Rochelle Buffenstein, PhD, professor, University of Texas Health Science Center at San Antonio and Luigi Fontana, MD, PhD, research associate professor, Washington University in St. Louis, were selected as recipients of the Breakthroughs in Gerontology (BIG) Award sponsored by the Glenn Foundation for Medical Research and the American Federation for Aging Research (AFAR). Established in 2005, the BIG Award provides $200,000 grants for high risk, original research that offers significant promise of yielding transforming discoveries in the fundamental biology of aging.
Dr. Buffenstein will investigate how regulation by the Nrf2 signaling pathway-a major detoxification pathway-protects long-lived species such as the naked mole rat from cellular stress that contributes to age-related diseases. The naked mole rat is the longest-lived rodent known, living 8.6 times longer than similar-sized mice, and maintains cancer-free, good health for more than 85% of its 30-year lifespan. Its tissues show pronounced cellular resistance to most noxious agents. In contrast, most short-lived species, rather than fending off threats to their tissues, direct many of their resources into rapid growth and early reproduction and readily succumb to age-related diseases such as cancer. Understanding the mechanisms involved in this pathway may provide pivotal insights into aging.
Dr. Fontana seeks to better understand caloric restriction (CR), which has been shown to slow aging in certain laboratory animals. The precise molecular mechanisms responsible for this effect are not known, but likely involve the regulation of gene function. Recent findings in individuals on long-term CR with adequate nutrition observed protection against diabetes, hypertension, inflammation, clogged arteries and deterioration of heart function with aging. This is consistent with long-term effects of CR in monkeys and rodents. However, little is known about the effects of long-term CR in humans on gene function modifications, which may be involved in mediating some of the longevity results. Dr. Fontana will study whether long-term CR with adequate protein and micronutrients intake results in some of the same changes in gene function that have been shown in calorically restricted mice and monkeys. By elucidating the molecular mechanisms underlying the effects of CR in humans, Dr. Fontana's research may identify potential biomarkers of aging and longevity that could assist clinicians in predicting many different age-associated diseases in humans.
"We created the BIG award to encourage scientists to engage in bolder research pursuits, those that are higher-risk but which offer the potential for greater reward in our understanding of basic mechanisms that affect aging and age-related diseases," said Mark R. Collins, president of the Glenn Foundation for Medical Research. "Our hope is that these awards will lead to new insights into the molecular factors that coordinate aging in multiple cells and tissues," he added.
"The BIG program is a novel approach to funding science that rewards innovative thinking, which may ultimately increase the odds that we will all live healthier for a much longer period of time," said Stephanie Lederman, executive director, American Federation for Aging Research.
Source:
Stacey Harris
American Federation for Aging Research
вторник, 31 мая 2011 г.
понедельник, 30 мая 2011 г.
Neuroscientists Hope To Get People Walking Again
Neuroscience researchers at the University of Louisville will be the only team collaborating with an international group of scientists that last week announced they had enabled paralyzed rats to walk while supporting their own weight.
Dr. Susan Harkema, the University of Louisville's Owsley Brown Frazier Chair in Neurological Rehabilitation, rehabilitation director at the university's Kentucky Spinal Cord Injury Research Center (KSCIRC) and the director of research at Frazier Rehab Institute, is evaluating how to translate into humans the success accomplished in the animals.
"We have been collaborating with this particular group of researchers for a number of years," Harkema said. "The results they have shown are very exciting and we look forward to determining how to take their animal findings and move it into applications for humans."
The research team at UCLA found that a combination of drugs, electrical stimulation and regular exercise was enough to allow the rats to walk. One of the key things demonstrated is that regeneration of severed nerve fibers is not required for the animals to learn to walk again.
"Spine cells in mammals generate a current that helps make muscles and parts of the body move. If we can find ways to harness that current and stimulate appropriate areas with electrical stimulation to enhance that current, we may be able to help people who have complete spinal cord injuries stand and walk on their own," Harkema said.
Statistics from the University of Alabama National Spinal Cord Injury Statistical Center show that approximately 250,000 Americans are spinal cord injured. Fifty two percent of spinal cord injured individuals are considered paraplegic and 47% quadriplegic. Approximately 11,000 new injuries occur each year. Fifty-six percent of injuries occur between the ages of 16 and 30. The average age of a spinal cord injured person is 31.
Source:
Gary Mans
University of Louisville Health Sciences Center
Dr. Susan Harkema, the University of Louisville's Owsley Brown Frazier Chair in Neurological Rehabilitation, rehabilitation director at the university's Kentucky Spinal Cord Injury Research Center (KSCIRC) and the director of research at Frazier Rehab Institute, is evaluating how to translate into humans the success accomplished in the animals.
"We have been collaborating with this particular group of researchers for a number of years," Harkema said. "The results they have shown are very exciting and we look forward to determining how to take their animal findings and move it into applications for humans."
The research team at UCLA found that a combination of drugs, electrical stimulation and regular exercise was enough to allow the rats to walk. One of the key things demonstrated is that regeneration of severed nerve fibers is not required for the animals to learn to walk again.
"Spine cells in mammals generate a current that helps make muscles and parts of the body move. If we can find ways to harness that current and stimulate appropriate areas with electrical stimulation to enhance that current, we may be able to help people who have complete spinal cord injuries stand and walk on their own," Harkema said.
Statistics from the University of Alabama National Spinal Cord Injury Statistical Center show that approximately 250,000 Americans are spinal cord injured. Fifty two percent of spinal cord injured individuals are considered paraplegic and 47% quadriplegic. Approximately 11,000 new injuries occur each year. Fifty-six percent of injuries occur between the ages of 16 and 30. The average age of a spinal cord injured person is 31.
Source:
Gary Mans
University of Louisville Health Sciences Center
воскресенье, 29 мая 2011 г.
Genzyme Announces Positive Initial Observations In Trial Evaluating Novel Oral Treatment For Gaucher Disease
Genzyme Corp.
(Nasdaq: GENZ) announced today that it has completed enrollment in the
ongoing Phase 2 trial of Genz-112638, a novel oral therapy being developed
for the treatment of Gaucher disease. Based on positive results seen in the
trial to date, Genzyme intends to meet with regulatory agencies in the
coming weeks to discuss an expedited development strategy.
Initial observations from the first five patients suggest that
Genz-112638 may produce a rapid and meaningful impact on important clinical
endpoints including reductions in spleen and liver volume, and an increase
in platelet counts and hemoglobin concentration. Safety observations from
all patients enrolled to date suggest that the only drug-related adverse
events seen in the trial have been mild and transient in nature, including
one possibly related serious adverse event that is currently being
investigated. These early findings will be presented today at Genzyme's
Analyst Day, and full trial results will be available in mid-2008.
If these early improvements continue and are observed in other patients
enrolled in the trial, Genz-112638 may represent a promising novel approach
to treating patients with Gaucher disease.
"We are very encouraged by our first observations from this trial,"
said David Meeker MD, president of the Lysosomal Storage Disorder business.
"Cerezyme has had a remarkable effect on the lives of patients with Gaucher
Disease. We have set a very high bar for ourselves in trying to develop a
convenient oral therapy that can provide a safe and effective choice for
patients. We look forward to developing this molecule further and exploring
the role it may play in the treatment of patients with Gaucher disease."
The open-label trial has enrolled patients with Type 1 Gaucher disease
at medical centers in Europe, Israel, North America and South America.
About Genz-112638
Genz-112638, a novel ceramide analog given orally, is designed to
inhibit the enzyme glucosylceramide synthase, which results in reduced
production of glucocerebroside. This is the substance that builds up in the
cells and tissues of people with Gaucher disease. In preclinical studies,
the molecule has shown high potency and specificity. In addition to Gaucher
disease, there are a variety of other conditions that can be caused by
malfunctions in the pathway targeted by this molecule, such as Fabry
disease, and Genzyme intends to explore studies in this area.
Initiation of the Phase 2 program followed completion of an extensive
pre- clinical research effort and a Phase 1 program that involved more than
120 subjects in three separate studies.
Genzyme's Commitment to Gaucher Disease
Development of Genz-112638 reflects Genzyme's long-standing commitment
to improving the care of patients with Gaucher disease. Since introducing
Ceredase in 1991, Genzyme has engaged in extensive basic science research
to further improve the management of Gaucher patients. Post-approval
experience has helped to demonstrate the positive and enduring impact
Ceredase and Cerezyme can have on different manifestations of the disease,
such as anemia, thrombocytopenia, hepatosplenomegaly, and bone involvement.
Data generated by the Gaucher Registry, the largest database of its kind,
have yielded insights that have shaped how physicians and their patients
manage Gaucher disease. Genzyme has also conducted extensive research into
gene therapy for single gene disorders like Gaucher disease.
About Genzyme
One of the world's leading biotechnology companies, Genzyme is
dedicated to making a major positive impact on the lives of people with
serious diseases. Since 1981, the company has grown from a small start-up
to a diversified enterprise with more than 9,000 employees in locations
spanning the globe and 2006 revenues of $3.2 billion. Genzyme has been
selected by FORTUNE as one of the "100 Best Companies to Work for" in the
United States. With many established products and services helping patients
in nearly 90 countries, Genzyme is a leader in the effort to develop and
apply the most advanced technologies in the life sciences. The company's
products and services are focused on rare inherited disorders, kidney
disease, orthopaedics, cancer, transplant, and diagnostic testing.
Genzyme's commitment to innovation continues today with a substantial
development program focused on these fields, as well as immune disease,
infectious disease, and other areas of unmet medical need.
Forward Looking Statements
This press release contains forward-looking statements regarding
Genzyme's business plans and strategies, including: Genzyme's intention to
meet with regulatory authorities to discuss an expedited regulatory
strategy and the expected timing of that meeting; the potential of
Genz-112638 to treat Gaucher disease; and Genzyme's intention to pursue
studies of Genz-112638 for treatment of other diseases. These statements
are subject to risks and uncertainties that could cause actual results to
differ materially from those forecast in these forward-looking statements.
These risks and uncertainties include, among others, Genzyme's ability to
successfully complete clinical development of, and secure regulatory
approvals for, Genz-112638 for the treatment of Gaucher disease; that early
improvements in patients are not observed in new patients and/or over a
longer period of time; the willingness of regulatory authorities to meet
with Genzyme and approve an expedited regulatory strategy; and the risks
and uncertainties described in Genzyme's SEC reports filed under the
Securities Exchange Act of 1934, including the factors discussed under the
caption "Risk Factors" in Genzyme's Quarterly Report on Form 10-Q for the
period ended March 31, 2007. Genzyme cautions investors not to place
substantial reliance on the forward-looking statements contained in this
press release. These statements speak only as of the date of this press
release and Genzyme undertakes no obligation to update or revise the
statements.
Genzyme(R) is a registered trademark of Genzyme Corporation. All rights
reserved.
Genzyme Corp.
genzyme
(Nasdaq: GENZ) announced today that it has completed enrollment in the
ongoing Phase 2 trial of Genz-112638, a novel oral therapy being developed
for the treatment of Gaucher disease. Based on positive results seen in the
trial to date, Genzyme intends to meet with regulatory agencies in the
coming weeks to discuss an expedited development strategy.
Initial observations from the first five patients suggest that
Genz-112638 may produce a rapid and meaningful impact on important clinical
endpoints including reductions in spleen and liver volume, and an increase
in platelet counts and hemoglobin concentration. Safety observations from
all patients enrolled to date suggest that the only drug-related adverse
events seen in the trial have been mild and transient in nature, including
one possibly related serious adverse event that is currently being
investigated. These early findings will be presented today at Genzyme's
Analyst Day, and full trial results will be available in mid-2008.
If these early improvements continue and are observed in other patients
enrolled in the trial, Genz-112638 may represent a promising novel approach
to treating patients with Gaucher disease.
"We are very encouraged by our first observations from this trial,"
said David Meeker MD, president of the Lysosomal Storage Disorder business.
"Cerezyme has had a remarkable effect on the lives of patients with Gaucher
Disease. We have set a very high bar for ourselves in trying to develop a
convenient oral therapy that can provide a safe and effective choice for
patients. We look forward to developing this molecule further and exploring
the role it may play in the treatment of patients with Gaucher disease."
The open-label trial has enrolled patients with Type 1 Gaucher disease
at medical centers in Europe, Israel, North America and South America.
About Genz-112638
Genz-112638, a novel ceramide analog given orally, is designed to
inhibit the enzyme glucosylceramide synthase, which results in reduced
production of glucocerebroside. This is the substance that builds up in the
cells and tissues of people with Gaucher disease. In preclinical studies,
the molecule has shown high potency and specificity. In addition to Gaucher
disease, there are a variety of other conditions that can be caused by
malfunctions in the pathway targeted by this molecule, such as Fabry
disease, and Genzyme intends to explore studies in this area.
Initiation of the Phase 2 program followed completion of an extensive
pre- clinical research effort and a Phase 1 program that involved more than
120 subjects in three separate studies.
Genzyme's Commitment to Gaucher Disease
Development of Genz-112638 reflects Genzyme's long-standing commitment
to improving the care of patients with Gaucher disease. Since introducing
Ceredase in 1991, Genzyme has engaged in extensive basic science research
to further improve the management of Gaucher patients. Post-approval
experience has helped to demonstrate the positive and enduring impact
Ceredase and Cerezyme can have on different manifestations of the disease,
such as anemia, thrombocytopenia, hepatosplenomegaly, and bone involvement.
Data generated by the Gaucher Registry, the largest database of its kind,
have yielded insights that have shaped how physicians and their patients
manage Gaucher disease. Genzyme has also conducted extensive research into
gene therapy for single gene disorders like Gaucher disease.
About Genzyme
One of the world's leading biotechnology companies, Genzyme is
dedicated to making a major positive impact on the lives of people with
serious diseases. Since 1981, the company has grown from a small start-up
to a diversified enterprise with more than 9,000 employees in locations
spanning the globe and 2006 revenues of $3.2 billion. Genzyme has been
selected by FORTUNE as one of the "100 Best Companies to Work for" in the
United States. With many established products and services helping patients
in nearly 90 countries, Genzyme is a leader in the effort to develop and
apply the most advanced technologies in the life sciences. The company's
products and services are focused on rare inherited disorders, kidney
disease, orthopaedics, cancer, transplant, and diagnostic testing.
Genzyme's commitment to innovation continues today with a substantial
development program focused on these fields, as well as immune disease,
infectious disease, and other areas of unmet medical need.
Forward Looking Statements
This press release contains forward-looking statements regarding
Genzyme's business plans and strategies, including: Genzyme's intention to
meet with regulatory authorities to discuss an expedited regulatory
strategy and the expected timing of that meeting; the potential of
Genz-112638 to treat Gaucher disease; and Genzyme's intention to pursue
studies of Genz-112638 for treatment of other diseases. These statements
are subject to risks and uncertainties that could cause actual results to
differ materially from those forecast in these forward-looking statements.
These risks and uncertainties include, among others, Genzyme's ability to
successfully complete clinical development of, and secure regulatory
approvals for, Genz-112638 for the treatment of Gaucher disease; that early
improvements in patients are not observed in new patients and/or over a
longer period of time; the willingness of regulatory authorities to meet
with Genzyme and approve an expedited regulatory strategy; and the risks
and uncertainties described in Genzyme's SEC reports filed under the
Securities Exchange Act of 1934, including the factors discussed under the
caption "Risk Factors" in Genzyme's Quarterly Report on Form 10-Q for the
period ended March 31, 2007. Genzyme cautions investors not to place
substantial reliance on the forward-looking statements contained in this
press release. These statements speak only as of the date of this press
release and Genzyme undertakes no obligation to update or revise the
statements.
Genzyme(R) is a registered trademark of Genzyme Corporation. All rights
reserved.
Genzyme Corp.
genzyme
Bionanomachines: Proteins As Resistance Fighters
Friction limits the speed and efficiency of macroscopic engines. Is this also true for nanomachines? A Dresden research team used laser tweezers to measure the friction between a single motor protein molecule and its track. The team found that also within our cells, motors work against the resistance of friction and are restrained in its operation - usually by far not as much though as their macroscopic counterparts. These first experimental measurements of protein friction could help researchers to better understand key cellular processes such as cell division which is driven by such molecular machines. (Science, August 14, 2009)
Friction is the force that resists the relative motion of two bodies in contact. The same is true on the nanoscale: Molecular motors have to fight the friction created between them and their tracks. However, since the frictional forces acting on such motors had not been measured before, it was not known how they depend on the speed and the direction of motion.
Friction Slows Down Proteins
Scientists in Dresden at the Biotechnology Center (BIO-TEC) of the Technical University of Dresden and at the Max Planck Institute of Molecular Cell Biology and Genetics (MPI-CBG) immobilized the molecular motor kinesin on a microsphere which was held by laser tweezers and dragged over its track, a so-called microtubule. In this manner, the friction force between the motor and its microtubule track was measured very precisely. "Just like for macroscopic machines, protein friction limits the speed and efficiency of the small bio-motors", says Erik Schäffer, group leader at the BIOTEC and Jonathon Howard, director and group leader at the MPI-CBG.
The researchers explain that the protein, in the absence of an energy source, takes eight nanometer (a millionth of a millimeter) wide "diffusive hops", corresponding to the length of the tubulin subunits that make up a microtubule. The motors step from one tubulin subunit to the adjacent one by forming a new bond with the microtubule filament as another bond is broken. When pulled by the tweezers, the energy released from these breaking bonds is lost as friction.
Efficient nanomachines
Protein friction also gives insight into the efficiency of kinesin. "About half of the energy from the motor's fuel ATP is dissipated as friction between the motor and its substrate" Howard comments. Schäffer adds: "What remains after further dissipation inside the motor is used for mechanical work - the efficiency is usually much better than for man-made machines". The dissipated energy is eventually converted to heat, that contributes to the heating of our body. Thus, for example our muscles are partly heated by protein friction as the muscle motor proteins do their work.
Original work:
Volker Bormuth, Vladimir Varga, Jonathon Howard, Erik Schäffer
Protein friction limits diffusive and directed movements of kinesin motors on microtubules
Science 325, 870 (August 14, 2009) doi:10.1126/science.1174923
Source:
Florian Frisch
Max-Planck-Gesellschaft
Friction is the force that resists the relative motion of two bodies in contact. The same is true on the nanoscale: Molecular motors have to fight the friction created between them and their tracks. However, since the frictional forces acting on such motors had not been measured before, it was not known how they depend on the speed and the direction of motion.
