Zuoren Yu, Zhaozhu Qiu, Anna Martling, Gedas Greicius, Sonal Thakar, Timothy Catchpole, Michael J. Chumley, Sofia Zdunek, Chenguang Wang, Torbjörn Holm, Stephen P. Goff, Sven Pettersson, Richard G. Pestell, Mark Henkemeyer & Jonas Frisén
Dissociation of EphB2 Signaling Pathways Mediating Progenitor Cell Proliferation and Tumor Suppression
Cell, print issue, 13 Nov 2009
Source: Press Officer Katarina Sternudd
Karolinska Institutet
суббота, 24 сентября 2011 г.
Anti-inflammatory Effects Of Pomegranate In Rabbits: A Potential Treatment In Humans?
Oral ingestion of pomegranate extract reduces the production of chemicals that cause inflammation suggests a study published in BioMed Central's open access Journal of Inflammation. The findings indicate that pomegranate extract may provide humans with relief of chronic inflammatory conditions.
The group from the Department of Medicine of Case Western Reserve University, Cleveland Ohio, led by Tariq Haqqi, showed that blood samples collected from rabbits fed pomegranate extract inhibited inflammation.
Pomegranate extract is already used as a treatment in alternative medicine for inflammatory conditions, such as arthritis. Although pomegranate extract has antioxidant and anti-inflammatory actions in experiments on isolated tissues, it is not known whether ingestion of it can produce the same anti-inflammatory effects in living systems, either because the active compounds are not absorbed from the gut or because the levels of these compounds in the blood are not high enough.
Pomegranate extract, the equivalent of 175mls of pomegranate juice, was given to rabbits orally. The levels of antioxidants were measured in blood samples obtained after drinking the pomegranate extract and compared to blood samples collected before ingestion of pomegranate extract.
Plasma collected from rabbits following ingestion of pomegranate extract contained significantly higher levels of antioxidants than samples collected before ingestion of pomegranate extract; the extract also significantly reduced the activity of proteins that cause inflammation, specifically cyclooxygenase-2. It also reduced the production of pro-inflammatory compounds produced by cells isolated from cartilage.
The results of this study indicate the beneficial effects of pomegranate extract when ingested. According to Haqqi "the use of dietary nutrients or drugs based on them as an adjunct in the treatment of chronic inflammatory conditions may benefit patients". He adds that, "Current treatment with anti-inflammatory drugs can have serious side effects following long-term use. Further research is needed, however, especially on the absorption of orally ingested substances into the blood."
Notes:
1. Bioavailable Metabolites of Pomegranate (Punica granatum L) Fruit Extract Preferentially Inhibit COX2 Activity ex vivo and IL-1b-induced PGE2 Production in Articular Cartilage Chondrocytes in vitro.
Meenakshi Shukla, Kalpana Gupta, Zafar Rasheed, Khursheed A Khan and Tariq M Haqqi
Journal of Inflammation (in press)
Article available at the journal website: journal-inflammation/
All articles are available free of charge, according to BioMed Central's open access policy.
2. Tariq Haqqi is now with the Department of Pathology, Microbiology & Immunology, School of Medicine, at the University of South Carolina, Columbia.
3. Journal of Inflammation is an Open Access, peer-reviewed online journal on all aspects of research into inflammation.
4. BioMed Central (biomedcentral/) is an independent online publishing house committed to providing immediate access without charge to the peer-reviewed biological and medical research it publishes. This commitment is based on the view that open access to research is essential to the rapid and efficient communication of science.
Source: Charlotte Webber
BioMed Central
The group from the Department of Medicine of Case Western Reserve University, Cleveland Ohio, led by Tariq Haqqi, showed that blood samples collected from rabbits fed pomegranate extract inhibited inflammation.
Pomegranate extract is already used as a treatment in alternative medicine for inflammatory conditions, such as arthritis. Although pomegranate extract has antioxidant and anti-inflammatory actions in experiments on isolated tissues, it is not known whether ingestion of it can produce the same anti-inflammatory effects in living systems, either because the active compounds are not absorbed from the gut or because the levels of these compounds in the blood are not high enough.
Pomegranate extract, the equivalent of 175mls of pomegranate juice, was given to rabbits orally. The levels of antioxidants were measured in blood samples obtained after drinking the pomegranate extract and compared to blood samples collected before ingestion of pomegranate extract.
Plasma collected from rabbits following ingestion of pomegranate extract contained significantly higher levels of antioxidants than samples collected before ingestion of pomegranate extract; the extract also significantly reduced the activity of proteins that cause inflammation, specifically cyclooxygenase-2. It also reduced the production of pro-inflammatory compounds produced by cells isolated from cartilage.
The results of this study indicate the beneficial effects of pomegranate extract when ingested. According to Haqqi "the use of dietary nutrients or drugs based on them as an adjunct in the treatment of chronic inflammatory conditions may benefit patients". He adds that, "Current treatment with anti-inflammatory drugs can have serious side effects following long-term use. Further research is needed, however, especially on the absorption of orally ingested substances into the blood."
Notes:
1. Bioavailable Metabolites of Pomegranate (Punica granatum L) Fruit Extract Preferentially Inhibit COX2 Activity ex vivo and IL-1b-induced PGE2 Production in Articular Cartilage Chondrocytes in vitro.
Meenakshi Shukla, Kalpana Gupta, Zafar Rasheed, Khursheed A Khan and Tariq M Haqqi
Journal of Inflammation (in press)
Article available at the journal website: journal-inflammation/
All articles are available free of charge, according to BioMed Central's open access policy.
2. Tariq Haqqi is now with the Department of Pathology, Microbiology & Immunology, School of Medicine, at the University of South Carolina, Columbia.
3. Journal of Inflammation is an Open Access, peer-reviewed online journal on all aspects of research into inflammation.
4. BioMed Central (biomedcentral/) is an independent online publishing house committed to providing immediate access without charge to the peer-reviewed biological and medical research it publishes. This commitment is based on the view that open access to research is essential to the rapid and efficient communication of science.
Source: Charlotte Webber
BioMed Central
среда, 21 сентября 2011 г.
Study Finds That Blood Test Can Gauge Prostate Cancer Risk
New genomics research has found that a simple blood test can determine which men are likely to develop prostate cancer. Researchers at Wake Forest University School of Medicine and colleagues found that five genetic variants previously associated with prostate cancer risk have a strong cumulative effect.
Reporting in New England Journal of Medicine, researchers found that a man with four of the five variants has an increased risk of 400 to 500 percent compared to men with none of the variants. The researchers then added a family history of prostate cancer to the equation for a total of six risk factors. A man with at least five of the six factors had increased risk of more than 900 percent.
The article was published "Online First" today and will be included in the Feb. 28 print issue.
The scientists say each variant was independently associated with prostate cancer risk and that the variants are fairly common in the population. Together, these five variants and a family history accounted for almost half (46 percent) of prostate cancer patients. The study involved analyzing DNA samples from 2,893 men with prostate cancer and 1,781 healthy individuals of similar ages all participants of a prostate cancer study in Sweden.
"This is significant and could affect clinical care," said senior researcher Jianfeng Xu, M.D., Dr. PH., professor of epidemiology and cancer biology. "The information could substantially improve physicians' ability to assess risk and determine the need for more aggressive screening or even a biopsy."
For example, the test may be especially useful in men with a family history of prostate cancer or those who have a marginally elevated PSA (prostate specific antigen), he said.
The study is also important because it is one of the first to illustrate how a combination of several genes can affect risk of disease. Genomics teams nationwide are currently searching for combinations of genes that may underlie common diseases such as cancer, diabetes and asthma.
Currently, age, race and family history are the three factors associated with increased risk of prostate cancer. Family history is believed to account for about 10 percent of prostate cancer cases. Strikingly, researchers estimated that the five variants combined could account for about 40 percent of cases.
"Our finding provides an opportunity to supplement the well-established risk factors by looking at how many of these variants a man has inherited," said Xu. "It may provide a much better weapon to guide clinicians."
Until last year, no specific genetic variants had been consistently identified as markers for prostate cancer risk. Then, advances in technology allowed researchers to take a more systematic approach to looking at the entire genome. Instead of solely studying genes that they suspected were related to disease susceptibility, they could study the entire genome and look for associations.
Through these searches, several research teams identified five genetic locations associated with risk of developing prostate cancer: three on chromosome 8q24, one on chromosome 17q12 and one on 17q24.3.
Each variant alone was associated with moderate risk, but the effect wasn't considered significant enough to justify testing individuals. The current study was the first to evaluate whether there is a cumulative effect from having multiple variants.
"When we considered the variants together we discovered their potential for predicting individual risk," said Xu. "Because of the cumulative effects of these risk variants and family history, for the first time associations found through genome-wide screening appear to be useful in clinical practice."
The researchers said further study is needed to determine how their findings of genetic testing may complement PSA (prostate-specific antigen) testing. The researchers found that the risk associated with the genetic variants is independent of PSA results.
"This suggests that a subset of men deemed to have a low risk of prostate cancer based on their PSA levels may in fact be at significantly elevated risk due to inheriting one or more of the genetic variants," said S. Lilly Zheng, M.D., associate professor of internal medicine and the first author of the paper.
Genetic testing of these five variants will soon be offered at a CLIA (Clinical Laboratory Improvement Amendments)-certified laboratory at Wake Forest University School of Medicine.
Co-researchers include senior author Henrik Gronberg, M.D., Ph.D. professor at the Karolinska Institutet in Stockholm, Sweden, and William B. Isaacs, Ph.D, professor at Johns Hopkins Medical Institutions in Baltimore, Md.
Wake Forest University Baptist Medical Center is an academic health system comprised of North Carolina Baptist Hospital and Wake Forest University Health Sciences, which operates the university's School of Medicine. U.S. News & World Report ranks Wake Forest University School of Medicine 18th in family medicine, 20th in geriatrics, 25th in primary care and 41st in research among the nation's medical schools. It ranks 35th in research funding by the National Institutes of Health. Almost 150 members of the medical school faculty are listed in Best Doctors in America.
Wake Forest University Baptist Medical Center
Medical Center Blvd.
Winston-Salem, NC 27157-1015
United States
www1.wfubmc
Reporting in New England Journal of Medicine, researchers found that a man with four of the five variants has an increased risk of 400 to 500 percent compared to men with none of the variants. The researchers then added a family history of prostate cancer to the equation for a total of six risk factors. A man with at least five of the six factors had increased risk of more than 900 percent.
The article was published "Online First" today and will be included in the Feb. 28 print issue.
The scientists say each variant was independently associated with prostate cancer risk and that the variants are fairly common in the population. Together, these five variants and a family history accounted for almost half (46 percent) of prostate cancer patients. The study involved analyzing DNA samples from 2,893 men with prostate cancer and 1,781 healthy individuals of similar ages all participants of a prostate cancer study in Sweden.
"This is significant and could affect clinical care," said senior researcher Jianfeng Xu, M.D., Dr. PH., professor of epidemiology and cancer biology. "The information could substantially improve physicians' ability to assess risk and determine the need for more aggressive screening or even a biopsy."
For example, the test may be especially useful in men with a family history of prostate cancer or those who have a marginally elevated PSA (prostate specific antigen), he said.
The study is also important because it is one of the first to illustrate how a combination of several genes can affect risk of disease. Genomics teams nationwide are currently searching for combinations of genes that may underlie common diseases such as cancer, diabetes and asthma.
