Atrazine, one of the world's most widely used pesticides, wreaks havoc with the sex lives of adult male frogs, emasculating three-quarters of them and turning one in 10 into females, according to a new study by University of California, Berkeley, biologists.
The 75 percent that are chemically castrated are essentially "dead" because of their inability to reproduce in the wild, reports UC Berkeley's Tyrone B. Hayes, professor of integrative biology.
"These male frogs are missing testosterone and all the things that testosterone controls, including sperm. So their fertility is as low as 10 percent in some cases, and that is only if we isolate those animals and pair them with females," he said. "In an environment where they are competing with unexposed animals, they have zero chance of reproducing."
The 10 percent or more that turn from males into females - something not known to occur under natural conditions in amphibians - can successfully mate with male frogs but, because they are genetically male, all their offspring are male.
"When we grow these guys up, depending on the family, we will get anywhere from 10 to 50 percent females," Hayes said. "In a population, the genetically male females can decrease or wipe out a population just because they skew sex ratios so badly."
Though the experiments were performed on a common laboratory frog, the African clawed frog (Xenopus laevis), field studies indicate that atrazine, a potent endocrine disruptor, similarly affects frogs in the wild, and could possibly be one of the causes of amphibian declines around the globe, Hayes said.
Hayes and his UC Berkeley colleagues report their results in this week's online early edition of the journal Proceedings of the National Academy of Sciences. Last week, Hayes and colleagues published a review of pesticide's effects on amphibians in the Journal of Experimental Biology, concluding that atrazine is a likely contributor to worldwide amphibian declines.
"These kinds of problems, like sex-reversing animals skewing sex ratios, are much more dangerous than any chemical that would kill off a population of frogs," he said. "In exposed populations, it looks like there are frogs breeding but, in fact, the population is being very slowly degraded by the introduction of these altered animals."
Some 80 million pounds of the herbicide atrazine are applied annually in the United States on corn and sorghum to control weeds and increase crop yield, but such widespread use also makes atrazine the most common pesticide contaminant of ground and surface water, according to various studies.
More and more research, however, is showing that atrazine interferes with endocrine hormones, such as estrogen and testosterone - in fish, amphibians, birds, reptiles, laboratory rodents and even human cell lines at levels of parts per billion. Recent studies also found a possible link between human birth defects and low birth weight and atrazine exposure in the womb.
As a result of these studies, the Environmental Protection Agency (EPA) is reviewing its regulations on use of the pesticide. Several states are considering banning atrazine, and six class action lawsuits have been filed seeking to eliminate its use. The European Union already bars the use of atrazine.
Hayes's studies in the early 2000s were the first to show that the hormonal effects of atrazine disrupt sexual development in amphibians. Working with the African clawed frog, Hayes and his colleagues showed in 2002 that tadpoles raised in atrazine-contaminated water become hermaphrodites - they develop both female (ovaries) and male (testes) gonads. This occurred at atrazine levels as low as 0.1 parts per billion (ppb), 30 times lower than levels allowed in drinking water by the EPA (3 ppb).
Subsequent studies showed that native leopard frogs (Rana pipiens) collected from atrazine-contaminated streams in the Midwest, including from areas up to 1,000 miles from where atrazine is applied, often had eggs in their testes. And many males had lower testosterone levels than normal females and smaller than normal voice boxes, presumably limiting their ability to call mates.
Hayes' research also established that many frogs in Midwestern streams contaminated by atrazine and other pesticides have compromised immune systems, leading to increased mortality from bacterial disease.
Those early studies were hampered by the inability to easily distinguish genetically male from genetically female frogs. Male frogs have two identical sex chromosomes (ZZ) while females have both a Z and a W - the opposite of XX female and XY male humans. But because all frog chromosomes look the same under a light microscope, it's not simple to distinguish male from female.
To overcome this, Hayes' colleague Roger Liu developed a line of all-male frogs so that the genetics would be unequivocal.
"Before, we knew we got fewer males than we should have, and we got hermaphrodites. Now, we have clearly shown that many of these animals are sex-reversed males," Hayes said. "We have animals that are females, in the sense that they behave like females: They have estrogen, lay eggs, they mate with other males. Atrazine has caused a hormonal imbalance that has made them develop into the wrong sex, in terms of their genetic constitution."
Coincidentally, another lab in 2008 discovered a sex-linked genetic marker in Xenopus, which has allowed Hayes to confirm the genetic sex of his frogs.
In Hayes' study, where 40 frogs lived for about three years after hatching in water with 2.5 ppb atrazine, about 10 percent of the frogs appeared to be resistant to the effects of the pesticide. In ongoing studies, Hayes is investigating whether this apparent resistance is inherited, as well as whether the sex-reversed males have more susceptible offspring.
Syngenta, which manufactures atrazine, disputes many of these studies, including Hayes', that show adverse effects of the presticide. But Hayes said that "when you have studies all over the world showing problems with atrazine in every vertebrate that has been looked at - fish, frogs, reptiles, birds, mammals - all of them can't be wrong."
"What people have to realize is that, just as with taking pharmaceuticals, they have to decide whether the benefits outweigh the costs," he said. "Not every frog or every human will be affected by atrazine, but do you want to take a chance, what with all the other things that we know atrazine does, not just to humans but to rodents and frogs and fish?"
Hayes' long-term studies of the effects of atrazine on frogs have been assisted by many UC Berkeley undergraduate students, including co-authors on the current paper: Vicky Khoury, Anne Narayan, Mariam Nazir, Andrew Park, Lillian Adame, Elton Chan, and graduate students Travis Brown, Daniel Buchholz, Sherrie Gallipeau and Theresa Stueve.
The work was funded by the Park Water Co., Mitch Kapor, Freada Klein, the Mitch Kapor Foundation, the David Foundation, the Cornell-Douglas Foundation, the Wallace Foundation, the UC Berkeley Class of '43 endowed chair and the Howard Hughes Biology Fellows Program.
Source:
Robert Sanders
University of California - Berkeley
четверг, 20 октября 2011 г.
понедельник, 17 октября 2011 г.
Novel Evolutionary Tools For Studying Human Populations Using The X Chromosome
Research in the Department of Genetics at University of Leicester is well-known for its human population studies with the Y chromosome, including the relationship between the male surname and the Y chromosome, as well as a better understanding of the Viking settlement in the Northwest England.
Now a new research project using the X chromosome (present in one copy in men but two in women) will be the first readily applicable non sex-specific evolutionary tool to provide a more sex-balanced view in human population studies.
Although the Y chromosome is a better established evolutionary tool and has been used in many evolutionary studies, apart from ease of usage, it has a lot of limitations preventing it becoming the most evolutionary informative DNA segments in the Human genome.
Now as part of her doctoral studies, Holly Leung is investigating the potential of the X chromosome as another evolutionary informative segment in the human genome.
Holly said: "This may be the real key to solving many existing mysteries of human population evolution, for example the 'out of Africa' theory and the Neolithic expansion in Europe.
"The Y chromosome is the most common evolutionary tool we use in population studies but it doesn't mean that it is the most evolutionary informative DNA segment in the human genome.
"There are many limitations with the use of the Y chromosome which make it non-applicable to every evolutionary study because of its male specific lineage. It provides sex-biased information to the male and as a single genetic marker restricts the diversity of information source.
"The aim of my research is to produce and assess the usefulness of the evolutionary information provided by the X chromosome. It shares some properties with the Y chromosome, but provides an expanded view of human evolution because of its presence in males and females and the many independent genetic markers it contains."
Holly Leung is 24 years old, graduate from the BSc Medical Genetics in the University of Leicester in 2006. In the same year, she continues her study in the Department of Genetics doing PhD Genetics research as she discovered her interest in Evolutionary Genetics specifically in the study of evolutionary history of Human population.
The research is being presented to the public at the University of Leicester on Thursday 26th June. The Festival of Postgraduate Research introduces employers and the public to the next generation of innovators and cutting-edge researchers, and gives postgraduate researchers the opportunity to explain the real world implications of their research to a wide ranging audience.
More information about the Festival of Postgraduate Research is available at: le.ac.uk/gradschool/festival
UNIVERSITY OF LEICESTER
Founded in 1921, the University of Leicester has 19,000 students from 136 countries. Teaching in 18 subject areas has been graded Excellent by the Quality Assurance Agency- including 14 successive scores - a consistent run of success matched by just one other UK University. Leicester is world renowned for the invention of DNA Fingerprinting by Professor Sir Alec Jeffreys and houses Europe's biggest academic Space Research Centre. 90% of staff are actively engaged in high quality research and 13 subject areas have been awarded the highest rating of 5* and 5 for research quality, demonstrating excellence at an international level. The University's research grant income places it among the top 20 UK research universities. The University employs over 3,000 people, has an annual turnover of ВЈ184m, covers an estate of 94 hectares and is engaged in a ВЈ300m investment programme- among the biggest of any UK university.
Source:
le.ac.uk
Now a new research project using the X chromosome (present in one copy in men but two in women) will be the first readily applicable non sex-specific evolutionary tool to provide a more sex-balanced view in human population studies.
Although the Y chromosome is a better established evolutionary tool and has been used in many evolutionary studies, apart from ease of usage, it has a lot of limitations preventing it becoming the most evolutionary informative DNA segments in the Human genome.
Now as part of her doctoral studies, Holly Leung is investigating the potential of the X chromosome as another evolutionary informative segment in the human genome.
Holly said: "This may be the real key to solving many existing mysteries of human population evolution, for example the 'out of Africa' theory and the Neolithic expansion in Europe.
"The Y chromosome is the most common evolutionary tool we use in population studies but it doesn't mean that it is the most evolutionary informative DNA segment in the human genome.
"There are many limitations with the use of the Y chromosome which make it non-applicable to every evolutionary study because of its male specific lineage. It provides sex-biased information to the male and as a single genetic marker restricts the diversity of information source.
"The aim of my research is to produce and assess the usefulness of the evolutionary information provided by the X chromosome. It shares some properties with the Y chromosome, but provides an expanded view of human evolution because of its presence in males and females and the many independent genetic markers it contains."
Holly Leung is 24 years old, graduate from the BSc Medical Genetics in the University of Leicester in 2006. In the same year, she continues her study in the Department of Genetics doing PhD Genetics research as she discovered her interest in Evolutionary Genetics specifically in the study of evolutionary history of Human population.
The research is being presented to the public at the University of Leicester on Thursday 26th June. The Festival of Postgraduate Research introduces employers and the public to the next generation of innovators and cutting-edge researchers, and gives postgraduate researchers the opportunity to explain the real world implications of their research to a wide ranging audience.
More information about the Festival of Postgraduate Research is available at: le.ac.uk/gradschool/festival
UNIVERSITY OF LEICESTER
Founded in 1921, the University of Leicester has 19,000 students from 136 countries. Teaching in 18 subject areas has been graded Excellent by the Quality Assurance Agency- including 14 successive scores - a consistent run of success matched by just one other UK University. Leicester is world renowned for the invention of DNA Fingerprinting by Professor Sir Alec Jeffreys and houses Europe's biggest academic Space Research Centre. 90% of staff are actively engaged in high quality research and 13 subject areas have been awarded the highest rating of 5* and 5 for research quality, demonstrating excellence at an international level. The University's research grant income places it among the top 20 UK research universities. The University employs over 3,000 people, has an annual turnover of ВЈ184m, covers an estate of 94 hectares and is engaged in a ВЈ300m investment programme- among the biggest of any UK university.
Source:
le.ac.uk
пятница, 14 октября 2011 г.
2007 Class Of Distinguished Young Scholars In Medical Research Announced By W.M. Keck Foundation
The W.M. Keck Foundation, a leading supporter of high-impact medical research, science and engineering, has announced the 2007 class of grant recipients under its Distinguished Young Scholars in Medical Research Program.
Robert A. Day, Chairman and Chief Executive Officer said: "Now in its ninth year, our Young Scholars program is designed to give the nation's most promising young scientists the resources they need to pursue potentially breakthrough research projects in biomedicine. We are very pleased to support this group of Young Scholars who clearly exhibit extraordinary promise for future research and academic leadership."
Under the program, each grant recipient's sponsoring institution receives an award of up to $1 million to support the scientist's research activities for a period of up to five years, as well as to enable the institution to purchase necessary equipment and resources to facilitate the scientist's ongoing study. It is hoped that the investment in the Keck Scholars will greatly benefit society for generations to come with continued advances in understanding -- and combating -- the fundamental mechanisms of human disease.
The Young Scholars Program was initiated in 1999 and has awarded grants totalling nearly $45 million to date. Each grant applicant must be nominated by his or her research institution and then evaluated by the Foundation's Medical Research Board and a Scientific Advisory Committee and unanimously approved by the Foundation's Board of Directors. Nominations are accepted on an invitation-only basis.
The 2007 class of Distinguished Young Scholars is:
* Job Dekker, Ph.D., Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School -- Dr. Dekker has developed a system to study the complex way in which chromosomes are regulated. By comparing cancer and normal cells, the research has the potential to uncover defects in chromosome regulation that cause malignancy, which may lead to advances in combating cancerous cells in the body.
* Wallace Marshall, Ph.D., Department of Biochemistry, University of California, San Francisco -- Dr Marshall investigates how cilia, the hair-like projections that move substances over a cell, are involved as key factors in debilitating human diseases. By studying blue-green algae, Dr. Marshall's research may lead to new insights into human ciliary disorders, such as polycystic kidney disease and retinal degeneration.
* Amy Wagers, Ph.D., Harvard Stem Cell Institute, Section on Developmental and Stem Cell Biology at Joslin Diabetes Center, Harvard Medical School -- Dr. Wagers investigates the decline with age in the body's ability to maintain homeostatic cell replacement and to regenerate cells after injury. Building on previous research of the relationship between the age of stem cells and their ability to regenerate themselves, Dr. Wagers hopes to discover a method to slow down or reverse the natural process of aging, which may potentially lead to advances in treating age-related illnesses, such as diabetes, immune deficiencies, muscle weakness, and cancer.
* Xander Wehrens, M.D., Ph.D., Department of Molecular Physiology & Biophysics, Baylor College of Medicine -- Dr. Wehrens hopes to define the mechanisms of specialized protein complexes in excitable cells, such as heart muscle. His research has the potential to explain the underlying causes of certain types of heart failure and cardiomyopathy.
* Jennifer Zallen, Ph.D., Developmental Biology Program, Memorial Sloan-Kettering Cancer Center -- Dr. Zallen's work on the nature of three-dimensional Rosetta cell structures combines molecular genetics, live imaging, and quantitative statistical analysis. Her study of a fruit fly's cell structure may be applied to other organisms' cell structures, with the potential to develop approaches to analyze cell behavior and structure in living embryos.
The Foundation's Board of Directors has unanimously approved the recommendations made by the Scientific Advisory Committee.
Based in Los Angeles, the W.M. Keck Foundation was established in 1954 by the late W.M. Keck, founder of the Superior Oil Company. The Foundation's grant making is focused primarily on pioneering efforts in the areas of medical research, science and engineering. The Foundation also maintains a Southern California grant program that provides support in the areas of civic and community services with a special emphasis on children and youth.
For more information about the W.M. Keck Foundation and the Young scholars program, please visit the Foundation's web site at wmkeck/programs/scholars.html.
Source: Louise Weston
W. M. Keck Foundation
Robert A. Day, Chairman and Chief Executive Officer said: "Now in its ninth year, our Young Scholars program is designed to give the nation's most promising young scientists the resources they need to pursue potentially breakthrough research projects in biomedicine. We are very pleased to support this group of Young Scholars who clearly exhibit extraordinary promise for future research and academic leadership."
Under the program, each grant recipient's sponsoring institution receives an award of up to $1 million to support the scientist's research activities for a period of up to five years, as well as to enable the institution to purchase necessary equipment and resources to facilitate the scientist's ongoing study. It is hoped that the investment in the Keck Scholars will greatly benefit society for generations to come with continued advances in understanding -- and combating -- the fundamental mechanisms of human disease.