Friction Slows Down Proteins
Scientists in Dresden at the Biotechnology Center (BIO-TEC) of the Technical University of Dresden and at the Max Planck Institute of Molecular Cell Biology and Genetics (MPI-CBG) immobilized the molecular motor kinesin on a microsphere which was held by laser tweezers and dragged over its track, a so-called microtubule. In this manner, the friction force between the motor and its microtubule track was measured very precisely. "Just like for macroscopic machines, protein friction limits the speed and efficiency of the small bio-motors", says Erik Schäffer, group leader at the BIOTEC and Jonathon Howard, director and group leader at the MPI-CBG.
The researchers explain that the protein, in the absence of an energy source, takes eight nanometer (a millionth of a millimeter) wide "diffusive hops", corresponding to the length of the tubulin subunits that make up a microtubule. The motors step from one tubulin subunit to the adjacent one by forming a new bond with the microtubule filament as another bond is broken. When pulled by the tweezers, the energy released from these breaking bonds is lost as friction.
Efficient nanomachines
Protein friction also gives insight into the efficiency of kinesin. "About half of the energy from the motor's fuel ATP is dissipated as friction between the motor and its substrate" Howard comments. Schäffer adds: "What remains after further dissipation inside the motor is used for mechanical work - the efficiency is usually much better than for man-made machines". The dissipated energy is eventually converted to heat, that contributes to the heating of our body. Thus, for example our muscles are partly heated by protein friction as the muscle motor proteins do their work.
Original work:
Volker Bormuth, Vladimir Varga, Jonathon Howard, Erik Schäffer
Protein friction limits diffusive and directed movements of kinesin motors on microtubules
Science 325, 870 (August 14, 2009) doi:10.1126/science.1174923
Source:
Florian Frisch
Max-Planck-Gesellschaft
суббота, 28 мая 2011 г.
BioTime, Inc. And Embryome Sciences, Inc. Launch Embryome And The International Embryome Initiative
BioTime, Inc., (OTCBB:BTIM) and its wholly-owned subsidiary Embryome Sciences, Inc. announced the launch of Embryome and the International Embryome Initiative, an international collaboration with scientists around the world to create the first systematic map of all the cell types derived from human embryonic stem cells. In a paper published titled "The International Embryome Initiative: A Collaborative Database for Navigating the Complexities of Human Embryonic Stem Cell Differentiation," available online at futuremedicine/loi/rme, BioTime and Embryome Sciences describe the collaboration to map the "embryome" in a manner similar to the international initiatives to map the human DNA or genome in the 1990s. While the database launched at .Embryome is currently populated with nearly 2,000 distinct cell types, the complete map will require the collective efforts of hundreds of scientists over the coming months.
The California Institute for Regenerative Medicine, which is the funding arm of the $3 billion California stem cell initiative, has agreed to be the first subscriber to all features of the database on behalf of all researchers residing within the state of California. Details are available at log in to the database at embryome.
"Human embryonic stem (hES) cells have the innate potential to become all of the diverse cell types of the human body," said Dr. Michael D. West, CEO of BioTime and Embryome Sciences. "However, understanding how to control and use that potential is the greatest challenge in the field of regenerative medicine today. The sheer complexity of cell types and the lack of an international standard of the markers that distinguish the cell types are slowing the advance of the field. We hope this collaborative map will speed the day when life-saving therapies can be translated from the laboratory to the host of patients suffering from life-threatening disease." Like other collaborative databases, Embryome offers an online discussion forum where scientists can debate issues, exchange ideas, and transmit data related to stem cell research for the data base. An editorial board will ultimately control the content of the site.
At Embryome, Embryome Sciences and other companies will market a host of specialty research products and supplies, including ESpanTM cell culture media, for scientists to use in the field of stem cell research. Other products that Embryome Sciences has planned for future sale on Embryome include ESpyTM cell lines, which will be gene trapped and constitutive derivatives of hES cells that send beacons of light in response to the activation of particular genes. The progenitor ESpy™ cell lines will be produced and distributed in joint efforts with Lifeline Cell Technology, LLC utilizing Embryome Sciences' proprietary "Embryomics™" technology, International Stem Cell's proprietary parthenogenetic stem cell lines derived from unfertilized human eggs, and technology and approved hES cell lines licensed by BioTime from the Wisconsin Alumni Research Foundation (WARF). Data on these cell lines also will be presented on the embryome online database.
According to Dr. West, "While many have focused on the therapeutic opportunities of hES cells, and the generous $3 billion of funding provided by the State of California to fund this research, we believe that the greatest rate of return on investment may be in commercializing research products. We intend to win the race to profitability in this important field of medicine."
About BioTime, Inc. (BTIM.OB)
BioTime, headquartered in Alameda, California, develops blood plasma volume expanders, blood replacement solutions for hypothermic (low temperature) surgery, organ preservation solutions, and technology for use in surgery, emergency trauma treatment and other applications. BioTime's lead product Hextend® is manufactured and distributed in the U.S. by Hospira, Inc. and in South Korea by CJ Corp. under exclusive licensing agreements. BioTime has recently entered the field of regenerative medicine through its wholly owned subsidiary Embryome Sciences, Inc. where it plans to develop new medical and research products using embryonic stem cell technology. Additional information about BioTime can be found on the web at biotimeinc. Hextend®, PentaLyte®, HetaCool®, EmbryomicsTM, ESpyTM, and ESpanTM are trademarks of BioTime, Inc.
Forward-Looking Statements
Statements pertaining to future financial and/or operating results, future growth in research, technology, clinical development and potential opportunities for the company and its subsidiary, along with other statements about the future expectations, beliefs, goals, plans, or prospects expressed by management constitute forward-looking statements. Any statements that are not historical fact (including, but not limited to statements that contain words such as "will," "believes," "plans," "anticipates," "expects," "estimates,") should also be considered to be forward-looking statements. Forward-looking statements involve risks and uncertainties, including, without limitation, risks inherent in the development and/or commercialization of potential products, uncertainty in the results of clinical trials or regulatory approvals, need and ability to obtain future capital, and maintenance of intellectual property rights. Actual results may differ materially from the results anticipated in these forward-looking statements and as such should be evaluated together with the many uncertainties that affect the company's business, particularly those mentioned in the cautionary statements found in the company's Securities and Exchange Commission filings. The company disclaims any intent or obligation to update these forward-looking statements.
BioTime, Inc.
The California Institute for Regenerative Medicine, which is the funding arm of the $3 billion California stem cell initiative, has agreed to be the first subscriber to all features of the database on behalf of all researchers residing within the state of California. Details are available at log in to the database at embryome.
"Human embryonic stem (hES) cells have the innate potential to become all of the diverse cell types of the human body," said Dr. Michael D. West, CEO of BioTime and Embryome Sciences. "However, understanding how to control and use that potential is the greatest challenge in the field of regenerative medicine today. The sheer complexity of cell types and the lack of an international standard of the markers that distinguish the cell types are slowing the advance of the field. We hope this collaborative map will speed the day when life-saving therapies can be translated from the laboratory to the host of patients suffering from life-threatening disease." Like other collaborative databases, Embryome offers an online discussion forum where scientists can debate issues, exchange ideas, and transmit data related to stem cell research for the data base. An editorial board will ultimately control the content of the site.
At Embryome, Embryome Sciences and other companies will market a host of specialty research products and supplies, including ESpanTM cell culture media, for scientists to use in the field of stem cell research. Other products that Embryome Sciences has planned for future sale on Embryome include ESpyTM cell lines, which will be gene trapped and constitutive derivatives of hES cells that send beacons of light in response to the activation of particular genes. The progenitor ESpy™ cell lines will be produced and distributed in joint efforts with Lifeline Cell Technology, LLC utilizing Embryome Sciences' proprietary "Embryomics™" technology, International Stem Cell's proprietary parthenogenetic stem cell lines derived from unfertilized human eggs, and technology and approved hES cell lines licensed by BioTime from the Wisconsin Alumni Research Foundation (WARF). Data on these cell lines also will be presented on the embryome online database.
According to Dr. West, "While many have focused on the therapeutic opportunities of hES cells, and the generous $3 billion of funding provided by the State of California to fund this research, we believe that the greatest rate of return on investment may be in commercializing research products. We intend to win the race to profitability in this important field of medicine."
About BioTime, Inc. (BTIM.OB)
BioTime, headquartered in Alameda, California, develops blood plasma volume expanders, blood replacement solutions for hypothermic (low temperature) surgery, organ preservation solutions, and technology for use in surgery, emergency trauma treatment and other applications. BioTime's lead product Hextend® is manufactured and distributed in the U.S. by Hospira, Inc. and in South Korea by CJ Corp. under exclusive licensing agreements. BioTime has recently entered the field of regenerative medicine through its wholly owned subsidiary Embryome Sciences, Inc. where it plans to develop new medical and research products using embryonic stem cell technology. Additional information about BioTime can be found on the web at biotimeinc. Hextend®, PentaLyte®, HetaCool®, EmbryomicsTM, ESpyTM, and ESpanTM are trademarks of BioTime, Inc.
Forward-Looking Statements
Statements pertaining to future financial and/or operating results, future growth in research, technology, clinical development and potential opportunities for the company and its subsidiary, along with other statements about the future expectations, beliefs, goals, plans, or prospects expressed by management constitute forward-looking statements. Any statements that are not historical fact (including, but not limited to statements that contain words such as "will," "believes," "plans," "anticipates," "expects," "estimates,") should also be considered to be forward-looking statements. Forward-looking statements involve risks and uncertainties, including, without limitation, risks inherent in the development and/or commercialization of potential products, uncertainty in the results of clinical trials or regulatory approvals, need and ability to obtain future capital, and maintenance of intellectual property rights. Actual results may differ materially from the results anticipated in these forward-looking statements and as such should be evaluated together with the many uncertainties that affect the company's business, particularly those mentioned in the cautionary statements found in the company's Securities and Exchange Commission filings. The company disclaims any intent or obligation to update these forward-looking statements.
BioTime, Inc.
пятница, 27 мая 2011 г.
Leukocyte InFusion Therapy Begins Clinical Trial Following Cancer 'Cure' In Mice
Scientists at Wake Forest University Baptist Medical Center are about to embark on a human trial to test whether a new cancer treatment will be as effective at eradicating cancer in humans as it has proven to be in mice.
The treatment will involve transfusing specific white blood cells, called granulocytes, from select donors, into patients with advanced forms of cancer. A similar treatment using white blood cells from cancer-resistant mice has previously been highly successful, curing 100 percent of lab mice afflicted with advanced malignancies.
Zheng Cui, Ph.D., lead researcher and associate professor of pathology, announced the study June 28 at the Understanding Aging conference in Los Angeles.
The study, given the go-ahead by the U.S. Food and Drug Administration, will involve treating human cancer patients with white blood cells from healthy young people whose immune systems produce cells with high levels of cancer-fighting activity.
The basis of the study is the scientists' discovery, published five years ago, of a cancer-resistant mouse and their subsequent finding that white blood cells from that mouse and its offspring cured advanced cancers in ordinary laboratory mice. They have since identified similar cancer-killing activity in the white blood cells of some healthy humans.
"In mice, we've been able to eradicate even highly aggressive forms of malignancy with extremely large tumors," Cui said. "Hopefully, we will see the same results in humans. Our laboratory studies indicate that this cancer-fighting ability is even stronger in healthy humans."
The team has tested human cancer-fighting cells from healthy donors against human cervical, prostate and breast cancer cells in the laboratory - with surprisingly good results. The scientists say the anti-tumor response primarily involves granulocytes of the innate immune system, a system known for fighting off infections.
Granulocytes are the most abundant type of white blood cells and can account for as much as 60 percent of total circulating white blood cells in healthy humans. Donors can give granulocytes specifically without losing other components of blood through a process called apheresis that separates granulocytes and returns other blood components back to donors.
In a small study of human volunteers, the scientists found that cancer-killing activity in the granulocytes was highest in people under age 50. They also found that this activity can be lowered by factors such as winter or emotional stress. They said the key to the success for the new therapy is to transfuse sufficient granulocytes from healthy donors while their cancer-killing activities are at their peak level.
For the upcoming study, the researchers are currently recruiting 500 local potential donors who are 50 years old or younger and in good health to have their blood tested. Of those, 100 volunteers with high cancer-killing activity will be asked to donate white blood cells for the study. Cell recipients will include 22 cancer patients who have solid tumors that either didn't respond originally, or no longer respond, to conventional therapies. The study will cost $100,000 per patient receiving therapy, and for many patients (those living in 22 states, including North Carolina) the costs may be covered by their insurance company. There is no cost to donate blood. Click here for general information about insurance coverage of clinical trials.
For more information about qualifications for donors and participants, go to wfubmc/LIFT (Web site will be available the evening of 6/27.) Cancer-killing ability in these cells is highest during the summer, so researchers are hoping to find volunteers who can afford the therapy quickly.
"If the study is effective, it would be another arrow in the quiver of treatments aimed at cancer," said Mark Willingham, M.D., a co-researcher and professor of pathology. "It is based on 10 years of work since the cancer-resistant mouse was first discovered."
Volunteers who are selected as donors - based on the observed potential cancer-fighting activity of their white cells - will complete the apheresis, a two- to three-hour process similar to platelet donation, to collect their granulocytes. The cancer patients will then receive the granulocytes through a transfusion - a safe process that has been used for more than 30 years. Normally, the treatment is used for patients who have antibiotic-resistant infectious diseases. The treatment will be given for three to four consecutive days on an outpatient basis. Up to three donors may be necessary to collect enough blood product for one study participant.
"The difference between our study and the traditional white cell therapy is that we're selecting the healthy donors based on the cancer-killing ability of their white blood cells," said Cui. The scientists are calling the therapy Leukocyte InFusion Therapy (LIFT).
The goal of the phase II study is to determine whether patients can tolerate a sufficient amount of transfused granulocytes for the treatment. Participants will be monitored on a regular basis, and after three months scientists will evaluate whether the treatment results in clear clinical benefits for the patients. If this phase of the study is successful, scientists will expand the study to determine if the treatment is best suited to certain types of cancer.
Yikong Keung, M.D., a medical oncologist, is the chief clinical investigator of the study. Gregory Pomper, M.D., assistant professor of pathology and the director of the Wake Forest Baptist blood bank, will oversee the blood banking portion of the study.
Wake Forest University Baptist Medical Center (wfubmc/) is an academic health system comprised of North Carolina Baptist Hospital, Brenner Children's Hospital, Wake Forest University Physicians, and Wake Forest University Health Sciences, which operates the university's School of Medicine and Piedmont Triad Research Park. The system comprises 1,154 acute care, rehabilitation and long-term care beds and has been ranked as one of "America's Best Hospitals" by U.S. News & World Report since 1993. Wake Forest Baptist is ranked 32nd in the nation by America's Top Doctors for the number of its doctors considered best by their peers. The institution ranks in the top third in funding by the National Institutes of Health and fourth in the Southeast in revenues from its licensed intellectual property.
Source: Jonnie Rohrer
Wake Forest University Baptist Medical Center
The treatment will involve transfusing specific white blood cells, called granulocytes, from select donors, into patients with advanced forms of cancer. A similar treatment using white blood cells from cancer-resistant mice has previously been highly successful, curing 100 percent of lab mice afflicted with advanced malignancies.
Zheng Cui, Ph.D., lead researcher and associate professor of pathology, announced the study June 28 at the Understanding Aging conference in Los Angeles.
The study, given the go-ahead by the U.S. Food and Drug Administration, will involve treating human cancer patients with white blood cells from healthy young people whose immune systems produce cells with high levels of cancer-fighting activity.
The basis of the study is the scientists' discovery, published five years ago, of a cancer-resistant mouse and their subsequent finding that white blood cells from that mouse and its offspring cured advanced cancers in ordinary laboratory mice. They have since identified similar cancer-killing activity in the white blood cells of some healthy humans.
"In mice, we've been able to eradicate even highly aggressive forms of malignancy with extremely large tumors," Cui said. "Hopefully, we will see the same results in humans. Our laboratory studies indicate that this cancer-fighting ability is even stronger in healthy humans."
The team has tested human cancer-fighting cells from healthy donors against human cervical, prostate and breast cancer cells in the laboratory - with surprisingly good results. The scientists say the anti-tumor response primarily involves granulocytes of the innate immune system, a system known for fighting off infections.
Granulocytes are the most abundant type of white blood cells and can account for as much as 60 percent of total circulating white blood cells in healthy humans. Donors can give granulocytes specifically without losing other components of blood through a process called apheresis that separates granulocytes and returns other blood components back to donors.
In a small study of human volunteers, the scientists found that cancer-killing activity in the granulocytes was highest in people under age 50. They also found that this activity can be lowered by factors such as winter or emotional stress. They said the key to the success for the new therapy is to transfuse sufficient granulocytes from healthy donors while their cancer-killing activities are at their peak level.
For the upcoming study, the researchers are currently recruiting 500 local potential donors who are 50 years old or younger and in good health to have their blood tested. Of those, 100 volunteers with high cancer-killing activity will be asked to donate white blood cells for the study. Cell recipients will include 22 cancer patients who have solid tumors that either didn't respond originally, or no longer respond, to conventional therapies. The study will cost $100,000 per patient receiving therapy, and for many patients (those living in 22 states, including North Carolina) the costs may be covered by their insurance company. There is no cost to donate blood. Click here for general information about insurance coverage of clinical trials.
For more information about qualifications for donors and participants, go to wfubmc/LIFT (Web site will be available the evening of 6/27.) Cancer-killing ability in these cells is highest during the summer, so researchers are hoping to find volunteers who can afford the therapy quickly.
"If the study is effective, it would be another arrow in the quiver of treatments aimed at cancer," said Mark Willingham, M.D., a co-researcher and professor of pathology. "It is based on 10 years of work since the cancer-resistant mouse was first discovered."