Currently, age, race and family history are the three factors associated with increased risk of prostate cancer. Family history is believed to account for about 10 percent of prostate cancer cases. Strikingly, researchers estimated that the five variants combined could account for about 40 percent of cases.
"Our finding provides an opportunity to supplement the well-established risk factors by looking at how many of these variants a man has inherited," said Xu. "It may provide a much better weapon to guide clinicians."
Until last year, no specific genetic variants had been consistently identified as markers for prostate cancer risk. Then, advances in technology allowed researchers to take a more systematic approach to looking at the entire genome. Instead of solely studying genes that they suspected were related to disease susceptibility, they could study the entire genome and look for associations.
Through these searches, several research teams identified five genetic locations associated with risk of developing prostate cancer: three on chromosome 8q24, one on chromosome 17q12 and one on 17q24.3.
Each variant alone was associated with moderate risk, but the effect wasn't considered significant enough to justify testing individuals. The current study was the first to evaluate whether there is a cumulative effect from having multiple variants.
"When we considered the variants together we discovered their potential for predicting individual risk," said Xu. "Because of the cumulative effects of these risk variants and family history, for the first time associations found through genome-wide screening appear to be useful in clinical practice."
The researchers said further study is needed to determine how their findings of genetic testing may complement PSA (prostate-specific antigen) testing. The researchers found that the risk associated with the genetic variants is independent of PSA results.
"This suggests that a subset of men deemed to have a low risk of prostate cancer based on their PSA levels may in fact be at significantly elevated risk due to inheriting one or more of the genetic variants," said S. Lilly Zheng, M.D., associate professor of internal medicine and the first author of the paper.
Genetic testing of these five variants will soon be offered at a CLIA (Clinical Laboratory Improvement Amendments)-certified laboratory at Wake Forest University School of Medicine.
Co-researchers include senior author Henrik Gronberg, M.D., Ph.D. professor at the Karolinska Institutet in Stockholm, Sweden, and William B. Isaacs, Ph.D, professor at Johns Hopkins Medical Institutions in Baltimore, Md.
Wake Forest University Baptist Medical Center is an academic health system comprised of North Carolina Baptist Hospital and Wake Forest University Health Sciences, which operates the university's School of Medicine. U.S. News & World Report ranks Wake Forest University School of Medicine 18th in family medicine, 20th in geriatrics, 25th in primary care and 41st in research among the nation's medical schools. It ranks 35th in research funding by the National Institutes of Health. Almost 150 members of the medical school faculty are listed in Best Doctors in America.
Wake Forest University Baptist Medical Center
Medical Center Blvd.
Winston-Salem, NC 27157-1015
United States
www1.wfubmc
воскресенье, 18 сентября 2011 г.
Strategic Approach To Early-Detection Of Pancreatic Cancer Biomarkers
A cancer scientist from Johns Hopkins has convinced an international group of colleagues to delay their race to find new cancer biomarkers and instead begin a 7,000-hour slog through a compendium of 50,000 scientific articles already published to assemble, decode and analyze the molecules that might herald the furtive presence of pancreatic cancer.
With limited resources available for the exhaustive and expensive testing that needs to be done before any candidate can be considered a bona fide biomarker of clinical value, it's important to take stock of the big picture and strategize, says Akhilesh Pandey, M.D., Ph.D., an associate professor in the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, and founder and director of the Institute of Bioinformatics in Bangalore, India.
Having mined the literature to amass 2,516 potential biomarkers of pancreatic cancer, Pandey and his team published their compendium on April 6 in PLoS Medicine. They systematically cataloged the genes and proteins that are overexpressed in pancreatic cancer patients, then characterized and compared these biomarker candidates in terms of how worthy each is of further study.
More than 200 genes are shortlisted because they were reported in four or more published studies to be overexpressed - meaning that the proteins they make are in higher abundance in people with pancreatic cancer than in people without the disease. This qualifies them as "excellent candidates" for the further studies that are needed to validate them as sensitive and specific biomarkers, note the authors.
Pandey says he was motivated by the fact that even leading cancer investigators had no real idea about how many candidate biomarkers for pancreatic cancer had already been identified, much less how they stacked up against each other in terms of clinical value in detecting early stages of the disease. Such biomarkers are highly valued because they gallop Paul Revere-like through the bloodstream and can signal early warnings of clinically invisible cancers and other diseases.
"Curation and databases are not very sexy concepts," says Pandey. "But we can't keep doing the exciting new discovery stuff and never take the time to catalog our results and share them."
Taking pancreatic cancer biomarkers to prove the value of such a strategic "big picture" approach, Pandey says it could serve as a basis for other disease-marker research.
"For the first time with pancreatic cancer - and potentially with any cancer - we have a handle on the number of candidates already identified and a real sense of how big an army we should send on the mission of further testing them," says Pandey.
Pandey's ultimate goal is to ferret out the best protein biomarker for pancreatic cancer - a molecule that reveals itself in an accessible bodily fluid and therefore can be detected with ease and accuracy - just like the protein biomarker that's made early on by a developing fetus and is exploited by at-home pregnancy tests.
The "gold standard" pancreatic cancer biomarker would possess both high sensitivity and specificity for early diagnosis. Cancer, at its most basic, is an abnormal population of cells that produce specific molecules - biomarkers - which healthy, cancer-free bodies do not. Cancer also tends to be incipient, Pandey says.
The ideal biomarker would allow for easy diagnosis when a cancer is still young, before it spreads to other organs. It could also help clinicians make informed decisions about treatments and better predict of outcomes, Pandey says: "Biomarkers could tell us who should undergo surgery, who should get chemotherapy, and in which people a cancer is likely to recur."
Biomarker discovery is an exploding area of research, Pandey says, yielding ever-increasing amounts of data - more than any one person can hope to keep track of, unless it's all strategically collected for widespread study.
"We want to initiate a trend by proving the importance of collection and cataloging," Pandey says, "which are exercises that many might view as tedious."
The team's next step is to create a searchable Web database that is universally available and free.
Notes:
The research was supported in part by the Lustgarten Foundation for Pancreatic Cancer Research.
Authors of the paper, in addition to Pandey, are H.C. Harsha and Arivusudar Marimuthu of the Institute of Bioinformatics, Bangalore, India; Manipal University, Karnataka, India; and McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University. Also, Kumaran Kandasamy, Suresh Mathivanan, and Manoj Kashyap of the Institute of Bioinformatics, Bangalore, India, and the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University. Prathibha Ranganathan, Sandhya Rani, Subhashri Ramabadran, Sashikanth Gollapudi, Lavanya Balakrishman, Sutopa B. Dwivedi, Deepthi Telikicherla, Lakshmi Dhevi N. Selvan, and Renu Goel, of the Institute of Bioinformatics, Bangalore, India; Robert Vizza of The Lustgarten Foundation for Pancreatic Cancer Research, New York; Robert J. Mayer and James A. DeCaprio of the Dana-Farber Cancer Institute, Boston; Sudhir Srivastava of the Cancer Biomarkers Research Group, NIH; Samir M. Hanash of the Fred Hutchinson Cancer Research Center, Seattle; and Ralph H. Hruban of the Departments of Pathology and Oncology at the Sol Goldman Pancreatic Cancer Institute, Johns Hopkins.
Source:
Maryalice Yakutchik
Johns Hopkins Medical Institutions
With limited resources available for the exhaustive and expensive testing that needs to be done before any candidate can be considered a bona fide biomarker of clinical value, it's important to take stock of the big picture and strategize, says Akhilesh Pandey, M.D., Ph.D., an associate professor in the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, and founder and director of the Institute of Bioinformatics in Bangalore, India.
Having mined the literature to amass 2,516 potential biomarkers of pancreatic cancer, Pandey and his team published their compendium on April 6 in PLoS Medicine. They systematically cataloged the genes and proteins that are overexpressed in pancreatic cancer patients, then characterized and compared these biomarker candidates in terms of how worthy each is of further study.
More than 200 genes are shortlisted because they were reported in four or more published studies to be overexpressed - meaning that the proteins they make are in higher abundance in people with pancreatic cancer than in people without the disease. This qualifies them as "excellent candidates" for the further studies that are needed to validate them as sensitive and specific biomarkers, note the authors.
Pandey says he was motivated by the fact that even leading cancer investigators had no real idea about how many candidate biomarkers for pancreatic cancer had already been identified, much less how they stacked up against each other in terms of clinical value in detecting early stages of the disease. Such biomarkers are highly valued because they gallop Paul Revere-like through the bloodstream and can signal early warnings of clinically invisible cancers and other diseases.
"Curation and databases are not very sexy concepts," says Pandey. "But we can't keep doing the exciting new discovery stuff and never take the time to catalog our results and share them."
Taking pancreatic cancer biomarkers to prove the value of such a strategic "big picture" approach, Pandey says it could serve as a basis for other disease-marker research.
"For the first time with pancreatic cancer - and potentially with any cancer - we have a handle on the number of candidates already identified and a real sense of how big an army we should send on the mission of further testing them," says Pandey.
Pandey's ultimate goal is to ferret out the best protein biomarker for pancreatic cancer - a molecule that reveals itself in an accessible bodily fluid and therefore can be detected with ease and accuracy - just like the protein biomarker that's made early on by a developing fetus and is exploited by at-home pregnancy tests.
The "gold standard" pancreatic cancer biomarker would possess both high sensitivity and specificity for early diagnosis. Cancer, at its most basic, is an abnormal population of cells that produce specific molecules - biomarkers - which healthy, cancer-free bodies do not. Cancer also tends to be incipient, Pandey says.
The ideal biomarker would allow for easy diagnosis when a cancer is still young, before it spreads to other organs. It could also help clinicians make informed decisions about treatments and better predict of outcomes, Pandey says: "Biomarkers could tell us who should undergo surgery, who should get chemotherapy, and in which people a cancer is likely to recur."
Biomarker discovery is an exploding area of research, Pandey says, yielding ever-increasing amounts of data - more than any one person can hope to keep track of, unless it's all strategically collected for widespread study.
"We want to initiate a trend by proving the importance of collection and cataloging," Pandey says, "which are exercises that many might view as tedious."
The team's next step is to create a searchable Web database that is universally available and free.
Notes:
The research was supported in part by the Lustgarten Foundation for Pancreatic Cancer Research.
Authors of the paper, in addition to Pandey, are H.C. Harsha and Arivusudar Marimuthu of the Institute of Bioinformatics, Bangalore, India; Manipal University, Karnataka, India; and McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University. Also, Kumaran Kandasamy, Suresh Mathivanan, and Manoj Kashyap of the Institute of Bioinformatics, Bangalore, India, and the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University. Prathibha Ranganathan, Sandhya Rani, Subhashri Ramabadran, Sashikanth Gollapudi, Lavanya Balakrishman, Sutopa B. Dwivedi, Deepthi Telikicherla, Lakshmi Dhevi N. Selvan, and Renu Goel, of the Institute of Bioinformatics, Bangalore, India; Robert Vizza of The Lustgarten Foundation for Pancreatic Cancer Research, New York; Robert J. Mayer and James A. DeCaprio of the Dana-Farber Cancer Institute, Boston; Sudhir Srivastava of the Cancer Biomarkers Research Group, NIH; Samir M. Hanash of the Fred Hutchinson Cancer Research Center, Seattle; and Ralph H. Hruban of the Departments of Pathology and Oncology at the Sol Goldman Pancreatic Cancer Institute, Johns Hopkins.