The Young Scholars Program was initiated in 1999 and has awarded grants totalling nearly $45 million to date. Each grant applicant must be nominated by his or her research institution and then evaluated by the Foundation's Medical Research Board and a Scientific Advisory Committee and unanimously approved by the Foundation's Board of Directors. Nominations are accepted on an invitation-only basis.
The 2007 class of Distinguished Young Scholars is:
* Job Dekker, Ph.D., Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School -- Dr. Dekker has developed a system to study the complex way in which chromosomes are regulated. By comparing cancer and normal cells, the research has the potential to uncover defects in chromosome regulation that cause malignancy, which may lead to advances in combating cancerous cells in the body.
* Wallace Marshall, Ph.D., Department of Biochemistry, University of California, San Francisco -- Dr Marshall investigates how cilia, the hair-like projections that move substances over a cell, are involved as key factors in debilitating human diseases. By studying blue-green algae, Dr. Marshall's research may lead to new insights into human ciliary disorders, such as polycystic kidney disease and retinal degeneration.
* Amy Wagers, Ph.D., Harvard Stem Cell Institute, Section on Developmental and Stem Cell Biology at Joslin Diabetes Center, Harvard Medical School -- Dr. Wagers investigates the decline with age in the body's ability to maintain homeostatic cell replacement and to regenerate cells after injury. Building on previous research of the relationship between the age of stem cells and their ability to regenerate themselves, Dr. Wagers hopes to discover a method to slow down or reverse the natural process of aging, which may potentially lead to advances in treating age-related illnesses, such as diabetes, immune deficiencies, muscle weakness, and cancer.
* Xander Wehrens, M.D., Ph.D., Department of Molecular Physiology & Biophysics, Baylor College of Medicine -- Dr. Wehrens hopes to define the mechanisms of specialized protein complexes in excitable cells, such as heart muscle. His research has the potential to explain the underlying causes of certain types of heart failure and cardiomyopathy.
* Jennifer Zallen, Ph.D., Developmental Biology Program, Memorial Sloan-Kettering Cancer Center -- Dr. Zallen's work on the nature of three-dimensional Rosetta cell structures combines molecular genetics, live imaging, and quantitative statistical analysis. Her study of a fruit fly's cell structure may be applied to other organisms' cell structures, with the potential to develop approaches to analyze cell behavior and structure in living embryos.
The Foundation's Board of Directors has unanimously approved the recommendations made by the Scientific Advisory Committee.
Based in Los Angeles, the W.M. Keck Foundation was established in 1954 by the late W.M. Keck, founder of the Superior Oil Company. The Foundation's grant making is focused primarily on pioneering efforts in the areas of medical research, science and engineering. The Foundation also maintains a Southern California grant program that provides support in the areas of civic and community services with a special emphasis on children and youth.
For more information about the W.M. Keck Foundation and the Young scholars program, please visit the Foundation's web site at wmkeck/programs/scholars.html.
Source: Louise Weston
W. M. Keck Foundation
вторник, 11 октября 2011 г.
Cancer Biologist Dario Altieri To Lead The Wistar Institute Cancer Center
The Wistar Institute announces that cancer biologist Dario C. Altieri, M.D., has been appointed director of Wistar's Cancer Center, a National Cancer Institute-designated Cancer Center since 1972. Altieri will also take on the role of the Institute's Chief Scientific Officer and professor in the Wistar Molecular and Cellular Oncogenesis Program.
Altieri will join Wistar full-time in September from his previous appointment as professor and chair of the Department of Cancer Biology at the University of Massachusetts Medical School.
The Wistar Institute recruited Altieri after an extensive search for a cancer biologist to lead the scientific faculty of the Wistar Cancer Center. Current Cancer Center Director Russel E. Kaufman, M.D., steps away from his Wistar Cancer Center leadership position to focus on his role as president and CEO of The Wistar Institute.
"The Wistar Institute Cancer Center recently achieved a very successful NCI review and renewal of its Cancer Center Support Grant, and now is the ideal time to pass on the leadership," Kaufman said. "Dario Altieri has the experience and intellect we desired in a candidate to further our progress in both basic cancer science and our ongoing efforts in translating scientific discovery into practical therapies to prevent and cure cancer."
"Throughout his career, he has shown excellent leadership and a remarkable ability to recruit top-notch scientific talent, capabilities that we plan to utilize in earnest as we expand our research faculty," Kaufman added.
At Wistar, Altieri will continue his laboratory's successful research program on the mechanisms that underlie how tumor cells survive and proliferate in cancer. In particular, his laboratory is interested in how tumor cells evade the normal processes that cause cells with genetic faults to self-destruct. Understanding these mechanisms could provide new therapeutic targets and novel approaches for virtually every type of human cancer. To date, his research has resulted in nine patents and over 160 scientific articles.
Born in Milan, Italy, and educated at the University of Milan School of Medicine, Altieri became a practicing clinician at the university, where he would later earn a postgraduate specialty degree in clinical and experimental hematology. In 1987, he joined the Scripps Clinic and Research Foundation in La Jolla, Calif., first as a research fellow and later as a member of the faculty.
In 1994, Altieri became an associate professor at the Yale University School of Medicine, was named professor in 1999, and served in that role for some time before being recruited as the founding chair of the Department of Cancer Biology at the University of Massachusetts.
Altieri is also an accomplished scientific citizen of the international cancer research community. He is currently on the editorial board of seven scientific publications and a reviewer for 16 such journals. As a mentor, he has guided the careers of over 40 men and women, from undergraduates to postdoctoral fellows. In 2005, he co-founded both the National Cancer Biology Training Consortium, an effort to promote scientific excellence in the next generation of cancer researchers, and the Pancreatic Cancer Alliance, an all-volunteer patient advocacy organization devoted to supporting the efforts of pancreatic cancer research.
Source:
Wistar Institute
Altieri will join Wistar full-time in September from his previous appointment as professor and chair of the Department of Cancer Biology at the University of Massachusetts Medical School.
The Wistar Institute recruited Altieri after an extensive search for a cancer biologist to lead the scientific faculty of the Wistar Cancer Center. Current Cancer Center Director Russel E. Kaufman, M.D., steps away from his Wistar Cancer Center leadership position to focus on his role as president and CEO of The Wistar Institute.
"The Wistar Institute Cancer Center recently achieved a very successful NCI review and renewal of its Cancer Center Support Grant, and now is the ideal time to pass on the leadership," Kaufman said. "Dario Altieri has the experience and intellect we desired in a candidate to further our progress in both basic cancer science and our ongoing efforts in translating scientific discovery into practical therapies to prevent and cure cancer."
"Throughout his career, he has shown excellent leadership and a remarkable ability to recruit top-notch scientific talent, capabilities that we plan to utilize in earnest as we expand our research faculty," Kaufman added.
At Wistar, Altieri will continue his laboratory's successful research program on the mechanisms that underlie how tumor cells survive and proliferate in cancer. In particular, his laboratory is interested in how tumor cells evade the normal processes that cause cells with genetic faults to self-destruct. Understanding these mechanisms could provide new therapeutic targets and novel approaches for virtually every type of human cancer. To date, his research has resulted in nine patents and over 160 scientific articles.
Born in Milan, Italy, and educated at the University of Milan School of Medicine, Altieri became a practicing clinician at the university, where he would later earn a postgraduate specialty degree in clinical and experimental hematology. In 1987, he joined the Scripps Clinic and Research Foundation in La Jolla, Calif., first as a research fellow and later as a member of the faculty.
In 1994, Altieri became an associate professor at the Yale University School of Medicine, was named professor in 1999, and served in that role for some time before being recruited as the founding chair of the Department of Cancer Biology at the University of Massachusetts.
Altieri is also an accomplished scientific citizen of the international cancer research community. He is currently on the editorial board of seven scientific publications and a reviewer for 16 such journals. As a mentor, he has guided the careers of over 40 men and women, from undergraduates to postdoctoral fellows. In 2005, he co-founded both the National Cancer Biology Training Consortium, an effort to promote scientific excellence in the next generation of cancer researchers, and the Pancreatic Cancer Alliance, an all-volunteer patient advocacy organization devoted to supporting the efforts of pancreatic cancer research.
Source:
Wistar Institute
суббота, 8 октября 2011 г.
Brain Tumor Growth Linked To Lowered Expression Of Hundreds Of Immune Function Genes
A new study links progression of a lethal type of brain tumor with reduced expression of more than 600 immune system genes, suggesting how complex the immune response is to the cancer and the resulting difficulty in targeting specific immune system proteins for treatment.
Previous research found that people with allergies were less likely to be diagnosed with this type of brain cancer, called glioblastoma multiforme. However, it was not clear whether allergies reduce brain tumor risk or whether the growing tumor "cures" allergies.
To further explore the relationship between these two conditions, scientists examined almost 1,000 genes associated with allergies, immunity and inflammation to learn how they were affected once these tumors were present in the brain.
The researchers expected to see that allergy gene function was low in brain tumor tissue, which would be consistent with the known immune system suppression that is associated with these tumors.
What they found was a surprise: Allergy genes were not the only immune function genes suppressed during tumor growth. Instead, in almost 70 percent of the 919 genes examined, the genes' activity was decreased as the brain tumors progressed.
"This result provides evidence that there is a relationship between glioblastoma and allergies specifically, high tumor aggressiveness is associated with low allergy-related gene function," said Judith Schwartzbaum, lead author of the study and an associate professor of epidemiology at Ohio State University. "But it still does not tell us whether allergies inhibit tumor growth or tumors block allergies."
The findings also show that immune function in the brain continues to change as these tumors grow.
"As the tumor progresses, the majority of the immune-function genes express themselves at lower levels," Schwartzbaum said. "So we know that with progression there is less immune function, but we don't know which came first, the lowered immune function or the cancer."
The cause of this kind of cancer remains unknown, and there is no cure. The complexity of the immune response to this tumor suggests that it will be difficult to identify key immune function proteins that inhibit tumor growth. Schwartzbaum said that in addition to using information about the immune system to treat tumors, researchers must also study the immune system to find ways to prevent these aggressive tumors.
The study is published in a recent issue of the journal Neuro-Oncology.
Glioblastomas constitute up to 60 percent of adult primary brain tumors in the United States, affecting an estimated 3 in 100,000 people. Patients who undergo surgery, radiation and chemotherapy survive on average for about one year, with fewer than a quarter of patients surviving up to two years and fewer than 10 percent surviving up to five years.
The researchers used publicly available data from genetic analysis of 142 brain tumor tissue samples collected from patients with glioblastoma multiforme tumors as part of the National Cancer Institute's The Cancer Genome Atlas project.
The scientists used levels of expression of the CD133 gene as an indicator of tumor progression. Previous studies had suggested that activation of this gene is related to tumor aggression and a poor clinical outcome.
With these data, Schwartzbaum and colleagues then plotted expression of immune function genes against levels of CD133 expression in these tumors.
Gene expression refers to the switching on or activation of genes. Schwartzbaum and her colleagues analyzed mRNA expression data in their study; mRNA synthesis is the first step in gene expression and may lead to creation of functional proteins.
The analysis showed that higher levels of CD133 expression were associated with lower levels of immune function gene expression in 69 percent of the genes examined.
There were, however, immune function genes whose expression increased with CD133 expression, including a cytokine gene called interleukin-17 that is linked to inflammation, and a gene related to suppression of immune function called NCAM-1.
The genes whose function was lowered with tumor progression included most of those associated with allergies, as well as, paradoxically, many of those that counteract allergy genes. In another surprising finding, many genes known to suppress immune function were also expressed at lower levels as the tumor progressed.
"That was a surprise because you'd think that genes that suppress the immune system would be more active in these tumors, which may be lethal, in part, because they are immunosuppressive. But we didn't see that," Schwartzbaum said.
Schwartzbaum is planning to focus her subsequent research on the end products of genetic activation, immune function proteins or cytokines.
She plans to analyze 1,200 samples from the Janus Serum Bank in Norway, which were collected on average 10 years before brain tumor diagnosis, to find out whether the presence of certain cytokines in those samples might offer clues that will help identify people at high risk for brain tumor development.
This work was supported by the National Cancer Institute and the Neurosciences Signature Program in the Ohio State College of Medicine.
Schwartzbaum conducted the research with Kun Huang and Jianhua Yu of Ohio State's Comprehensive Cancer Center; Sean Lawler and E. Antonio Chiocca of Ohio State's Department of Neurological Surgery; and Bo Ding of the Institute of Environmental Medicine at the Karolinska Institutet in Stockholm, where Schwartzbaum is a visiting researcher.
Source: Ohio State University
Previous research found that people with allergies were less likely to be diagnosed with this type of brain cancer, called glioblastoma multiforme. However, it was not clear whether allergies reduce brain tumor risk or whether the growing tumor "cures" allergies.
To further explore the relationship between these two conditions, scientists examined almost 1,000 genes associated with allergies, immunity and inflammation to learn how they were affected once these tumors were present in the brain.
The researchers expected to see that allergy gene function was low in brain tumor tissue, which would be consistent with the known immune system suppression that is associated with these tumors.
What they found was a surprise: Allergy genes were not the only immune function genes suppressed during tumor growth. Instead, in almost 70 percent of the 919 genes examined, the genes' activity was decreased as the brain tumors progressed.
"This result provides evidence that there is a relationship between glioblastoma and allergies specifically, high tumor aggressiveness is associated with low allergy-related gene function," said Judith Schwartzbaum, lead author of the study and an associate professor of epidemiology at Ohio State University. "But it still does not tell us whether allergies inhibit tumor growth or tumors block allergies."
The findings also show that immune function in the brain continues to change as these tumors grow.
"As the tumor progresses, the majority of the immune-function genes express themselves at lower levels," Schwartzbaum said. "So we know that with progression there is less immune function, but we don't know which came first, the lowered immune function or the cancer."
The cause of this kind of cancer remains unknown, and there is no cure. The complexity of the immune response to this tumor suggests that it will be difficult to identify key immune function proteins that inhibit tumor growth. Schwartzbaum said that in addition to using information about the immune system to treat tumors, researchers must also study the immune system to find ways to prevent these aggressive tumors.
The study is published in a recent issue of the journal Neuro-Oncology.
Glioblastomas constitute up to 60 percent of adult primary brain tumors in the United States, affecting an estimated 3 in 100,000 people. Patients who undergo surgery, radiation and chemotherapy survive on average for about one year, with fewer than a quarter of patients surviving up to two years and fewer than 10 percent surviving up to five years.
The researchers used publicly available data from genetic analysis of 142 brain tumor tissue samples collected from patients with glioblastoma multiforme tumors as part of the National Cancer Institute's The Cancer Genome Atlas project.
The scientists used levels of expression of the CD133 gene as an indicator of tumor progression. Previous studies had suggested that activation of this gene is related to tumor aggression and a poor clinical outcome.
With these data, Schwartzbaum and colleagues then plotted expression of immune function genes against levels of CD133 expression in these tumors.
Gene expression refers to the switching on or activation of genes. Schwartzbaum and her colleagues analyzed mRNA expression data in their study; mRNA synthesis is the first step in gene expression and may lead to creation of functional proteins.
The analysis showed that higher levels of CD133 expression were associated with lower levels of immune function gene expression in 69 percent of the genes examined.
There were, however, immune function genes whose expression increased with CD133 expression, including a cytokine gene called interleukin-17 that is linked to inflammation, and a gene related to suppression of immune function called NCAM-1.
The genes whose function was lowered with tumor progression included most of those associated with allergies, as well as, paradoxically, many of those that counteract allergy genes. In another surprising finding, many genes known to suppress immune function were also expressed at lower levels as the tumor progressed.
"That was a surprise because you'd think that genes that suppress the immune system would be more active in these tumors, which may be lethal, in part, because they are immunosuppressive. But we didn't see that," Schwartzbaum said.
Schwartzbaum is planning to focus her subsequent research on the end products of genetic activation, immune function proteins or cytokines.
She plans to analyze 1,200 samples from the Janus Serum Bank in Norway, which were collected on average 10 years before brain tumor diagnosis, to find out whether the presence of certain cytokines in those samples might offer clues that will help identify people at high risk for brain tumor development.