Volunteers who are selected as donors - based on the observed potential cancer-fighting activity of their white cells - will complete the apheresis, a two- to three-hour process similar to platelet donation, to collect their granulocytes. The cancer patients will then receive the granulocytes through a transfusion - a safe process that has been used for more than 30 years. Normally, the treatment is used for patients who have antibiotic-resistant infectious diseases. The treatment will be given for three to four consecutive days on an outpatient basis. Up to three donors may be necessary to collect enough blood product for one study participant.
"The difference between our study and the traditional white cell therapy is that we're selecting the healthy donors based on the cancer-killing ability of their white blood cells," said Cui. The scientists are calling the therapy Leukocyte InFusion Therapy (LIFT).
The goal of the phase II study is to determine whether patients can tolerate a sufficient amount of transfused granulocytes for the treatment. Participants will be monitored on a regular basis, and after three months scientists will evaluate whether the treatment results in clear clinical benefits for the patients. If this phase of the study is successful, scientists will expand the study to determine if the treatment is best suited to certain types of cancer.
Yikong Keung, M.D., a medical oncologist, is the chief clinical investigator of the study. Gregory Pomper, M.D., assistant professor of pathology and the director of the Wake Forest Baptist blood bank, will oversee the blood banking portion of the study.
Wake Forest University Baptist Medical Center (wfubmc/) is an academic health system comprised of North Carolina Baptist Hospital, Brenner Children's Hospital, Wake Forest University Physicians, and Wake Forest University Health Sciences, which operates the university's School of Medicine and Piedmont Triad Research Park. The system comprises 1,154 acute care, rehabilitation and long-term care beds and has been ranked as one of "America's Best Hospitals" by U.S. News & World Report since 1993. Wake Forest Baptist is ranked 32nd in the nation by America's Top Doctors for the number of its doctors considered best by their peers. The institution ranks in the top third in funding by the National Institutes of Health and fourth in the Southeast in revenues from its licensed intellectual property.
Source: Jonnie Rohrer
Wake Forest University Baptist Medical Center
четверг, 26 мая 2011 г.
Scientists See ATP Open The Door
ATP - adenosine tri-phosphate - is of fundamental importance to Biology,
because it provides energy to power cellular processes. One way cells use
ATP is to open and close membrane channels - the doors between cells and
the outside. Channel opening/closing is achieved by a change in channel
structure and new work, published in this week's issue of PLoS Biology,
describes the use of a novel technology to see directly how channel
structure changes when ATP binds.
A growing body of evidence has demonstrated that the ATP receptor-channel
family plays an important role in various disease states, but channel
structure is not fully understood. Dr. Youichi Shinozaki and colleagues
from Japanese universities studied the shape of a particular channel,
called
P2X receptor. This ATP receptor is known to have a trimeric structure and
opens its transmembrane pore when ATP binds to it. In addition to allowing
sodium and calcium ions to flow through it, P2X receptors are known to
allow larger-sized molecules through as well. This phenomenon is called as
"pore dilation." This big pore is supposed to participate in various
pathophysiologial events (e.g. a release of inflammatory cytokines, and
changes in intercellular signal transduction, et al.). It has previously
been unclear whether P2X receptor itself makes a big pore or whether other
accessory proteins are required. To address this issue, Shinozaki et al.
employed a new technique atomic force microscopy (AFM) to observe the
surface
topology of single P2X receptors.
Using AFM the research team showed that in the absence of ATP to open the
channel, P2X4Rs was circular, and that when stimulated by ATP the P2X4Rs
had
a trimeric structure. ATP-induced conformational changes in P2X4R were
successfully observed using fast-scanning AFM. The trimeric topology was
correspondent to the normal and Calcium permeable state, and the pore
dilation-like structure exhibited permeability to the large-sized
molecule.
This work will prompt further studies into how the single receptor changes
its structure to exhibit its physiological function.
Citation:
"Direct observation of ATP-induced conformational changes in single P2X4 receptors."
Shinozaki Y, Sumitomo K, Tsuda M, Koizumi S, Inoue K, et al. (2009)
PLoS Biol 7(5): e1000103. doi:10.1371/journal.pbio.1000103
Source
Plos Biology
because it provides energy to power cellular processes. One way cells use
ATP is to open and close membrane channels - the doors between cells and
the outside. Channel opening/closing is achieved by a change in channel
structure and new work, published in this week's issue of PLoS Biology,
describes the use of a novel technology to see directly how channel
structure changes when ATP binds.
A growing body of evidence has demonstrated that the ATP receptor-channel
family plays an important role in various disease states, but channel
structure is not fully understood. Dr. Youichi Shinozaki and colleagues
from Japanese universities studied the shape of a particular channel,
called
P2X receptor. This ATP receptor is known to have a trimeric structure and
opens its transmembrane pore when ATP binds to it. In addition to allowing
sodium and calcium ions to flow through it, P2X receptors are known to
allow larger-sized molecules through as well. This phenomenon is called as
"pore dilation." This big pore is supposed to participate in various
pathophysiologial events (e.g. a release of inflammatory cytokines, and
changes in intercellular signal transduction, et al.). It has previously
been unclear whether P2X receptor itself makes a big pore or whether other
accessory proteins are required. To address this issue, Shinozaki et al.
employed a new technique atomic force microscopy (AFM) to observe the
surface
topology of single P2X receptors.
Using AFM the research team showed that in the absence of ATP to open the
channel, P2X4Rs was circular, and that when stimulated by ATP the P2X4Rs
had
a trimeric structure. ATP-induced conformational changes in P2X4R were
successfully observed using fast-scanning AFM. The trimeric topology was
correspondent to the normal and Calcium permeable state, and the pore
dilation-like structure exhibited permeability to the large-sized
molecule.
This work will prompt further studies into how the single receptor changes
its structure to exhibit its physiological function.
Citation:
"Direct observation of ATP-induced conformational changes in single P2X4 receptors."
Shinozaki Y, Sumitomo K, Tsuda M, Koizumi S, Inoue K, et al. (2009)
PLoS Biol 7(5): e1000103. doi:10.1371/journal.pbio.1000103
Source
Plos Biology
Human Collagen Has Been Made In The Lab By Wisconsin Scientists
MADISON - Of all of the materials that make up our bodies, nothing is more ubiquitous than collagen.
It is the most important structural protein in the body, reinforcing connective tissue, bones and teeth, and forming long, fibrous cables to strengthen tendons. Collagen forms sheets of tissue that support the skin and every internal organ. There is nothing in the body, in fact, that does not depend in some way on collagen.
In medicine, collagen from animals, principally cows, is used to rebuild tissue destroyed by burns and wounds. Commonly, it is employed in plastic surgery to augment the lips and cheeks of starlets and others seeking perpetual youth. Catgut, the biodegradable sutures made from cow or horse intestines and used in surgery to minimize scarring, is also a form of collagen.
But for such a commonplace and useful protein, collagen has defied the efforts of biomedical researchers who have tried mightily to synthesize it for use in applications ranging from new wound-healing technologies to alleviating arthritis. The reason: Scientists were unable to synthesize the human protein because they had no way to link the easily made short snippets of collagen into the long, fibrous molecules necessary to mimic the real thing.
But now a team of scientists from the University of Wisconsin-Madison, writing this week (Feb. 13, 2006) in the Proceedings of the National Academy of Sciences (PNAS), reports the discovery of a method for making human collagen in the lab.
The work is important because it opens a door to producing a material that can have broad use in medicine and replace the animal products that are now used but that can also harbor pathogens or spark undesirable immune responses. What's more, the new work may also lay the foundation for applications in nanotechnology -- such as microscopic sensors that could be implanted in humans to confront the effects of disease -- because it gives scientists a way to precisely manipulate the lengthy molecules and add elements to collagen that confer new abilities.
"We can make collagen that duplicates nature exactly, but we can diverge from that when it is desirable," says Ronald T. Raines, a UW-Madison professor of biochemistry who, with postdoctoral fellow Frank W. Kotch, authored the new PNAS study.
Scientists have been seeking a way to make synthetic collagen for at least 30 years. In clinical settings, human collagen would be preferred over bovine collagen because the material now gleaned from cows can prompt an unwanted immune response in patients and it can harbor animal pathogens that might infect humans.
The Wisconsin team discovered a way to make the long, slender collagen molecules, in essence, by having the protein assemble itself. What was required, Raines explains, was a way to give the collagen snippets that scientists could easily make a way to "self assemble" into the long, thin fibers of native collagen. The Wisconsin team was able to modify the ends of the snippets so they could fit together and stick to form long collagen fibers.
"Now we can make synthetic collagen that's longer than natural collagen," says Raines, who previously authored a paper in the journal Nature that demonstrated how to make synthetic collagen that is stronger than natural collagen. "We just don't have to take what nature gives us. We can make it longer and stronger."
In medicine, synthetic human collagen could be used as "solder" to speed healing of large wounds. In the context of nanotechnology, collagen has appeal as a type of nanowire because it is thin -- thinner even than the vaunted carbon nanotubes hailed by nanotechnologists -- and long.
Coated with gold or silver, human collagen could form the basis of implantable electric sensors. By attaching certain biological molecules to the wire, it would be possible to create sensors that might, for example, quickly alert a diabetic to falling insulin levels. Similarly, equipped with molecules to recognize specific pathogens, such a sensor could stand perpetual guard in the body and provide instant warning of invading viruses or bacteria.
"We can have total control of what goes on these very thin extended fibers," says Raines. "We are able to build these molecules up one atom at a time and we can manipulate them in very precise ways."
The new Wisconsin study, which was supported by grants from the National Institutes of Health, lays a foundation for bringing human collagen to the clinic, says Raines. But he notes there is still some work to be done to perfect the technology.
For example, while the new work enables the researchers to make collagen molecules that are long and strong, ways to precisely control the self-assembly of collagen to molecules of a specified size remain to be worked out, according to Raines.
-- Terry Devitt (608) 262-8282, trdevittwisc
PHOTO EDITORS: High-resolution images are available for downloading at photos.news.wisc/hsview.php?id=2752
Contact: Ronald Raines
rainesbiochem.wisc
University of Wisconsin-Madison
It is the most important structural protein in the body, reinforcing connective tissue, bones and teeth, and forming long, fibrous cables to strengthen tendons. Collagen forms sheets of tissue that support the skin and every internal organ. There is nothing in the body, in fact, that does not depend in some way on collagen.
In medicine, collagen from animals, principally cows, is used to rebuild tissue destroyed by burns and wounds. Commonly, it is employed in plastic surgery to augment the lips and cheeks of starlets and others seeking perpetual youth. Catgut, the biodegradable sutures made from cow or horse intestines and used in surgery to minimize scarring, is also a form of collagen.
But for such a commonplace and useful protein, collagen has defied the efforts of biomedical researchers who have tried mightily to synthesize it for use in applications ranging from new wound-healing technologies to alleviating arthritis. The reason: Scientists were unable to synthesize the human protein because they had no way to link the easily made short snippets of collagen into the long, fibrous molecules necessary to mimic the real thing.
But now a team of scientists from the University of Wisconsin-Madison, writing this week (Feb. 13, 2006) in the Proceedings of the National Academy of Sciences (PNAS), reports the discovery of a method for making human collagen in the lab.
The work is important because it opens a door to producing a material that can have broad use in medicine and replace the animal products that are now used but that can also harbor pathogens or spark undesirable immune responses. What's more, the new work may also lay the foundation for applications in nanotechnology -- such as microscopic sensors that could be implanted in humans to confront the effects of disease -- because it gives scientists a way to precisely manipulate the lengthy molecules and add elements to collagen that confer new abilities.
"We can make collagen that duplicates nature exactly, but we can diverge from that when it is desirable," says Ronald T. Raines, a UW-Madison professor of biochemistry who, with postdoctoral fellow Frank W. Kotch, authored the new PNAS study.
Scientists have been seeking a way to make synthetic collagen for at least 30 years. In clinical settings, human collagen would be preferred over bovine collagen because the material now gleaned from cows can prompt an unwanted immune response in patients and it can harbor animal pathogens that might infect humans.
The Wisconsin team discovered a way to make the long, slender collagen molecules, in essence, by having the protein assemble itself. What was required, Raines explains, was a way to give the collagen snippets that scientists could easily make a way to "self assemble" into the long, thin fibers of native collagen. The Wisconsin team was able to modify the ends of the snippets so they could fit together and stick to form long collagen fibers.
"Now we can make synthetic collagen that's longer than natural collagen," says Raines, who previously authored a paper in the journal Nature that demonstrated how to make synthetic collagen that is stronger than natural collagen. "We just don't have to take what nature gives us. We can make it longer and stronger."
In medicine, synthetic human collagen could be used as "solder" to speed healing of large wounds. In the context of nanotechnology, collagen has appeal as a type of nanowire because it is thin -- thinner even than the vaunted carbon nanotubes hailed by nanotechnologists -- and long.
Coated with gold or silver, human collagen could form the basis of implantable electric sensors. By attaching certain biological molecules to the wire, it would be possible to create sensors that might, for example, quickly alert a diabetic to falling insulin levels. Similarly, equipped with molecules to recognize specific pathogens, such a sensor could stand perpetual guard in the body and provide instant warning of invading viruses or bacteria.
"We can have total control of what goes on these very thin extended fibers," says Raines. "We are able to build these molecules up one atom at a time and we can manipulate them in very precise ways."
The new Wisconsin study, which was supported by grants from the National Institutes of Health, lays a foundation for bringing human collagen to the clinic, says Raines. But he notes there is still some work to be done to perfect the technology.
For example, while the new work enables the researchers to make collagen molecules that are long and strong, ways to precisely control the self-assembly of collagen to molecules of a specified size remain to be worked out, according to Raines.
-- Terry Devitt (608) 262-8282, trdevittwisc
PHOTO EDITORS: High-resolution images are available for downloading at photos.news.wisc/hsview.php?id=2752
Contact: Ronald Raines
rainesbiochem.wisc
University of Wisconsin-Madison
среда, 25 мая 2011 г.
Physics gravity model applicable to disease spread
Tracking the spread of new or reemergent diseases like SARS or smallpox is essential in controlling disease epidemics, but horse-and-buggy concepts of how diseases spread have been supplanted by 21st-century realities.
"In the past, one expected the spread of disease to be based on distance, and the closest town would be the location of the next outbreak," says Dr. Ottar Bjornstad, assistant professor of entomology and biology. "Today, it is very different. Even excluding air transportation, someone like me is more likely to go to New York City than Lewistown, Pa., even though Lewistown is closer to where I live."
Borrowing from physics and transportation theory, the researchers are using an empirical gravity model along with the distance-based models to define a network of spatial spread of contagious disease.
"We are combining the basic theory of epidemiology with models from sociology and transportation theory to see what networks might look like," Bjornstad told attendees today (Aug. 5) at the annual meeting of the Ecological Society of America. Bjornstad is working with Bryan T. Grenfell and Xia Yingcun, University of Cambridge, U.K.
Cities are like planets -- the larger they are, the more attractive they are, but the degree of attraction decreases with distance. From Central Pennsylvania, New York City or Philadelphia would be more an attractive destination than Chicago.
To test their model, the researchers used British data on the childhood disease measles because British records dating from 1940 to today are relatively complete. The records show, week-by-week and community-by-community, the spread of measles outbreaks. The U.K. has about 1,000 cities and 450 rural areas that report and outbreaks occur about every two years.
Measles belongs to an ecological class of disease that includes the traditional childhood illnesses - mumps, rubella, chickenpox, whooping cough - that are extremely contagious, but short-lived in the air. Smallpox, before eradication, was considered one of these diseases as well. To a smaller extent, influenza is also included in this category, although because influenza mutates so rapidly, each year brings a slightly different virus to infect even those who have contracted previous strains.
"We now have a class of models that bears great promise in capturing the transmission of known childhood infections," says Bjornstad. "We have just started work to see if the models are relevant to diseases of wildlife."
Laura M. Warlow, Penn State graduate student in biology, is working with Bjornstad on a wildlife model. Investigating the spread of distemper in harbor seals, Warlow looked first at a distance model and then at the gravity model. Unlike humans, harbor seals are not attracted to big city bright lights, but they are more attracted to large beaches close to food than to smaller beaches.
"The seals form clumps on beaches called haul-outs," Warlow described during her poster session at the Ecological Society of America meeting. "The clump size is related to the size of the beach and the closeness to food."
Harbor seals, like children, spread the disease by coughing on each other. Two recent outbreaks in 1988 and 2002 have decimated the population in the North Sea. Working with St. Andrews University, Warlow uses geographic positioning system tag data, aerial photos and actual counts of seals to study the 1988 outbreak.
"We looked at the 1988 data with the simple distance model first," says Warlow. "Then we used the gravity model. The gravity model more accurately predicted the spread of phocine distemper."
After modeling a children's disease and an animal disease, the researchers are now looking at how adult diseases spread.
"Transmission of measles depends on the movement of children," says Bjornstad. "We need to think about applying the models to adult populations and to populations that have partial immunity."
The researchers are working with the National Institutes of Health John E. Fogerty International Center for Advanced Study in the Health Sciences. Influenza is one adult disease the group is studying but is a difficult one. Influenza, at least in the U.S., is not a disease that must be reported so data is spotty. The virus also mutates from year to year.
Contact: A'ndrea Elyse Messer
aem1psu
814-865-9481
Penn State
"In the past, one expected the spread of disease to be based on distance, and the closest town would be the location of the next outbreak," says Dr. Ottar Bjornstad, assistant professor of entomology and biology. "Today, it is very different. Even excluding air transportation, someone like me is more likely to go to New York City than Lewistown, Pa., even though Lewistown is closer to where I live."
Borrowing from physics and transportation theory, the researchers are using an empirical gravity model along with the distance-based models to define a network of spatial spread of contagious disease.
"We are combining the basic theory of epidemiology with models from sociology and transportation theory to see what networks might look like," Bjornstad told attendees today (Aug. 5) at the annual meeting of the Ecological Society of America. Bjornstad is working with Bryan T. Grenfell and Xia Yingcun, University of Cambridge, U.K.
Cities are like planets -- the larger they are, the more attractive they are, but the degree of attraction decreases with distance. From Central Pennsylvania, New York City or Philadelphia would be more an attractive destination than Chicago.
To test their model, the researchers used British data on the childhood disease measles because British records dating from 1940 to today are relatively complete. The records show, week-by-week and community-by-community, the spread of measles outbreaks. The U.K. has about 1,000 cities and 450 rural areas that report and outbreaks occur about every two years.