Source:
Maryalice Yakutchik
Johns Hopkins Medical Institutions
четверг, 15 сентября 2011 г.
Canada's New Government Invests $583 Million In The Next Generation Of Canadian Researchers
Dr. Colin Carrie, Parliamentary Secretary to the Honourable Maxime Bernier, Minister of Industry and Minister responsible for the Natural Sciences and Engineering Research Council of Canada (NSERC), and Dr. Suzanne Fortier, President of NSERC, have announced the results of the 2007 Grants and Scholarships awards, which will see $583 million disbursed to 10,000 professors and students across Canada.
As a result of the current competition, some 3,300 professors from across Canada will receive $458.8 million in Discovery Grants to support their research in the natural sciences and engineering. (These awards are normally paid out over five years.)
In addition, 2,402 young university researchers - 2,148 at the graduate level and 254 at the postdoctoral level - will receive $99.2 million to pursue their studies in these fields, while 4,296 undergraduate students will receive Undergraduate Student Research Awards worth a total of $19.3 million to give them hands-on research experience in a laboratory.
"Our newly released science and technology strategy - Mobilizing Science and Technology to Canada's Advantage - recognizes the importance of doing more to turn ideas into innovations that provide solutions to our environmental, health and other important challenges, and to improve Canada's economic competitiveness," said Parliamentary Secretary Carrie. "These awards will help ensure that this country's best and brightest professors and students can continue their work and their contribution to the prosperity and well-being of all Canadians."
This year also sees the introduction of the Discovery Accelerator Supplements, a new NSERC initiative to foster research excellence. With a total of $6 million in new funding, this initiative will provide significant supplements to a select group of researchers in order to boost their productivity at a critical juncture in their careers.
"These new grants target 50 outstanding researchers. Based on their success and accomplishments so far, we believe they are poised to make real breakthroughs in their fields, and we believe it is critically important to support them financially at this time," observed Dr. Fortier.
NSERC is a federal agency whose role is to make investments in people, discovery and innovation for the benefit of all Canadians. The agency invests in people by supporting some 23,000 university students and postdoctoral fellows in their advanced studies. NSERC promotes discovery by funding more than 11,000 university professors every year and helps make innovation happen by encouraging about 1,300 Canadian companies to invest in university research and training. Over the past 10 years, NSERC has invested $6 billion in basic research, university-industry projects, and the training of Canada's next generation of scientists and engineers.
For more information, contact:
Isabelle Fontaine
Office of the Honourable Maxime Bernier
Minister of Industry
Background Information
The 15 universities receiving the largest allocation of NSERC grants and scholarships this year are:
University of Toronto: $65.8 million
University of British Columbia: $46.4 million
McGill University: $38.6 million
University of Alberta: $31.9 million
University of Waterloo: $29.9 million
The University of Western Ontario: $21.2 million
Universite de Montreal: $19.7 million
University of Calgary: $18.5 million
Dalhousie University: $18.0 million
Universite de Sherbrooke: $17.8 million
Universite Laval: $17.6 million
McMaster University: $17.3 million
Queen's University: $16.0 million
University of Ottawa: $15.7 million
University of Manitoba: $14.0 million
Contact: Michael Dwyer
Natural Sciences and Engineering Research Council
As a result of the current competition, some 3,300 professors from across Canada will receive $458.8 million in Discovery Grants to support their research in the natural sciences and engineering. (These awards are normally paid out over five years.)
In addition, 2,402 young university researchers - 2,148 at the graduate level and 254 at the postdoctoral level - will receive $99.2 million to pursue their studies in these fields, while 4,296 undergraduate students will receive Undergraduate Student Research Awards worth a total of $19.3 million to give them hands-on research experience in a laboratory.
"Our newly released science and technology strategy - Mobilizing Science and Technology to Canada's Advantage - recognizes the importance of doing more to turn ideas into innovations that provide solutions to our environmental, health and other important challenges, and to improve Canada's economic competitiveness," said Parliamentary Secretary Carrie. "These awards will help ensure that this country's best and brightest professors and students can continue their work and their contribution to the prosperity and well-being of all Canadians."
This year also sees the introduction of the Discovery Accelerator Supplements, a new NSERC initiative to foster research excellence. With a total of $6 million in new funding, this initiative will provide significant supplements to a select group of researchers in order to boost their productivity at a critical juncture in their careers.
"These new grants target 50 outstanding researchers. Based on their success and accomplishments so far, we believe they are poised to make real breakthroughs in their fields, and we believe it is critically important to support them financially at this time," observed Dr. Fortier.
NSERC is a federal agency whose role is to make investments in people, discovery and innovation for the benefit of all Canadians. The agency invests in people by supporting some 23,000 university students and postdoctoral fellows in their advanced studies. NSERC promotes discovery by funding more than 11,000 university professors every year and helps make innovation happen by encouraging about 1,300 Canadian companies to invest in university research and training. Over the past 10 years, NSERC has invested $6 billion in basic research, university-industry projects, and the training of Canada's next generation of scientists and engineers.
For more information, contact:
Isabelle Fontaine
Office of the Honourable Maxime Bernier
Minister of Industry
Background Information
The 15 universities receiving the largest allocation of NSERC grants and scholarships this year are:
University of Toronto: $65.8 million
University of British Columbia: $46.4 million
McGill University: $38.6 million
University of Alberta: $31.9 million
University of Waterloo: $29.9 million
The University of Western Ontario: $21.2 million
Universite de Montreal: $19.7 million
University of Calgary: $18.5 million
Dalhousie University: $18.0 million
Universite de Sherbrooke: $17.8 million
Universite Laval: $17.6 million
McMaster University: $17.3 million
Queen's University: $16.0 million
University of Ottawa: $15.7 million
University of Manitoba: $14.0 million
Contact: Michael Dwyer
Natural Sciences and Engineering Research Council
понедельник, 12 сентября 2011 г.
Only Two Genes Make The Difference Between Herbaceous Plants And Trees
Scientists from VIB at Ghent University have succeeded in converting annual plants into perennials. They discovered that the deactivation of two genes in annuals led to the formation of structures that converted the plant into a perennial. This was most likely an important mechanism in plant evolution, initiating the formation of trees.
Annuals and perennials
Annual crops grow, blossom and die within one year. Perennials overwinter and grow again the following year. The life strategy of many annuals consists of rapid growth following germination and rapid transition to flower and seed formation, thus preventing the loss of energy needed to create permanent structures. They germinate quickly after the winter so that they come out before other plants, thus eliminating the need to compete for food and light. The trick is basically to make as many seeds as possible in as short a time as possible.
Perennials have more evolved life strategies for surviving in poor conditions. They compose perennial structures such as overwintering buds, bulbs or tubers. These structures contain groups with cells that are not yet specialised, but which can later be converted when required into new organs such as stalks and leaves.
The flowering of annuals
Annual crops consume all the non-specialised cells in developing their flowers. Thus the appearance of the flower signals means the end of the plant. But fortunately they have left seeds that sense - after winter - that the moment has come to start up. Plants are able to register the lengthening of the days. With the advent of longer days in the spring, a signal is sent from the leaves to the growth tops to activate a limited number of blooming-induction genes.
Deactivating two genes
VIB researchers, such as Siegbert Melzer in Tom Beeckman's group, have studied two such flower-inducing genes. They have deactivated them in thale cress (Arabidopsis thaliana), a typical annual. The VIB researchers found that mutant plants can no longer induce flowering, but they can continue to grow vegetatively or come into flower much later. Melzer had found that modified crops did not use up their store of non-specialised cells, enabling perennial growth. They can therefore continue to grow for a very long time.
As with real perennials these plants show secondary growth with wood formation creating shrub-like Arabidopsis plants.
Raising the veil of evolution
Researchers have been fascinated for a long time by the evolution of herbaceous to woody structures. This research clearly shows only two genes are in fact necessary in this process. This has probably been going on throughout the evolution of plants. Furthermore it is not inconceivable this happened independently on multiple occasions.
Relevant scientific publication
The research appears in the leading journal Nature Genetics (Siegbert Melzer et al., Flowering-time genes modulate meristem determinacy and growth form in Arabidopsis thaliana).
Funding
This research was financed by VIB, UGent, IWT, FWO.
Tom Beeckman is in charge of the Root Development research group in the VIB Plant Systems Biology department, UGent - under the management of Dirk InzГ©. Click here for more information.
VIB is a non-profit research institute in life sciences. Approximately 1100 scientists and technicians perform basic research into the molecular mechanisms that are responsible for the functioning of the human body, plants and micro-organisms. By means of a strong partnership with four Flemish universities - UGent, K.U.Leuven, Universiteit Antwerpen and Vrije Universiteit Brussel - and a robust investment programme, VIB bundles the strengths of 65 research groups into one institute. Their research aims at fundamentally pushing out the boundaries of our knowledge. With its technology transfer activities VIB aims to convert research results into products for the consumer and the patient. VIB develops and disseminates a broad range of scientifically based information on all aspects of biotechnology. More information on vib.be.
The Universiteit Gent (UGent) is one of the largest Dutch-speaking universities, with more than 30,000 students. The course options include almost all academic courses that are offered in Flanders.
The UGent prides itself on being an open, socially engaged and pluralistic university with an international perspective. More information on ugent.be.
Universiteit Gent
Annuals and perennials
Annual crops grow, blossom and die within one year. Perennials overwinter and grow again the following year. The life strategy of many annuals consists of rapid growth following germination and rapid transition to flower and seed formation, thus preventing the loss of energy needed to create permanent structures. They germinate quickly after the winter so that they come out before other plants, thus eliminating the need to compete for food and light. The trick is basically to make as many seeds as possible in as short a time as possible.
Perennials have more evolved life strategies for surviving in poor conditions. They compose perennial structures such as overwintering buds, bulbs or tubers. These structures contain groups with cells that are not yet specialised, but which can later be converted when required into new organs such as stalks and leaves.
The flowering of annuals
Annual crops consume all the non-specialised cells in developing their flowers. Thus the appearance of the flower signals means the end of the plant. But fortunately they have left seeds that sense - after winter - that the moment has come to start up. Plants are able to register the lengthening of the days. With the advent of longer days in the spring, a signal is sent from the leaves to the growth tops to activate a limited number of blooming-induction genes.
Deactivating two genes
VIB researchers, such as Siegbert Melzer in Tom Beeckman's group, have studied two such flower-inducing genes. They have deactivated them in thale cress (Arabidopsis thaliana), a typical annual. The VIB researchers found that mutant plants can no longer induce flowering, but they can continue to grow vegetatively or come into flower much later. Melzer had found that modified crops did not use up their store of non-specialised cells, enabling perennial growth. They can therefore continue to grow for a very long time.
As with real perennials these plants show secondary growth with wood formation creating shrub-like Arabidopsis plants.
Raising the veil of evolution
Researchers have been fascinated for a long time by the evolution of herbaceous to woody structures. This research clearly shows only two genes are in fact necessary in this process. This has probably been going on throughout the evolution of plants. Furthermore it is not inconceivable this happened independently on multiple occasions.
Relevant scientific publication
The research appears in the leading journal Nature Genetics (Siegbert Melzer et al., Flowering-time genes modulate meristem determinacy and growth form in Arabidopsis thaliana).