This work was supported by the National Cancer Institute and the Neurosciences Signature Program in the Ohio State College of Medicine.
Schwartzbaum conducted the research with Kun Huang and Jianhua Yu of Ohio State's Comprehensive Cancer Center; Sean Lawler and E. Antonio Chiocca of Ohio State's Department of Neurological Surgery; and Bo Ding of the Institute of Environmental Medicine at the Karolinska Institutet in Stockholm, where Schwartzbaum is a visiting researcher.
Source: Ohio State University
среда, 5 октября 2011 г.
New Test For Safer Biomedical Research Results
In cancer research, as in most other biomedical sciences, they are playing a key role: living cells, kept in sterile plastic containers with red culture media populating incubators in laboratories around the world. But do researchers always know what is really living in their culture dishes? Under the microscope, different cell lines are almost impossible to distinguish from each other. When these important research objects stop growing without apparent reason - is it because of the manipulations by the scientists or because of an invisible viral or bacterial infection?
Contaminations with other cell lines or pathogenic agents are a common and well-known problem. Often they are the reason why cell experiments fail to produce useable or reproducible results. Even worse, laboratory staff can get infected with dangerous pathogens from a cell culture.
To make those important cell culture experiments safer, DKFZ researchers Dr. Markus Schmitt and Dr. Michael Pawlita have developed a test which is able to identify 37 different cell contaminations in a single run. The researchers have tested the system in over 700 samples from different research labs and have now published their results.
The method called "Multiplex cell Contamination Test" (McCT) detects not only wide-spread viruses but also a number of mycoplasmas, which are considered the major contaminators of cell cultures. In addition, the test checks the cells for their origin. Thus, if dog genetic material is found in what are supposed to be monkey cells, then a contamination of the cell culture is obvious. The test also includes detection of commonly used standard cell lines. Contamination with the fast-growing cancer cell line HeLa, for example, is a dreaded source of false results.
Pawlita and Schmitt found contaminations in a high percentage of cell samples. Twenty-two percent of tested cultures were contaminated with one of the various types of the parasitic bacterium called mycoplasma. "What we noticed about the results," says Markus Schmitt, "was that contaminations were frequent in some laboratories, while others sent in cultures that were constantly clean. Thus, care in laboratory work seems to play an important role."
The test is highly specific and needs no more than ten copies of foreign DNA in the cell sample to be positive. This is a sensitivity which is comparable to or even higher than those of previously available commercial mycoplasma tests. McCT results are reproducible to 99.6 percent. The method is based on multiplication of specific DNA sequences by polymerase chain reaction and subsequent detection of the multiplied DNA regions. A special advantage of the new test is that it can be carried out on a high-throughput basis. The DKFZ researchers can manage up to 1,000 tests per week.
Markus Schmitt und Michael Pawlita: High-throughput detection and multiplex identification of cell contaminations. Nucleic Acids Research 2009, DOI: 10.1093/nar/gkp581
Source:
Dr. Sibylle Kohlstädt
Helmholtz Association of German Research Centres
Contaminations with other cell lines or pathogenic agents are a common and well-known problem. Often they are the reason why cell experiments fail to produce useable or reproducible results. Even worse, laboratory staff can get infected with dangerous pathogens from a cell culture.
To make those important cell culture experiments safer, DKFZ researchers Dr. Markus Schmitt and Dr. Michael Pawlita have developed a test which is able to identify 37 different cell contaminations in a single run. The researchers have tested the system in over 700 samples from different research labs and have now published their results.
The method called "Multiplex cell Contamination Test" (McCT) detects not only wide-spread viruses but also a number of mycoplasmas, which are considered the major contaminators of cell cultures. In addition, the test checks the cells for their origin. Thus, if dog genetic material is found in what are supposed to be monkey cells, then a contamination of the cell culture is obvious. The test also includes detection of commonly used standard cell lines. Contamination with the fast-growing cancer cell line HeLa, for example, is a dreaded source of false results.
Pawlita and Schmitt found contaminations in a high percentage of cell samples. Twenty-two percent of tested cultures were contaminated with one of the various types of the parasitic bacterium called mycoplasma. "What we noticed about the results," says Markus Schmitt, "was that contaminations were frequent in some laboratories, while others sent in cultures that were constantly clean. Thus, care in laboratory work seems to play an important role."
The test is highly specific and needs no more than ten copies of foreign DNA in the cell sample to be positive. This is a sensitivity which is comparable to or even higher than those of previously available commercial mycoplasma tests. McCT results are reproducible to 99.6 percent. The method is based on multiplication of specific DNA sequences by polymerase chain reaction and subsequent detection of the multiplied DNA regions. A special advantage of the new test is that it can be carried out on a high-throughput basis. The DKFZ researchers can manage up to 1,000 tests per week.
Markus Schmitt und Michael Pawlita: High-throughput detection and multiplex identification of cell contaminations. Nucleic Acids Research 2009, DOI: 10.1093/nar/gkp581
Source:
Dr. Sibylle Kohlstädt
Helmholtz Association of German Research Centres
воскресенье, 2 октября 2011 г.
Scientists Use RNA To Reprogram One Cell Type Into Another
For the past decade, researchers have tried to tweak cells at the gene and nucleus level to reprogram their identity. Now, working on the idea that the signature of a cell is defined by molecules called messenger RNAs, which contain the chemical blueprint for how to make a protein, researchers at the University of Pennsylvania School of Medicine, School of Arts and Sciences and School of Engineering have found another way to change one cell type into another.
By simply flooding one cell type, a nerve cell, with the an abundance of a specific type of messenger RNA (mRNA) from another cell type, the investigators changed a neuron into an astrocyte-like cell, a star-shaped brain cell that helps to maintain the blood-brain barrier, regulates the chemical environment around cells, responds to injury, and releases regulatory substances.
James Eberwine, PhD, Elmer Holmes Bobst Professor of Pharmacology, Junhyong Kim, PhD, Edmund J. and Louise W. Kahn Term Endowed Professor of Biology and first author Jai-Yoon Sul, PhD, Assistant Professor of Pharmacology, and colleagues report their findings online this week in the Proceedings of the National Academy of Sciences. This approach offers the possibility for a new type of cell-based therapy for neurodegenerative and other diseases.
"In some ways, this is akin to what a virus does," explains Eberwine, "When a virus infects a cell it affects the host cell genome and the RNAs that it can make." By putting the RNA of one cell type, in the correct amounts, into another cell type, we were able to change its function."
"This research overturns the notion that all cells are permanently hardwired with little ability to change their physiology," notes Sul.
"What's new about this approach is that we didn't have to make the host cell pluripotent, that is the ability to develop into any of three major tissue types, we can directly convert from one cell type to another, without the intermediate step," explains Eberwine. The scientists put in an excess of astrocyte messenger RNAs into the neuron cell body using phototransfection, a method they created a few years ago that creates temporary pores in the cell membrane. "The RNA population was then diffused into the cell and the host cell did the rest," adds Eberwine.
"We liken the differentiated cells to ecological communities, forests and meadows," notes Kim. "Each have similar organisms but have settled on particular characteristics that we recognize as distinct. And, just as ecological communities can be nudged from one type to another, we thought we could nudge differentiated cells from one type to another through the use of the RNA population. So, we like to think of cells as an ecological community of molecules, with dynamic molecular interactions producing a larger system-level cell function similar to how organism interactions generate forests and meadows.
The approach they used, called Transcriptome induced phenotype remodeling, or TIPeR, is distinct from the induced pluripotent stem cell (iPS) approach in that host cells do not have to be dedifferentiated to a pluripotent state and then redifferentiated with growth factors to the destination cell type. This work is more similar to the prior nuclear transfer work in which the nucleus of one cell is transferred into another cell where upon the transferred nucleus then directs the cell to change phenotype based upon the RNAs that are made.
TIPeR uses RNA populations to direct the DNA in the host nucleus to change the cell's RNA populations to that of the destination cell type, which in turn changes the phenotype of the cell.
There are about 100,000 mRNA molecules in a neuron at any one time. The researchers transferred nearly double that: About 200,000 astrocyte mRNAs were transferred into the neuron, effectively dampening the neuron mRNA's ability to be translated and made into protein.
Essentially the team extracted and produced mRNA from an astrocyte, then used phototransfection to create pores in the neuron cell membrane to flood it with an excess of astrocyte mRNAs, which reside in the neuron host cell cytoplasm. Because there are now so many astrocyte mRNAs versus neuron mRNAs, they take over like a virus and the astrocyte mRNAs are translated into astrocyte proteins in the cytoplasm. These astrocyte proteins then influence gene expression in the host nucleus so that astrocyte genes are turned on and astrocyte cell-enriched proteins are made.
To track the change from a neuron to an astrocyte, the team looked at the RNA profile, shape, and physiology of the new cell. "For now, these are astrocyte-like cells," says Eberwine. "While the cells don't look like neurons any longer, they don't have the mature star-like astrocyte shape, but rather look like immature astrocytes. The new cell expresses astrocyte proteins and has an astrocyte-like physiology. We start to see changes within a week and they are stable over the life of the primary cell culture."
These studies were enabled through the collaboration of a number of investigators spanning multiple disciplines including David Meaney from Bioengineering, Vijay Kumar and David Cappelleri from Mechanical Engineering and Junhyong Kim and Miler Lee from Biology. The additional Pharmacology Department contributors include Chia-wen Wu, Fanyi Zeng, Jeanine Jochems, Tae Kyung Kim, Tiina Peritz, Peter Buckley and Minsun Kim.
Future studies are envisioned towards the generation of distinct cell types and dissection of the core set of RNAs responsible for the generation of particular cellular phenotypes.
This work was funded by grants from the W. M. Keck Foundation, the National Institutes of Health, and the State of Pennsylvania.
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: University of Pennsylvania School of Medicine
By simply flooding one cell type, a nerve cell, with the an abundance of a specific type of messenger RNA (mRNA) from another cell type, the investigators changed a neuron into an astrocyte-like cell, a star-shaped brain cell that helps to maintain the blood-brain barrier, regulates the chemical environment around cells, responds to injury, and releases regulatory substances.
James Eberwine, PhD, Elmer Holmes Bobst Professor of Pharmacology, Junhyong Kim, PhD, Edmund J. and Louise W. Kahn Term Endowed Professor of Biology and first author Jai-Yoon Sul, PhD, Assistant Professor of Pharmacology, and colleagues report their findings online this week in the Proceedings of the National Academy of Sciences. This approach offers the possibility for a new type of cell-based therapy for neurodegenerative and other diseases.
"In some ways, this is akin to what a virus does," explains Eberwine, "When a virus infects a cell it affects the host cell genome and the RNAs that it can make." By putting the RNA of one cell type, in the correct amounts, into another cell type, we were able to change its function."
"This research overturns the notion that all cells are permanently hardwired with little ability to change their physiology," notes Sul.
"What's new about this approach is that we didn't have to make the host cell pluripotent, that is the ability to develop into any of three major tissue types, we can directly convert from one cell type to another, without the intermediate step," explains Eberwine. The scientists put in an excess of astrocyte messenger RNAs into the neuron cell body using phototransfection, a method they created a few years ago that creates temporary pores in the cell membrane. "The RNA population was then diffused into the cell and the host cell did the rest," adds Eberwine.
"We liken the differentiated cells to ecological communities, forests and meadows," notes Kim. "Each have similar organisms but have settled on particular characteristics that we recognize as distinct. And, just as ecological communities can be nudged from one type to another, we thought we could nudge differentiated cells from one type to another through the use of the RNA population. So, we like to think of cells as an ecological community of molecules, with dynamic molecular interactions producing a larger system-level cell function similar to how organism interactions generate forests and meadows.
The approach they used, called Transcriptome induced phenotype remodeling, or TIPeR, is distinct from the induced pluripotent stem cell (iPS) approach in that host cells do not have to be dedifferentiated to a pluripotent state and then redifferentiated with growth factors to the destination cell type. This work is more similar to the prior nuclear transfer work in which the nucleus of one cell is transferred into another cell where upon the transferred nucleus then directs the cell to change phenotype based upon the RNAs that are made.
TIPeR uses RNA populations to direct the DNA in the host nucleus to change the cell's RNA populations to that of the destination cell type, which in turn changes the phenotype of the cell.
There are about 100,000 mRNA molecules in a neuron at any one time. The researchers transferred nearly double that: About 200,000 astrocyte mRNAs were transferred into the neuron, effectively dampening the neuron mRNA's ability to be translated and made into protein.
Essentially the team extracted and produced mRNA from an astrocyte, then used phototransfection to create pores in the neuron cell membrane to flood it with an excess of astrocyte mRNAs, which reside in the neuron host cell cytoplasm. Because there are now so many astrocyte mRNAs versus neuron mRNAs, they take over like a virus and the astrocyte mRNAs are translated into astrocyte proteins in the cytoplasm. These astrocyte proteins then influence gene expression in the host nucleus so that astrocyte genes are turned on and astrocyte cell-enriched proteins are made.
To track the change from a neuron to an astrocyte, the team looked at the RNA profile, shape, and physiology of the new cell. "For now, these are astrocyte-like cells," says Eberwine. "While the cells don't look like neurons any longer, they don't have the mature star-like astrocyte shape, but rather look like immature astrocytes. The new cell expresses astrocyte proteins and has an astrocyte-like physiology. We start to see changes within a week and they are stable over the life of the primary cell culture."
These studies were enabled through the collaboration of a number of investigators spanning multiple disciplines including David Meaney from Bioengineering, Vijay Kumar and David Cappelleri from Mechanical Engineering and Junhyong Kim and Miler Lee from Biology. The additional Pharmacology Department contributors include Chia-wen Wu, Fanyi Zeng, Jeanine Jochems, Tae Kyung Kim, Tiina Peritz, Peter Buckley and Minsun Kim.
Future studies are envisioned towards the generation of distinct cell types and dissection of the core set of RNAs responsible for the generation of particular cellular phenotypes.
This work was funded by grants from the W. M. Keck Foundation, the National Institutes of Health, and the State of Pennsylvania.
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: University of Pennsylvania School of Medicine
четверг, 29 сентября 2011 г.
New Radon Data For England And Wales
The Health Protection Agency and the British Geological Survey have jointly produced new information on radon Affected Areas in England and Wales. There is detailed information for individual properties available from a new website and a new atlas* published today giving an overview of radon Affected Areas by 1-km squares of the national grid. This material replaces the existing Radon Atlas of England and Wales (NRPB-W26) and copies of the new atlas have been sent to every local authority in England and Wales .
Professor Pat Troop, Chief Executive of the Health Protection Agency said, "We are very pleased to be able to make this new information available to the public. Radon gas levels in some properties need to be reduced, and this can be achieved by relatively simple means. High quality information on radon Affected Areas is the best starting point for achieving a reduction in levels."
Professor John Ludden, Executive Director of the British Geological Survey said, "Collaboration between scientists in the two organisations over several years has succeeded in combining the latest geological knowledge with the many existing radon measurements to make the best available assessment of radon Affected Areas."
Radon is a naturally occurring radioactive gas that is present in all rocks and soils. Radon decay produces alpha radiation and high exposures to such radiation are known to increase the risk of lung cancer. Recent studies show that the risk from radon to smokers is particular high and it is estimated that 1,000 to 2,000 cases of lung cancer are caused by indoor radon in the UK each year.
Radon enters buildings from the ground beneath and indoor levels vary depending on several factors including the underlying geology, the method of building construction and the way a building is heated and ventilated. The new dataset combines the latest results of measurements in over 450,000 homes and takes account of the local geology. This provides a more informed estimate of the probability of a high radon level in a home than was previously available.
The radon Affected Area status of a property is an important tool in programmes to control and reduce the exposure of the population to this known cause of cancer. In addition, the information is required during the property transaction process. The new dataset is too large to publish in full detail as a printed map but it is important that the detailed information is readily available in digital and other formats. The estimated radon potential for any individual home in England and Wales can be obtained by members of the public for a small fee (ВЈ3 plus VAT) from a dedicated web site (UKradon). Licensing arrangements for multiple users are also available from the British Geological Survey (enquiriesbgs.ac.uk )
* J C H Miles, J D Appleton et al. Indicative Atlas of Radon in England and Wales. HPA-RPD-033. November 2007. ISBN 978-0-85951-608-2. Available to download free from the Health Protection Agency website here.