Measles belongs to an ecological class of disease that includes the traditional childhood illnesses - mumps, rubella, chickenpox, whooping cough - that are extremely contagious, but short-lived in the air. Smallpox, before eradication, was considered one of these diseases as well. To a smaller extent, influenza is also included in this category, although because influenza mutates so rapidly, each year brings a slightly different virus to infect even those who have contracted previous strains.
"We now have a class of models that bears great promise in capturing the transmission of known childhood infections," says Bjornstad. "We have just started work to see if the models are relevant to diseases of wildlife."
Laura M. Warlow, Penn State graduate student in biology, is working with Bjornstad on a wildlife model. Investigating the spread of distemper in harbor seals, Warlow looked first at a distance model and then at the gravity model. Unlike humans, harbor seals are not attracted to big city bright lights, but they are more attracted to large beaches close to food than to smaller beaches.
"The seals form clumps on beaches called haul-outs," Warlow described during her poster session at the Ecological Society of America meeting. "The clump size is related to the size of the beach and the closeness to food."
Harbor seals, like children, spread the disease by coughing on each other. Two recent outbreaks in 1988 and 2002 have decimated the population in the North Sea. Working with St. Andrews University, Warlow uses geographic positioning system tag data, aerial photos and actual counts of seals to study the 1988 outbreak.
"We looked at the 1988 data with the simple distance model first," says Warlow. "Then we used the gravity model. The gravity model more accurately predicted the spread of phocine distemper."
After modeling a children's disease and an animal disease, the researchers are now looking at how adult diseases spread.
"Transmission of measles depends on the movement of children," says Bjornstad. "We need to think about applying the models to adult populations and to populations that have partial immunity."
The researchers are working with the National Institutes of Health John E. Fogerty International Center for Advanced Study in the Health Sciences. Influenza is one adult disease the group is studying but is a difficult one. Influenza, at least in the U.S., is not a disease that must be reported so data is spotty. The virus also mutates from year to year.
Contact: A'ndrea Elyse Messer
aem1psu
814-865-9481
Penn State
вторник, 24 мая 2011 г.
GE Healthcare Introduces New Purifcation Kits For Improved DNA Analysis
GE Healthcare, a unit of General Electric Company (NYSE:GE), today launched several new additions to its illustra line of nucleic acid purification and amplification products within the company's Life Sciences business.
From its leadership in protein purification and separation technologies, GE Healthcare has developed a range of new DNA purification kits designed to deliver optimal yield and purity from a variety of sample sources including blood, cells, bacteria and animal tissue.
The illustra product has been designed to ensure that they provide high quality DNA output and simplify the DNA purification process, by reducing total protocol or hands on time and improving ease of use with color coded caps to match protocol steps and minimal pipetting changes.
"This launch is part of GE Healthcare's drive to simplify the DNA sample preparation workflow for research scientists," said Eric Roman, general manager of the Genomic Sciences business for GE Healthcare. "These new products join the illustra range as tools to help our customers separate target DNA (genomic DNA or plasmid DNA) - providing high quality, pure DNA to perform further research."
Based on addressing different research needs, these new illustra products include:
Plasmid DNA purification kits:
-- illustra plasmidPrep Midi Flow - designed for the purification of high yields of transfection-grade plasmid DNA. The procedure utilizes the superior capacity and selectivity of the Fast Flow plasmid purification medium to facilitate processing of larger culture volumes providing greater overall yields of plasmid DNA with low levels of endotoxin contamination.
-- illustra plasmidPrep Mini Spin - uses a simple plasmid DNA purification protocol involving a modified alkaline lysis procedure and a novel silica-based membrane to achieve highly efficient plasmid DNA purification.
Genomic DNA purification kits:
-- illustra blood genomicPrep Mini Spin - designed for the rapid extraction and purification of high molecular weight genomic DNA (gDNA) from whole blood, buffy coat, bone marrow, and nucleated red blood cells.
-- illustra blood genomicPrep Midi Flow - designed for high yield extraction and purification of genomic DNA (gDNA) from up to 8 ml of whole blood.
-- illustra tissue & cells genomicPrep Mini Spin - designed for the rapid extraction and purification of high molecular weight genomic DNA (gDNA) from a variety of animal tissues and mammalian cell cultures.
-- illustra tissue & cells genomicPrep Midi Flow - designed for high yield extraction and purification of genomic DNA (gDNA) from tissue ranging from 50 to 200 mg.
-- illustra bacteria genomicPrep Mini Spin - designed specifically for the rapid extraction and purification of high molecular weight genomic DNA (gDNA) from Gram-positive and Gram-negative bacterial strains.
DNA clean-up kits
-- illustra GFX PCR DNA and Gel Band Purification Kit - designed for rapid isolation and concentration of DNA fragments (50 bp to 10 kb) from PCR mixtures, agarose gel bands, enzyme-based DNA modifications, and restriction enzyme digestions.
"Our new illustra products will enable scientist to prepare their DNA sample up to 50% faster while maintaining high purity and DNA yield," said Roman. "GE is an industry leader in the development of separation media and application chemistry for the purification of Biomolecules - specifically proteins, peptides and nucleic acids."
About GE Healthcare
GE Healthcare provides transformational medical technologies and services that are shaping a new age of patient care. Our expertise in medical imaging and information technologies, medical diagnostics, patient monitoring systems, performance improvement, drug discovery, and biopharmaceutical manufacturing technologies is helping clinicians around the world re-imagine new ways to predict, diagnose, inform, treat and monitor disease, so patients can live their lives to the fullest.
GE Healthcare's broad range of products and services enable healthcare providers to better diagnose and treat cancer, heart disease, neurological diseases and other conditions earlier. Our vision for the future is to enable a new "early health" model of care focused on earlier diagnosis, pre-symptomatic disease detection and disease prevention. Headquartered in the United Kingdom, GE Healthcare is a $17 billion unit of General Electric Company (NYSE: GE). Worldwide, GE Healthcare employs more than 46,000 people committed to serving healthcare professionals and their patients in more than 100 countries. For more information about GE Healthcare, visit our website at gehealthcare.
From its leadership in protein purification and separation technologies, GE Healthcare has developed a range of new DNA purification kits designed to deliver optimal yield and purity from a variety of sample sources including blood, cells, bacteria and animal tissue.
The illustra product has been designed to ensure that they provide high quality DNA output and simplify the DNA purification process, by reducing total protocol or hands on time and improving ease of use with color coded caps to match protocol steps and minimal pipetting changes.
"This launch is part of GE Healthcare's drive to simplify the DNA sample preparation workflow for research scientists," said Eric Roman, general manager of the Genomic Sciences business for GE Healthcare. "These new products join the illustra range as tools to help our customers separate target DNA (genomic DNA or plasmid DNA) - providing high quality, pure DNA to perform further research."
Based on addressing different research needs, these new illustra products include:
Plasmid DNA purification kits:
-- illustra plasmidPrep Midi Flow - designed for the purification of high yields of transfection-grade plasmid DNA. The procedure utilizes the superior capacity and selectivity of the Fast Flow plasmid purification medium to facilitate processing of larger culture volumes providing greater overall yields of plasmid DNA with low levels of endotoxin contamination.
-- illustra plasmidPrep Mini Spin - uses a simple plasmid DNA purification protocol involving a modified alkaline lysis procedure and a novel silica-based membrane to achieve highly efficient plasmid DNA purification.
Genomic DNA purification kits:
-- illustra blood genomicPrep Mini Spin - designed for the rapid extraction and purification of high molecular weight genomic DNA (gDNA) from whole blood, buffy coat, bone marrow, and nucleated red blood cells.
-- illustra blood genomicPrep Midi Flow - designed for high yield extraction and purification of genomic DNA (gDNA) from up to 8 ml of whole blood.
-- illustra tissue & cells genomicPrep Mini Spin - designed for the rapid extraction and purification of high molecular weight genomic DNA (gDNA) from a variety of animal tissues and mammalian cell cultures.
-- illustra tissue & cells genomicPrep Midi Flow - designed for high yield extraction and purification of genomic DNA (gDNA) from tissue ranging from 50 to 200 mg.
-- illustra bacteria genomicPrep Mini Spin - designed specifically for the rapid extraction and purification of high molecular weight genomic DNA (gDNA) from Gram-positive and Gram-negative bacterial strains.
DNA clean-up kits
-- illustra GFX PCR DNA and Gel Band Purification Kit - designed for rapid isolation and concentration of DNA fragments (50 bp to 10 kb) from PCR mixtures, agarose gel bands, enzyme-based DNA modifications, and restriction enzyme digestions.
"Our new illustra products will enable scientist to prepare their DNA sample up to 50% faster while maintaining high purity and DNA yield," said Roman. "GE is an industry leader in the development of separation media and application chemistry for the purification of Biomolecules - specifically proteins, peptides and nucleic acids."
About GE Healthcare
GE Healthcare provides transformational medical technologies and services that are shaping a new age of patient care. Our expertise in medical imaging and information technologies, medical diagnostics, patient monitoring systems, performance improvement, drug discovery, and biopharmaceutical manufacturing technologies is helping clinicians around the world re-imagine new ways to predict, diagnose, inform, treat and monitor disease, so patients can live their lives to the fullest.
GE Healthcare's broad range of products and services enable healthcare providers to better diagnose and treat cancer, heart disease, neurological diseases and other conditions earlier. Our vision for the future is to enable a new "early health" model of care focused on earlier diagnosis, pre-symptomatic disease detection and disease prevention. Headquartered in the United Kingdom, GE Healthcare is a $17 billion unit of General Electric Company (NYSE: GE). Worldwide, GE Healthcare employs more than 46,000 people committed to serving healthcare professionals and their patients in more than 100 countries. For more information about GE Healthcare, visit our website at gehealthcare.
понедельник, 23 мая 2011 г.
TAU Identifies Features Of Copper Transfer That May Improve Chemotherapy Treatments
Information on proteins is critical for understanding how cells function in health and disease. But while regular proteins are easy to extract and study, it is far more difficult to gather information about membrane proteins, which are responsible for exchanging elements essential to our health, like copper, between a cell and its surrounding tissues.
Now Prof. Nir Ben-Tal and his graduate students Maya Schushan and Yariv Barkan of Tel Aviv University's Department of Biochemistry and Molecular Biology have investigated how a type of membrane protein transfers essential copper ions throughout the body. This mechanism, Schushan says, could also be responsible for how the body absorbs Cisplatin, a common chemotherapy drug used to fight cancer. In the future, this new knowledge may allow scientists to improve the way the drug is transferred throughout the body, she continues.
Their breakthrough discovery was detailed in a recent issue of PNAS (Proceedings of the National Academy of Sciences).
Cellular gatekeepers and chaperones
Most proteins are water soluble, which allows for easy treatment and study. But membrane proteins reside in the greasy membrane that surrounds a cell. If researchers attempt to study them with normal technology of solubilization in water, they are destroyed - and can't be studied.
Copper, which is absorbed into the body through a membrane protein, is necessary to the healthy functioning of the human body. A deficiency can give rise to disease, while loss of regulation is toxic. Therefore, the cell handles copper ions with special care. One chaperone molecule delivers the copper ion to an "entrance gate" outside the cell; another chaperone then picks it up and carries it to various destinations inside the cell.
The researchers suggest that this delicate system is maintained by passing one copper ion at a time by the copper transporter, allowing for maximum control of the copper ions. "This way, there is no risk of bringing several copper ions into the protein at the same time, which ultimately prevents harmful chemical reactions between the ions and the abundant chemical reagents within the cell," explains Prof. Ben-Tal. Once the ion has passed through the transporter into the cell, the transporter is ready to receive another copper ion if necessary.
Improving cancer drugs - and more
The mechanism which transfers copper throughout the body may also be responsible for the transfer of the common chemotherapy drug Cisplatin. By studying how copper is transferred throughout the body, researchers may also gain a better understanding of how this medication and others are transferred into the cell.
With this information, says Prof. Ben-Tal, scientists could improve the transfer of the drug throughout the body, or develop a more effective chemotherapy drug. And that's not the only pharmaceutical dependent on the functioning of membrane proteins. "Sixty percent of drugs target membrane proteins," he explains, "so it's critical to learn how they function."
This work was done in collaboration with Prof. Turkan Haliloglu from Bogazici University, Istanbul.
Source:
George Hunka
American Friends of Tel Aviv University
Now Prof. Nir Ben-Tal and his graduate students Maya Schushan and Yariv Barkan of Tel Aviv University's Department of Biochemistry and Molecular Biology have investigated how a type of membrane protein transfers essential copper ions throughout the body. This mechanism, Schushan says, could also be responsible for how the body absorbs Cisplatin, a common chemotherapy drug used to fight cancer. In the future, this new knowledge may allow scientists to improve the way the drug is transferred throughout the body, she continues.
Their breakthrough discovery was detailed in a recent issue of PNAS (Proceedings of the National Academy of Sciences).
Cellular gatekeepers and chaperones
Most proteins are water soluble, which allows for easy treatment and study. But membrane proteins reside in the greasy membrane that surrounds a cell. If researchers attempt to study them with normal technology of solubilization in water, they are destroyed - and can't be studied.
Copper, which is absorbed into the body through a membrane protein, is necessary to the healthy functioning of the human body. A deficiency can give rise to disease, while loss of regulation is toxic. Therefore, the cell handles copper ions with special care. One chaperone molecule delivers the copper ion to an "entrance gate" outside the cell; another chaperone then picks it up and carries it to various destinations inside the cell.
The researchers suggest that this delicate system is maintained by passing one copper ion at a time by the copper transporter, allowing for maximum control of the copper ions. "This way, there is no risk of bringing several copper ions into the protein at the same time, which ultimately prevents harmful chemical reactions between the ions and the abundant chemical reagents within the cell," explains Prof. Ben-Tal. Once the ion has passed through the transporter into the cell, the transporter is ready to receive another copper ion if necessary.
Improving cancer drugs - and more
The mechanism which transfers copper throughout the body may also be responsible for the transfer of the common chemotherapy drug Cisplatin. By studying how copper is transferred throughout the body, researchers may also gain a better understanding of how this medication and others are transferred into the cell.
With this information, says Prof. Ben-Tal, scientists could improve the transfer of the drug throughout the body, or develop a more effective chemotherapy drug. And that's not the only pharmaceutical dependent on the functioning of membrane proteins. "Sixty percent of drugs target membrane proteins," he explains, "so it's critical to learn how they function."
This work was done in collaboration with Prof. Turkan Haliloglu from Bogazici University, Istanbul.
Source:
George Hunka
American Friends of Tel Aviv University
воскресенье, 22 мая 2011 г.
Why Some Drugs Pack Such A Punch
By studying the intricate mechanisms at work in protein production, a Princeton-led team has discovered why certain kinds of antibiotics are so effective. In doing so, they also have discovered how one protein protects against cell death, shedding light on a natural cancer-fighting process.
In a study appearing in the Aug. 7 edition of the journal Science, Thomas Silhavy, Princeton's Warner-Lambert Parke-Davis Professor of Molecular Biology, and Johna van Stelten, a graduate student, working with two Swiss researchers have uncovered how some antibiotics in common use for 50 years -- tetracycline and chloramphenicol -- can be so lethal against certain strains of bacteria.
Simply put, these drugs plug things up.
Silhavy and van Stelten had been studying the mechanism by which proteins -- from antibodies to hormones -- are produced in bacteria's cytoplasm, the gooey substance that makes up the cell's interior, and then transported where they are needed. The spaghetti-like proteins exit the bacteria's cytoplasm through microscopic tubes known as translocators.
Sometimes, proteins fold up accidentally and jam the translocator. "Proteins go through the translocator, like a piece of spaghetti through a hole," Silhavy said. "But if you can imagine if you were to tie knots in the spaghetti, it wouldn't be able to get through; it gets stuck."
What happens then is ugly, according to Silhavy and van Stelten, who were the first ever to observe the event.
The bacterial cell actually attacks the jammed translocator, decimating it.
The researchers wondered what might happen in a more complex scenario, such as if antibiotics were introduced into the cell cytoplasm to purposely thwart bacteria.
The scientists found that the antibiotics tetracycline and chloramphenicol cause the ribosomes, a cell's protein-producing machines, to stop midway through the process of making proteins, leaving partially constructed proteins stuck to the ribosome, jamming the translocator in the bacteria.
"This is very similar to plugging the translocator with a folded protein and, sure enough, this also causes translocator destruction," Silhavy said. "It's like putting an anchor on the spaghetti instead of a knot. They are stuck and dead forever."
Researchers had been confused as to why these antibiotics seemed to be so adept at killing some kinds of bacteria more quickly than others. These experiments provide an explanation. Translocators are essential for life and, if some bacteria have fewer translocators from the start, then they are more vulnerable to such an attack.
"While it has been known for many years that these antibiotics work by inhibiting bacterial protein synthesis, it was not clear why some bacteria in a population appeared more susceptible than others," van Stelten said. "Our work has identified a new reason why these antibiotics are lethal to bacteria that may help explain these earlier findings."
The researchers made their discovery not because of a new piece of equipment or a new technique. "Like the vast majority of advancements in science and medicine, we happened upon this remarkable answer through basic research," van Stelten said.
The finding could have important implications for medicine.
"If we are to have any hope of outpacing the antibiotic resistance obtained by bacteria, it is paramount that we fully understand the mechanism of action of the antibiotics we currently use," van Stelten said. "Unfortunately, this is often very difficult as evidenced by the fact that, 50 years on, we are still learning new things about them."
Their work also produced another important result. When the translocators in bacteria became jammed by errant proteins, the researchers observed that the translocators emitted a molecular signal -- a stress response -- that called in a destructive enzyme known as the FtsH protease. Under normal circumstances, the FtsH protease chops up the jammed translocators, contributing to cell death.
The scientists found, however, that when they increased the amount of YccA, a protein that is present in the bacterial cell, YccA proteins protected the translocators from the FtsH attackers. YccA, it turns out, is very similar to a human protein known as Bax Inhibitor-1 (BI-1) that is of great interest to cancer researchers because cancer proliferates when it malfunctions.
"We have determined how YccA works in preventing stress-induced death in bacteria," van Stelten said. "We hope this new information will shed light on the mechanism of BI-1 in humans."