Funding
This research was financed by VIB, UGent, IWT, FWO.
Tom Beeckman is in charge of the Root Development research group in the VIB Plant Systems Biology department, UGent - under the management of Dirk InzГ©. Click here for more information.
VIB is a non-profit research institute in life sciences. Approximately 1100 scientists and technicians perform basic research into the molecular mechanisms that are responsible for the functioning of the human body, plants and micro-organisms. By means of a strong partnership with four Flemish universities - UGent, K.U.Leuven, Universiteit Antwerpen and Vrije Universiteit Brussel - and a robust investment programme, VIB bundles the strengths of 65 research groups into one institute. Their research aims at fundamentally pushing out the boundaries of our knowledge. With its technology transfer activities VIB aims to convert research results into products for the consumer and the patient. VIB develops and disseminates a broad range of scientifically based information on all aspects of biotechnology. More information on vib.be.
The Universiteit Gent (UGent) is one of the largest Dutch-speaking universities, with more than 30,000 students. The course options include almost all academic courses that are offered in Flanders.
The UGent prides itself on being an open, socially engaged and pluralistic university with an international perspective. More information on ugent.be.
Universiteit Gent
пятница, 9 сентября 2011 г.
New Protocol Quickly And Efficiently Differentiates Human Embryonic Stem Cells Into Committed Neural Precursor Cells
Investigators at the Burnham Institute for Medical Research (Burnham) have developed a protocol to rapidly differentiate human embryonic stem cells (hESCs) into neural progenitor cells that may be ideal for transplantation. The research, conducted by Alexei Terskikh, Ph.D., and colleagues, outlines a method to create these committed neural precursor cells (C-NPCs) that is replicable, does not produce mutations in the cells and could be useful for clinical applications. The research was published on March 13 in the journal Cell Death and Differentiation.
When the C-NPCs created using the Terskikh protocol were transplanted into mice, they became active neurons and integrated into the cortex and olfactory bulb. The transplanted cells did not generate tumor outgrowth.
"The uniform conversion of embryonic stem cells into neural progenitors is the first step in the development of cell-based therapies for neurodegenerative disorders or spinal injuries," said Dr. Terskikh. "Many of the methods used to generate neural precursor cells for research in the lab would never work in therapeutic applications. This protocol is very well suited for clinical application because it is robust, controllable and reproducible."
Dr. Terskikh notes that the extensive passaging (moving cells from plate to plate) required by some protocols to expand the numbers of neural precursor cells limits the plasticity of the cells, can introduce mutations and may lead to the expression of oncogenes. The Terskikh protocol avoids this by using efficient conversion of hESCs into primary neuroepithelial cells without the extensive passaging.
The scientists were able to rapidly neuralize the hESCs by culturing them in small clusters in a liquid suspension. The cells developed the characteristic "rosettes" seen in neuroepithelial cells. The C-NPCs were then cultured in monolayers. Immunochemical and RT-PCR analysis of the cells demonstrated that they were uniformly C-NPCs. Whole-genome analysis confirmed this finding. Immunostaining and imaging showed that the cells could be differentiated into three distinct types of neural cells. The team then demonstrated that the C-NPCs differentiated into neurons after transplantation into the brains of neonatal mice.
Notes:
This research received funding from the National Institutes of Health and the California Institute for Regenerative Medicine.
About Burnham Institute for Medical Research
Burnham Institute for Medical Research is dedicated to revealing the fundamental molecular causes of disease and devising the innovative therapies of tomorrow. Burnham, with operations in California and Florida, is one of the fastest-growing research institutes in the country. The Institute ranks among the top-four institutions nationally for NIH grant funding and among the top-25 organizations worldwide for its research impact. Burnham utilizes a unique, collaborative approach to medical research and has established major research programs in cancer, neurodegeneration, diabetes, infectious and inflammatory and childhood diseases. The Institute is known for its world-class capabilities in stem cell research and drug discovery technologies. Burnham is a nonprofit, public benefit corporation.
Source:
Josh Baxt
Burnham Institute
When the C-NPCs created using the Terskikh protocol were transplanted into mice, they became active neurons and integrated into the cortex and olfactory bulb. The transplanted cells did not generate tumor outgrowth.
"The uniform conversion of embryonic stem cells into neural progenitors is the first step in the development of cell-based therapies for neurodegenerative disorders or spinal injuries," said Dr. Terskikh. "Many of the methods used to generate neural precursor cells for research in the lab would never work in therapeutic applications. This protocol is very well suited for clinical application because it is robust, controllable and reproducible."
Dr. Terskikh notes that the extensive passaging (moving cells from plate to plate) required by some protocols to expand the numbers of neural precursor cells limits the plasticity of the cells, can introduce mutations and may lead to the expression of oncogenes. The Terskikh protocol avoids this by using efficient conversion of hESCs into primary neuroepithelial cells without the extensive passaging.
The scientists were able to rapidly neuralize the hESCs by culturing them in small clusters in a liquid suspension. The cells developed the characteristic "rosettes" seen in neuroepithelial cells. The C-NPCs were then cultured in monolayers. Immunochemical and RT-PCR analysis of the cells demonstrated that they were uniformly C-NPCs. Whole-genome analysis confirmed this finding. Immunostaining and imaging showed that the cells could be differentiated into three distinct types of neural cells. The team then demonstrated that the C-NPCs differentiated into neurons after transplantation into the brains of neonatal mice.
Notes:
This research received funding from the National Institutes of Health and the California Institute for Regenerative Medicine.
About Burnham Institute for Medical Research
Burnham Institute for Medical Research is dedicated to revealing the fundamental molecular causes of disease and devising the innovative therapies of tomorrow. Burnham, with operations in California and Florida, is one of the fastest-growing research institutes in the country. The Institute ranks among the top-four institutions nationally for NIH grant funding and among the top-25 organizations worldwide for its research impact. Burnham utilizes a unique, collaborative approach to medical research and has established major research programs in cancer, neurodegeneration, diabetes, infectious and inflammatory and childhood diseases. The Institute is known for its world-class capabilities in stem cell research and drug discovery technologies. Burnham is a nonprofit, public benefit corporation.
Source:
Josh Baxt
Burnham Institute
вторник, 6 сентября 2011 г.
Brain Protein Reduces Alzheimer's Plaques In Mice
Increasing levels of a protein that helps the brain use cholesterol may slow the development of Alzheimer's disease changes in the brain, according to researchers studying a mouse model of the disease at Washington University School of Medicine in St. Louis.
Elevated levels of the protein ABCA1 sharply reduced buildup of brain plaques that are a hallmark of Alzheimer's disease, according to senior author David M. Holtzman, M.D., the Andrew and Gretchen Jones Professor and chair of the Department of Neurology at the School of Medicine and neurologist-in-chief at Barnes-Jewish Hospital.
The study, appearing this month in The Journal of Clinical Investigation, highlights a new possibility for potential Alzheimer's treatment: altering the brain's use of lipids, a class of fat-soluble compounds that includes cholesterol.
"It's becoming clear that ABCA1 may be a good drug target for Alzheimer's therapies," Holtzman says. "There are known drugs that can increase ABCA1 levels, and with some further development of this or similar classes of drugs and additional insights into how ABCA1 slows down plaque deposition, there may be a way to create a new approach to Alzheimer's treatment."
Discovered in 2001, ABCA1 is a naturally occurring enzyme already under study for its potential to treat heart disease. Lipids like cholesterol aren't soluble, so to be transported through the bloodstream and into and out of cells and organs, they have to be associated with molecules known as apolipoproteins. ABCA1 facilitates this process, which is known as lipidation.
In the circulatory system, ABCA1 lipidates HDL with cholesterol to form fully functioning HDL, the "good" cholesterol thought to decrease risk of heart disease. Cardiovascular researchers are testing drugs that increase ABCA1 levels, hoping eventually to use them to prevent or alleviate atherosclerosis.
Holtzman was intrigued by the connection between ABCA1 and lipidation because a primary risk factor for Alzheimer's disease is an apolipoprotein known as apoE. Different genetic forms of apoE are linked to significant changes in an individual's risk of developing late-onset Alzheimer's disease.
In earlier research, Holtzman's lab revealed that ABCA1 also lipidates good cholesterol in the brain. When they utilized mice lacking the gene for ABCA1 and bred them to mouse model of Alzheimer's disease, the animals developed a much great number of the brain plaques that are characteristic of the disease.
For the new experiment, Holtzman laboratory members Suzanne Wahrle, an M.D./Ph.D. student, and Hong Jiang, a senior research technician, created a line of mice genetically altered to make unusually high levels of ABCA1 in the brain. When they crossbred that line with their Alzheimer's disease mouse model, they found mice with high ABCA1 levels built up plaques in their brains much more slowly and to a much lesser extent than those with normal ABCA1 levels.
The work showed that ABCA1 is facilitating the lipidation of HDL and apoE. Holtzman theorizes that this allows apoE to better scavenge amyloid beta, the main ingredient of plaques, from the brain in a way that decreases the chances that plaques will begin to form. An earlier experiment by other scientists showed that lipidated apoE binds more tightly to soluble amyloid beta than non-lipidated apoE. But further research is needed to prove this theory.
A class of drugs is already available that increases ABCA1 levels: LXR (liver X receptor) agonists. However, Holtzman notes, these drugs need to be fine-tuned to avoid an undesirable side effect that increases fat buildup in the liver.
Holtzman is conducting additional studies to clarify the details of the relationship between ABCA1, apoE and amyloid beta.
Wahrle SE, Jiang H, Parsadanian M, Kim J, Li A, Knoten A, Jain S, Hirsch-Reinshagen V, Wellington CL, Bales KR, Paul SM, Holtzman DM. Overexpression of ABCA1 reduces amyloid deposition in the PDAPP mouse model of Alzheimer's disease. Journal of Clinical Investigation, February 2008 (online January 17)
Funding from the National Institutes of Health, the O'Brien Center for Kidney Disease Research, Eli Lilly and Co, the Canadian Institutes of Health Research and the American Health Assistance Foundation supported this research.
Washington University School of Medicine's 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children's hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked fourth in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children's hospitals, the School of Medicine is linked to BJC HealthCare.
Washington University in St. Louis
One Brookings Dr., Campus Box 1070
St. Louis, MO 63130
United States
wustl
Elevated levels of the protein ABCA1 sharply reduced buildup of brain plaques that are a hallmark of Alzheimer's disease, according to senior author David M. Holtzman, M.D., the Andrew and Gretchen Jones Professor and chair of the Department of Neurology at the School of Medicine and neurologist-in-chief at Barnes-Jewish Hospital.
The study, appearing this month in The Journal of Clinical Investigation, highlights a new possibility for potential Alzheimer's treatment: altering the brain's use of lipids, a class of fat-soluble compounds that includes cholesterol.
"It's becoming clear that ABCA1 may be a good drug target for Alzheimer's therapies," Holtzman says. "There are known drugs that can increase ABCA1 levels, and with some further development of this or similar classes of drugs and additional insights into how ABCA1 slows down plaque deposition, there may be a way to create a new approach to Alzheimer's treatment."
Discovered in 2001, ABCA1 is a naturally occurring enzyme already under study for its potential to treat heart disease. Lipids like cholesterol aren't soluble, so to be transported through the bloodstream and into and out of cells and organs, they have to be associated with molecules known as apolipoproteins. ABCA1 facilitates this process, which is known as lipidation.