Notes:
1. The Health Protection Agency is an independent organisation dedicated to protecting people's health in the United Kingdom. The Agency does this by providing impartial advice and authoritative information on health protection issues to the public, to professionals and to government. It combines public health and scientific expertise, research, and emergency planning within one organisation. It works at international, national, regional and local levels and has links with many other organisations around the world. This means it can respond quickly and effectively to new and existing national and global threats to health, including environmental hazards such as radon. The Agency defines radon Affected Areas as parts of the country where the probability of present or future homes exceeding the Action Level is estimated to be 1% or more. It recommends that existing homes within Affected Areas should have radon measurements.
2. The British Geological Survey (BGS), a component body of the Natural Environment Research Council (NERC), is the nation's principal supplier of objective, impartial and up-to-date geological expertise and information for decision making for governmental, commercial and individual users. The BGS maintains and develops the nation's understanding of its geology to improve policy making, enhance national wealth and reduce risk. It also collaborates with the national and international scientific community in carrying out research in strategic areas, including energy and natural resources, our vulnerability to environmental change and hazards, and our general knowledge of the Earth system. More about the BGS can be found at bgs.ac.uk/
3. The Agency and BGS have developed a new analytical method to take advantage of the large number of radon results and of the BGS's digital geological data. In order to define radon Affected Areas, the results of radon measurements are grouped first by geological boundaries and then by 1-km grid squares. The new method allows variations in radon potential (the estimated percentage of homes in an area above the Action Level) both between and within geological units to be analysed. The resulting dataset, which defines radon Affected Areas in England and Wales, includes much more detail than could be shown in an atlas.
4. The new radon data are presented in two ways: as a simplified Indicative Atlas of Radon, and as a full electronic dataset. This provides the information required during the property transaction process (question 3.13 on the CON 29 form; local authority search form). The Indicative Atlas is divided into 1-km grid squares, and each square is coloured according to the highest radon potential found within the square in the full dataset.
5. The full detail is available as a dataset for Geographical Information Systems, which can be licensed by users such as local authorities.
6. The average radon level for all UK dwellings is 20 Bq m-3 and the Action Level is 200 Bq m-3. At or above the Action Level, remedial action to reduce radon is recommended.
7. Radon has been recognised as a cause of lung cancer in humans for many years. Because of the risk from radon, the Agency (and previously the National Radiological Protection Board, NRPB, now incorporated into the Agency) advised that excessive exposures to radon should be reduced. NRPB proposed a comprehensive control strategy based on the concept of a radon Action Level and the identification of radon Affected Areas. The Government accepted this advice.
8. The new radon map will assist in implementing the Agency's radon policies that:
- existing homes in Affected Areas should have radon measurements
- radon concentrations at or above the Action Level of 200 Bq m-3 should be reduced to as low as reasonably practicable
- new homes built within localities delimited by the appropriate Government authorities should be constructed with precautions against radon.
Health Protection Agency
Professor Pat Troop, Chief Executive of the Health Protection Agency said, "We are very pleased to be able to make this new information available to the public. Radon gas levels in some properties need to be reduced, and this can be achieved by relatively simple means. High quality information on radon Affected Areas is the best starting point for achieving a reduction in levels."
Professor John Ludden, Executive Director of the British Geological Survey said, "Collaboration between scientists in the two organisations over several years has succeeded in combining the latest geological knowledge with the many existing radon measurements to make the best available assessment of radon Affected Areas."
Radon is a naturally occurring radioactive gas that is present in all rocks and soils. Radon decay produces alpha radiation and high exposures to such radiation are known to increase the risk of lung cancer. Recent studies show that the risk from radon to smokers is particular high and it is estimated that 1,000 to 2,000 cases of lung cancer are caused by indoor radon in the UK each year.
Radon enters buildings from the ground beneath and indoor levels vary depending on several factors including the underlying geology, the method of building construction and the way a building is heated and ventilated. The new dataset combines the latest results of measurements in over 450,000 homes and takes account of the local geology. This provides a more informed estimate of the probability of a high radon level in a home than was previously available.
The radon Affected Area status of a property is an important tool in programmes to control and reduce the exposure of the population to this known cause of cancer. In addition, the information is required during the property transaction process. The new dataset is too large to publish in full detail as a printed map but it is important that the detailed information is readily available in digital and other formats. The estimated radon potential for any individual home in England and Wales can be obtained by members of the public for a small fee (ВЈ3 plus VAT) from a dedicated web site (UKradon). Licensing arrangements for multiple users are also available from the British Geological Survey (enquiriesbgs.ac.uk )
* J C H Miles, J D Appleton et al. Indicative Atlas of Radon in England and Wales. HPA-RPD-033. November 2007. ISBN 978-0-85951-608-2. Available to download free from the Health Protection Agency website here.
Notes:
1. The Health Protection Agency is an independent organisation dedicated to protecting people's health in the United Kingdom. The Agency does this by providing impartial advice and authoritative information on health protection issues to the public, to professionals and to government. It combines public health and scientific expertise, research, and emergency planning within one organisation. It works at international, national, regional and local levels and has links with many other organisations around the world. This means it can respond quickly and effectively to new and existing national and global threats to health, including environmental hazards such as radon. The Agency defines radon Affected Areas as parts of the country where the probability of present or future homes exceeding the Action Level is estimated to be 1% or more. It recommends that existing homes within Affected Areas should have radon measurements.
2. The British Geological Survey (BGS), a component body of the Natural Environment Research Council (NERC), is the nation's principal supplier of objective, impartial and up-to-date geological expertise and information for decision making for governmental, commercial and individual users. The BGS maintains and develops the nation's understanding of its geology to improve policy making, enhance national wealth and reduce risk. It also collaborates with the national and international scientific community in carrying out research in strategic areas, including energy and natural resources, our vulnerability to environmental change and hazards, and our general knowledge of the Earth system. More about the BGS can be found at bgs.ac.uk/
3. The Agency and BGS have developed a new analytical method to take advantage of the large number of radon results and of the BGS's digital geological data. In order to define radon Affected Areas, the results of radon measurements are grouped first by geological boundaries and then by 1-km grid squares. The new method allows variations in radon potential (the estimated percentage of homes in an area above the Action Level) both between and within geological units to be analysed. The resulting dataset, which defines radon Affected Areas in England and Wales, includes much more detail than could be shown in an atlas.
4. The new radon data are presented in two ways: as a simplified Indicative Atlas of Radon, and as a full electronic dataset. This provides the information required during the property transaction process (question 3.13 on the CON 29 form; local authority search form). The Indicative Atlas is divided into 1-km grid squares, and each square is coloured according to the highest radon potential found within the square in the full dataset.
5. The full detail is available as a dataset for Geographical Information Systems, which can be licensed by users such as local authorities.
6. The average radon level for all UK dwellings is 20 Bq m-3 and the Action Level is 200 Bq m-3. At or above the Action Level, remedial action to reduce radon is recommended.
7. Radon has been recognised as a cause of lung cancer in humans for many years. Because of the risk from radon, the Agency (and previously the National Radiological Protection Board, NRPB, now incorporated into the Agency) advised that excessive exposures to radon should be reduced. NRPB proposed a comprehensive control strategy based on the concept of a radon Action Level and the identification of radon Affected Areas. The Government accepted this advice.
8. The new radon map will assist in implementing the Agency's radon policies that:
- existing homes in Affected Areas should have radon measurements
- radon concentrations at or above the Action Level of 200 Bq m-3 should be reduced to as low as reasonably practicable
- new homes built within localities delimited by the appropriate Government authorities should be constructed with precautions against radon.
Health Protection Agency
понедельник, 26 сентября 2011 г.
Genetic Architecture And The Evolution Of RNA Viruses
In biology and genetics, the concept of epistasis is what gives rise to the whole being more (or less) than the sum of its parts. The quantitative effect of a given mutation upon the traits of an organism has the potential to depend strongly upon the gene versions present in other parts of the genome, or even other mutations co-occurring in that gene. These genetic interactions, termed epistasis, can impact all aspects of organisms and play a pivotal role in the manifestation of sex, ploidy, modularity, robustness, reproductive isolation and the origin of species, the rate of adaptation, and the emergence of genetic mutations within individuals and populations. A recent article in the journal Chaos, published by the American Institute of Physics, examines the possibility of using epistasis to predict the outcome of the evolutionary processes, especially when the evolving units are pathogens such as viruses.
The article looks at three topics: empirical evidence from the RNA virus world, mathematical tools, and the application of these tools to particular problems. Santiago Elena and colleagues at Instituto de BiologГa Molecular y Celular de Plantas have surveyed past work in this field and concluded that even though RNA viruses have small genomes composed of few genes that encode a limited number of proteins, epistasis is abundant and conditions their evolution. The next steps may range from characterizing the statistical distributions of epistasis across hosts, which has tremendous relevance for the emergence of new viruses, to drawing the most likely evolutionary paths a virus may follow in response to treatments with antiviral drugs.
While this research is still in the early stages, Elena sees great potential.
"By increasing our ability to predict the most likely evolutionary paths a virus may follow in response to clinical treatments, we could get a step ahead of them and, perhaps, create new and more durable antiviral therapies," he says.
The article
"Simple genomes, complex interactions: Epistasis in RNA virus" by Santiago F. Elena,2, Ricard V. SolГ©, and Josep SardanyГ©s was published online in the journal Chaos on June 30, 2010.
Source:
Jason Socrates Bardi
American Institute of Physics
The article looks at three topics: empirical evidence from the RNA virus world, mathematical tools, and the application of these tools to particular problems. Santiago Elena and colleagues at Instituto de BiologГa Molecular y Celular de Plantas have surveyed past work in this field and concluded that even though RNA viruses have small genomes composed of few genes that encode a limited number of proteins, epistasis is abundant and conditions their evolution. The next steps may range from characterizing the statistical distributions of epistasis across hosts, which has tremendous relevance for the emergence of new viruses, to drawing the most likely evolutionary paths a virus may follow in response to treatments with antiviral drugs.
While this research is still in the early stages, Elena sees great potential.
"By increasing our ability to predict the most likely evolutionary paths a virus may follow in response to clinical treatments, we could get a step ahead of them and, perhaps, create new and more durable antiviral therapies," he says.
The article
"Simple genomes, complex interactions: Epistasis in RNA virus" by Santiago F. Elena,2, Ricard V. SolГ©, and Josep SardanyГ©s was published online in the journal Chaos on June 30, 2010.
Source:
Jason Socrates Bardi
American Institute of Physics
пятница, 23 сентября 2011 г.
New Hope In Fight Against Huntington's Disease
Hope for new ways of treating devastating neurodegenerative disorders such as Huntington's disease has been raised by a trans-Atlantic team of researchers thanks to the use of cutting-edge genetic techniques.
Led by the University of Leicester, scientists from the University of Lisbon (led by Dr Tiago Outeiro) and University of California at San Francisco (led by Dr Paul Muchowski) collaborated to generate novel approaches for tackling the diseases. Their work, funded by the Medical Research Council, is published in The Journal of Biological Chemistry.
At Leicester, working simply with baker's yeast, a team of biological scientists examined aspects of Huntington's disease. These yeast are extremely well-characterised and have powerful and facile genetics which allow researchers to rapidly interrogate this system at a genome-wide level. Research in recent years has found that baker's yeast can be used to study mechanisms underlying disease pathology, and this simple organism has been used to identify several promising candidate drug targets for neurodegenerative disorders, including Huntington's disease.
Flaviano Giorgini, lead author of the research paper at the University of Leicester, said: "My research group is interested in using genetics and genomics approaches to better understand the fatal neurodegenerative disorders of Huntington's disease and Parkinson's disease.
"By clarifying the genes and cellular pathways involved in these diseases we hope to identify novel strategies for treatment and therapy of these disorders. In our work we use simple, yet powerful genetic organisms such as baker's yeast and fruit flies to model aspects of these devastating diseases.
"In the current study we have used a novel functional genomics profiling approach to identify genes which can protect these simple organisms from disease symptoms. We then used computational approaches to uncover a network of interactions amongst these genes, which has shed light on the mechanisms underlying this disorder."
Using the approach above, the scientists found that many of the protective genes are involved in translation - a cellular process in which messenger RNA (mRNA) is decoded by the ribosome to produce specific proteins. This is particularly intriguing as this process has not been implicated in Huntington's disease in the past.
This is important because recent work indicates that pharmacological modulation of translation may represent a promising avenue for treatment of Parkinson's disease. Therefore, this new research strongly dovetails with these observations and suggests that similar drug treatment may be beneficial in Huntington's disease.
Dr Giorgini, of the Department of Genetics, said: "Our research has taken advantage of cutting edge genomics approaches using a simple model organism to identify a novel area for potential therapeutic intervention for Huntington's disease.
"If our findings are validated by further studies, it might suggest a novel therapeutic approach for this devastating disorder - which is critical as currently there are no treatments for onset or progression of symptoms."
Citation:
Functional Gene Expression Profiling in Yeast Implicates Translational Dysfunction in Mutant Huntington Toxicity
The Journal of Biological Chemistry, Vol. 286, Issue 1, 410-419, January 7, 2011
Eran Tauber; Leonor Miller-Fleming; Robert P. Mason; Jannine Clapp; Nicola J. Butler; Flaviano Giorgini University of Leicester
Leonor Miller-Fleming; Tiago F. Outeiro
Universidade de Lisboa
Wanda Kwan; Paul J. Muchowski
University of California at San Francisco
Article #10.1074/jbc.M110.101527
About Huntington's Disease
- Huntington's disease is an inherited disease of the brain
- The disease damages the nerve cells in the brain, causing deterioration and gradual loss of function of areas of the brain. This affects movement, cognition (perception, awareness, thinking, judgement) and behaviour.
- Early symptoms such as personality changes, mood swings and bizarre behaviour are often overlooked at first and attributed to something else.
- Huntington's disease was originally called Huntington's chorea, after the Greek word for dancing, as the associated involuntary movements can look like jerky dancing.
- Both men and women with a family history of Huntington's can inherit the disease and symptoms usually start to show in adulthood.
- Juvenile (children's) Huntington's disease develops before the age of 20 years. Only 5-10% of people with Huntington's develop the condition at a very young age, and the pattern of features may be different.
- UK studies have found that approximately 6-7 people per 100,000 of the population are affected by Huntington's disease. However, it is likely that the true figure is much higher.
- There is no cure for Huntington's disease and its progress cannot be reversed or slowed down.
- Medication can be used to manage some of the symptoms, and therapies (such as speech and language therapy and occupational therapy) can help with communication and day-to-day living
Source:
University Of Leicester
Medical Research Council
Led by the University of Leicester, scientists from the University of Lisbon (led by Dr Tiago Outeiro) and University of California at San Francisco (led by Dr Paul Muchowski) collaborated to generate novel approaches for tackling the diseases. Their work, funded by the Medical Research Council, is published in The Journal of Biological Chemistry.
At Leicester, working simply with baker's yeast, a team of biological scientists examined aspects of Huntington's disease. These yeast are extremely well-characterised and have powerful and facile genetics which allow researchers to rapidly interrogate this system at a genome-wide level. Research in recent years has found that baker's yeast can be used to study mechanisms underlying disease pathology, and this simple organism has been used to identify several promising candidate drug targets for neurodegenerative disorders, including Huntington's disease.
Flaviano Giorgini, lead author of the research paper at the University of Leicester, said: "My research group is interested in using genetics and genomics approaches to better understand the fatal neurodegenerative disorders of Huntington's disease and Parkinson's disease.
"By clarifying the genes and cellular pathways involved in these diseases we hope to identify novel strategies for treatment and therapy of these disorders. In our work we use simple, yet powerful genetic organisms such as baker's yeast and fruit flies to model aspects of these devastating diseases.