Other researchers on the paper included Filo Silva and Dominique Belin from the University of Geneva in Switzerland.
The work was supported by the National Institute of General Medical Sciences of the National Institutes of Health, the New Jersey Commission on Cancer Research, the Canton de Geneve and the Swiss National Science Foundation.
Source:
Kitta MacPherson
Princeton University
In a study appearing in the Aug. 7 edition of the journal Science, Thomas Silhavy, Princeton's Warner-Lambert Parke-Davis Professor of Molecular Biology, and Johna van Stelten, a graduate student, working with two Swiss researchers have uncovered how some antibiotics in common use for 50 years -- tetracycline and chloramphenicol -- can be so lethal against certain strains of bacteria.
Simply put, these drugs plug things up.
Silhavy and van Stelten had been studying the mechanism by which proteins -- from antibodies to hormones -- are produced in bacteria's cytoplasm, the gooey substance that makes up the cell's interior, and then transported where they are needed. The spaghetti-like proteins exit the bacteria's cytoplasm through microscopic tubes known as translocators.
Sometimes, proteins fold up accidentally and jam the translocator. "Proteins go through the translocator, like a piece of spaghetti through a hole," Silhavy said. "But if you can imagine if you were to tie knots in the spaghetti, it wouldn't be able to get through; it gets stuck."
What happens then is ugly, according to Silhavy and van Stelten, who were the first ever to observe the event.
The bacterial cell actually attacks the jammed translocator, decimating it.
The researchers wondered what might happen in a more complex scenario, such as if antibiotics were introduced into the cell cytoplasm to purposely thwart bacteria.
The scientists found that the antibiotics tetracycline and chloramphenicol cause the ribosomes, a cell's protein-producing machines, to stop midway through the process of making proteins, leaving partially constructed proteins stuck to the ribosome, jamming the translocator in the bacteria.
"This is very similar to plugging the translocator with a folded protein and, sure enough, this also causes translocator destruction," Silhavy said. "It's like putting an anchor on the spaghetti instead of a knot. They are stuck and dead forever."
Researchers had been confused as to why these antibiotics seemed to be so adept at killing some kinds of bacteria more quickly than others. These experiments provide an explanation. Translocators are essential for life and, if some bacteria have fewer translocators from the start, then they are more vulnerable to such an attack.
"While it has been known for many years that these antibiotics work by inhibiting bacterial protein synthesis, it was not clear why some bacteria in a population appeared more susceptible than others," van Stelten said. "Our work has identified a new reason why these antibiotics are lethal to bacteria that may help explain these earlier findings."
The researchers made their discovery not because of a new piece of equipment or a new technique. "Like the vast majority of advancements in science and medicine, we happened upon this remarkable answer through basic research," van Stelten said.
The finding could have important implications for medicine.
"If we are to have any hope of outpacing the antibiotic resistance obtained by bacteria, it is paramount that we fully understand the mechanism of action of the antibiotics we currently use," van Stelten said. "Unfortunately, this is often very difficult as evidenced by the fact that, 50 years on, we are still learning new things about them."
Their work also produced another important result. When the translocators in bacteria became jammed by errant proteins, the researchers observed that the translocators emitted a molecular signal -- a stress response -- that called in a destructive enzyme known as the FtsH protease. Under normal circumstances, the FtsH protease chops up the jammed translocators, contributing to cell death.
The scientists found, however, that when they increased the amount of YccA, a protein that is present in the bacterial cell, YccA proteins protected the translocators from the FtsH attackers. YccA, it turns out, is very similar to a human protein known as Bax Inhibitor-1 (BI-1) that is of great interest to cancer researchers because cancer proliferates when it malfunctions.
"We have determined how YccA works in preventing stress-induced death in bacteria," van Stelten said. "We hope this new information will shed light on the mechanism of BI-1 in humans."
Other researchers on the paper included Filo Silva and Dominique Belin from the University of Geneva in Switzerland.
The work was supported by the National Institute of General Medical Sciences of the National Institutes of Health, the New Jersey Commission on Cancer Research, the Canton de Geneve and the Swiss National Science Foundation.
Source:
Kitta MacPherson
Princeton University
суббота, 21 мая 2011 г.
Cells Reorganize Shape To Fit The Situation, Discovery By Penn Scientists
Flip open any biology textbook and you're bound to see a complicated diagram of the inner workings of a cell, with its internal scaffolding, the cytoskeleton, and how it maintains a cell's shape. Yet the fundamental question remains, which came first: the shape, or the skeleton?
Now a research team led by Phong Tran, PhD, Assistant Professor of Cell and Developmental Biology at the University of Pennsylvania School of Medicine, has the answer: Both.
The findings, published online this week in the journal Current Biology by co-senior authors Tran and Matthieu Piel of the Institut Curie, Paris, combine genetics, live-cell imaging, and microfluidics technology. They were able to force normally rod-shaped yeast cells to grow within tiny curved channels. Using the channels, they made rod-shaped cells deform into curved-shaped mutant cells and conversely, curved-shaped cells straighten out into a rod. The surprising finding: as the cells bend, they reorganize their cytoskeleton, and as they reorganize their internal skeletons, the cells further adjust their shape.
Cell shape gone awry has been implicated in some forms of cancer. In the future, one potential implication of Tran's findings is that it might be possible to rescue certain disease states via squeezing or otherwise applying mechanical pressure to tissues or organs. But that, he concedes, is "completely science fiction on my part." Instead, he says at this point this study is pure, basic research. "It was just a cool experiment."
The findings point to a type of feedback loop. "The cytoskeleton changes the shape of the cell and the shape of the cell also changes the organization of the cytoskeleton," he says. "In fact they feed back on each other, so any perturbation on one system will change the other, and visa versa."
The results validate a common belief among cell biologists, says Tran - that to cause a cell to form a branching projection, such as filopodia or dendrite, or new shape, simply adjust the cytoskeleton accordingly, and the shape will follow suit.
"Our demonstration is a conclusive and direct demonstration of that theory because we used normally rod-shaped cells, as opposed to indirect proof of the concept using mutant cell shapes," he says.
At least five cellular components are required for making changes to the organization of the cytoskeleton and therefore the shape of a cell: microtubules, actin filaments, the cell membrane, and two protein complexes. Microtubules are hollow protein pipes that arrange themselves in bundles down the long axis of the cell. As they extend from the cell center towards the periphery, they carry with them one of the protein complexes, so that when they finally dock with a protein receptor at the cell membrane, the effect is to deliver the complex to the desired growth point. What follows is a cascade of events: This complex recruits the second protein complex, which in turn recruits the protein actin. Filaments of actin from this site bring the transport machinery necessary for new cell membrane to extend in the intended direction - generally, further along the long axis of the cell.
Essentially, what Tran's team, led by technician Courtney Terenna, found was that if normal yeast cells are forced to bend, their microtubules can no longer reach the old tip of the cell and so form new growth tips. Conversely, they also found that mutant yeast cells normally grow bent or round, if forced to grow in straight channels, will adopt cytoskeletal structures that are the normal rod-shape.
This, says Tran, could in theory partially explain why some cells from mouse knock-outs, when grown in two-dimensional tissue culture, have more severe problems than when grown in a three-dimensional animal. The researchers surmise that the three-dimensional architecture of a tissue inside a living organ rescues cytoskeletal abnormalities that otherwise arise in an artificial two-dimensional construct.
The study stems from an international collaboration between the microfluidics experts in Piel's group and the biology experts in Tran's. Co-first authors Terenna and Tatyana Makushok, a graduate student in Piel's group, funded by a Human Frontier Science Program (HFSP), an international organization funded by various countries, traveled to Paris and Philadelphia, respectively, to learn their counterpart's secrets so they could then proceed independently.
Now Tran's group is working to address several questions that arise from this research. First, how long can mutant cells maintain their wild-type phenotype once they are removed from the physical constraints of the microfluidic channel? How do the two protein complexes work together to affect cell shape? And, what effects do other environmental variables, such as temperature, have on cytoskeletal dynamics?
Tran's lab is funded by the National Institutes of Health, the American Cancer Society, and the HFSP.
PENN Medicine is a $3.6 billion enterprise dedicated to the related missions of medical education, biomedical research, and excellence in patient care. PENN Medicine consists of the University of Pennsylvania School of Medicine (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System.
Penn's School of Medicine is currently ranked #4 in the nation in U.S.News & World Report's survey of top research-oriented medical schools; and, according to most recent data from the National Institutes of Health, received over $379 million in NIH research funds in the 2006 fiscal year. Supporting 1,700 fulltime faculty and 700 students, the School of Medicine is recognized worldwide for its superior education and training of the next generation of physician-scientists and leaders of academic medicine.
The University of Pennsylvania Health System (UPHS) includes its flagship hospital, the Hospital of the University of Pennsylvania, rated one of the nation's top ten "Honor Roll" hospitals by U.S.News & World Report; Pennsylvania Hospital, the nation's first hospital; and Penn Presbyterian Medical Center. In addition UPHS includes a primary-care provider network; a faculty practice plan; home care, hospice, and nursing home; three multispecialty satellite facilities; as well as the Penn Medicine at Rittenhouse campus, which offers comprehensive inpatient rehabilitation facilities and outpatient services in multiple specialties.
Source: Karen Kreeger
University of Pennsylvania School of Medicine
Now a research team led by Phong Tran, PhD, Assistant Professor of Cell and Developmental Biology at the University of Pennsylvania School of Medicine, has the answer: Both.
The findings, published online this week in the journal Current Biology by co-senior authors Tran and Matthieu Piel of the Institut Curie, Paris, combine genetics, live-cell imaging, and microfluidics technology. They were able to force normally rod-shaped yeast cells to grow within tiny curved channels. Using the channels, they made rod-shaped cells deform into curved-shaped mutant cells and conversely, curved-shaped cells straighten out into a rod. The surprising finding: as the cells bend, they reorganize their cytoskeleton, and as they reorganize their internal skeletons, the cells further adjust their shape.
Cell shape gone awry has been implicated in some forms of cancer. In the future, one potential implication of Tran's findings is that it might be possible to rescue certain disease states via squeezing or otherwise applying mechanical pressure to tissues or organs. But that, he concedes, is "completely science fiction on my part." Instead, he says at this point this study is pure, basic research. "It was just a cool experiment."
The findings point to a type of feedback loop. "The cytoskeleton changes the shape of the cell and the shape of the cell also changes the organization of the cytoskeleton," he says. "In fact they feed back on each other, so any perturbation on one system will change the other, and visa versa."
The results validate a common belief among cell biologists, says Tran - that to cause a cell to form a branching projection, such as filopodia or dendrite, or new shape, simply adjust the cytoskeleton accordingly, and the shape will follow suit.
"Our demonstration is a conclusive and direct demonstration of that theory because we used normally rod-shaped cells, as opposed to indirect proof of the concept using mutant cell shapes," he says.
At least five cellular components are required for making changes to the organization of the cytoskeleton and therefore the shape of a cell: microtubules, actin filaments, the cell membrane, and two protein complexes. Microtubules are hollow protein pipes that arrange themselves in bundles down the long axis of the cell. As they extend from the cell center towards the periphery, they carry with them one of the protein complexes, so that when they finally dock with a protein receptor at the cell membrane, the effect is to deliver the complex to the desired growth point. What follows is a cascade of events: This complex recruits the second protein complex, which in turn recruits the protein actin. Filaments of actin from this site bring the transport machinery necessary for new cell membrane to extend in the intended direction - generally, further along the long axis of the cell.
Essentially, what Tran's team, led by technician Courtney Terenna, found was that if normal yeast cells are forced to bend, their microtubules can no longer reach the old tip of the cell and so form new growth tips. Conversely, they also found that mutant yeast cells normally grow bent or round, if forced to grow in straight channels, will adopt cytoskeletal structures that are the normal rod-shape.
This, says Tran, could in theory partially explain why some cells from mouse knock-outs, when grown in two-dimensional tissue culture, have more severe problems than when grown in a three-dimensional animal. The researchers surmise that the three-dimensional architecture of a tissue inside a living organ rescues cytoskeletal abnormalities that otherwise arise in an artificial two-dimensional construct.
The study stems from an international collaboration between the microfluidics experts in Piel's group and the biology experts in Tran's. Co-first authors Terenna and Tatyana Makushok, a graduate student in Piel's group, funded by a Human Frontier Science Program (HFSP), an international organization funded by various countries, traveled to Paris and Philadelphia, respectively, to learn their counterpart's secrets so they could then proceed independently.
Now Tran's group is working to address several questions that arise from this research. First, how long can mutant cells maintain their wild-type phenotype once they are removed from the physical constraints of the microfluidic channel? How do the two protein complexes work together to affect cell shape? And, what effects do other environmental variables, such as temperature, have on cytoskeletal dynamics?
Tran's lab is funded by the National Institutes of Health, the American Cancer Society, and the HFSP.
PENN Medicine is a $3.6 billion enterprise dedicated to the related missions of medical education, biomedical research, and excellence in patient care. PENN Medicine consists of the University of Pennsylvania School of Medicine (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System.
Penn's School of Medicine is currently ranked #4 in the nation in U.S.News & World Report's survey of top research-oriented medical schools; and, according to most recent data from the National Institutes of Health, received over $379 million in NIH research funds in the 2006 fiscal year. Supporting 1,700 fulltime faculty and 700 students, the School of Medicine is recognized worldwide for its superior education and training of the next generation of physician-scientists and leaders of academic medicine.
The University of Pennsylvania Health System (UPHS) includes its flagship hospital, the Hospital of the University of Pennsylvania, rated one of the nation's top ten "Honor Roll" hospitals by U.S.News & World Report; Pennsylvania Hospital, the nation's first hospital; and Penn Presbyterian Medical Center. In addition UPHS includes a primary-care provider network; a faculty practice plan; home care, hospice, and nursing home; three multispecialty satellite facilities; as well as the Penn Medicine at Rittenhouse campus, which offers comprehensive inpatient rehabilitation facilities and outpatient services in multiple specialties.
Source: Karen Kreeger
University of Pennsylvania School of Medicine
пятница, 20 мая 2011 г.
Mutations Extending Lifespan Induce Expression Of Germline Genes In Somatic Cells
In the sense that organisms existing today are connected through a chain of life - through their parents, grandparents and other ancestors - almost a billion years back to the first animals of the pre-Cambrian era, an animal's reproductive cells can be considered to be immortal. These germline cells generate their offspring's somatic cells - other cells involved in all aspects of growth, metabolism and behavior, which have a set lifespan - and new germline cells that continue on, generation after generation.
Now in a dramatic finding, researchers from the Massachusetts General Hospital (MGH) Department of Molecular Biology have found that certain genetic mutations known to extend the lifespan of the C. elegans roundworm induce 'mortal' somatic cells to express some of the genes that allow the 'immortality' of reproductive germline cells. Their report will appear in the journal Nature and is receiving advance online release.
"C. elegans mutants with extreme longevity accomplish this feat, in part, by adopting genetic programs normally restricted to the germline into somatic cells," says Sean Curran, PhD, of MGH Molecular Biology, the study's lead author. "We know that germline cells are more stable than somatic cells - they live longer and are more resistant to stresses that damage other cells - and understanding the molecular pathways involved in that stability may someday allow us to devise therapies protective against age-related decline in other tissues."
Curran is a research fellow in the laboratory of MGH investigator Gary Ruvkun, PhD, whose work focuses on the development, longevity and metabolism of C. elegans, a tiny worm broadly used as a model for studying basic biological systems. Ruvkun and other researchers discovered that simple mutations in genetic pathways conserved throughout evolution can double or triple the lifespan of C. elegans, and that similar mutations in the corresponding pathways also dramatically extend mammalian lifespan.
Longevity-associated mutations have been shown to lead to enhanced immune response - including increased control of gene expression through RNA interference (RNAi) - in somatic cells. Since it is known that RNAi is among the mechanisms underlying germline cells' enhanced resistance to pathogens and other stresses, the researchers examined whether the reactivation of germline genetic programs was involved in the extended lifespan of C. elegans mutants.
A series of experiments demonstrated that worms with increased longevity induced by mutations in the insulin-like signaling pathway did exhibit somatic cell expression of genes usually active only in germline cells. The mutant worms also were protected from stresses that damaged the DNA of non-mutant worms. The researchers also found that inactivating germline-expressed genes in the mutant worms eliminated the increased lifespan and that longevity-associated mutations in two genes from a different metabolic pathway - one involved with detoxification and stress response - also increased the expression of germline markers.
"The idea that somatic cells can reacquire genetic pathways usually restricted to germline cells is fascinating, and since germline protection is seen across species, the activity of these genes may play a role in controlling mammalian lifespan," says Ruvkun, senior author of the Nature paper. "Understanding the mechanisms involved in this transformation could help us develop new ways to repair and even regenerate key cells and tissues." A professor of Genetics at Harvard Medical School, Ruvkun was a co-recipient of the 2008 Lasker Award for Basic Medical Research for his role in discovering that tiny molecules of RNA can control the activity of critical genes
Co-authors of the Nature paper are Xiaoyun Wu, PhD, and Christian Riedel, PhD, MGH Molecular Biology. The study was supported by grants from the National Institutes of Health, the National Institute on Aging, the European Molecular Biology Organization and the Human Frontier Science Program.
Source:
Sue McGreevey
Massachusetts General Hospital
Now in a dramatic finding, researchers from the Massachusetts General Hospital (MGH) Department of Molecular Biology have found that certain genetic mutations known to extend the lifespan of the C. elegans roundworm induce 'mortal' somatic cells to express some of the genes that allow the 'immortality' of reproductive germline cells. Their report will appear in the journal Nature and is receiving advance online release.
"C. elegans mutants with extreme longevity accomplish this feat, in part, by adopting genetic programs normally restricted to the germline into somatic cells," says Sean Curran, PhD, of MGH Molecular Biology, the study's lead author. "We know that germline cells are more stable than somatic cells - they live longer and are more resistant to stresses that damage other cells - and understanding the molecular pathways involved in that stability may someday allow us to devise therapies protective against age-related decline in other tissues."
Curran is a research fellow in the laboratory of MGH investigator Gary Ruvkun, PhD, whose work focuses on the development, longevity and metabolism of C. elegans, a tiny worm broadly used as a model for studying basic biological systems. Ruvkun and other researchers discovered that simple mutations in genetic pathways conserved throughout evolution can double or triple the lifespan of C. elegans, and that similar mutations in the corresponding pathways also dramatically extend mammalian lifespan.