In the circulatory system, ABCA1 lipidates HDL with cholesterol to form fully functioning HDL, the "good" cholesterol thought to decrease risk of heart disease. Cardiovascular researchers are testing drugs that increase ABCA1 levels, hoping eventually to use them to prevent or alleviate atherosclerosis.
Holtzman was intrigued by the connection between ABCA1 and lipidation because a primary risk factor for Alzheimer's disease is an apolipoprotein known as apoE. Different genetic forms of apoE are linked to significant changes in an individual's risk of developing late-onset Alzheimer's disease.
In earlier research, Holtzman's lab revealed that ABCA1 also lipidates good cholesterol in the brain. When they utilized mice lacking the gene for ABCA1 and bred them to mouse model of Alzheimer's disease, the animals developed a much great number of the brain plaques that are characteristic of the disease.
For the new experiment, Holtzman laboratory members Suzanne Wahrle, an M.D./Ph.D. student, and Hong Jiang, a senior research technician, created a line of mice genetically altered to make unusually high levels of ABCA1 in the brain. When they crossbred that line with their Alzheimer's disease mouse model, they found mice with high ABCA1 levels built up plaques in their brains much more slowly and to a much lesser extent than those with normal ABCA1 levels.
The work showed that ABCA1 is facilitating the lipidation of HDL and apoE. Holtzman theorizes that this allows apoE to better scavenge amyloid beta, the main ingredient of plaques, from the brain in a way that decreases the chances that plaques will begin to form. An earlier experiment by other scientists showed that lipidated apoE binds more tightly to soluble amyloid beta than non-lipidated apoE. But further research is needed to prove this theory.
A class of drugs is already available that increases ABCA1 levels: LXR (liver X receptor) agonists. However, Holtzman notes, these drugs need to be fine-tuned to avoid an undesirable side effect that increases fat buildup in the liver.
Holtzman is conducting additional studies to clarify the details of the relationship between ABCA1, apoE and amyloid beta.
Wahrle SE, Jiang H, Parsadanian M, Kim J, Li A, Knoten A, Jain S, Hirsch-Reinshagen V, Wellington CL, Bales KR, Paul SM, Holtzman DM. Overexpression of ABCA1 reduces amyloid deposition in the PDAPP mouse model of Alzheimer's disease. Journal of Clinical Investigation, February 2008 (online January 17)
Funding from the National Institutes of Health, the O'Brien Center for Kidney Disease Research, Eli Lilly and Co, the Canadian Institutes of Health Research and the American Health Assistance Foundation supported this research.
Washington University School of Medicine's 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children's hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked fourth in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children's hospitals, the School of Medicine is linked to BJC HealthCare.
Washington University in St. Louis
One Brookings Dr., Campus Box 1070
St. Louis, MO 63130
United States
wustl
суббота, 3 сентября 2011 г.
Using Probes To Control Chemistry - Molecule By Molecule
Using probes originally designed to detect and image topographical features on surfaces, scientists at the U.S. Department of Energy's Brookhaven National Laboratory have demonstrated the ability to initiate and spatially localize chemical reactions on the submicron scale. They have been able to reliably manipulate chemistry on a very, very small scale in contrast to normal beaker-type reactions carried out in bulk. Such "site-selective" chemistry, taken down to the molecule-by-molecule level, could lead to new ways to etch small-scale electronic circuits, the development of extremely sensitive chemical sensors, as well as a better understanding and control of chemical reactions such as those used to convert sunlight into electricity in solar cells.
"Atomic force microscopy (AFM) uses probes that are analogous to the stylus on an old-style record player," says Brookhaven Lab materials scientist Stanislaus S. Wong. However, as opposed to "feeling" the nature of slight variations of pits within record grooves, AFM probes normally detect intermolecular interactions, related to changes in surface chemistry. "What we've demonstrated in our work is the ability to alter the AFM probe so it can be used not just passively, to sense chemistry, but actively, to initiate or control chemical reactions on a surface," Wong said.
In their proof-of-principle experiment, Wong's group attached titanium dioxide nanoparticles to the end of a conventional AFM probe and used it to photocatalytically oxidize selected sites on a thin film of photoreactive dye -- a model for understanding photocatalysis in solar cells. Mandakini Kanungo, a postdoctoral researcher in Wong's lab, will describe this work in a talk at the 231st national meeting of the American Chemical Society (ACS) in Atlanta, Georgia, on Thursday, March 30, 2006.
In the experiment, oxidized and unaffected areas of the dye were often separated by a mere 0.1 microns (millionths of a meter). The hope is to increase the spatial resolution of the technique to affect changes molecule by molecule, or at the one-nanometer (billionths of a meter) scale, Wong says.
Being able to control chemistry at this level has many potential applications. First, it gives the scientists deeper insight into the kinetics of reactions at the molecular level when, for example, a catalyst triggers the in situ oxidation of a chemical in the presence of light. This reaction is important toward understanding how to convert sunlight into useable forms of energy such as electricity. A "close-up" view of the chemistry will allow scientists to experiment with different types of catalyst particles, sizes and shapes of particles, and other characteristics to see precisely how these changes affect the kinetics and other dynamic properties associated with the photocatalytic process. This work could ultimately lead to the design of more efficient catalysts and more efficient solar cells.
In another application, Wong says, "You can use the AFM tip almost like an ultrafine pencil to draw out areas that you would like to react. This creates nanometer-scale 'lines' that are different from the chemistry of surrounding areas on the substrate." In essence, he says, you can etch out such "lines of reactivity," using chemistry to "draw," for example, nanoscale circuits. Such small-scale circuits could further shrink the scale of electronic devices, as well as increase the efficiency and/or speed of data storage and retrieval.
One important benefit of this technique is that it is environmentally friendly, Wong says, using no electric current or potentially harmful reaction conditions. Furthermore, the technique has such high specificity that it offers the potential for single-molecule detection and analysis -- a benefit with possible applications in refined chemical sensor technology. Such sensors might be able to detect as little as a single molecule of a potentially hazardous material released, for example, in a terror attack.
To learn more about the technique, recent results, and potential applications, attend Kanungo's ACS talk on Thursday, March 30, 2006 at 2:30 p.m. in Room B213 of the Georgia World Congress Center.
This research was funded by the Office of Basic Energy Sciences within the U.S. Department of Energy's Office of Science.
One of ten national laboratories overseen and primarily funded by the Office of Science of the U.S. Department of Energy (DOE), Brookhaven National Laboratory conducts research in the physical, biomedical, and environmental sciences, as well as in energy technologies and national security. Brookhaven Lab also builds and operates major scientific facilities available to university, industry and government researchers. Brookhaven is operated and managed for DOE's Office of Science by Brookhaven Science Associates, a limited-liability company founded by the Research Foundation of State University of New York on behalf of Stony Brook University, the largest academic user of Laboratory facilities, and Battelle, a nonprofit, applied science and technology organization. Visit Brookhaven Lab's electronic newsroom for links, news archives, graphics, and more: bnl/newsroom
Contact: Karen McNulty Walsh
kmcnultybnl
DOE/Brookhaven National Laboratory
"Atomic force microscopy (AFM) uses probes that are analogous to the stylus on an old-style record player," says Brookhaven Lab materials scientist Stanislaus S. Wong. However, as opposed to "feeling" the nature of slight variations of pits within record grooves, AFM probes normally detect intermolecular interactions, related to changes in surface chemistry. "What we've demonstrated in our work is the ability to alter the AFM probe so it can be used not just passively, to sense chemistry, but actively, to initiate or control chemical reactions on a surface," Wong said.
In their proof-of-principle experiment, Wong's group attached titanium dioxide nanoparticles to the end of a conventional AFM probe and used it to photocatalytically oxidize selected sites on a thin film of photoreactive dye -- a model for understanding photocatalysis in solar cells. Mandakini Kanungo, a postdoctoral researcher in Wong's lab, will describe this work in a talk at the 231st national meeting of the American Chemical Society (ACS) in Atlanta, Georgia, on Thursday, March 30, 2006.
In the experiment, oxidized and unaffected areas of the dye were often separated by a mere 0.1 microns (millionths of a meter). The hope is to increase the spatial resolution of the technique to affect changes molecule by molecule, or at the one-nanometer (billionths of a meter) scale, Wong says.
Being able to control chemistry at this level has many potential applications. First, it gives the scientists deeper insight into the kinetics of reactions at the molecular level when, for example, a catalyst triggers the in situ oxidation of a chemical in the presence of light. This reaction is important toward understanding how to convert sunlight into useable forms of energy such as electricity. A "close-up" view of the chemistry will allow scientists to experiment with different types of catalyst particles, sizes and shapes of particles, and other characteristics to see precisely how these changes affect the kinetics and other dynamic properties associated with the photocatalytic process. This work could ultimately lead to the design of more efficient catalysts and more efficient solar cells.
In another application, Wong says, "You can use the AFM tip almost like an ultrafine pencil to draw out areas that you would like to react. This creates nanometer-scale 'lines' that are different from the chemistry of surrounding areas on the substrate." In essence, he says, you can etch out such "lines of reactivity," using chemistry to "draw," for example, nanoscale circuits. Such small-scale circuits could further shrink the scale of electronic devices, as well as increase the efficiency and/or speed of data storage and retrieval.
One important benefit of this technique is that it is environmentally friendly, Wong says, using no electric current or potentially harmful reaction conditions. Furthermore, the technique has such high specificity that it offers the potential for single-molecule detection and analysis -- a benefit with possible applications in refined chemical sensor technology. Such sensors might be able to detect as little as a single molecule of a potentially hazardous material released, for example, in a terror attack.
To learn more about the technique, recent results, and potential applications, attend Kanungo's ACS talk on Thursday, March 30, 2006 at 2:30 p.m. in Room B213 of the Georgia World Congress Center.
This research was funded by the Office of Basic Energy Sciences within the U.S. Department of Energy's Office of Science.
One of ten national laboratories overseen and primarily funded by the Office of Science of the U.S. Department of Energy (DOE), Brookhaven National Laboratory conducts research in the physical, biomedical, and environmental sciences, as well as in energy technologies and national security. Brookhaven Lab also builds and operates major scientific facilities available to university, industry and government researchers. Brookhaven is operated and managed for DOE's Office of Science by Brookhaven Science Associates, a limited-liability company founded by the Research Foundation of State University of New York on behalf of Stony Brook University, the largest academic user of Laboratory facilities, and Battelle, a nonprofit, applied science and technology organization. Visit Brookhaven Lab's electronic newsroom for links, news archives, graphics, and more: bnl/newsroom
Contact: Karen McNulty Walsh
kmcnultybnl
DOE/Brookhaven National Laboratory
среда, 31 августа 2011 г.
Protein Identified That Regulates Effectiveness Of Taxol Chemotherapy In Breast Cancer
Cancer researchers at Georgetown University Medical Center have taken a step towards understanding how and why a widely used chemotherapy drug works in patients with breast cancer.
In laboratory studies, the researchers isolated a protein, caveolin-1, showing that in breast cancer cells this protein can enhance cell death in response to the use of Taxol, one of two taxane chemotherapy drugs used to treat advanced breast and ovarian cancer. But in order to work, they found the protein needs to be "switched on," or phosphorylated. The results were reported in the Journal of Biological Chemistry.