"In the current study we have used a novel functional genomics profiling approach to identify genes which can protect these simple organisms from disease symptoms. We then used computational approaches to uncover a network of interactions amongst these genes, which has shed light on the mechanisms underlying this disorder."
Using the approach above, the scientists found that many of the protective genes are involved in translation - a cellular process in which messenger RNA (mRNA) is decoded by the ribosome to produce specific proteins. This is particularly intriguing as this process has not been implicated in Huntington's disease in the past.
This is important because recent work indicates that pharmacological modulation of translation may represent a promising avenue for treatment of Parkinson's disease. Therefore, this new research strongly dovetails with these observations and suggests that similar drug treatment may be beneficial in Huntington's disease.
Dr Giorgini, of the Department of Genetics, said: "Our research has taken advantage of cutting edge genomics approaches using a simple model organism to identify a novel area for potential therapeutic intervention for Huntington's disease.
"If our findings are validated by further studies, it might suggest a novel therapeutic approach for this devastating disorder - which is critical as currently there are no treatments for onset or progression of symptoms."
Citation:
Functional Gene Expression Profiling in Yeast Implicates Translational Dysfunction in Mutant Huntington Toxicity
The Journal of Biological Chemistry, Vol. 286, Issue 1, 410-419, January 7, 2011
Eran Tauber; Leonor Miller-Fleming; Robert P. Mason; Jannine Clapp; Nicola J. Butler; Flaviano Giorgini University of Leicester
Leonor Miller-Fleming; Tiago F. Outeiro
Universidade de Lisboa
Wanda Kwan; Paul J. Muchowski
University of California at San Francisco
Article #10.1074/jbc.M110.101527
About Huntington's Disease
- Huntington's disease is an inherited disease of the brain
- The disease damages the nerve cells in the brain, causing deterioration and gradual loss of function of areas of the brain. This affects movement, cognition (perception, awareness, thinking, judgement) and behaviour.
- Early symptoms such as personality changes, mood swings and bizarre behaviour are often overlooked at first and attributed to something else.
- Huntington's disease was originally called Huntington's chorea, after the Greek word for dancing, as the associated involuntary movements can look like jerky dancing.
- Both men and women with a family history of Huntington's can inherit the disease and symptoms usually start to show in adulthood.
- Juvenile (children's) Huntington's disease develops before the age of 20 years. Only 5-10% of people with Huntington's develop the condition at a very young age, and the pattern of features may be different.
- UK studies have found that approximately 6-7 people per 100,000 of the population are affected by Huntington's disease. However, it is likely that the true figure is much higher.
- There is no cure for Huntington's disease and its progress cannot be reversed or slowed down.
- Medication can be used to manage some of the symptoms, and therapies (such as speech and language therapy and occupational therapy) can help with communication and day-to-day living
Source:
University Of Leicester
Medical Research Council
вторник, 20 сентября 2011 г.
Researchers Call For Improvements In Trial Design To Test Biomedical Interventions To Prevent HIV
It is "imperative to prioritize the identification and implementation of more effective behavioral and nonvaccine biomedical interventions" to prevent HIV, as well as to "design, fund and conduct these trials in ways that give them the best chance of success," Stephen Lagakos, professor of biostatistics at the Harvard School of Public Health, and Alicia Gable, a senior program officer at the Institute of Medicine, write in a New England Journal of Medicine perspective piece. The authors note that many late-stage biomedical trials -- including those studying the use of vaginal microbicide gels, diaphragms, pre-exposure prophylaxis and two types of HIV vaccines -- failed to demonstrate a benefit in preventing HIV. In addition, while research has shown that several behavioral interventions have reduced the rates of sexually transmitted infections, none showed a reduction in HIV infection, Lagakos and Gable write.
According to Lagakos and Gable, the failure of recent late-stage biomedical HIV-prevention trials reveals the "[s]hortcomings" in research design. They write, "Design deficiencies led to premature termination of some trials because of inadequate research before the trial began, poor site preparation or lack of community engagement." The authors note that "key" problems with trial design include estimating the expected HIV incidence in the trial population, assessing participants' adherence and risk-behavior, and the lack of reliable end points.
They call on researchers and trial sponsors to "intensify" investment in the development of "safe, easy-to-use biomedical interventions," as well as improve "preclinical and early-stage clinical testing, and prioritization of products for later-stage testing." In addition, they recommend that future trials be adequately planned and include "reliable estimations of the rates of HIV infection, pregnancy, loss to follow-up and nonadherence to determine an adequate sample size and trial duration" (Lagakos/Gable, NEJM, 4/10).
The perspective is available online.
Reprinted with kind permission from kaisernetwork. You can view the entire Kaiser Daily Health Policy Report, search the archives, or sign up for email delivery at kaisernetwork/dailyreports/healthpolicy. The Kaiser Daily Health Policy Report is published for kaisernetwork, a free service of The Henry J. Kaiser Family Foundation© 2005 Advisory Board Company and Kaiser Family Foundation. All rights reserved.
According to Lagakos and Gable, the failure of recent late-stage biomedical HIV-prevention trials reveals the "[s]hortcomings" in research design. They write, "Design deficiencies led to premature termination of some trials because of inadequate research before the trial began, poor site preparation or lack of community engagement." The authors note that "key" problems with trial design include estimating the expected HIV incidence in the trial population, assessing participants' adherence and risk-behavior, and the lack of reliable end points.
They call on researchers and trial sponsors to "intensify" investment in the development of "safe, easy-to-use biomedical interventions," as well as improve "preclinical and early-stage clinical testing, and prioritization of products for later-stage testing." In addition, they recommend that future trials be adequately planned and include "reliable estimations of the rates of HIV infection, pregnancy, loss to follow-up and nonadherence to determine an adequate sample size and trial duration" (Lagakos/Gable, NEJM, 4/10).
The perspective is available online.
Reprinted with kind permission from kaisernetwork. You can view the entire Kaiser Daily Health Policy Report, search the archives, or sign up for email delivery at kaisernetwork/dailyreports/healthpolicy. The Kaiser Daily Health Policy Report is published for kaisernetwork, a free service of The Henry J. Kaiser Family Foundation© 2005 Advisory Board Company and Kaiser Family Foundation. All rights reserved.
суббота, 17 сентября 2011 г.
How Tumor Suppress Or Inhibits Cell Growth
Genes that inhibit the spontaneous development of cancer are called tumor suppressor genes. One of the major tumor suppressors is p53, a protein that acts in the cell nucleus to control the expression of other genes whose products can inhibit cell proliferation (increase in cell number) and cell growth (increase in cell size). Abnormal cell proliferation and growth are characteristics of cancer. Scientists previously knew which p53 target genes inhibit cell proliferation, but those required for inhibition of cell growth were unknown.
New work by researchers at the University of California, San Diego School of Medicine describes the mechanism by which p53 regulates cells and protects them against DNA damage that might lead to cancer. The study shows that two p53 target genes called Sestrin1 and Sestrin2 provide an important link between p53 and a protein kinase called mTOR, a central regulator of cell growth. mTOR is the target for the inhibitory activity of the immunosuppressive drug rapamycin, recently found to have anti-cancer activity.
The discovery by Michael Karin, Ph.D., professor of pharmacology in the Laboratory of Gene Regulation and Signal Transduction at the UC San Diego School of Medicine, and postdoctoral research fellow Andrei V. Budanov, Ph.D, will be published in the August 8 issue of the journal Cell.
"The two Sestrin genes appear to be the missing piece of the puzzle that explains how p53 can inhibit the mTOR pathway and thereby negatively regulate cell growth," said Budanov, who added that while the connection between the two was known, the mechanism wasn't previously understood. The finding may prove to be very important in scientists' search for novel inhibitors that stop or slow cancer tumor growth.
In fact, Budanov obtained results suggesting that the two Sestrins may be tumor suppressors in their own right. DNA damage (genotoxic stress) triggers two major biological responses in mammals: cell cycle arrest, which allows repair and survival of the cell; and apoptosis or cell death a process in which damaged cells, which could otherwise give rise to cancer, are eliminated.
The major tumor suppressor p53 can either inhibit cell proliferation and cell growth or induce cell death; its different functions are mediated through numerous target genes and depend on the extent of damage to the cell. As more than half of human cancers either lost p53 expression or express a defective version of p53, understanding the mechanisms by which p53 accomplishes its critical tumor suppressive function may lead to development of new cancer preventives and therapeutics.
The UCSD researchers wondered what target genes would allow p53 to inhibit cell growth. The central regulator of cell growth is the protein kinase mTOR, whose activity is inhibited by rapamycin, which is used in prevention of organ transplant rejection. Recent work indicates that rapamycin may also be used to inhibit the growth of tumors and render them more susceptible to chemotherapy.
Previous studies conducted by Budanov showed that the Sestrin1 and Sestrin2 proteins, which are expressed in response to genotoxic stress, serve a protective function and may also inhibit cell growth. It has also been shown that Sestrin1 and 2, as well as their master regulator p53, can control the accumulation of reactive oxygen species (ROS), which play important roles in cell signaling. Under genotoxic stress, ROS levels can increase dramatically, which can lead to significant damage to cell structures, resulting in oxidative stress.
"We have now shown that in addition to controlling ROS accumulation, Sestrins and p53 also inhibit cell growth by inhibiting the activity of mTOR. This explains how p53 functions as a potent regulator of so many aspects of cell physiology and provides protection against DNA damage and stress," said Budanov.
Knockout mouse models of Sestrin1 and 2 will be an important tool for studying their role in carcinogenesis, according to the researchers. Karin adds that small molecules that mimic the molecular actions of the Sestrins can be used to control cell metabolism and regain control over cancer cells that have lost their p53.
Funding for this study was provided by grants from the Tobacco Related Disease Research Program, the National Institute of Environmental Health Science and the Superfund Basic Research Program.
University of California, San Diego
University Communications, 0938 9500 Gilman Dr.
LaJolla, CA 92093
United States
ucsd
New work by researchers at the University of California, San Diego School of Medicine describes the mechanism by which p53 regulates cells and protects them against DNA damage that might lead to cancer. The study shows that two p53 target genes called Sestrin1 and Sestrin2 provide an important link between p53 and a protein kinase called mTOR, a central regulator of cell growth. mTOR is the target for the inhibitory activity of the immunosuppressive drug rapamycin, recently found to have anti-cancer activity.
The discovery by Michael Karin, Ph.D., professor of pharmacology in the Laboratory of Gene Regulation and Signal Transduction at the UC San Diego School of Medicine, and postdoctoral research fellow Andrei V. Budanov, Ph.D, will be published in the August 8 issue of the journal Cell.
"The two Sestrin genes appear to be the missing piece of the puzzle that explains how p53 can inhibit the mTOR pathway and thereby negatively regulate cell growth," said Budanov, who added that while the connection between the two was known, the mechanism wasn't previously understood. The finding may prove to be very important in scientists' search for novel inhibitors that stop or slow cancer tumor growth.
In fact, Budanov obtained results suggesting that the two Sestrins may be tumor suppressors in their own right. DNA damage (genotoxic stress) triggers two major biological responses in mammals: cell cycle arrest, which allows repair and survival of the cell; and apoptosis or cell death a process in which damaged cells, which could otherwise give rise to cancer, are eliminated.
The major tumor suppressor p53 can either inhibit cell proliferation and cell growth or induce cell death; its different functions are mediated through numerous target genes and depend on the extent of damage to the cell. As more than half of human cancers either lost p53 expression or express a defective version of p53, understanding the mechanisms by which p53 accomplishes its critical tumor suppressive function may lead to development of new cancer preventives and therapeutics.
The UCSD researchers wondered what target genes would allow p53 to inhibit cell growth. The central regulator of cell growth is the protein kinase mTOR, whose activity is inhibited by rapamycin, which is used in prevention of organ transplant rejection. Recent work indicates that rapamycin may also be used to inhibit the growth of tumors and render them more susceptible to chemotherapy.
Previous studies conducted by Budanov showed that the Sestrin1 and Sestrin2 proteins, which are expressed in response to genotoxic stress, serve a protective function and may also inhibit cell growth. It has also been shown that Sestrin1 and 2, as well as their master regulator p53, can control the accumulation of reactive oxygen species (ROS), which play important roles in cell signaling. Under genotoxic stress, ROS levels can increase dramatically, which can lead to significant damage to cell structures, resulting in oxidative stress.
"We have now shown that in addition to controlling ROS accumulation, Sestrins and p53 also inhibit cell growth by inhibiting the activity of mTOR. This explains how p53 functions as a potent regulator of so many aspects of cell physiology and provides protection against DNA damage and stress," said Budanov.
Knockout mouse models of Sestrin1 and 2 will be an important tool for studying their role in carcinogenesis, according to the researchers. Karin adds that small molecules that mimic the molecular actions of the Sestrins can be used to control cell metabolism and regain control over cancer cells that have lost their p53.
Funding for this study was provided by grants from the Tobacco Related Disease Research Program, the National Institute of Environmental Health Science and the Superfund Basic Research Program.
University of California, San Diego
University Communications, 0938 9500 Gilman Dr.
LaJolla, CA 92093
United States
ucsd
среда, 14 сентября 2011 г.
Scorpion Peptide May Be Key To Secretory Diseases
Researchers have discovered a peptide in scorpion venom that may hold the key to understanding and controlling cystic fibrosis and other secretory diseases.
In the December 28 issue of the Journal of Biological Chemistry, an international team of researchers describes how this novel peptide, called GaTx1, can control the movement of ions and water out of cells by interacting with a crucial chloride channel. This research was funded by the National Institutes of Health, National Science Foundation and Cystic Fibrosis Foundation.
"Peptide toxins from scorpions, snakes, snails and spiders paralyze prey by blocking nerve or muscle ion channels so the prey can't get away," explained Nael A. McCarty, an associate professor in the Georgia Institute of Technology's School of Biology. "Those toxins have been enormously useful for studying the potassium, calcium, and sodium channels that they interact with, but this is the first toxin discovered that potently binds to and selectively and reversibly inhibits a chloride channel of known molecular identity."
Chloride channels are crucial for secretion in many epithelial tissues, but little has been known about their structures and mechanisms. Researchers do know that chloride channels open to allow millions of chloride ions to travel through them and out of epithelial cells. This movement creates an osmotic gradient that allows water to flow.
For the more than 70,000 people worldwide affected by cystic fibrosis, a lack of water flow in airway cells results in abnormally thick, sticky mucus that commonly causes blockages that obstruct airways and glands. The lack of water flow stems from a problem in a chloride channel called the cystic fibrosis transmembrane conductance regulator (CFTR) protein.
In individuals with cystic fibrosis, the CFTR protein is mutated, often with one or more amino acids deleted, and consequently misfolded. In the most common CFTR mutation leading to cystic fibrosis, the location of the deletion causes the chaperone proteins which are responsible for quality assurance within cells to bind to the misfolded proteins and discard them from the cell. Loss of CFTR proteins stops water from flowing into or out of the cells, thereby altering the conditions in the airway, leading to cystic fibrosis.
In other diseases, CFTR channels are overactive, which also causes problems. These include secretory diarrhea, a worldwide health concern causing thousands of deaths per year; diarrhea-predominant inflammatory bowel disease; and autosomal dominant polycystic kidney diseases, the fourth leading cause of end-stage renal disease in the United States.
With collaborators at the Hungarian Academy of Sciences, Emory University and the University of Calgary, the researchers used reversed-phase high-performance liquid chromatography (HPLC) to extract the novel GaTx1 peptide from the complex venom of the Giant Israeli Scorpion, Leiurus quinquestriatus hebraeus.
"We chose this technique because each different peptide has slightly different water solubility and hydrophobicity properties, allowing them to be separated," explained Julia Kubanek, an associate professor with joint appointments in the Georgia Tech School of Biology and School of Chemistry and Biochemistry.
Former Emory University graduate student Matthew Fuller and Georgia Tech graduate student Christopher Thompson collected individual peptides separated by the HPLC system and then applied each to chloride channels to see which peptide was responsible for the overall effects of the venom. They discovered a novel peptide that bound to the cytoplasmic side of the CFTR protein and weighed 3.7 kilodaltons they called it GaTx1.