Longevity-associated mutations have been shown to lead to enhanced immune response - including increased control of gene expression through RNA interference (RNAi) - in somatic cells. Since it is known that RNAi is among the mechanisms underlying germline cells' enhanced resistance to pathogens and other stresses, the researchers examined whether the reactivation of germline genetic programs was involved in the extended lifespan of C. elegans mutants.
A series of experiments demonstrated that worms with increased longevity induced by mutations in the insulin-like signaling pathway did exhibit somatic cell expression of genes usually active only in germline cells. The mutant worms also were protected from stresses that damaged the DNA of non-mutant worms. The researchers also found that inactivating germline-expressed genes in the mutant worms eliminated the increased lifespan and that longevity-associated mutations in two genes from a different metabolic pathway - one involved with detoxification and stress response - also increased the expression of germline markers.
"The idea that somatic cells can reacquire genetic pathways usually restricted to germline cells is fascinating, and since germline protection is seen across species, the activity of these genes may play a role in controlling mammalian lifespan," says Ruvkun, senior author of the Nature paper. "Understanding the mechanisms involved in this transformation could help us develop new ways to repair and even regenerate key cells and tissues." A professor of Genetics at Harvard Medical School, Ruvkun was a co-recipient of the 2008 Lasker Award for Basic Medical Research for his role in discovering that tiny molecules of RNA can control the activity of critical genes
Co-authors of the Nature paper are Xiaoyun Wu, PhD, and Christian Riedel, PhD, MGH Molecular Biology. The study was supported by grants from the National Institutes of Health, the National Institute on Aging, the European Molecular Biology Organization and the Human Frontier Science Program.
Source:
Sue McGreevey
Massachusetts General Hospital
четверг, 19 мая 2011 г.
SSRIs And Cardiovascular Health
A class of antidepressants known as selective serotonin reuptake inhibitors (SSRIs) may provide a boost to cardiovascular health by affecting the way platelets, small cells in the blood involved in clotting, clump together, say researchers at the Loyola University Medical Center in Maywood, Ill.
In a study of 50 adults, the researchers found that platelets were slower to clump together, or aggregate, in participants who were taking an SSRI to treat depression. As depression is associated with an increased risk of cardiovascular disease, this finding could indicate a beneficial side effect for people who take SSRIs to treat depression, said Evangelos Litinas, MD, Research Associate in the Center's Pathology Department. Dr. Litinas will present the team's research at the American Physiological Society's annual Experimental Biology 2010 conference being held in Anaheim, CA from April 24-28.
SSRIs and Platelet Function
SSRIs function to modulate the effect of serotonin in the brain. Neurotransmitters, like serotonin, are messages sent across the gap called the synapse between nerve cells in the brain. The cell sending the message, called the pre-synaptic cell, releases serotonin into the synapse. The serotonin is taken in by the receiving, post-synaptic cell, or be taken back by the pre-synaptic cell.
In a depressed patient, the post-synaptic cell doesn't take in enough serotonin and the message gets lost. To treat the depression, SSRIs decrease the ability of the pre-synaptic cell to reuptake the serotonin, leaving the message in the synapse longer and giving the post-synaptic cell a better chance of receiving the serotonin.
However, this blocking activity of SSRIs may have an effect on other cells in the body that require serotonin uptake. Small cells called platelets, which are involved in blood clotting, absorb serotonin only once and use it for their activation in response to injury.
When a blood vessel is injured in a healthy patient, their platelets are exposed to proteins that normally reside beneath the endothelium, the thin layer of cells lining blood vessel walls. These proteins activate the platelets and prompt them to send out finger-like projections that grab onto each other. This also activates the clotting system so that a clot will form at the wound site. This kind of platelet activation also occurs when blood vessel walls become inflamed in atherosclerosis ("hardening of the arteries").
Once activated, the platelets release the contents of small packages that they carry called delta granules. These packages contain calcium, various energy-containing molecules, and serotonin. When the delta granules are released by activated platelets, the serotonin and other molecules work in the injured area to amplify the coagulation response.
However, Dr. Litinas and his team believe that in depressed patients who have an associated risk of cardiovascular problems, the blocking activity of SSRIs may have a side-effect of preventing the serotonin uptake by platelets, making them less responsive to aggregation and may thereby improving the patients' cardiovascular health.
To test their hypothesis, the researchers recruited 50 volunteers, 25 who were healthy and were not taking antidepressant medications and 25 who were being treated for depression with an SSRI. The team collected blood samples from each volunteer at the beginning of the protocol and again at the study's fourth week and eighth week. After each round of blood-drawing, the team separated the blood into its components to obtain the platelet-rich plasma for study.
The researchers then treated all of the samples with platelet-activating substances and with saline, which does not activate platelets. They observed platelet activity and quantified the amount of aggregation in each sample by using an aggregometer, a machine that aims light into liquid samples. Cells that do not aggregate tend to prevent light from getting all the way through a sample to the other side, whereas cells that aggregate form large clusters that sink down out of the way, allowing the light to shine through.
When the platelets from healthy volunteers were treated with platelet-activating substances at the 4-week time point, 95% of the cells aggregated. In contrast, the platelets of participants taking an SSRI showed only 37% aggregation, indicating that the SSRI had somehow inhibited or changed the platelets' ability to clump together.
As the study progressed, the researchers noticed something peculiar: The platelets taken from SSRI-treated patients at the 8-week mark aggregated more than those drawn at the 4-week mark. This suggested that SSRIs have the greatest impact on preventing platelet activation early on in treatment. Dr. Litinas and his team believe this may be because the body takes several weeks to start modulating SSRIs in the body. The team has extended the study to include samples drawn at the 12-week mark. They will also conduct a study using another brand of SSRI.
"The reason we're doing this is to better the lives of depressed patients," said Dr. Litinas. "There is clear evidence that depressed patients have a higher risk of cardiovascular disease, and we want to eliminate that. Since depression can be treated with an SSRI, maybe the cardiovascular disease risk can also be decreased. We want our patients to live longer and happier lives, without depression or the risk of heart problems."
Dr. Litinas' colleagues for this study are Dr. Jawed Fareed and Dr. Omer Iqbal, both of whom are affiliated with the Department of Pathology, Loyola University Medical Center, Maywood, IL; and Erin Tobin, Dr. John Piletz, Dr. Edwin Meresh, and Dr. Angelos Halaris, all of the Department of Psychiatry, Loyola University Medical Center.
Source: Federation of American Societies for Experimental Biology (FASEB)
In a study of 50 adults, the researchers found that platelets were slower to clump together, or aggregate, in participants who were taking an SSRI to treat depression. As depression is associated with an increased risk of cardiovascular disease, this finding could indicate a beneficial side effect for people who take SSRIs to treat depression, said Evangelos Litinas, MD, Research Associate in the Center's Pathology Department. Dr. Litinas will present the team's research at the American Physiological Society's annual Experimental Biology 2010 conference being held in Anaheim, CA from April 24-28.
SSRIs and Platelet Function
SSRIs function to modulate the effect of serotonin in the brain. Neurotransmitters, like serotonin, are messages sent across the gap called the synapse between nerve cells in the brain. The cell sending the message, called the pre-synaptic cell, releases serotonin into the synapse. The serotonin is taken in by the receiving, post-synaptic cell, or be taken back by the pre-synaptic cell.
In a depressed patient, the post-synaptic cell doesn't take in enough serotonin and the message gets lost. To treat the depression, SSRIs decrease the ability of the pre-synaptic cell to reuptake the serotonin, leaving the message in the synapse longer and giving the post-synaptic cell a better chance of receiving the serotonin.
However, this blocking activity of SSRIs may have an effect on other cells in the body that require serotonin uptake. Small cells called platelets, which are involved in blood clotting, absorb serotonin only once and use it for their activation in response to injury.
When a blood vessel is injured in a healthy patient, their platelets are exposed to proteins that normally reside beneath the endothelium, the thin layer of cells lining blood vessel walls. These proteins activate the platelets and prompt them to send out finger-like projections that grab onto each other. This also activates the clotting system so that a clot will form at the wound site. This kind of platelet activation also occurs when blood vessel walls become inflamed in atherosclerosis ("hardening of the arteries").
Once activated, the platelets release the contents of small packages that they carry called delta granules. These packages contain calcium, various energy-containing molecules, and serotonin. When the delta granules are released by activated platelets, the serotonin and other molecules work in the injured area to amplify the coagulation response.
However, Dr. Litinas and his team believe that in depressed patients who have an associated risk of cardiovascular problems, the blocking activity of SSRIs may have a side-effect of preventing the serotonin uptake by platelets, making them less responsive to aggregation and may thereby improving the patients' cardiovascular health.
To test their hypothesis, the researchers recruited 50 volunteers, 25 who were healthy and were not taking antidepressant medications and 25 who were being treated for depression with an SSRI. The team collected blood samples from each volunteer at the beginning of the protocol and again at the study's fourth week and eighth week. After each round of blood-drawing, the team separated the blood into its components to obtain the platelet-rich plasma for study.
The researchers then treated all of the samples with platelet-activating substances and with saline, which does not activate platelets. They observed platelet activity and quantified the amount of aggregation in each sample by using an aggregometer, a machine that aims light into liquid samples. Cells that do not aggregate tend to prevent light from getting all the way through a sample to the other side, whereas cells that aggregate form large clusters that sink down out of the way, allowing the light to shine through.
When the platelets from healthy volunteers were treated with platelet-activating substances at the 4-week time point, 95% of the cells aggregated. In contrast, the platelets of participants taking an SSRI showed only 37% aggregation, indicating that the SSRI had somehow inhibited or changed the platelets' ability to clump together.
As the study progressed, the researchers noticed something peculiar: The platelets taken from SSRI-treated patients at the 8-week mark aggregated more than those drawn at the 4-week mark. This suggested that SSRIs have the greatest impact on preventing platelet activation early on in treatment. Dr. Litinas and his team believe this may be because the body takes several weeks to start modulating SSRIs in the body. The team has extended the study to include samples drawn at the 12-week mark. They will also conduct a study using another brand of SSRI.
"The reason we're doing this is to better the lives of depressed patients," said Dr. Litinas. "There is clear evidence that depressed patients have a higher risk of cardiovascular disease, and we want to eliminate that. Since depression can be treated with an SSRI, maybe the cardiovascular disease risk can also be decreased. We want our patients to live longer and happier lives, without depression or the risk of heart problems."
Dr. Litinas' colleagues for this study are Dr. Jawed Fareed and Dr. Omer Iqbal, both of whom are affiliated with the Department of Pathology, Loyola University Medical Center, Maywood, IL; and Erin Tobin, Dr. John Piletz, Dr. Edwin Meresh, and Dr. Angelos Halaris, all of the Department of Psychiatry, Loyola University Medical Center.
Source: Federation of American Societies for Experimental Biology (FASEB)
среда, 18 мая 2011 г.
Improving Calcium Supplement With The Help OF Crustaceans
Ben-Gurion University of the Negev (BGU) researchers have developed a unique technology that stabilizes an otherwise unstable form of calcium carbonate. This mineral form provides significantly higher biological absorption and retention rates than other sources presently used as dietary calcium supplements.
Calcium is considered to be one of the most important minerals in the human body for maintaining bone mass and coronary health. Insufficient dietary calcium intake can induce osteoporosis and poor blood-clotting.
"Since most adults today achieve their daily dietary intake of calcium with supplements, this new form will prove to be substantially more beneficial," according to Dr. Amir Berman, a researcher and a member of the BGU Ilse Katz Institute for Nanoscale Science and Technology.
According to the new study published in the Journal of Bone and Mineral Research, this type of Amorphous Calcium Carbonate (ACC) consists of unstable, nano-sized particles. Several species of crustaceans, including freshwater crayfish, are capable of stabilizing this mineral form so they can efficiently store and rapidly re-use large calcium quantities. Using new technology inspired by the crustaceans' natural process, the BGU researchers tested this synthetic ACC compound against other commonly used calcium supplements.
Results of experiments performed on laboratory animals showed that the absorption and retention rates were up to 40 percent higher in the blood and 30 percent higher in bone when the ACC compound is compared to other calcium sources. Such dramatic enhancement in absorption may be useful in reducing the necessary dosage of calcium, lowering side effects and increasing a patient's compliance.
Notes:
This research was supported by a grant from Amorphical, Ltd., through B.G. Negev, Ltd. Amorphical Ltd. will be introducing a dietary supplement utilizing the ACC compound in 2011.
Solubility and Bioavailability of Stabilized Amorphous Calcium Carbonate
Oren E Meiron,1,5 Elad Bar-David,1,5 Eliahu D Aflalo,1,3 Assaf Shechter,5 David Stepensky,4 Amir Berman,2,3 and Amir Sagi 1,3 J. Bone and Mineral Res. 26(2) 364-372 URL: DOI 10.1002/jbmr.196
1 Department of Life Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel
2 Department of Biotechnology Engineering, Ben-Gurion University of the Negev, Beer-Sheva, Israel
3 National Institute for Biotechnology in the Negev (NIBN), Ben-Gurion University of the Negev, Beer-Sheva, Israel
4 Department of Pharmacology, Ben-Gurion University of the Negev, Beer-Sheva, Israel
5 Amorphical, Ltd., Beer Sheva, Israel
Source:
Andy Lavin
American Associates, Ben-Gurion University of the Negev
Calcium is considered to be one of the most important minerals in the human body for maintaining bone mass and coronary health. Insufficient dietary calcium intake can induce osteoporosis and poor blood-clotting.
"Since most adults today achieve their daily dietary intake of calcium with supplements, this new form will prove to be substantially more beneficial," according to Dr. Amir Berman, a researcher and a member of the BGU Ilse Katz Institute for Nanoscale Science and Technology.
According to the new study published in the Journal of Bone and Mineral Research, this type of Amorphous Calcium Carbonate (ACC) consists of unstable, nano-sized particles. Several species of crustaceans, including freshwater crayfish, are capable of stabilizing this mineral form so they can efficiently store and rapidly re-use large calcium quantities. Using new technology inspired by the crustaceans' natural process, the BGU researchers tested this synthetic ACC compound against other commonly used calcium supplements.
Results of experiments performed on laboratory animals showed that the absorption and retention rates were up to 40 percent higher in the blood and 30 percent higher in bone when the ACC compound is compared to other calcium sources. Such dramatic enhancement in absorption may be useful in reducing the necessary dosage of calcium, lowering side effects and increasing a patient's compliance.
Notes:
This research was supported by a grant from Amorphical, Ltd., through B.G. Negev, Ltd. Amorphical Ltd. will be introducing a dietary supplement utilizing the ACC compound in 2011.
Solubility and Bioavailability of Stabilized Amorphous Calcium Carbonate
Oren E Meiron,1,5 Elad Bar-David,1,5 Eliahu D Aflalo,1,3 Assaf Shechter,5 David Stepensky,4 Amir Berman,2,3 and Amir Sagi 1,3 J. Bone and Mineral Res. 26(2) 364-372 URL: DOI 10.1002/jbmr.196
1 Department of Life Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel
2 Department of Biotechnology Engineering, Ben-Gurion University of the Negev, Beer-Sheva, Israel
3 National Institute for Biotechnology in the Negev (NIBN), Ben-Gurion University of the Negev, Beer-Sheva, Israel
4 Department of Pharmacology, Ben-Gurion University of the Negev, Beer-Sheva, Israel
5 Amorphical, Ltd., Beer Sheva, Israel
Source:
Andy Lavin
American Associates, Ben-Gurion University of the Negev
вторник, 17 мая 2011 г.
Simple Equations Track Listeria Trails
Circles, slaloms, figure eights, and loop-the-loops - biologists studying the motion of Listeria monocytogenes sensed that these paths were related, but they didn't have a good way to define what fit in and what didn't. A remarkably simple new mathematical description, published online in the Proceedings of the National Academy of Sciences [Abstract], reproduces all these shapes with just one pair of equations and only two key variables. Besides helping to identify bacterial mutants, the equations suggest which mechanisms could be driving the motion.
Last winter, Vivek Shenoy, an associate professor of engineering at Brown University, was matched with Julie Theriot, an associate professor at the Stanford School of Medicine, at a biophysics "boot camp" run by Rob Phillips at the California Institute of Technology. Theriot studies Listeria, a disease-causing bacterium that hijacks the actin network of an infected cell to propel itself. Embedded in a network of actin fibers, the bacterium keeps adding actin molecules at its back end, pushing itself forward and leaving behind an actin tail tracing its path.
Those paths intrigued Shenoy as soon as he saw Theriot's movies of Listeria traveling in the two-dimensional world of a microscope slide. Some bacteria spun in circles, others followed a sine curve, some followed a path like the cloverleaf exchange on a highway. The circles, he thought, were easy to explain. If an actin filament pushed just a bit off center, the bacterium would go in circles, like a swimmer who paddles harder on one side.
With a bit more thought, he cracked the sine curve. What if that off-center point rotated around the axis of motion" When it pushed harder on the right, the bacterium would move to the left; when it pushed to the left of center, the cell would move to the right. If the bacterium moved forward faster than it curved around, a swerving pattern would result.
The clincher came as Shenoy worked out the mathematics to describe this kind of motion. The exact same equation, it turned out, also described the figure-eights, cloverleaves and other looping patterns they had observed. In fact, nearly every time they recorded a new pattern, they found it fit the equation. An equation that can predict observations clearly has a lot going for it, but a mathematical description is not the same thing as a biological mechanism.
"If we can understand things is a simpler setting, such as this one," said Shenoy, "then we can use those insights to study more complex phenomena."
As the team works to fully explain the motion they observe, Shenoy's equations can narrow the possibilities, ruling out mechanisms that cannot generate both the circular and the spinning component of the motion.
With just two variables - an offset distance and an angle relative to the forward motion - they could reproduce every track they saw, except those produced by mutant microbes that Theriot introduced. The mutants stood out as different. They produced a skidding kind of pattern instead of the graceful curves that most of the bacteria traced.
"The human visual cortex is really good at seeing patterns," said Theriot, "but this gives us a quantitative framework for asking questions that before we could only ask qualitatively."