Their finding suggests it may eventually be possible to test individual breast cancer patients for the status of such molecular markers as caveolin-1 in their tumors to determine the efficacy-to-toxicity ratio for Taxol, said the study's first author, postdoctoral fellow Ayesha Shajahan, Ph.D., of Lombardi Comprehensive Cancer Center at Georgetown.
"Because breast tumors are not all the same, it is important to know the cancer's molecular makeup in order to increase the efficiency, and lower the toxicity, of chemotherapy drugs, and this work takes us some steps forward in this goal," she said. "It also offers insights into why some breast cancer cells can become resistant to therapeutic drugs."
Additionally, the study identifies caveolin-1 as a new molecular target for increasing the efficacy of taxanes, according to the study's lead investigator, Robert Clarke, Ph.D., D.Sc., a Professor of Oncology and Physiology & Biophysics. "This is important because the taxanes are active drugs in breast cancer, so now that we know caveolin-1 is a new mechanism to explain how these drugs kill breast cancer cells, we can potentially take advantage of that fact to improve these agents."
The taxanes are Taxol (also known as paclitaxel) and Taxotere (docetaxel). Taxol was originally derived from the Pacific yew tree, and Taxotere is a semi-synthetic version of Taxol with slight chemical changes. These drugs stabilize a cell's "microtubules," the road-like protein structures that send chemical signals to all parts of the cell, and which must be flexible if a cell is to divide. Taxanes lock these structures into place, not allowing them to change when the cell begins to divide - which is necessary for tumor growth. Research has also indicated that the drugs induce programmed cell death (apoptosis) in cancer cells by inactivating an "apoptosis stopping protein" called BCL2, thus stopping it from inhibiting cell death.
Caveolin-1 is a protein that is found in most cells under normal conditions and it is involved in an array of cellular events that ranges from vesicle trafficking to cell migration. It is, therefore, as a key regulator of multiple events within the cell.
In cancer, the expression level of caveolin-1 can vary depending on cell type. However, the precise role of caveolin-1 in cancer has been controversial: whether it acts as a suppressor or facilitator of tumor formation depends on the cell type. In human breast cancer, caveolin-1 has been known to act as a tumor suppressor since caveolin-1 expression is down-regulated during the primary stages of breast cancer. More recent studies indicate that that caveolin-1 expression is increased in more aggressive types of breast cancer.
Under the mentorship of Clarke, Shajahan sought to determine factors that regulate expression and function of caveolin-1 in the breast. In this study, the researchers show that in their breast cancer cell model that phosphorylated caveolin-1 increased cell death by activating other key regulators vital to both breast cancer progression and cell death, including BCL2, the same protein that Taxol works on; p21, which controls cell cycle progression; and the tumor suppressor p53.
If caveolin-1 isn't phosphorylated, breast cancer cells appear to be resistant to Taxol treatment, the researchers conclude. "Thus, this study opens an area of investigation in our lab that will concentrate on understanding how this multi-tasking protein can serve as a marker for chemotherapeutic drug efficacy," Shajahan said.
The study was supported by grants from the National Institute of Health, and the Department of Defense to Clarke and a postdoctoral fellowship award from Susan G. Komen Breast Cancer Foundation to Shajahan. The other co-authors for this study were Aifen Wang, M.Sc., Markus Decker, B.Sc., and . Minetta C. Liu, M.D. from Georgetown University Medical Center, and Richard D. Minshall, Ph.D. from the University of Illinois at Chicago.
About Georgetown University Medical Center
Georgetown University Medical Center is an internationally recognized academic medical center with a three-part mission of research, teaching and patient care (through our partnership with MedStar Health). Our mission is carried out with a strong emphasis on public service and a dedication to the Catholic, Jesuit principle of cura personalis -- or "care of the whole person." The Medical Center includes the School of Medicine and the School of Nursing & Health Studies, both nationally ranked, the world-renowned Lombardi Comprehensive Cancer Center and the Biomedical Graduate Research Organization (BGRO).
Contact: Laura Cavender
Georgetown University Medical Center
View drug information on Taxol; Taxotere.
In laboratory studies, the researchers isolated a protein, caveolin-1, showing that in breast cancer cells this protein can enhance cell death in response to the use of Taxol, one of two taxane chemotherapy drugs used to treat advanced breast and ovarian cancer. But in order to work, they found the protein needs to be "switched on," or phosphorylated. The results were reported in the Journal of Biological Chemistry.
Their finding suggests it may eventually be possible to test individual breast cancer patients for the status of such molecular markers as caveolin-1 in their tumors to determine the efficacy-to-toxicity ratio for Taxol, said the study's first author, postdoctoral fellow Ayesha Shajahan, Ph.D., of Lombardi Comprehensive Cancer Center at Georgetown.
"Because breast tumors are not all the same, it is important to know the cancer's molecular makeup in order to increase the efficiency, and lower the toxicity, of chemotherapy drugs, and this work takes us some steps forward in this goal," she said. "It also offers insights into why some breast cancer cells can become resistant to therapeutic drugs."
Additionally, the study identifies caveolin-1 as a new molecular target for increasing the efficacy of taxanes, according to the study's lead investigator, Robert Clarke, Ph.D., D.Sc., a Professor of Oncology and Physiology & Biophysics. "This is important because the taxanes are active drugs in breast cancer, so now that we know caveolin-1 is a new mechanism to explain how these drugs kill breast cancer cells, we can potentially take advantage of that fact to improve these agents."
The taxanes are Taxol (also known as paclitaxel) and Taxotere (docetaxel). Taxol was originally derived from the Pacific yew tree, and Taxotere is a semi-synthetic version of Taxol with slight chemical changes. These drugs stabilize a cell's "microtubules," the road-like protein structures that send chemical signals to all parts of the cell, and which must be flexible if a cell is to divide. Taxanes lock these structures into place, not allowing them to change when the cell begins to divide - which is necessary for tumor growth. Research has also indicated that the drugs induce programmed cell death (apoptosis) in cancer cells by inactivating an "apoptosis stopping protein" called BCL2, thus stopping it from inhibiting cell death.
Caveolin-1 is a protein that is found in most cells under normal conditions and it is involved in an array of cellular events that ranges from vesicle trafficking to cell migration. It is, therefore, as a key regulator of multiple events within the cell.
In cancer, the expression level of caveolin-1 can vary depending on cell type. However, the precise role of caveolin-1 in cancer has been controversial: whether it acts as a suppressor or facilitator of tumor formation depends on the cell type. In human breast cancer, caveolin-1 has been known to act as a tumor suppressor since caveolin-1 expression is down-regulated during the primary stages of breast cancer. More recent studies indicate that that caveolin-1 expression is increased in more aggressive types of breast cancer.
Under the mentorship of Clarke, Shajahan sought to determine factors that regulate expression and function of caveolin-1 in the breast. In this study, the researchers show that in their breast cancer cell model that phosphorylated caveolin-1 increased cell death by activating other key regulators vital to both breast cancer progression and cell death, including BCL2, the same protein that Taxol works on; p21, which controls cell cycle progression; and the tumor suppressor p53.
If caveolin-1 isn't phosphorylated, breast cancer cells appear to be resistant to Taxol treatment, the researchers conclude. "Thus, this study opens an area of investigation in our lab that will concentrate on understanding how this multi-tasking protein can serve as a marker for chemotherapeutic drug efficacy," Shajahan said.
The study was supported by grants from the National Institute of Health, and the Department of Defense to Clarke and a postdoctoral fellowship award from Susan G. Komen Breast Cancer Foundation to Shajahan. The other co-authors for this study were Aifen Wang, M.Sc., Markus Decker, B.Sc., and . Minetta C. Liu, M.D. from Georgetown University Medical Center, and Richard D. Minshall, Ph.D. from the University of Illinois at Chicago.
About Georgetown University Medical Center
Georgetown University Medical Center is an internationally recognized academic medical center with a three-part mission of research, teaching and patient care (through our partnership with MedStar Health). Our mission is carried out with a strong emphasis on public service and a dedication to the Catholic, Jesuit principle of cura personalis -- or "care of the whole person." The Medical Center includes the School of Medicine and the School of Nursing & Health Studies, both nationally ranked, the world-renowned Lombardi Comprehensive Cancer Center and the Biomedical Graduate Research Organization (BGRO).
Contact: Laura Cavender
Georgetown University Medical Center
View drug information on Taxol; Taxotere.
воскресенье, 28 августа 2011 г.
Easily Blocked Protein May Help Stop Parasites
Researchers at Washington University School of Medicine in St. Louis have identified a parasite protein that has all the makings of a microbial glass jaw: it's essential, it's vulnerable and humans have nothing like it, meaning scientists can take pharmacological swings at it with minimal fear of collateral damage.
The protein, calcium dependent protein kinase 1 (CDPK1), is made by Toxoplasma gondii, the toxoplasmosis parasite; cryptosporidium, which causes diarrhea; plasmodium, which causes malaria; and other similar parasites known as apicomplexans.
In the May 20 issue of Nature, researchers report that genetically suppressing CDPK1 blocks the signals that toxoplasma parasites use to control their movement, preventing them from moving in and out of host cells. They also found that toxoplasma's version of CDPK1 is easier to disable than expected and identified a compound that effectively blocks its signaling ability.
"Kinases are proteins that are common throughout biology, but the structures of CDPKs in apicomplexans much more closely resemble those found in plants than they do those of animals," says senior author L. David Sibley, PhD, professor of molecular microbiology. "We showed that these differences can be exploited to identify potent and specific inhibitors that may provide new interventions against disease."
Infection with toxoplasma is most familiar to the general public from the recommendation that pregnant women avoid changing cat litter. Cats are commonly infected with the parasite, as are many livestock and wildlife. Humans also can become infected by eating undercooked meat or by drinking water contaminated with spores shed by cats.
Epidemiologists estimate that as many as one in every four humans worldwide is infected with toxoplasma. Infections are typically asymptomatic, only causing serious disease in patients with weakened immune systems. In some rare cases, though, infection in patients with healthy immune systems leads to serious eye or central nervous system disease, or congenital defects in the fetuses of pregnant women.
Sibley studies toxoplasma both to find ways to reduce human infection rates and as a model for learning about other apicomplexans, such as plasmodium, that are more significant sources of disease and death.
The new study, led by graduate student Sebastian Lourido, began as an effort to determine what CDPK1 does for toxoplasma. Researchers genetically modified the parasite, eliminating its normal copy of CDPK1 and replacing it with a version of the gene that they could turn on and off. When they turned the new gene off, they found that they had paralyzed the parasite, preventing it from moving and from breaking into and out of host cells. Turning the gene back on restored these abilities.
Further tests revealed that CDPK1 controls toxoplasma's ability to secrete microneme proteins, sticky proteins that act as handholds and allow the parasites to move about their environment and pass through host cell membranes.
In a separate collaborative paper published earlier this month in Nature Structural and Molecular Biology, scientists in the laboratory of co-author Raymond Hui, PhD, principal investigator of parasitology at the Structural Genomics Consortium of the University of Toronto, determined the three dimensional structure of the CDPK1 protein. Researchers found that the area drugs would normally bind in order to disable the protein was more accessible than in virtually all other kinases, including those that control signaling in humans.