The researchers plan to use GaTx1 as a molecular probe to learn more about how chloride channels are structured and regulated. They also plan to study how this peptide can be useful in treating secretory diseases. For people with illnesses like secretory diarrhea, GaTx1 could be used to inhibit the channels from opening, in turn decreasing production of the watery diarrhea that often leads to death in patients suffering from cholera and other diarrheal diseases, said McCarty.
To treat patients with cystic fibrosis, GaTx1 could possibly be used to increase water production, by binding to the chaperone binding sites on the chloride channel. By blocking chaperones from binding, CFTR proteins would not be discarded and thus ions and water would flow from the cells to thin the mucus in the airway, according to McCarty.
"Even though the channels would be misfolded and probably only function at 50 percent capacity, chloride ions and water would still be transported through the cell," said McCarty. "This is better than the alternative of allowing the chaperones to discard all of the CFTR proteins."
McCarty has been studying CFTR for his entire research career and as he moves to a new position as associate professor in pediatrics and senior cystic fibrosis scientist at Emory University, he will continue this work in collaboration with researchers at Georgia Tech.
"GaTx1 has the potential to be used as a drug to help patients with cystic fibrosis and these other secretory diseases," added McCarty. "My new role at Emory will allow me to conduct pre-clinical studies to explore experimental drug treatment options based on this toxin."
Georgia Institute of Technology, Research Communications
75 Fifth St. NW Ste. 100
Atlanta, GA 30308
United States
gatech
In the December 28 issue of the Journal of Biological Chemistry, an international team of researchers describes how this novel peptide, called GaTx1, can control the movement of ions and water out of cells by interacting with a crucial chloride channel. This research was funded by the National Institutes of Health, National Science Foundation and Cystic Fibrosis Foundation.
"Peptide toxins from scorpions, snakes, snails and spiders paralyze prey by blocking nerve or muscle ion channels so the prey can't get away," explained Nael A. McCarty, an associate professor in the Georgia Institute of Technology's School of Biology. "Those toxins have been enormously useful for studying the potassium, calcium, and sodium channels that they interact with, but this is the first toxin discovered that potently binds to and selectively and reversibly inhibits a chloride channel of known molecular identity."
Chloride channels are crucial for secretion in many epithelial tissues, but little has been known about their structures and mechanisms. Researchers do know that chloride channels open to allow millions of chloride ions to travel through them and out of epithelial cells. This movement creates an osmotic gradient that allows water to flow.
For the more than 70,000 people worldwide affected by cystic fibrosis, a lack of water flow in airway cells results in abnormally thick, sticky mucus that commonly causes blockages that obstruct airways and glands. The lack of water flow stems from a problem in a chloride channel called the cystic fibrosis transmembrane conductance regulator (CFTR) protein.
In individuals with cystic fibrosis, the CFTR protein is mutated, often with one or more amino acids deleted, and consequently misfolded. In the most common CFTR mutation leading to cystic fibrosis, the location of the deletion causes the chaperone proteins which are responsible for quality assurance within cells to bind to the misfolded proteins and discard them from the cell. Loss of CFTR proteins stops water from flowing into or out of the cells, thereby altering the conditions in the airway, leading to cystic fibrosis.
In other diseases, CFTR channels are overactive, which also causes problems. These include secretory diarrhea, a worldwide health concern causing thousands of deaths per year; diarrhea-predominant inflammatory bowel disease; and autosomal dominant polycystic kidney diseases, the fourth leading cause of end-stage renal disease in the United States.
With collaborators at the Hungarian Academy of Sciences, Emory University and the University of Calgary, the researchers used reversed-phase high-performance liquid chromatography (HPLC) to extract the novel GaTx1 peptide from the complex venom of the Giant Israeli Scorpion, Leiurus quinquestriatus hebraeus.
"We chose this technique because each different peptide has slightly different water solubility and hydrophobicity properties, allowing them to be separated," explained Julia Kubanek, an associate professor with joint appointments in the Georgia Tech School of Biology and School of Chemistry and Biochemistry.
Former Emory University graduate student Matthew Fuller and Georgia Tech graduate student Christopher Thompson collected individual peptides separated by the HPLC system and then applied each to chloride channels to see which peptide was responsible for the overall effects of the venom. They discovered a novel peptide that bound to the cytoplasmic side of the CFTR protein and weighed 3.7 kilodaltons they called it GaTx1.
The researchers plan to use GaTx1 as a molecular probe to learn more about how chloride channels are structured and regulated. They also plan to study how this peptide can be useful in treating secretory diseases. For people with illnesses like secretory diarrhea, GaTx1 could be used to inhibit the channels from opening, in turn decreasing production of the watery diarrhea that often leads to death in patients suffering from cholera and other diarrheal diseases, said McCarty.
To treat patients with cystic fibrosis, GaTx1 could possibly be used to increase water production, by binding to the chaperone binding sites on the chloride channel. By blocking chaperones from binding, CFTR proteins would not be discarded and thus ions and water would flow from the cells to thin the mucus in the airway, according to McCarty.
"Even though the channels would be misfolded and probably only function at 50 percent capacity, chloride ions and water would still be transported through the cell," said McCarty. "This is better than the alternative of allowing the chaperones to discard all of the CFTR proteins."
McCarty has been studying CFTR for his entire research career and as he moves to a new position as associate professor in pediatrics and senior cystic fibrosis scientist at Emory University, he will continue this work in collaboration with researchers at Georgia Tech.
"GaTx1 has the potential to be used as a drug to help patients with cystic fibrosis and these other secretory diseases," added McCarty. "My new role at Emory will allow me to conduct pre-clinical studies to explore experimental drug treatment options based on this toxin."
Georgia Institute of Technology, Research Communications
75 Fifth St. NW Ste. 100
Atlanta, GA 30308
United States
gatech
воскресенье, 11 сентября 2011 г.
Water-Borne Pathogen Now Under Attack Thanks To Breakthrough Research
Cryptosporidium parvum is a tiny yet insidious waterborne parasite that wreaks havoc worldwide. This parasite is a major cause of diarrhea and malnutrition in small children in developing countries, and causes severe disease in AIDS and other immune compromised patients in the developed world. Cryptosporidium is resistant to water chlorination and has caused massive outbreaks in the U.S., which has led to the concern that the parasite could be used as a bio-terrorism agent. There are neither vaccines nor effective drugs available to respond to these multiple threats to human health.
In this week's issue of Chemistry and Biology, researchers at Brandeis University and the University of Georgia report they have identified lead compounds that inhibit Cryptosporidium's parasitic punch, paving the way for an effective antibiotic treatment. In all, scientists identified ten new compounds, four of which are better at fighting Cryptosporidium than the antibiotic paromomycin, the current gold standard for evaluating anticryptosporidial activity.
"These are promising new compounds and this research provides an avenue of much needed therapy for this disease," said Brandeis biochemist Lizbeth Hedstrom, whose lab identified the compounds together with parasitologist Boris Striepen of the University of Georgia.
While there are many drugs to treat bacterial infections, it has been very difficult to find drugs against pathogens like Cryptosporidium because the proteins of these parasites are actually very similar to those of their human host. Scientists have been further thwarted because little was known about Cryptosporidium metabolism. This situation recently changed dramatically when genome sequencing provided a genetic blueprint of Cryptosporidium.
In work leading up to the current study, Hedstrom and Striepen used this blueprint to show that Cryptosporidium has a very simple process to produce the building blocks of DNA and RNA. Surprisingly, the researchers also discovered that Cryptosporidium stole a critical gene in this pathway from intestinal bacteria. This unusually large evolutionary divergence between parasite and host proteins provides an unexpected platform for novel drug design.
The stolen bacterial gene encodes a gatekeeper protein, known as IMPDH, which is essential for parasite growth. Hedstrom and her colleagues set out to find compounds that bind to the part of the parasite's IMPDH that is most different from human IMPDH. They tested 40,000 compounds using the facilities of the National Screening Laboratory for the Regional Centers of Excellence in BioDefense and Emerging Infectious Disease (NSRB/NERCE) at Harvard Medical School, and identified ten compounds that inhibited the parasite protein, but not the human counterpart. Four of these compounds are effective in stopping Cryptosporidium infection in the laboratory.
"The quest to develop drugs to treat this debilitating disease has been almost futile," said Hedstrom. "We are still a long way from an actual anticryptosporidial drug, but we are very encouraged by these results."
Source: Laura Gardner
Brandeis University
In this week's issue of Chemistry and Biology, researchers at Brandeis University and the University of Georgia report they have identified lead compounds that inhibit Cryptosporidium's parasitic punch, paving the way for an effective antibiotic treatment. In all, scientists identified ten new compounds, four of which are better at fighting Cryptosporidium than the antibiotic paromomycin, the current gold standard for evaluating anticryptosporidial activity.
"These are promising new compounds and this research provides an avenue of much needed therapy for this disease," said Brandeis biochemist Lizbeth Hedstrom, whose lab identified the compounds together with parasitologist Boris Striepen of the University of Georgia.
While there are many drugs to treat bacterial infections, it has been very difficult to find drugs against pathogens like Cryptosporidium because the proteins of these parasites are actually very similar to those of their human host. Scientists have been further thwarted because little was known about Cryptosporidium metabolism. This situation recently changed dramatically when genome sequencing provided a genetic blueprint of Cryptosporidium.
In work leading up to the current study, Hedstrom and Striepen used this blueprint to show that Cryptosporidium has a very simple process to produce the building blocks of DNA and RNA. Surprisingly, the researchers also discovered that Cryptosporidium stole a critical gene in this pathway from intestinal bacteria. This unusually large evolutionary divergence between parasite and host proteins provides an unexpected platform for novel drug design.
The stolen bacterial gene encodes a gatekeeper protein, known as IMPDH, which is essential for parasite growth. Hedstrom and her colleagues set out to find compounds that bind to the part of the parasite's IMPDH that is most different from human IMPDH. They tested 40,000 compounds using the facilities of the National Screening Laboratory for the Regional Centers of Excellence in BioDefense and Emerging Infectious Disease (NSRB/NERCE) at Harvard Medical School, and identified ten compounds that inhibited the parasite protein, but not the human counterpart. Four of these compounds are effective in stopping Cryptosporidium infection in the laboratory.
"The quest to develop drugs to treat this debilitating disease has been almost futile," said Hedstrom. "We are still a long way from an actual anticryptosporidial drug, but we are very encouraged by these results."
Source: Laura Gardner
Brandeis University
четверг, 8 сентября 2011 г.
Advanced Life Sciences Announces Cethromycin Granted FDA Orphan Drug Designation For Anthrax
Advanced Life
Sciences Holdings, Inc. (Nasdaq: ADLS) today announced that the United
States Food and Drug Administration (FDA) has granted Orphan Drug
Designation to cethromycin for the prophylactic treatment of patients
exposed to inhalation anthrax.
The FDA's U.S. Orphan Drug Act is intended to assist and encourage
companies to develop safe and effective therapies for the treatment of rare
diseases and disorders. Orphan Drug designation is awarded to compounds
that offer potential therapeutic value in the treatment of rare diseases,
defined as those affecting fewer than 200,000 Americans. This designation
provides companies with financial and regulatory benefits such as
eligibility for a special seven-year period of market exclusivity upon
approval for the compound and indication with orphan designation, potential
tax credits for research, potential grant funding for research and
development, reduced filing fees for marketing applications, and assistance
with clinical trial protocol review.
Michael T. Flavin, Ph.D., chairman and chief executive officer of
Advanced Life Sciences, commented on the notice of designation saying that
"We are very pleased to receive this Orphan Drug designation and we believe
that it represents the achievement of another important milestone in the
development of cethromycin. This designation will benefit us as we continue
to build the cethromycin safety and efficacy database and will ultimately
help position cethromycin as a potentially important antibiotic for the
U.S. Government's Strategic National Stockpile."
Advanced Life Sciences has established collaborations with U.S. Army
Medical Research Institute of Infectious Diseases (USAMRIID) and the NIH's
National Institute of Allergy and Infectious Disease (NIAID) for the
research and development of cethromycin against anthrax and other
biowarfare agents.
About Cethromycin
Advanced Life Sciences' most advanced product candidate, cethromycin,
is a second generation ketolide antibiotic in Phase III clinical
development for the treatment of respiratory tract infections. Cethromycin
has been tested in over 4,400 human subjects and is currently in Pivotal
Phase III trials for the treatment of mild-to-moderate community acquired
pneumonia (CAP). Cethromycin has also been demonstrated to have significant
in vitro activity against over 30 anthrax (Bacillus anthracis) strains. It
is currently being tested in non- human primates to determine its potential
efficacy for the prophylactic treatment of patients exposed to inhalation
anthrax.
About Advanced Life Sciences
Advanced Life Sciences is a biopharmaceutical company engaged in the
discovery, development and commercialization of novel drugs in the
therapeutic areas of infection, cancer and inflammation. Visit us on the
web at advancedlifesciences.
Any statements contained in this presentation that relate to future
plans, events or performance are forward-looking statements within the
meaning of the Private Securities Litigation Reform Act of 1995. These
forward-looking statements are subject to a number of risks and
uncertainties that could cause actual results to differ materially from
those described in the forward- looking statements. These risks and
uncertainties include, among others, those relating to technology and
product development, market acceptance, government regulation and
regulatory approval processes, intellectual property rights and litigation,
dependence on collaborative relationships, ability to obtain financing,
competitive products, industry trends and other risks identified in
Advanced Life Sciences' filings with the Securities and Exchange
Commission. Advanced Life Sciences undertakes no obligation to update or
alter these forward-looking statements as a result of new information,
future events or otherwise.
Advanced Life Sciences Holdings, Inc.
advancedlifesciences
Sciences Holdings, Inc. (Nasdaq: ADLS) today announced that the United
States Food and Drug Administration (FDA) has granted Orphan Drug
Designation to cethromycin for the prophylactic treatment of patients
exposed to inhalation anthrax.
The FDA's U.S. Orphan Drug Act is intended to assist and encourage
companies to develop safe and effective therapies for the treatment of rare
diseases and disorders. Orphan Drug designation is awarded to compounds
that offer potential therapeutic value in the treatment of rare diseases,
defined as those affecting fewer than 200,000 Americans. This designation
provides companies with financial and regulatory benefits such as
eligibility for a special seven-year period of market exclusivity upon
approval for the compound and indication with orphan designation, potential
tax credits for research, potential grant funding for research and
development, reduced filing fees for marketing applications, and assistance
with clinical trial protocol review.
Michael T. Flavin, Ph.D., chairman and chief executive officer of
Advanced Life Sciences, commented on the notice of designation saying that
"We are very pleased to receive this Orphan Drug designation and we believe
that it represents the achievement of another important milestone in the
development of cethromycin. This designation will benefit us as we continue
to build the cethromycin safety and efficacy database and will ultimately
help position cethromycin as a potentially important antibiotic for the
U.S. Government's Strategic National Stockpile."
Advanced Life Sciences has established collaborations with U.S. Army
Medical Research Institute of Infectious Diseases (USAMRIID) and the NIH's
National Institute of Allergy and Infectious Disease (NIAID) for the
research and development of cethromycin against anthrax and other
biowarfare agents.
About Cethromycin
Advanced Life Sciences' most advanced product candidate, cethromycin,
is a second generation ketolide antibiotic in Phase III clinical
development for the treatment of respiratory tract infections. Cethromycin
has been tested in over 4,400 human subjects and is currently in Pivotal
Phase III trials for the treatment of mild-to-moderate community acquired
pneumonia (CAP). Cethromycin has also been demonstrated to have significant
in vitro activity against over 30 anthrax (Bacillus anthracis) strains. It
is currently being tested in non- human primates to determine its potential
efficacy for the prophylactic treatment of patients exposed to inhalation
anthrax.
About Advanced Life Sciences
Advanced Life Sciences is a biopharmaceutical company engaged in the
discovery, development and commercialization of novel drugs in the
therapeutic areas of infection, cancer and inflammation. Visit us on the
web at advancedlifesciences.