Being able to pinpoint just how different the mutants are is valuable, said Theriot, because they often are less infectious than normal Listeria. Once Listeria invades a host cell, it uses the actin mechanism to move from cell to cell, never again exposing itself to the organism's extracellular immune system. A microbe with a deficient movement mechanism is a microbe with less ability to invade neighboring cells.
The National Science Foundation funded the research.
Contact: Martha Downs
Brown University
Last winter, Vivek Shenoy, an associate professor of engineering at Brown University, was matched with Julie Theriot, an associate professor at the Stanford School of Medicine, at a biophysics "boot camp" run by Rob Phillips at the California Institute of Technology. Theriot studies Listeria, a disease-causing bacterium that hijacks the actin network of an infected cell to propel itself. Embedded in a network of actin fibers, the bacterium keeps adding actin molecules at its back end, pushing itself forward and leaving behind an actin tail tracing its path.
Those paths intrigued Shenoy as soon as he saw Theriot's movies of Listeria traveling in the two-dimensional world of a microscope slide. Some bacteria spun in circles, others followed a sine curve, some followed a path like the cloverleaf exchange on a highway. The circles, he thought, were easy to explain. If an actin filament pushed just a bit off center, the bacterium would go in circles, like a swimmer who paddles harder on one side.
With a bit more thought, he cracked the sine curve. What if that off-center point rotated around the axis of motion" When it pushed harder on the right, the bacterium would move to the left; when it pushed to the left of center, the cell would move to the right. If the bacterium moved forward faster than it curved around, a swerving pattern would result.
The clincher came as Shenoy worked out the mathematics to describe this kind of motion. The exact same equation, it turned out, also described the figure-eights, cloverleaves and other looping patterns they had observed. In fact, nearly every time they recorded a new pattern, they found it fit the equation. An equation that can predict observations clearly has a lot going for it, but a mathematical description is not the same thing as a biological mechanism.
"If we can understand things is a simpler setting, such as this one," said Shenoy, "then we can use those insights to study more complex phenomena."
As the team works to fully explain the motion they observe, Shenoy's equations can narrow the possibilities, ruling out mechanisms that cannot generate both the circular and the spinning component of the motion.
With just two variables - an offset distance and an angle relative to the forward motion - they could reproduce every track they saw, except those produced by mutant microbes that Theriot introduced. The mutants stood out as different. They produced a skidding kind of pattern instead of the graceful curves that most of the bacteria traced.
"The human visual cortex is really good at seeing patterns," said Theriot, "but this gives us a quantitative framework for asking questions that before we could only ask qualitatively."
Being able to pinpoint just how different the mutants are is valuable, said Theriot, because they often are less infectious than normal Listeria. Once Listeria invades a host cell, it uses the actin mechanism to move from cell to cell, never again exposing itself to the organism's extracellular immune system. A microbe with a deficient movement mechanism is a microbe with less ability to invade neighboring cells.
The National Science Foundation funded the research.
Contact: Martha Downs
Brown University
понедельник, 16 мая 2011 г.
How Tumor Cells Move
If cancer cells lack a certain protein, it could be much easier for them to penetrate healthy body tissue, the first step towards forming metastases. Scientists at the Pharmacology Institute of the University of Heidelberg have discovered the previously unknown cell signal factor SCAI (suppressor of cancer cell invasion), which inhibits the movement and spread of tumor cells in laboratory tests. When the factor's functioning was disrupted, the cancer cells moved much more effectively in what are known as three-dimensional matrix systems, which imitate some of the tissue properties of the human body.
"The protein is apparently suppressed in many types of tumors, e.g. breast, lung, or thyroid," explains Dr. Robert Grosse, head of the Emmy Noether Junior Research Group funded by the German Research Association (DFG) at the Pharmacology Institute. The new factor could be an interesting starting point for research into new mechanisms for fighting cancer. The research team's results have now been published online in the prestigious international journal Nature Cell Biology.
Focus on particularly aggressive cancers
Tumor cells are extremely mobile and "adept" at penetrating healthy tissue to form metastases. They adapt to the consistency of the respective tissue by changing their shapes constantly and attach flexibly to surrounding tissues during movement with the help of special surface structures (receptors).
One of these receptors is what is known as b1-integrin, which is frequently formed in many tumors such as metastasizing breast cancer. "The cell signal factor SCAI controls the formation and function of b1-integrin," says Dr. Robert Grosse. "If there is too little SCAI in tumor cells, then b1-integrin is overactive, so to speak. The cell can change more rapidly to a more aggressive form and penetrate surrounding tissue, a crucial step toward increased spreading of the tumor and the possible formation of metastases."
In their recently published study, the Heidelberg researchers examined cells from skin cancer (melanoma) and breast cancer. In other projects, Dr. Robert Grosse's team would like to study the function of the signal factor SCAI more closely in an animal model. "If the function of SCAI is confirmed to be decisive in the formation of especially aggressive tumor cells, this could be a promising starting point for developing new diagnostic methods or medication," says the pharmacologist. It could also be possible to develop an agent that prevents the genetic suppression of the signal factor in cancer cells. But first the researchers need to better understand how the signal factor itself is regulated in the cell.
Reference:
Dominique T. Brandt, Christian Baarlink, Thomas M. Kitzing, Elisabeth Kremmer, Johanna Ivaska, Peter Nollau and Robert Grosse: SCAI acts as a suppressor of cancer cell invasion through the transcriptional control of ОІ1-integrin. Nature Cell Biology. 6. April 2009. DOI:10.1038/ncb1862
Heidelberg University Hospital and Medical Faculty:
Internationally recognized patient care, research, and teaching
Heidelberg University Hospital is one of the largest and most prestigious medical centers in Germany. The Medical Faculty of Heidelberg University belongs to the internationally most renowned biomedical research institutions in Europe. Both institutions have the common goal of developing new therapies and implementing them rapidly for patients. With about 7,000 employees, training and qualification is an important issue. Every year, around 500,000 patients are treated on an inpatient or outpatient basis in more than 40 clinics and departments with 1,600 beds. Currently, about 3,100 future physicians are studying in Heidelberg; the reform Heidelberg Curriculum Medicinale (HeiCuMed) is one of the top medical training programs in Germany.
Source:
Dr. Robert Grosse
University Hospital Heidelberg
"The protein is apparently suppressed in many types of tumors, e.g. breast, lung, or thyroid," explains Dr. Robert Grosse, head of the Emmy Noether Junior Research Group funded by the German Research Association (DFG) at the Pharmacology Institute. The new factor could be an interesting starting point for research into new mechanisms for fighting cancer. The research team's results have now been published online in the prestigious international journal Nature Cell Biology.
Focus on particularly aggressive cancers
Tumor cells are extremely mobile and "adept" at penetrating healthy tissue to form metastases. They adapt to the consistency of the respective tissue by changing their shapes constantly and attach flexibly to surrounding tissues during movement with the help of special surface structures (receptors).
One of these receptors is what is known as b1-integrin, which is frequently formed in many tumors such as metastasizing breast cancer. "The cell signal factor SCAI controls the formation and function of b1-integrin," says Dr. Robert Grosse. "If there is too little SCAI in tumor cells, then b1-integrin is overactive, so to speak. The cell can change more rapidly to a more aggressive form and penetrate surrounding tissue, a crucial step toward increased spreading of the tumor and the possible formation of metastases."
In their recently published study, the Heidelberg researchers examined cells from skin cancer (melanoma) and breast cancer. In other projects, Dr. Robert Grosse's team would like to study the function of the signal factor SCAI more closely in an animal model. "If the function of SCAI is confirmed to be decisive in the formation of especially aggressive tumor cells, this could be a promising starting point for developing new diagnostic methods or medication," says the pharmacologist. It could also be possible to develop an agent that prevents the genetic suppression of the signal factor in cancer cells. But first the researchers need to better understand how the signal factor itself is regulated in the cell.
Reference:
Dominique T. Brandt, Christian Baarlink, Thomas M. Kitzing, Elisabeth Kremmer, Johanna Ivaska, Peter Nollau and Robert Grosse: SCAI acts as a suppressor of cancer cell invasion through the transcriptional control of ОІ1-integrin. Nature Cell Biology. 6. April 2009. DOI:10.1038/ncb1862
Heidelberg University Hospital and Medical Faculty:
Internationally recognized patient care, research, and teaching
Heidelberg University Hospital is one of the largest and most prestigious medical centers in Germany. The Medical Faculty of Heidelberg University belongs to the internationally most renowned biomedical research institutions in Europe. Both institutions have the common goal of developing new therapies and implementing them rapidly for patients. With about 7,000 employees, training and qualification is an important issue. Every year, around 500,000 patients are treated on an inpatient or outpatient basis in more than 40 clinics and departments with 1,600 beds. Currently, about 3,100 future physicians are studying in Heidelberg; the reform Heidelberg Curriculum Medicinale (HeiCuMed) is one of the top medical training programs in Germany.
Source:
Dr. Robert Grosse
University Hospital Heidelberg
воскресенье, 15 мая 2011 г.
More Evidence That Melanoma Does Not Conform To The Cancer Stem Cell Model
University of Michigan researchers have determined that most types of melanoma cells can form malignant tumors, providing new evidence that the deadliest form of skin cancer does not conform to the increasingly popular cancer stem cell model.
In addition, the researchers found that melanoma tumor cells can change their appearance by switching various genes on and off, making the malignant cells a stealthy, shape-shifting target for researchers seeking new treatments, according to a team led by Sean Morrison, director of the U-M Center for Stem Cell Biology.
Both findings fly in the face of the cancer stem cell model, which states that a handful of rare stem cells drive the formation, growth and progression of malignant tumors in many cancers. Some supporters of the model have suggested that melanoma might be more effectively treated by taking aim specifically at these rare cancer stems cells, rather than attempting to eliminate all melanoma cells.
But after conducting an exhaustive search for this elusive sub-population of tumor-forming melanoma cell, the U-M team concluded that it probably does not exist. The researchers analyzed 44 sub-populations of human melanoma cells, and all 44 had a similar ability to form tumors when transplanted into mice.
"Some have suggested that melanoma follows a cancer stem cell model in which only rare cells are able to proliferate extensively and form new tumors," said Morrison, a Howard Hughes Medical Institute investigator.
"Our results suggest that most melanoma cells are capable of driving disease progression and that it won't be possible to cure patients by targeting rare sub-populations of cells," Morrison said. "We think you need to kill all the cells."
The team's findings will be published Nov. 16 in the journal Cancer Cell. The first authors of the paper are Elsa Quintana of the U-M Center for Stem Cell Biology, based at the Life Sciences Institute, and Mark Shackleton, formerly with the Morrison lab and now at the Peter MacCallum Cancer Center in Melbourne, Australia.
The study found that tumor-forming melanoma cells have the ability to throw a genetic switch that changes the types of proteins expressed on the cells' surface. The study is the first to present evidence for this type of pervasive "phenotypic plasticity" among melanoma cells from patients.
Patterns of surface proteins are used to identify different cell types and are commonly called cell surface markers.
"The fact that these markers are turned on and off by melanoma cells raises the possibility that melanoma cells may also turn on and off genes that regulate clinically important characteristics like drug resistance and metastatic ability," Morrison said. "The ability to transition between various states may make melanoma more difficult to treat."
The authors stress that while their results argue against a cancer stem cell model for melanoma, their findings do not invalidate the model. In fact, certain leukemias and other cancers appear to follow the model.
"It will be critical to determine which cancers follow a stem cell model and which do not, so therapies designed to target rare sub-populations of cells are not inappropriately tested in patients whose disease is driven by many diverse cancer cells," Quintana said.
The cancer stem cell model assumes that cells differing in marker expression also differ in function, and that only a very small subset of cancer cells displaying the critical marker pattern - less than 1 percent of cancer cells - can form tumors. The model proposes that most of the cancer cells that compose tumors have little or no capacity to proliferate or to contribute to disease progression.
"The cancer stem cell model says that tumor cells are organized hierarchically, and that only the cells at the top of the hierarchy form tumors. Cells at the bottom of the hierarchy can't," Morrison said. However, the Morrison laboratory was unable to find any subset of melanoma cells that lacked the ability to form tumors.
"In our model, all these cells can form tumors," he said. "And they're phenotypically different from each other not because they're hierarchically organized but because they're just turning these surface markers on and off."
The U-M team found that all tumor-forming melanoma cells gave rise to progeny with a variety of marker patterns, and that all of those sub-populations retained the ability to form tumors. The marker changes appeared to be reversible, rather than being associated with a transition from tumor-forming to non-tumor-forming states, as the cancer stem cell model would predict.
The Cancer Cell paper follows up on work reported by the Morrison lab in the Dec. 4, 2008, edition of the journal Nature. The Nature article demonstrated that tumor-forming melanoma cells are not rare, as predicted by the cancer stem cell model. The researchers determined that at least one-quarter of melanoma cells have the ability to form new tumors.
Melanoma kills more than 8,000 Americans each year. The human melanoma cells used in this study were provided - with the patients' permission - from the U-M's Multidisciplinary Melanoma Program, one of the country's largest melanoma programs and part of the U-M Comprehensive Cancer Center.
"These new findings significantly advance our understanding of melanoma," said cutaneous oncologist Dr. Timothy Johnson, director of the U-M melanoma program and a co-author of the Cancer Cell paper.
"This type of groundbreaking discovery achieves our core objective of combining clinical studies with laboratory research to develop new and better treatments for optimal patient care," Johnson said.
In addition to Morrison, Quintana, Shackleton and Johnson, the paper's authors are Hannah Foster of the Center for Stem Cell Biology; Dr. Douglas Fullen, associate professor of pathology and associate professor of dermatology at the Medical School; and Dr. Michael Sabel, associate professor of surgery at the Medical School.
The work was supported by the Howard Hughes Medical Institute and the Allen H. Blondy Research Fellowship. The U-M Melanoma Bank was supported by a gift from Lewis and Lillian Becker. Flow cytometry was partially supported by a National Institutes of Health grant to the U-M Comprehensive Cancer Center.
Elsa Quintana was supported by the Marie Curie Outgoing International Fellowship from the European Commission. Mark Shackleton was supported by the Australian National Health and Medical Research Council, the Human Frontiers Science Program, and Australia Post.
Source:
Jim Erickson
University of Michigan
In addition, the researchers found that melanoma tumor cells can change their appearance by switching various genes on and off, making the malignant cells a stealthy, shape-shifting target for researchers seeking new treatments, according to a team led by Sean Morrison, director of the U-M Center for Stem Cell Biology.
Both findings fly in the face of the cancer stem cell model, which states that a handful of rare stem cells drive the formation, growth and progression of malignant tumors in many cancers. Some supporters of the model have suggested that melanoma might be more effectively treated by taking aim specifically at these rare cancer stems cells, rather than attempting to eliminate all melanoma cells.
But after conducting an exhaustive search for this elusive sub-population of tumor-forming melanoma cell, the U-M team concluded that it probably does not exist. The researchers analyzed 44 sub-populations of human melanoma cells, and all 44 had a similar ability to form tumors when transplanted into mice.
"Some have suggested that melanoma follows a cancer stem cell model in which only rare cells are able to proliferate extensively and form new tumors," said Morrison, a Howard Hughes Medical Institute investigator.
"Our results suggest that most melanoma cells are capable of driving disease progression and that it won't be possible to cure patients by targeting rare sub-populations of cells," Morrison said. "We think you need to kill all the cells."
The team's findings will be published Nov. 16 in the journal Cancer Cell. The first authors of the paper are Elsa Quintana of the U-M Center for Stem Cell Biology, based at the Life Sciences Institute, and Mark Shackleton, formerly with the Morrison lab and now at the Peter MacCallum Cancer Center in Melbourne, Australia.
The study found that tumor-forming melanoma cells have the ability to throw a genetic switch that changes the types of proteins expressed on the cells' surface. The study is the first to present evidence for this type of pervasive "phenotypic plasticity" among melanoma cells from patients.
Patterns of surface proteins are used to identify different cell types and are commonly called cell surface markers.
"The fact that these markers are turned on and off by melanoma cells raises the possibility that melanoma cells may also turn on and off genes that regulate clinically important characteristics like drug resistance and metastatic ability," Morrison said. "The ability to transition between various states may make melanoma more difficult to treat."
The authors stress that while their results argue against a cancer stem cell model for melanoma, their findings do not invalidate the model. In fact, certain leukemias and other cancers appear to follow the model.
"It will be critical to determine which cancers follow a stem cell model and which do not, so therapies designed to target rare sub-populations of cells are not inappropriately tested in patients whose disease is driven by many diverse cancer cells," Quintana said.
The cancer stem cell model assumes that cells differing in marker expression also differ in function, and that only a very small subset of cancer cells displaying the critical marker pattern - less than 1 percent of cancer cells - can form tumors. The model proposes that most of the cancer cells that compose tumors have little or no capacity to proliferate or to contribute to disease progression.
"The cancer stem cell model says that tumor cells are organized hierarchically, and that only the cells at the top of the hierarchy form tumors. Cells at the bottom of the hierarchy can't," Morrison said. However, the Morrison laboratory was unable to find any subset of melanoma cells that lacked the ability to form tumors.
"In our model, all these cells can form tumors," he said. "And they're phenotypically different from each other not because they're hierarchically organized but because they're just turning these surface markers on and off."
The U-M team found that all tumor-forming melanoma cells gave rise to progeny with a variety of marker patterns, and that all of those sub-populations retained the ability to form tumors. The marker changes appeared to be reversible, rather than being associated with a transition from tumor-forming to non-tumor-forming states, as the cancer stem cell model would predict.
The Cancer Cell paper follows up on work reported by the Morrison lab in the Dec. 4, 2008, edition of the journal Nature. The Nature article demonstrated that tumor-forming melanoma cells are not rare, as predicted by the cancer stem cell model. The researchers determined that at least one-quarter of melanoma cells have the ability to form new tumors.
Melanoma kills more than 8,000 Americans each year. The human melanoma cells used in this study were provided - with the patients' permission - from the U-M's Multidisciplinary Melanoma Program, one of the country's largest melanoma programs and part of the U-M Comprehensive Cancer Center.
"These new findings significantly advance our understanding of melanoma," said cutaneous oncologist Dr. Timothy Johnson, director of the U-M melanoma program and a co-author of the Cancer Cell paper.