"To our surprise, CDPK1 just has a naturally large keyhole for inhibitors to slide into," Lourido says. "This good fortune allowed us to exploit bulky kinase inhibitors that had been previously pioneered by the laboratory of Kevan Shokat, PhD, professor of cellular and molecular pharmacology at the University of California, San Francisco, and a Howard Hughes Medical Institute investigator."
When tested on parasites, the bulky inhibitors successfully blocked CDPK1 function and parasite infectivity without affecting human cells.
Lourido suspects CDPK1 may play a similar role in plasmodium, but its version of the protein is predicted to be harder to selectively target with inhibitors. Little is known about what CDPK1 does in cryptosporidium, but since it shares close similarity to toxoplasma, it may also be essential and susceptible to inhibition by similar compounds.
Sibley and Lourido plan to learn more of the details of how CDPK1 controls microneme secretion, using toxoplasma as a model to study the functions of parasites and how they differ from human cells. The successful toxoplasma inhibitor is now undergoing further testing in animals to see if it can eventually be adapted for clinical use to prevent infection in humans.
Lourido S, Shuman J, Zhang C, Shokat KM, Hui R, Sibley LD. Calcium-dependent protein kinase 1 is an essential regulator of exocytosis in Toxoplasma. Nature, May 20, 2010.
Funding from the American Heart Association and the National Institutes of Health supported this research.
Washington University School of Medicine's 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children's hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked fourth in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children's hospitals, the School of Medicine is linked to BJC HealthCare.
Source: Washington University in St. Louis
The protein, calcium dependent protein kinase 1 (CDPK1), is made by Toxoplasma gondii, the toxoplasmosis parasite; cryptosporidium, which causes diarrhea; plasmodium, which causes malaria; and other similar parasites known as apicomplexans.
In the May 20 issue of Nature, researchers report that genetically suppressing CDPK1 blocks the signals that toxoplasma parasites use to control their movement, preventing them from moving in and out of host cells. They also found that toxoplasma's version of CDPK1 is easier to disable than expected and identified a compound that effectively blocks its signaling ability.
"Kinases are proteins that are common throughout biology, but the structures of CDPKs in apicomplexans much more closely resemble those found in plants than they do those of animals," says senior author L. David Sibley, PhD, professor of molecular microbiology. "We showed that these differences can be exploited to identify potent and specific inhibitors that may provide new interventions against disease."
Infection with toxoplasma is most familiar to the general public from the recommendation that pregnant women avoid changing cat litter. Cats are commonly infected with the parasite, as are many livestock and wildlife. Humans also can become infected by eating undercooked meat or by drinking water contaminated with spores shed by cats.
Epidemiologists estimate that as many as one in every four humans worldwide is infected with toxoplasma. Infections are typically asymptomatic, only causing serious disease in patients with weakened immune systems. In some rare cases, though, infection in patients with healthy immune systems leads to serious eye or central nervous system disease, or congenital defects in the fetuses of pregnant women.
Sibley studies toxoplasma both to find ways to reduce human infection rates and as a model for learning about other apicomplexans, such as plasmodium, that are more significant sources of disease and death.
The new study, led by graduate student Sebastian Lourido, began as an effort to determine what CDPK1 does for toxoplasma. Researchers genetically modified the parasite, eliminating its normal copy of CDPK1 and replacing it with a version of the gene that they could turn on and off. When they turned the new gene off, they found that they had paralyzed the parasite, preventing it from moving and from breaking into and out of host cells. Turning the gene back on restored these abilities.
Further tests revealed that CDPK1 controls toxoplasma's ability to secrete microneme proteins, sticky proteins that act as handholds and allow the parasites to move about their environment and pass through host cell membranes.
In a separate collaborative paper published earlier this month in Nature Structural and Molecular Biology, scientists in the laboratory of co-author Raymond Hui, PhD, principal investigator of parasitology at the Structural Genomics Consortium of the University of Toronto, determined the three dimensional structure of the CDPK1 protein. Researchers found that the area drugs would normally bind in order to disable the protein was more accessible than in virtually all other kinases, including those that control signaling in humans.
"To our surprise, CDPK1 just has a naturally large keyhole for inhibitors to slide into," Lourido says. "This good fortune allowed us to exploit bulky kinase inhibitors that had been previously pioneered by the laboratory of Kevan Shokat, PhD, professor of cellular and molecular pharmacology at the University of California, San Francisco, and a Howard Hughes Medical Institute investigator."
When tested on parasites, the bulky inhibitors successfully blocked CDPK1 function and parasite infectivity without affecting human cells.
Lourido suspects CDPK1 may play a similar role in plasmodium, but its version of the protein is predicted to be harder to selectively target with inhibitors. Little is known about what CDPK1 does in cryptosporidium, but since it shares close similarity to toxoplasma, it may also be essential and susceptible to inhibition by similar compounds.
Sibley and Lourido plan to learn more of the details of how CDPK1 controls microneme secretion, using toxoplasma as a model to study the functions of parasites and how they differ from human cells. The successful toxoplasma inhibitor is now undergoing further testing in animals to see if it can eventually be adapted for clinical use to prevent infection in humans.
Lourido S, Shuman J, Zhang C, Shokat KM, Hui R, Sibley LD. Calcium-dependent protein kinase 1 is an essential regulator of exocytosis in Toxoplasma. Nature, May 20, 2010.
Funding from the American Heart Association and the National Institutes of Health supported this research.
Washington University School of Medicine's 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children's hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked fourth in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children's hospitals, the School of Medicine is linked to BJC HealthCare.
Source: Washington University in St. Louis
четверг, 25 августа 2011 г.
Medical Evacuation Procedures Targeted By US Air Force Grant
University of Cincinnati (UC) researchers have received a grant in excess of $2 million from the U.S. Air Force School of Aerospace Medicine to determine the ideal time to fly that minimizes health complications to injured soldiers due to the rush to move them from the battlefield into a safe zone.
"There is a sense of urgency about getting these wounded soldiers to a cleaner, safer environment," explains Col. Warren Dorlac, MD, co-principal investigator on the UC study. "Our overriding goal is to protect patients from anything that could potentially lead to a cascade of medical complications that will jeopardize survival. But the reality is that evacuation is happening at a time when they are most prone to a secondary hit."
According to U.S. military reports, about 30 to 50 soldiers are critically wounded each month and require medical evacuation out of a war zone. Most are in transit to a full-service hospital within 48 hours.
Avoiding this "second hit" - such as a serious infection or pneumonia - improves survival dramatically. Doing so is challenging, however, in the middle of a war zone where medical troops are being cared for in maze of canvas and plywood hospital tents.
Dorlac and his colleagues believe there may be a direct link between inflammatory changes in the body and the timing of strategic medical evacuation movements.
For this study, UC researchers will investigate how early evacuation of combat casualties affects the body's inflammatory response, possibly predisposing already critically wounded people to death from related complications.
"We need to understand the biological effects of the hypobaric environment so we can minimize the risk for additional injuries," says Dorlac, associate professor of surgery at UC and director of the Cincinnati Center for Sustainment and Readiness Skills (C-STARS) program housed in University Hospital.
Currently, no data exists on the impact of the hypobaric environment - characterized by reduced oxygen levels - and altitude on patients recovering from traumatic injuries.
"Determining the ideal time to fly could reduce infection, minimize hospital stays and result in fewer amputations and deaths for the soldiers defending our country," adds Dorlac.
Because of the nature of a combat zone, the average medical evaluation plane quickly ascends 8,000 feet within 10 minutes. The plane is very different than a hospital intensive care unit - 90 decibels of noise, lots of vibration and a pressurized environment that results in less oxygen to revive tissues and relieve stress on the body's systems.
This, says Dorlac, is far from the ideal setting for a traumatic brain-injured or other severely injured patient.
"When we send a patient up in an airplane, we're essentially putting them into an environment we know can't be good for them in an effort to move them to safety," he adds. "A dark, quiet intensive care unit with very little stimulation or distraction is preferable. Even minor movements can cause a change in intracranial pressure."
For this two-phase study, the UC team will create three animal models representative of traumatic military combat injuries: controlled hemorrhage, hepatic ischemia reperfusion and scald/burn.
The controlled hemorrhage model, characterized by a low but sustainable level of blood pressure, is meant to reflect a soldier who has experienced a heavy-bleeding wound but doesn't reach a field hospital to receive fluids for several hours.
Hepatic ischemia reperfusion model represents a patient who needs serious abdominal surgery that requires re-establishing blood flow to a major organ.
The scald/burn model corresponds to a blast burn wound from weapon fire.
"Each model has a different inflammatory response, all of them severe and relevant to injuries our soldiers are experiences during war," explains Alex Lentsch, PhD, co-principal investigator of the study and director of UC's surgical research unit.
"By understanding how the inflammatory response evolves over the course of different injuries, flight times and altitudes," he adds, "we will be able to better target care for patients who have been severely injured and need to be moved across country."
After taking baseline biological measurements, researchers will test whether moving to an altitude of 8,000 feet increases the body's inflammatory response. This information is necessary to determine an ideal to time to fly that minimizes the risk for additional medical complications.
Cellular inflammation markers in the blood will be measured before and after flight to determine how different altitudes affect the body's inflammatory response after injury.
"When a person experiences trauma and loses a lot of blood, the body sends warning signals and stimulates certain cells that will try to fix or repair the problem, causing inflammation," explains Lentsch. "But this storm of cellular response is unselective. This all eventually leads to multiple organ dysfunction."
The study's second phase will focus on a more complex brain injury model using concepts learned in the initial research. Researchers will continue to look at the effect of flight timing and altitude on the patient's inflammatory response but also monitor blood oxygenation levels and intracranial pressure.
Three areas have been shown to increase brain tissue loss and increase mortality in head injured patients: lack of oxygen (hypoxia); low blood pressure (hypotension); and increased intracranial pressure, which can be brought on by a low oxygen environment characteristic of a medical evacuation plane.
"There is nothing known beyond anecdotal evidence about inflammation's affects on the survival of patients with traumatic injuries, so we have a great opportunity to learn more about this problem and make an impact on the real world."
Timothy Pritts, MD, PhD, and Lt. Col. Gina Dorlac, MD, are co-investigators in this study. Maj Stephen Barnes, MD, previously of CSTARS Cincinnati will also stay involved. Testing will take place both at UC and Brooks Air Force Base in San Antonio, Texas.
Source: Amanda Harper
University of Cincinnati
"There is a sense of urgency about getting these wounded soldiers to a cleaner, safer environment," explains Col. Warren Dorlac, MD, co-principal investigator on the UC study. "Our overriding goal is to protect patients from anything that could potentially lead to a cascade of medical complications that will jeopardize survival. But the reality is that evacuation is happening at a time when they are most prone to a secondary hit."
According to U.S. military reports, about 30 to 50 soldiers are critically wounded each month and require medical evacuation out of a war zone. Most are in transit to a full-service hospital within 48 hours.
Avoiding this "second hit" - such as a serious infection or pneumonia - improves survival dramatically. Doing so is challenging, however, in the middle of a war zone where medical troops are being cared for in maze of canvas and plywood hospital tents.
Dorlac and his colleagues believe there may be a direct link between inflammatory changes in the body and the timing of strategic medical evacuation movements.
For this study, UC researchers will investigate how early evacuation of combat casualties affects the body's inflammatory response, possibly predisposing already critically wounded people to death from related complications.