Any statements contained in this presentation that relate to future
plans, events or performance are forward-looking statements within the
meaning of the Private Securities Litigation Reform Act of 1995. These
forward-looking statements are subject to a number of risks and
uncertainties that could cause actual results to differ materially from
those described in the forward- looking statements. These risks and
uncertainties include, among others, those relating to technology and
product development, market acceptance, government regulation and
regulatory approval processes, intellectual property rights and litigation,
dependence on collaborative relationships, ability to obtain financing,
competitive products, industry trends and other risks identified in
Advanced Life Sciences' filings with the Securities and Exchange
Commission. Advanced Life Sciences undertakes no obligation to update or
alter these forward-looking statements as a result of new information,
future events or otherwise.
Advanced Life Sciences Holdings, Inc.
advancedlifesciences
понедельник, 5 сентября 2011 г.
AMPK Signaling: Got Food?
A team of scientists at the Salk Institute for Biological Studies think they know how many if not most living organisms answer this question. They recently showed that when food supplies dwindle, mammals, fruitflies, or frogs probably activate the same ancient cell signaling pathway in order to conserve energy.
In a study published in the April 25, 2008 issue of Molecular Cell, investigators led by Reuben Shaw, Ph.D., assistant professor in the Molecular and Cell Biology Laboratory of the Dulbecco Center for Cancer Research, report that when mammalian cells sense that glucose and other nutrients are running short, they muffle a cellular protein called raptor, causing cells to slow their growth.
Not only do these studies reveal survival strategies likely common to complex and simple organisms alike, but they suggest an extremely intriguing link between cancer and diabetes.
"This paper provides the first direct biochemical explanation for how cell growth is inhibited under conditions when nutrients are low," reports Shaw. "This very simple bio-circuit is literally the bare bones signal that most organisms use to say, 'We've got food!' "
Researchers knew that when this circuit broke down, cells facing starvation simply continued to divide oblivious to hard times and spending energy currency like a frenzied credit card shopper until the cellular cash ran out and cells died. What Shaw wondered was whether all the circuit components had been identified.
Using mouse and human cells, Shaw and colleagues observed that when cells are kept hungry in a culture dish, a watchdog enzyme called AMPK jumps into action and attaches a chemical phosphate group to a target protein named raptor. As a result, raptor, whose job is to cradle a growth-promoting protein called mTOR, is disabled, inactivating mTOR and halting cell division. Cells then safely switch into energy conservation mode until plentiful times return.
Previously, Shaw and others had shown that although AMPK performs a critical growth-slowing function, it takes its orders from a biochemical big boss, the protein LKB1. LKB1 is a so-called tumor-suppressor, meaning that its loss correlates with formation of benign growths, called hamartomas, and some types of malignant lung and colon cancer. Once growth-regulating LKB1 was out of the picture, many of these tumors showed very high levels of unregulated mTOR activity.
That's where Shaw's latest investigations began. "We were trying to understand how mutation of the tumor suppressor LKB1 leads to colon cancer or sporadic lung cancer," he says. "I had shown that LKB1 turns AMPK on, so the next question was, what does that do? If it regulated cancer, there had to be components of the pathway that regulated cell growth that no one had discovered."
A collaborator, Benjamin Turk, Ph.D., of Yale University School of Medicine, helped Shaw identify that component. AMPK is a kinase, meaning that it adds phosphate groups which sometimes activate and other times inhibit to target proteins. Using Turk's data, Shaw combed through collections of protein fragments biochemically phosphorylated by AMPK and fished out one corresponding to a novel candidate raptor. Remarkably that tiny part of raptor protein looked similar in raptor proteins expressed in organisms ranging from slime molds to humans.
With raptor as the prime suspect, lead author and graduate student Dana Gwinn and other members of the Shaw lab undertook extensive biochemical studies to demonstrate that AMPK indeed directly phosphorylated raptor in response to energy stress, that mTOR activity then decreased, and that of all this kept starving cells from dividing until they dropped.
The study provides stunning insight into Mother Nature's reluctance to tinker with strategies that meet organisms' most basic needs. "Simply the most rudimentary information that any cell needs is to know whether there is food around that's what AMPK senses. If there is not, you need to turn off factors that make cells grow," explains Shaw, specifically to the growth-promoting team of raptor and mTOR.
And as if solving evolutionary puzzles and dissecting tumor suppressor pathways isn't enough, Shaw's work overall hints at an even more profound clinical association: the widely used type 2 diabetes drug metformin activates AMPK, suggesting that the LKB1/AMPK pathway is a molecular link between diabetes and cancer. "This circuit could in part explain the increased cancer risk seen in type 2 diabetic patients," says Shaw, noting many are predisposed to breast, prostate or colon cancer.
Could mutations in components of the LKB1/AMPK pathway underlie both pathologies? And if so, could drugs that effectively antagonize diabetes also antagonize tumor growth?
Those questions are next on Shaw's agenda. "Not only will we continue to dissect this pathway biochemically, but we will more directly test whether we can treat certain types of tumors in mouse models with diabetes drugs," Shaw says.
Also contributing to this study from the Shaw lab were postdoctoral fellows David Shackelford, Ph.D., and Annabelle Mery, Ph.D., graduate student Maria Mihaylova, and research assistants Debbie Vasquez and Daniel Egan.
The Salk Institute for Biological Studies in La Jolla, California, is an independent nonprofit organization dedicated to fundamental discoveries in the life sciences, the improvement of human health and the training of future generations of researchers. Jonas Salk, M.D., whose polio vaccine all but eradicated the crippling disease poliomyelitis in 1955, opened the Institute in 1965 with a gift of land from the City of San Diego and the financial support of the March of Dimes.
Salk Institute for Biological Studies
10010 North Torrey Pines Rd.
La Jolla, CA 92037-1099
United States
salk
In a study published in the April 25, 2008 issue of Molecular Cell, investigators led by Reuben Shaw, Ph.D., assistant professor in the Molecular and Cell Biology Laboratory of the Dulbecco Center for Cancer Research, report that when mammalian cells sense that glucose and other nutrients are running short, they muffle a cellular protein called raptor, causing cells to slow their growth.
Not only do these studies reveal survival strategies likely common to complex and simple organisms alike, but they suggest an extremely intriguing link between cancer and diabetes.
"This paper provides the first direct biochemical explanation for how cell growth is inhibited under conditions when nutrients are low," reports Shaw. "This very simple bio-circuit is literally the bare bones signal that most organisms use to say, 'We've got food!' "
Researchers knew that when this circuit broke down, cells facing starvation simply continued to divide oblivious to hard times and spending energy currency like a frenzied credit card shopper until the cellular cash ran out and cells died. What Shaw wondered was whether all the circuit components had been identified.
Using mouse and human cells, Shaw and colleagues observed that when cells are kept hungry in a culture dish, a watchdog enzyme called AMPK jumps into action and attaches a chemical phosphate group to a target protein named raptor. As a result, raptor, whose job is to cradle a growth-promoting protein called mTOR, is disabled, inactivating mTOR and halting cell division. Cells then safely switch into energy conservation mode until plentiful times return.
Previously, Shaw and others had shown that although AMPK performs a critical growth-slowing function, it takes its orders from a biochemical big boss, the protein LKB1. LKB1 is a so-called tumor-suppressor, meaning that its loss correlates with formation of benign growths, called hamartomas, and some types of malignant lung and colon cancer. Once growth-regulating LKB1 was out of the picture, many of these tumors showed very high levels of unregulated mTOR activity.
That's where Shaw's latest investigations began. "We were trying to understand how mutation of the tumor suppressor LKB1 leads to colon cancer or sporadic lung cancer," he says. "I had shown that LKB1 turns AMPK on, so the next question was, what does that do? If it regulated cancer, there had to be components of the pathway that regulated cell growth that no one had discovered."
A collaborator, Benjamin Turk, Ph.D., of Yale University School of Medicine, helped Shaw identify that component. AMPK is a kinase, meaning that it adds phosphate groups which sometimes activate and other times inhibit to target proteins. Using Turk's data, Shaw combed through collections of protein fragments biochemically phosphorylated by AMPK and fished out one corresponding to a novel candidate raptor. Remarkably that tiny part of raptor protein looked similar in raptor proteins expressed in organisms ranging from slime molds to humans.
With raptor as the prime suspect, lead author and graduate student Dana Gwinn and other members of the Shaw lab undertook extensive biochemical studies to demonstrate that AMPK indeed directly phosphorylated raptor in response to energy stress, that mTOR activity then decreased, and that of all this kept starving cells from dividing until they dropped.
The study provides stunning insight into Mother Nature's reluctance to tinker with strategies that meet organisms' most basic needs. "Simply the most rudimentary information that any cell needs is to know whether there is food around that's what AMPK senses. If there is not, you need to turn off factors that make cells grow," explains Shaw, specifically to the growth-promoting team of raptor and mTOR.
And as if solving evolutionary puzzles and dissecting tumor suppressor pathways isn't enough, Shaw's work overall hints at an even more profound clinical association: the widely used type 2 diabetes drug metformin activates AMPK, suggesting that the LKB1/AMPK pathway is a molecular link between diabetes and cancer. "This circuit could in part explain the increased cancer risk seen in type 2 diabetic patients," says Shaw, noting many are predisposed to breast, prostate or colon cancer.
Could mutations in components of the LKB1/AMPK pathway underlie both pathologies? And if so, could drugs that effectively antagonize diabetes also antagonize tumor growth?
Those questions are next on Shaw's agenda. "Not only will we continue to dissect this pathway biochemically, but we will more directly test whether we can treat certain types of tumors in mouse models with diabetes drugs," Shaw says.
Also contributing to this study from the Shaw lab were postdoctoral fellows David Shackelford, Ph.D., and Annabelle Mery, Ph.D., graduate student Maria Mihaylova, and research assistants Debbie Vasquez and Daniel Egan.
The Salk Institute for Biological Studies in La Jolla, California, is an independent nonprofit organization dedicated to fundamental discoveries in the life sciences, the improvement of human health and the training of future generations of researchers. Jonas Salk, M.D., whose polio vaccine all but eradicated the crippling disease poliomyelitis in 1955, opened the Institute in 1965 with a gift of land from the City of San Diego and the financial support of the March of Dimes.
Salk Institute for Biological Studies
10010 North Torrey Pines Rd.
La Jolla, CA 92037-1099
United States
salk
пятница, 2 сентября 2011 г.
Combining Two Peptide Inhibitors Might Block Tumor Growth
A new study suggests that combining two experimental anticancer peptide agents might simultaneously block formation of new tumor blood vessels while also inhibiting the growth of tumor cells.
This early test of the two agents in a breast cancer model suggests that the double hit can stifle tumor progression, avoid drug resistance and cause few side effects, say researchers at the Ohio State University Comprehensive Cancer Center - Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC - James) who developed the agents and evaluated their effectiveness in laboratory and animal tests.
The scientists designed one of the agents to prevent human epithelial growth factor from interacting with HER-2, a molecule that marks a particularly aggressive form of breast cancer. The other inhibitor blocks the action of vascular endothelial growth factor (VEGF), which stimulates the growth of new blood vessels that tumors need to grow beyond a certain size.
The findings are described in two papers published online in the Journal of Biological Chemistry. One presents the development of a novel VEGF inhibitor; the other describes the HER-2 inhibitor and the preclinical testing of the two agents together.
"When we combined our peptide HER-2 inhibitor with the VEGF peptide that inhibits angiogenesis, we observed significant additive benefits in reducing tumor burdens in preclinical studies," says principal investigator Pravin Kaumaya, professor of obstetrics and gynecology, of molecular and cellular biochemistry, and of microbiology, and director of the division of vaccine development at the OSUCCC - James.
The strategy of targeting both HER-2 and VEGF pathways should also discourage the development of drug resistance, Kaumaya says, because it simultaneously inhibits two pathways that are essential for tumor survival. "Combined peptide inhibitors might be appropriate in several types of cancer to overcome acquired resistance and provide clinical benefit," he adds.
Peptide inhibitors consist of short chains of amino acids (the VEGF inhibitor is 22 amino acids long) that conform in shape to the active site of the target receptor. In addition, Kaumaya engineered the VEGF peptide to be resistant to protease, an enzyme, thereby increasing its efficacy. The shape of the peptide HER-2 inhibitor engineered by Kaumaya and his colleagues, for example, is highly specific for the HER-2 receptor. It physically binds to the receptor, which prevents another substance, called epithelial growth factor, from contacting the receptor and stimulating the cancer cells to grow.
Other categories of targeted drugs in clinical use are humanized monoclonal antibodies and small-molecule TKI inhibitors. Both groups are associated with severe side effects and are very expensive, Kaumaya says. "We believe peptide inhibitors offer non-toxic, less-expensive alternatives to humanized monoclonal antibodies and small-molecule inhibitors for the treatment of solid tumors, with the potential for improved efficacy and better clinical outcomes," he says.
Funding from NIH supported this research.
Other Ohio State researchers involved in the two studies were Kevin C. Foy, Daniele Vicari, Eric Liotta, Zhenzhen Liu, Gary Phillips and Megan Miller.
The Ohio State University Comprehensive Cancer Center - Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (cancer.osu) is one of only 40 Comprehensive Cancer Centers in the United States designated by the National Cancer Institute. Ranked by U.S. News & World Report among the top cancer hospitals in the nation, The James is the 205-bed adult patient-care component of the cancer program at The Ohio State University. The OSUCCC-James is one of only seven funded programs in the country approved by the NCI to conduct both Phase I and Phase II clinical trials.
Source:
Darrell E. Ward
Ohio State University Medical Center
This early test of the two agents in a breast cancer model suggests that the double hit can stifle tumor progression, avoid drug resistance and cause few side effects, say researchers at the Ohio State University Comprehensive Cancer Center - Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC - James) who developed the agents and evaluated their effectiveness in laboratory and animal tests.
The scientists designed one of the agents to prevent human epithelial growth factor from interacting with HER-2, a molecule that marks a particularly aggressive form of breast cancer. The other inhibitor blocks the action of vascular endothelial growth factor (VEGF), which stimulates the growth of new blood vessels that tumors need to grow beyond a certain size.
The findings are described in two papers published online in the Journal of Biological Chemistry. One presents the development of a novel VEGF inhibitor; the other describes the HER-2 inhibitor and the preclinical testing of the two agents together.
"When we combined our peptide HER-2 inhibitor with the VEGF peptide that inhibits angiogenesis, we observed significant additive benefits in reducing tumor burdens in preclinical studies," says principal investigator Pravin Kaumaya, professor of obstetrics and gynecology, of molecular and cellular biochemistry, and of microbiology, and director of the division of vaccine development at the OSUCCC - James.
The strategy of targeting both HER-2 and VEGF pathways should also discourage the development of drug resistance, Kaumaya says, because it simultaneously inhibits two pathways that are essential for tumor survival. "Combined peptide inhibitors might be appropriate in several types of cancer to overcome acquired resistance and provide clinical benefit," he adds.
Peptide inhibitors consist of short chains of amino acids (the VEGF inhibitor is 22 amino acids long) that conform in shape to the active site of the target receptor. In addition, Kaumaya engineered the VEGF peptide to be resistant to protease, an enzyme, thereby increasing its efficacy. The shape of the peptide HER-2 inhibitor engineered by Kaumaya and his colleagues, for example, is highly specific for the HER-2 receptor. It physically binds to the receptor, which prevents another substance, called epithelial growth factor, from contacting the receptor and stimulating the cancer cells to grow.
Other categories of targeted drugs in clinical use are humanized monoclonal antibodies and small-molecule TKI inhibitors. Both groups are associated with severe side effects and are very expensive, Kaumaya says. "We believe peptide inhibitors offer non-toxic, less-expensive alternatives to humanized monoclonal antibodies and small-molecule inhibitors for the treatment of solid tumors, with the potential for improved efficacy and better clinical outcomes," he says.
Funding from NIH supported this research.
Other Ohio State researchers involved in the two studies were Kevin C. Foy, Daniele Vicari, Eric Liotta, Zhenzhen Liu, Gary Phillips and Megan Miller.