"This type of groundbreaking discovery achieves our core objective of combining clinical studies with laboratory research to develop new and better treatments for optimal patient care," Johnson said.
In addition to Morrison, Quintana, Shackleton and Johnson, the paper's authors are Hannah Foster of the Center for Stem Cell Biology; Dr. Douglas Fullen, associate professor of pathology and associate professor of dermatology at the Medical School; and Dr. Michael Sabel, associate professor of surgery at the Medical School.
The work was supported by the Howard Hughes Medical Institute and the Allen H. Blondy Research Fellowship. The U-M Melanoma Bank was supported by a gift from Lewis and Lillian Becker. Flow cytometry was partially supported by a National Institutes of Health grant to the U-M Comprehensive Cancer Center.
Elsa Quintana was supported by the Marie Curie Outgoing International Fellowship from the European Commission. Mark Shackleton was supported by the Australian National Health and Medical Research Council, the Human Frontiers Science Program, and Australia Post.
Source:
Jim Erickson
University of Michigan
суббота, 14 мая 2011 г.
Human Aggression Is Deep Rooted
Ape-like human ancestors known as australopiths maintained short legs for 2 million years because a squat physique and stance helped the males fight over access to females, a University of Utah study concludes.
"The old argument was that they retained short legs to help them climb trees that still were an important part of their habitat," says David Carrier, a professor of biology. "My argument is that they retained short legs because short legs helped them fight."
The study analyzed leg lengths and indicators of aggression in nine primate species, including human aborigines. It is in the March issue of the journal Evolution.
Creatures in the genus Australopithecus - immediate predecessors of the human genus Homo - had heights of about 3 feet 9 inches for females and 4 feet 6 inches for males. They lived from 4 million to 2 million years ago.
"For that entire period, they had relatively short legs - longer than chimps' legs but shorter than the legs of humans that came later," Carrier says.
"So the question is, why did australopiths retain short legs for 2 million years? Among experts on primates, the climbing hypothesis is the explanation. Mechanically, it makes sense. If you are walking on a branch high above the ground, stability is important because if you fall and you're big, you are going to die. Short legs would lower your center of mass and make you more stable."
Yet Carrier says his research suggests short legs helped australopiths fight because "with short legs, your center of mass is closer to the ground. It's going to make you more stable so that you can't be knocked off your feet as easily. And with short legs, you have greater leverage as you grapple with your opponent."
While Carrier says his aggression hypothesis does not rule out the possibility that short legs aided climbing, but "evidence is poor because the apes that have the shortest legs for their body size spend the least time in trees - male gorillas and orangutans."
He also notes that short legs must have made it harder for australopiths "to bridge gaps between possible sites of support when climbing and traveling through the canopy."
Nevertheless, he writes, "The two hypotheses for the evolution of relatively short legs in larger primates, specialization for climbing and specialization for aggression, are not mutually exclusive. Indeed, selection for climbing performance may result in the evolution of a body configuration that improves fighting performance and vice versa."
Great Apes' Short Legs Provide Evidence for Australopith Aggression
All modern great apes - humans, chimps, orangutans, gorillas and bonobos - engage in at least some aggression as males compete for females, Carrier says.
Carrier set out to find how aggression related to leg length. He compared Australian aborigines with eight primate species: gorillas, chimpanzees, bonobos, orangutans, black gibbons, siamang gibbons, olive baboons and dwarf guenon monkeys. Carrier used data on aborigines because they are a relatively natural population.
For the aborigines and each primate species, Carrier used the scientific literature to obtain typical hindlimb lengths and data on two physical features that previously have been shown to correlate with male-male competition and aggressiveness in primates:
* The weight difference between males and females in a species. Earlier studies found males fight more in species with larger male-female body size ratios.
* The male-female difference in the length of canine teeth, which are next to the incisors and are used for biting during fights.
Carrier used male-female body size ratios and canine tooth size ratios as numerical indicators for aggressiveness because field studies of primates have used varying criteria to rate aggression. He says it would be like having a different set of judges for each competitor in subjective Olympic events like diving or ice dancing.
The study found that hindlimb length correlated inversely with both indicators of aggressiveness: Primate species with greater male-female differences in body weight and length of the canine teeth had shorter legs, and thus display more male-male combat.
There was no correlation between arm length and the indicators of aggression. Carrier says arms are used for fighting, but "for other things as well: climbing, handling food, grooming. Thus, arm length is not related to aggression in any simple way."
Verifying the Findings
Carrier conducted various statistical analyses to verify his findings. First, he corrected for each species' limb lengths relative to their body size. Primates with larger body sizes tend to have shorter legs, humans excepted. Without taking that into account, the correlation between body size and aggression indicators might be false.
Another analysis corrected for the fact different primate species are related. For example, if three closely related species all have short legs, it might be due to the relationship - an ancestor with short legs - and not aggression.
Even with the corrections, short legs still correlated significantly with the two indicators of aggressiveness.
The study also found that females in each primate species except humans have relatively longer legs than males. "If it is mainly the males that need to be adapted for fighting, then you'd expect them to have shorter legs for their body size," Carrier says.
He notes there are exceptions to that rule. Bonobos have shorter legs than chimps, yet they are less aggressive. Carrier says the correlation between short legs and aggression may be imperfect because legs are used for many other purposes than fighting.
Humans "are a special case" and are not less aggressive because they have longer legs, Carrier says. There is a physical tradeoff between aggression and economical walking and running. Short, squat australopiths were strong and able to stand their ground when shoved, but their short legs made them ill-suited for distance running. Slender, long-legged humans excel at running. Yet, they also excel at fighting. In a 2004 study, Carrier made a case that australopiths evolved into lithe, long-legged early humans only when they learned to make weapons and fight with them.
Now he argues that even though australopiths walked upright on the ground, the reason they retained short legs for 2 million years was not so much that they spent time in trees, but "the same thing that selected for short legs in the other great apes: male-male aggression and competition over access to reproductively active females."
In other words, shorter legs increased the odds of victory when males fought over access to females - access that meant passing their genetic traits to offspring.
Yet, "we don't really know how aggressive australopiths were," Carrier says. "If they were more aggressive than modern humans, they were exceptionally nasty animals."
Why Should We Care that Australopiths Were Short and Nasty?
"Given the aggressive behavior of modern humans and apes, we should not be surprised to find fossil evidence of aggressive behavior in the ancestors of modern humans," Carrier says. "This is important because we have a real problem with violence in modern society. Part of the problem is that we don't recognize we are relatively violent animals. Many people argue we are not violent. But we are violent. If we want to prevent future violence we have to understand why we are violent."
"To some extent, our evolutionary past may help us to understand the circumstances in which humans behave violently," he adds. "There are a number of independent lines of evidence suggesting that much of human violence is related to male-male competition, and this study is consistent with that."
Nevertheless, male-male competition doesn't fully explain human violence, Carrier says, noting other factors such as hunting, competing with other species, defending territory and other resources, and feeding and protecting offspring.
Contact: David Carrier
University of Utah
"The old argument was that they retained short legs to help them climb trees that still were an important part of their habitat," says David Carrier, a professor of biology. "My argument is that they retained short legs because short legs helped them fight."
The study analyzed leg lengths and indicators of aggression in nine primate species, including human aborigines. It is in the March issue of the journal Evolution.
Creatures in the genus Australopithecus - immediate predecessors of the human genus Homo - had heights of about 3 feet 9 inches for females and 4 feet 6 inches for males. They lived from 4 million to 2 million years ago.
"For that entire period, they had relatively short legs - longer than chimps' legs but shorter than the legs of humans that came later," Carrier says.
"So the question is, why did australopiths retain short legs for 2 million years? Among experts on primates, the climbing hypothesis is the explanation. Mechanically, it makes sense. If you are walking on a branch high above the ground, stability is important because if you fall and you're big, you are going to die. Short legs would lower your center of mass and make you more stable."
Yet Carrier says his research suggests short legs helped australopiths fight because "with short legs, your center of mass is closer to the ground. It's going to make you more stable so that you can't be knocked off your feet as easily. And with short legs, you have greater leverage as you grapple with your opponent."
While Carrier says his aggression hypothesis does not rule out the possibility that short legs aided climbing, but "evidence is poor because the apes that have the shortest legs for their body size spend the least time in trees - male gorillas and orangutans."
He also notes that short legs must have made it harder for australopiths "to bridge gaps between possible sites of support when climbing and traveling through the canopy."
Nevertheless, he writes, "The two hypotheses for the evolution of relatively short legs in larger primates, specialization for climbing and specialization for aggression, are not mutually exclusive. Indeed, selection for climbing performance may result in the evolution of a body configuration that improves fighting performance and vice versa."
Great Apes' Short Legs Provide Evidence for Australopith Aggression
All modern great apes - humans, chimps, orangutans, gorillas and bonobos - engage in at least some aggression as males compete for females, Carrier says.
Carrier set out to find how aggression related to leg length. He compared Australian aborigines with eight primate species: gorillas, chimpanzees, bonobos, orangutans, black gibbons, siamang gibbons, olive baboons and dwarf guenon monkeys. Carrier used data on aborigines because they are a relatively natural population.
For the aborigines and each primate species, Carrier used the scientific literature to obtain typical hindlimb lengths and data on two physical features that previously have been shown to correlate with male-male competition and aggressiveness in primates:
* The weight difference between males and females in a species. Earlier studies found males fight more in species with larger male-female body size ratios.
* The male-female difference in the length of canine teeth, which are next to the incisors and are used for biting during fights.
Carrier used male-female body size ratios and canine tooth size ratios as numerical indicators for aggressiveness because field studies of primates have used varying criteria to rate aggression. He says it would be like having a different set of judges for each competitor in subjective Olympic events like diving or ice dancing.
The study found that hindlimb length correlated inversely with both indicators of aggressiveness: Primate species with greater male-female differences in body weight and length of the canine teeth had shorter legs, and thus display more male-male combat.
There was no correlation between arm length and the indicators of aggression. Carrier says arms are used for fighting, but "for other things as well: climbing, handling food, grooming. Thus, arm length is not related to aggression in any simple way."
Verifying the Findings
Carrier conducted various statistical analyses to verify his findings. First, he corrected for each species' limb lengths relative to their body size. Primates with larger body sizes tend to have shorter legs, humans excepted. Without taking that into account, the correlation between body size and aggression indicators might be false.
Another analysis corrected for the fact different primate species are related. For example, if three closely related species all have short legs, it might be due to the relationship - an ancestor with short legs - and not aggression.
Even with the corrections, short legs still correlated significantly with the two indicators of aggressiveness.
The study also found that females in each primate species except humans have relatively longer legs than males. "If it is mainly the males that need to be adapted for fighting, then you'd expect them to have shorter legs for their body size," Carrier says.
He notes there are exceptions to that rule. Bonobos have shorter legs than chimps, yet they are less aggressive. Carrier says the correlation between short legs and aggression may be imperfect because legs are used for many other purposes than fighting.
Humans "are a special case" and are not less aggressive because they have longer legs, Carrier says. There is a physical tradeoff between aggression and economical walking and running. Short, squat australopiths were strong and able to stand their ground when shoved, but their short legs made them ill-suited for distance running. Slender, long-legged humans excel at running. Yet, they also excel at fighting. In a 2004 study, Carrier made a case that australopiths evolved into lithe, long-legged early humans only when they learned to make weapons and fight with them.
Now he argues that even though australopiths walked upright on the ground, the reason they retained short legs for 2 million years was not so much that they spent time in trees, but "the same thing that selected for short legs in the other great apes: male-male aggression and competition over access to reproductively active females."
In other words, shorter legs increased the odds of victory when males fought over access to females - access that meant passing their genetic traits to offspring.
Yet, "we don't really know how aggressive australopiths were," Carrier says. "If they were more aggressive than modern humans, they were exceptionally nasty animals."
Why Should We Care that Australopiths Were Short and Nasty?
"Given the aggressive behavior of modern humans and apes, we should not be surprised to find fossil evidence of aggressive behavior in the ancestors of modern humans," Carrier says. "This is important because we have a real problem with violence in modern society. Part of the problem is that we don't recognize we are relatively violent animals. Many people argue we are not violent. But we are violent. If we want to prevent future violence we have to understand why we are violent."
"To some extent, our evolutionary past may help us to understand the circumstances in which humans behave violently," he adds. "There are a number of independent lines of evidence suggesting that much of human violence is related to male-male competition, and this study is consistent with that."
Nevertheless, male-male competition doesn't fully explain human violence, Carrier says, noting other factors such as hunting, competing with other species, defending territory and other resources, and feeding and protecting offspring.
Contact: David Carrier
University of Utah
пятница, 13 мая 2011 г.
Specialized Training In Medical Microbiology Provided By Fellowships
Beth Israel Deaconess Medical Center (BIDMC) recently received approval for two new medical microbiology fellowship programs to train the next generation of leaders in clinical and public-health microbiology.
With only a dozen of each type of training program nationwide, the two new fellowships at BIDMC are the only such programs in Massachusetts, and with one exception, in all of the Northeast.
"A quick glance at the news of recent months confirms that there is an urgent need for leaders in the field of medical microbiology," says BIDMC Chief of Pathology Jeffrey Saffitz, MD, PhD. "Hospital-borne infections, the risk of drug-resistant tuberculosis, and emerging infectious diseases, such as bird flu, are all posing potentially serious risks right now. From a public health standpoint, it is critically important that we have doctors who are specially trained in medical microbiology."
The first of the two fellowships is accredited by the American College of Graduate Medical Education (ACGME) and will be available starting July 1, 2008. One year in length, the program is designed to train fellows to assume leadership roles in academic, tertiary care or public health laboratories, according to James Kirby, MD, director of the fellowship programs and Medical Director of the Clinical Microbiology Laboratory at BIDMC. The second fellowship is accredited by the American College of Microbiology and is the only such training program in New England.
"Both of these programs will provide doctors with broad, in-depth training, including high-level understanding of bacterial agents, parasites, and viruses," explains Kirby. "We aim to train fellows not only to be expert microbiologists and to direct laboratories, but also to make use of some of today's amazing new technologies, including very powerful molecular methods to enable faster, more accurate diagnoses."
Each of the programs will include hands-on instruction of microbiological testing, as well as direct participation in the consultative and administrative activities of the microbiology laboratory.
"The goal," says Kirby, "is to build an comprehensive training program. Therefore, fellows will also participate in activities of the medical center's infectious diseases, pharmacy, and hospital epidemiology and infection control departments." In order to become expert in childhood infections and emerging public health menaces such as Eastern Equine Encephalitis and West Nile Virus, the fellowship participants will also train in microbiology at Children's Hospital Boston and at the Massachusetts Department of Public Health.
"We anticipate that many of the participants will combine their clinical training with further training in basic research, and will develop scientific careers that will contribute to our understanding of infectious agents and ways to detect them," says Kirby.
"We're now a global society," adds Saffitz. "As we recently saw with the case of the individual suspected of harboring extensively drug-resistant tuberculosis, we need to have medical leadership available throughout the world to help to manage the rapidly changing landscape of medical microbiology."
Beth Israel Deaconess Medical Center is a patient care, teaching and research affiliate of Harvard Medical School. It ranks third in National Institutes of Health funding among independent hospitals nationwide. BIDMC is clinically affiliated with the Joslin Diabetes Center and is a research partner of the Dana-Farber/Harvard Cancer Center. BIDMC is the official hospital of the Boston Red Sox. For more information, visit bidmc.harvard/.
Source: Bonnie Prescott
Beth Israel Deaconess Medical Center
With only a dozen of each type of training program nationwide, the two new fellowships at BIDMC are the only such programs in Massachusetts, and with one exception, in all of the Northeast.
"A quick glance at the news of recent months confirms that there is an urgent need for leaders in the field of medical microbiology," says BIDMC Chief of Pathology Jeffrey Saffitz, MD, PhD. "Hospital-borne infections, the risk of drug-resistant tuberculosis, and emerging infectious diseases, such as bird flu, are all posing potentially serious risks right now. From a public health standpoint, it is critically important that we have doctors who are specially trained in medical microbiology."
The first of the two fellowships is accredited by the American College of Graduate Medical Education (ACGME) and will be available starting July 1, 2008. One year in length, the program is designed to train fellows to assume leadership roles in academic, tertiary care or public health laboratories, according to James Kirby, MD, director of the fellowship programs and Medical Director of the Clinical Microbiology Laboratory at BIDMC. The second fellowship is accredited by the American College of Microbiology and is the only such training program in New England.
"Both of these programs will provide doctors with broad, in-depth training, including high-level understanding of bacterial agents, parasites, and viruses," explains Kirby. "We aim to train fellows not only to be expert microbiologists and to direct laboratories, but also to make use of some of today's amazing new technologies, including very powerful molecular methods to enable faster, more accurate diagnoses."
Each of the programs will include hands-on instruction of microbiological testing, as well as direct participation in the consultative and administrative activities of the microbiology laboratory.
"The goal," says Kirby, "is to build an comprehensive training program. Therefore, fellows will also participate in activities of the medical center's infectious diseases, pharmacy, and hospital epidemiology and infection control departments." In order to become expert in childhood infections and emerging public health menaces such as Eastern Equine Encephalitis and West Nile Virus, the fellowship participants will also train in microbiology at Children's Hospital Boston and at the Massachusetts Department of Public Health.
"We anticipate that many of the participants will combine their clinical training with further training in basic research, and will develop scientific careers that will contribute to our understanding of infectious agents and ways to detect them," says Kirby.
"We're now a global society," adds Saffitz. "As we recently saw with the case of the individual suspected of harboring extensively drug-resistant tuberculosis, we need to have medical leadership available throughout the world to help to manage the rapidly changing landscape of medical microbiology."
Beth Israel Deaconess Medical Center is a patient care, teaching and research affiliate of Harvard Medical School. It ranks third in National Institutes of Health funding among independent hospitals nationwide. BIDMC is clinically affiliated with the Joslin Diabetes Center and is a research partner of the Dana-Farber/Harvard Cancer Center. BIDMC is the official hospital of the Boston Red Sox. For more information, visit bidmc.harvard/.
Source: Bonnie Prescott
Beth Israel Deaconess Medical Center
Подписаться на:
Комментарии (Atom)