"We need to understand the biological effects of the hypobaric environment so we can minimize the risk for additional injuries," says Dorlac, associate professor of surgery at UC and director of the Cincinnati Center for Sustainment and Readiness Skills (C-STARS) program housed in University Hospital.
Currently, no data exists on the impact of the hypobaric environment - characterized by reduced oxygen levels - and altitude on patients recovering from traumatic injuries.
"Determining the ideal time to fly could reduce infection, minimize hospital stays and result in fewer amputations and deaths for the soldiers defending our country," adds Dorlac.
Because of the nature of a combat zone, the average medical evaluation plane quickly ascends 8,000 feet within 10 minutes. The plane is very different than a hospital intensive care unit - 90 decibels of noise, lots of vibration and a pressurized environment that results in less oxygen to revive tissues and relieve stress on the body's systems.
This, says Dorlac, is far from the ideal setting for a traumatic brain-injured or other severely injured patient.
"When we send a patient up in an airplane, we're essentially putting them into an environment we know can't be good for them in an effort to move them to safety," he adds. "A dark, quiet intensive care unit with very little stimulation or distraction is preferable. Even minor movements can cause a change in intracranial pressure."
For this two-phase study, the UC team will create three animal models representative of traumatic military combat injuries: controlled hemorrhage, hepatic ischemia reperfusion and scald/burn.
The controlled hemorrhage model, characterized by a low but sustainable level of blood pressure, is meant to reflect a soldier who has experienced a heavy-bleeding wound but doesn't reach a field hospital to receive fluids for several hours.
Hepatic ischemia reperfusion model represents a patient who needs serious abdominal surgery that requires re-establishing blood flow to a major organ.
The scald/burn model corresponds to a blast burn wound from weapon fire.
"Each model has a different inflammatory response, all of them severe and relevant to injuries our soldiers are experiences during war," explains Alex Lentsch, PhD, co-principal investigator of the study and director of UC's surgical research unit.
"By understanding how the inflammatory response evolves over the course of different injuries, flight times and altitudes," he adds, "we will be able to better target care for patients who have been severely injured and need to be moved across country."
After taking baseline biological measurements, researchers will test whether moving to an altitude of 8,000 feet increases the body's inflammatory response. This information is necessary to determine an ideal to time to fly that minimizes the risk for additional medical complications.
Cellular inflammation markers in the blood will be measured before and after flight to determine how different altitudes affect the body's inflammatory response after injury.
"When a person experiences trauma and loses a lot of blood, the body sends warning signals and stimulates certain cells that will try to fix or repair the problem, causing inflammation," explains Lentsch. "But this storm of cellular response is unselective. This all eventually leads to multiple organ dysfunction."
The study's second phase will focus on a more complex brain injury model using concepts learned in the initial research. Researchers will continue to look at the effect of flight timing and altitude on the patient's inflammatory response but also monitor blood oxygenation levels and intracranial pressure.
Three areas have been shown to increase brain tissue loss and increase mortality in head injured patients: lack of oxygen (hypoxia); low blood pressure (hypotension); and increased intracranial pressure, which can be brought on by a low oxygen environment characteristic of a medical evacuation plane.
"There is nothing known beyond anecdotal evidence about inflammation's affects on the survival of patients with traumatic injuries, so we have a great opportunity to learn more about this problem and make an impact on the real world."
Timothy Pritts, MD, PhD, and Lt. Col. Gina Dorlac, MD, are co-investigators in this study. Maj Stephen Barnes, MD, previously of CSTARS Cincinnati will also stay involved. Testing will take place both at UC and Brooks Air Force Base in San Antonio, Texas.
Source: Amanda Harper
University of Cincinnati
понедельник, 22 августа 2011 г.
Flies Show Link Between Sleep And Immune System
Go a few nights without enough sleep and you're more likely to get sick, but scientists have no real explanation for how sleep is related to the immune system. Now, researchers at the Stanford University School of Medicine are finding that fruit flies can point to the answers.
What they have learned thus far is that illness and sleep disruption may be a two-way street: sick flies can't sleep, and losing sleep makes them more susceptible to infection.
"When flies get sick, they stop sleeping," said David Schneider, PhD, assistant professor of microbiology and immunology. "Disrupting sleep in turn disrupts the immune system, which makes them even more infected and it's downhill from there in a 'spiral of death." Schneider is the senior author of a study on the sleep patterns of flies, published in Current Biology.
Schneider worked with postdoctoral scholar Mimi Shirasu-Hiza, PhD, who is the study's first author, to examine the connection between illness and sleep patterns by infecting fruit flies with one of two bacteria - Streptococcus pneumoniae or Listeria monocytogenes.
The infected flies lost their "day" and "night" patterns of activity, which are part of the regular changes that occur in the course of a day, called circadian rhythm. Uninfected flies alternate between 12 hours of high activity and 12 hours of low activity. The researchers found the sick flies had fewer sleep sessions and shorter periods of continuous sleep than did healthy flies. They basically just didn't sleep well, concluded the researchers.
The researchers can't say for sure whether a disruption of the brain's central clock, which is the area of the fly brain that exhibits circadian gene activity, was responsible for the changes seen in the sick flies; but the behavior of the ill flies looked a lot like that of flies known to have disruptions in their genes controlling circadian rhythm.
So the next step, after confirming that flies lost sleep when infected, was to ask the converse: when sleep is disrupted, does that affect immunity"
The challenge was how to disrupt the flies' sleep. Schneider tried building a machine that jostled the flies randomly. "All it was really good at doing was throwing the tubes around the room," said Schneider. "Also it was too regular, the flies got used to it so they could nap."
Another option was to keep the flies in continuous light. But Schneider and Shirasu-Hiza decided that an even better way would be to turn to established fly strains isolated decades ago that possess disruptions in their genes controlling circadian rhythm. In this case, these mutant flies could be kept under exactly the same light and temperature conditions as the normal flies.
They looked at flies that were defective in one of two genes, called "timeless" and "period". They found that the loss of either gene's function made the flies more sensitive to bacterial infections and these sick flies died significantly faster than control flies, which lived two to four times as long as the sick ones.
"We want to know how the internal clock knows the animal is infected, and how does the immune system know that you are not sleeping properly" said Schneider. "How do those messages get sent back and forth"
Their findings also raise the question of why the flies have a change in their sleep pattern when infected. The researchers speculate that from an evolutionary standpoint, there may be some microbes that are fought better when sleep is disrupted, although clearly not the two microbes they tested in the current study. "We think that is the reason flies do this," said Schneider, "but sometimes it's a good thing, sometimes it's a bad thing."
Building on their findings, they can begin to answer these questions. Shirasu-Hiza will be testing mutant flies with other circadian rhythm genes missing.
They hope their work inspires researchers who work on vertebrates to explore the molecular underpinnings of the interaction between sleep and immunity.
"The cool thing is that many of the clock genes are conserved between flies and vertebrates; we have 'period' and we have 'timeless'," said Schneider. "As usual, it doesn't work in exactly the same way, but what the fly does is let us find genes that are involved in the process, and then go figure out exactly how they are rewired to work in the human. The fly is really good for prospecting."
This work was funded by the National Institutes of Health, the Irvington Institution and the National Science Foundation. Other Stanford researchers who contributed to this study are: postdoctoral scholar Marc Dionne, PhD, graduate student Linh Pham, and graduate student Janelle Ayres.
Stanford University Medical Center integrates research, medical education and patient care at its three institutions - Stanford University School of Medicine, Stanford Hospital & Clinics and Lucile Packard Children's Hospital at Stanford. For more information, please visit the Web site of the medical center's Office of Communication & Public Affairs at mednews.stanford/.
Contact: Mitzi Baker
Stanford University Medical Center
What they have learned thus far is that illness and sleep disruption may be a two-way street: sick flies can't sleep, and losing sleep makes them more susceptible to infection.
"When flies get sick, they stop sleeping," said David Schneider, PhD, assistant professor of microbiology and immunology. "Disrupting sleep in turn disrupts the immune system, which makes them even more infected and it's downhill from there in a 'spiral of death." Schneider is the senior author of a study on the sleep patterns of flies, published in Current Biology.
Schneider worked with postdoctoral scholar Mimi Shirasu-Hiza, PhD, who is the study's first author, to examine the connection between illness and sleep patterns by infecting fruit flies with one of two bacteria - Streptococcus pneumoniae or Listeria monocytogenes.
The infected flies lost their "day" and "night" patterns of activity, which are part of the regular changes that occur in the course of a day, called circadian rhythm. Uninfected flies alternate between 12 hours of high activity and 12 hours of low activity. The researchers found the sick flies had fewer sleep sessions and shorter periods of continuous sleep than did healthy flies. They basically just didn't sleep well, concluded the researchers.
The researchers can't say for sure whether a disruption of the brain's central clock, which is the area of the fly brain that exhibits circadian gene activity, was responsible for the changes seen in the sick flies; but the behavior of the ill flies looked a lot like that of flies known to have disruptions in their genes controlling circadian rhythm.
So the next step, after confirming that flies lost sleep when infected, was to ask the converse: when sleep is disrupted, does that affect immunity"
The challenge was how to disrupt the flies' sleep. Schneider tried building a machine that jostled the flies randomly. "All it was really good at doing was throwing the tubes around the room," said Schneider. "Also it was too regular, the flies got used to it so they could nap."
Another option was to keep the flies in continuous light. But Schneider and Shirasu-Hiza decided that an even better way would be to turn to established fly strains isolated decades ago that possess disruptions in their genes controlling circadian rhythm. In this case, these mutant flies could be kept under exactly the same light and temperature conditions as the normal flies.
They looked at flies that were defective in one of two genes, called "timeless" and "period". They found that the loss of either gene's function made the flies more sensitive to bacterial infections and these sick flies died significantly faster than control flies, which lived two to four times as long as the sick ones.
"We want to know how the internal clock knows the animal is infected, and how does the immune system know that you are not sleeping properly" said Schneider. "How do those messages get sent back and forth"
Their findings also raise the question of why the flies have a change in their sleep pattern when infected. The researchers speculate that from an evolutionary standpoint, there may be some microbes that are fought better when sleep is disrupted, although clearly not the two microbes they tested in the current study. "We think that is the reason flies do this," said Schneider, "but sometimes it's a good thing, sometimes it's a bad thing."
Building on their findings, they can begin to answer these questions. Shirasu-Hiza will be testing mutant flies with other circadian rhythm genes missing.
They hope their work inspires researchers who work on vertebrates to explore the molecular underpinnings of the interaction between sleep and immunity.
"The cool thing is that many of the clock genes are conserved between flies and vertebrates; we have 'period' and we have 'timeless'," said Schneider. "As usual, it doesn't work in exactly the same way, but what the fly does is let us find genes that are involved in the process, and then go figure out exactly how they are rewired to work in the human. The fly is really good for prospecting."
This work was funded by the National Institutes of Health, the Irvington Institution and the National Science Foundation. Other Stanford researchers who contributed to this study are: postdoctoral scholar Marc Dionne, PhD, graduate student Linh Pham, and graduate student Janelle Ayres.
Stanford University Medical Center integrates research, medical education and patient care at its three institutions - Stanford University School of Medicine, Stanford Hospital & Clinics and Lucile Packard Children's Hospital at Stanford. For more information, please visit the Web site of the medical center's Office of Communication & Public Affairs at mednews.stanford/.
Contact: Mitzi Baker
Stanford University Medical Center
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