The Ohio State University Comprehensive Cancer Center - Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (cancer.osu) is one of only 40 Comprehensive Cancer Centers in the United States designated by the National Cancer Institute. Ranked by U.S. News & World Report among the top cancer hospitals in the nation, The James is the 205-bed adult patient-care component of the cancer program at The Ohio State University. The OSUCCC-James is one of only seven funded programs in the country approved by the NCI to conduct both Phase I and Phase II clinical trials.
Source:
Darrell E. Ward
Ohio State University Medical Center
вторник, 30 августа 2011 г.
Mystery Of A Third Olfactory System Unlocked By University Of Maryland Researchers
Researchers at the University of Maryland School of Medicine have found a "nose within the nose," a unique olfactory system within the noses of mice that is able to "smell" hormones involved in regulating water and salt balance in the body. This research may lead to new insights into the complex system of "chemical communication" between individuals. The findings are published in the Proceedings of the National Academy of Sciences, USA online early edition.
"The sense of smell provides an important way for humans and animals to interact with their environment, as well as with other members of their species," says Steven Munger, Ph.D., associate professor of anatomy and neurobiology at the University of Maryland School of Medicine and lead author on the paper. "It allows animals to detect food and determine that food's quality, it provides social information like sexual status about other animals, and it can warn an animal when a predator is present. Because of the great similarities between humans and animals when it comes to the sense of smell, the more we learn about the building blocks of the system, the more we will learn about how odors affect our lives."
The noses of mice and most other mammals contain both a main and accessory olfactory system. These two systems work together to detect general odors, including food odors, as well as pheromones, which carry important social information between members of the same species. However, previous work had suggested that a third group of olfactory cells in the nose, named "GC-D neurons" for their expression of the molecule GC-D, might play a unique role in sensing the odor environment.
To investigate these novel cells in the nose, Dr. Munger, graduate student Renee Cockerham, and their colleagues engineered a line of mice in which GC-D neurons were specifically labeled, making them easier to identify and characterize. In some mice, the GC-D gene was also "knocked out" completely, allowing the cells to be turned off. They then asked what odors might activate GC-D cells by exposing them to various compounds present in mouse urine.
"Urine contains a rich mixture of social signals for animals, including odors that communicate information about sex, dominance and genetic identity," says Dr. Munger. "We found that GC-D neurons responded to peptide hormones, such as uroguanylin and guanylin, found in the urine. These hormones are known to be involved in regulating fluid and salt balance in the body. Additionally, we found that the GC-D molecule itself is required for the neurons to respond to those hormones, which means that, in the absence of GC-D, these animals are 'blind' to these odors."
"This is evidence of an entirely different olfactory system mixed in with the main system in mice," says Dr. Munger. "It carries a very specific type of odor information that may communicate hormonal states between individuals. It's basically a 'nose within the nose.'"
According to Dr. Munger, animals may be able to detect the metabolic state of other animals by using this olfactory subsystem. "This system may tell a mouse that his brother needs a drink and that they must look for water or that another mouse has just had a big meal so food must be nearby," he says. "Throughout human evolution and for most wild animals today, food and water are scarce resources that need to be detected. This olfactory system is a mechanism by which these types of communication can occur."
The GC-D system is unlikely to be functional in humans because of a disruption in a necessary gene. "Even though this specific system may not be functional in humans, it is clear that a number of other ones involved in chemical communication between individuals are present and working," says Dr. Munger. "Having a better understanding of the complexity of chemical communication across all mammals will give us important insights into how humans use their sense of smell. Odors not only enrich the experience of tasting wine, for example, but enrich our interactions with each other."
The study was done in collaboration with Drs. Trese Leinders-Zufall and Frank Zufall of the University of Saarland in Germany, Drs. Stylianos Michalakis and Martin Biel of the Ludwig-Maximilians University in Germany, Dr. David Garbers of the University of Texas-Southwestern Medical Center and Dr. Randall Reed of Johns Hopkins University.
Source: Rebecca Ceraul
University of Maryland Medical Center
"The sense of smell provides an important way for humans and animals to interact with their environment, as well as with other members of their species," says Steven Munger, Ph.D., associate professor of anatomy and neurobiology at the University of Maryland School of Medicine and lead author on the paper. "It allows animals to detect food and determine that food's quality, it provides social information like sexual status about other animals, and it can warn an animal when a predator is present. Because of the great similarities between humans and animals when it comes to the sense of smell, the more we learn about the building blocks of the system, the more we will learn about how odors affect our lives."
The noses of mice and most other mammals contain both a main and accessory olfactory system. These two systems work together to detect general odors, including food odors, as well as pheromones, which carry important social information between members of the same species. However, previous work had suggested that a third group of olfactory cells in the nose, named "GC-D neurons" for their expression of the molecule GC-D, might play a unique role in sensing the odor environment.
To investigate these novel cells in the nose, Dr. Munger, graduate student Renee Cockerham, and their colleagues engineered a line of mice in which GC-D neurons were specifically labeled, making them easier to identify and characterize. In some mice, the GC-D gene was also "knocked out" completely, allowing the cells to be turned off. They then asked what odors might activate GC-D cells by exposing them to various compounds present in mouse urine.
"Urine contains a rich mixture of social signals for animals, including odors that communicate information about sex, dominance and genetic identity," says Dr. Munger. "We found that GC-D neurons responded to peptide hormones, such as uroguanylin and guanylin, found in the urine. These hormones are known to be involved in regulating fluid and salt balance in the body. Additionally, we found that the GC-D molecule itself is required for the neurons to respond to those hormones, which means that, in the absence of GC-D, these animals are 'blind' to these odors."
"This is evidence of an entirely different olfactory system mixed in with the main system in mice," says Dr. Munger. "It carries a very specific type of odor information that may communicate hormonal states between individuals. It's basically a 'nose within the nose.'"
According to Dr. Munger, animals may be able to detect the metabolic state of other animals by using this olfactory subsystem. "This system may tell a mouse that his brother needs a drink and that they must look for water or that another mouse has just had a big meal so food must be nearby," he says. "Throughout human evolution and for most wild animals today, food and water are scarce resources that need to be detected. This olfactory system is a mechanism by which these types of communication can occur."
The GC-D system is unlikely to be functional in humans because of a disruption in a necessary gene. "Even though this specific system may not be functional in humans, it is clear that a number of other ones involved in chemical communication between individuals are present and working," says Dr. Munger. "Having a better understanding of the complexity of chemical communication across all mammals will give us important insights into how humans use their sense of smell. Odors not only enrich the experience of tasting wine, for example, but enrich our interactions with each other."
The study was done in collaboration with Drs. Trese Leinders-Zufall and Frank Zufall of the University of Saarland in Germany, Drs. Stylianos Michalakis and Martin Biel of the Ludwig-Maximilians University in Germany, Dr. David Garbers of the University of Texas-Southwestern Medical Center and Dr. Randall Reed of Johns Hopkins University.
Source: Rebecca Ceraul
University of Maryland Medical Center
суббота, 27 августа 2011 г.
Research On Enzyme For Activating Promising Disease-Fighters Co-Authored By Middle School Students
Grown-ups aren't the only ones making exciting scientific discoveries these days. Two middle school students from Wisconsin joined a team of scientists who are reporting the first glimpse of the innermost structure of a key bacterial enzyme. It helps activate certain antibiotics and anti-cancer agents so that those substances do their job. Their study appears in ACS' weekly journal Biochemistry. The student co-authors of the study are from Edgewood Campus Middle School in Madison and participated in Project CRYSTAL, a special program that provides middle school students with hands-on laboratory experience.
In the report, study leader Hazel Holden and colleagues note intense scientific interest in a chemical process called methylation, which increases the activity of DNA, proteins, and other substances in the body by transferring methyl (CH3) groups to them. Special enzymes called methyltransferases make methylation possible, and these proteins are very important in a myriad of key biological processes.
Holden and colleagues studied a bacterial methyltransferase involved in the production of tetronitrose, a component of the promising anti-cancer agent, tetrocarcin, and the antibiotic kijanimicin. The methyltransferase seems to play a key role in activating these disease-fighters. The scientists identified the 3D structure of this methyltransferase, a key step in determining how it works and how it might be modified for potential use in medicine.
Article: "Molecular Architecture of a C-3'-Methyltransferase Involved in the Biosynthesis of D-Tetronitrose"
Source:
Michael Bernstein
American Chemical Society
In the report, study leader Hazel Holden and colleagues note intense scientific interest in a chemical process called methylation, which increases the activity of DNA, proteins, and other substances in the body by transferring methyl (CH3) groups to them. Special enzymes called methyltransferases make methylation possible, and these proteins are very important in a myriad of key biological processes.
Holden and colleagues studied a bacterial methyltransferase involved in the production of tetronitrose, a component of the promising anti-cancer agent, tetrocarcin, and the antibiotic kijanimicin. The methyltransferase seems to play a key role in activating these disease-fighters. The scientists identified the 3D structure of this methyltransferase, a key step in determining how it works and how it might be modified for potential use in medicine.
Article: "Molecular Architecture of a C-3'-Methyltransferase Involved in the Biosynthesis of D-Tetronitrose"
Source:
Michael Bernstein
American Chemical Society
среда, 24 августа 2011 г.
Stretch A DNA Loop, Turn Off Proteins
It may look like mistletoe wrapped around a flexible candy cane. But this molecular model shows how some proteins form loops in DNA when they chemically attach, or bind, at separate sites to the double-helical molecule that carries life's genetic blueprint.
Biologists have discovered that the physical manifestation of DNA loops are a consequence of many biochemical processes in the cell, such as the regulation of gene expression. In other words, these loops indicate the presence of enzymes or other proteins that are turned on. Now physicists at the University of California, San Diego have discovered that stretching the DNA molecule can also turn off the proteins known to cause loops in DNA
"We showed that certain enzymes acting on DNA could be switched off or on simply by applying a small amount of mechanical tension across the DNA molecule," said Douglas Smith, an assistant professor of physics at UCSD who headed the team that published the discovery in the December issue of the Biophysical Journal. "We showed this by mechanically manipulating and stretching single DNA molecules. This switching effect could provide a molecular mechanism for cells to be able to sense and respond to mechanical stresses that they may normally experience. Such stresses could be generated internally by the cells themselves, such as when the cell undergoes changes in shape during the cell cycle, or as external stresses from the environment."
The amount of tension or stretching that needs to be applied to the molecule is extremely small, Smith added, only one pico-Newton, or one-trillionth of the force generated by the weight of an apple.
Other members of the UCSD team were Gregory Gemmen, a physics graduate student, and Rachel Millin, a laboratory assistant. The study was supported by grants from the Burroughs Wellcome Fund, Kinship Foundation and Arnold and Mabel Beckman Foundation.
Contact: Kim McDonald
University of California - San Diego
Biologists have discovered that the physical manifestation of DNA loops are a consequence of many biochemical processes in the cell, such as the regulation of gene expression. In other words, these loops indicate the presence of enzymes or other proteins that are turned on. Now physicists at the University of California, San Diego have discovered that stretching the DNA molecule can also turn off the proteins known to cause loops in DNA
"We showed that certain enzymes acting on DNA could be switched off or on simply by applying a small amount of mechanical tension across the DNA molecule," said Douglas Smith, an assistant professor of physics at UCSD who headed the team that published the discovery in the December issue of the Biophysical Journal. "We showed this by mechanically manipulating and stretching single DNA molecules. This switching effect could provide a molecular mechanism for cells to be able to sense and respond to mechanical stresses that they may normally experience. Such stresses could be generated internally by the cells themselves, such as when the cell undergoes changes in shape during the cell cycle, or as external stresses from the environment."
The amount of tension or stretching that needs to be applied to the molecule is extremely small, Smith added, only one pico-Newton, or one-trillionth of the force generated by the weight of an apple.
Other members of the UCSD team were Gregory Gemmen, a physics graduate student, and Rachel Millin, a laboratory assistant. The study was supported by grants from the Burroughs Wellcome Fund, Kinship Foundation and Arnold and Mabel Beckman Foundation.
Contact: Kim McDonald
University of California - San Diego
воскресенье, 21 августа 2011 г.
RNA Binding Proteins At Heart Of Problem In Myotonic Dystrophy Type 1
A new mouse model for myotonic dystrophy -- the most common form of adult-onset muscular dystrophy -- helped Baylor College of Medicine researchers show that levels of CUGBP1, a protein that binds and controls the activity of the genetic material RNA, increase early in affected cells of the animals with the disease. This means CUGBP1 plays a key role in the disorder.
"We wanted to find out if this is a primary event associated with the disorder or if it is a secondary response to tissue injury," said Dr. Thomas A. Cooper, professor of pathology at BCM and senior author of the report that appears in the Journal of Clinical Investigation.
Myotonic dystrophy type 1 is associated with hundreds and even thousands of repeats of the nucleotides CTG within a gene called DM kinase protein gene or DMPK. [Cytosine (C), thymine (T), guanine (G) and adenine (A) are all nucleotides that make up DNA. C, G, A, and uracil (U) make up RNA.] In the mouse that Cooper and his colleagues specially bred, the repeats in the gene can be turned on in heart, skeletal muscle and brain tissue at any age.
The researchers found that within three hours of turning on the repeats, another RNA-binding protein called muscleblind like (MBNL) began to bind the genetic material in the nucleus of the cell. That mean the RNA was trapped in the nucleus and unable to take the genetic message about which proteins to make to the protein manufacturing areas in the cytoplasm of the cell.
Within six hours, levels of CUGBP1 begin to increase. The increased in CUGBP1 then alters how a number of other genes are regulated. At that point, the cascade of events that affect the heart starts.
"The heart doesn't even 'know' that it is sick yet," said Cooper. This finding shows that the increase levels of CUGBP1 is an early event and plays an important role in the development of the disease.
Others who took part in this research include Drs. Guey-Shin Wang, Debra L. Kearney, Mariella De Biasi and George Taffet, all of BCM. Funding for this research came from the National Institutes of Health and the Muscular Dystrophy Association.
Source: Graciela Gutierrez
Baylor College of Medicine
"We wanted to find out if this is a primary event associated with the disorder or if it is a secondary response to tissue injury," said Dr. Thomas A. Cooper, professor of pathology at BCM and senior author of the report that appears in the Journal of Clinical Investigation.
Myotonic dystrophy type 1 is associated with hundreds and even thousands of repeats of the nucleotides CTG within a gene called DM kinase protein gene or DMPK. [Cytosine (C), thymine (T), guanine (G) and adenine (A) are all nucleotides that make up DNA. C, G, A, and uracil (U) make up RNA.] In the mouse that Cooper and his colleagues specially bred, the repeats in the gene can be turned on in heart, skeletal muscle and brain tissue at any age.
The researchers found that within three hours of turning on the repeats, another RNA-binding protein called muscleblind like (MBNL) began to bind the genetic material in the nucleus of the cell. That mean the RNA was trapped in the nucleus and unable to take the genetic message about which proteins to make to the protein manufacturing areas in the cytoplasm of the cell.
Within six hours, levels of CUGBP1 begin to increase. The increased in CUGBP1 then alters how a number of other genes are regulated. At that point, the cascade of events that affect the heart starts.
"The heart doesn't even 'know' that it is sick yet," said Cooper. This finding shows that the increase levels of CUGBP1 is an early event and plays an important role in the development of the disease.
Others who took part in this research include Drs. Guey-Shin Wang, Debra L. Kearney, Mariella De Biasi and George Taffet, all of BCM. Funding for this research came from the National Institutes of Health and the Muscular Dystrophy Association.
Source: Graciela Gutierrez
Baylor College of Medicine
четверг, 18 августа 2011 г.
The Effect On Muscle Repair And Regeneration Of Cholesterol-Lowering Drugs
Statins are powerful drugs that reduce "bad" cholesterol and thus cut the risk of a heart attack. While these medications offer tremendous benefits to millions, they can carry side effects for some. The most frequently reported consequence is fatigue, and about nine percent of patients report statin-related pain. Both can be exacerbated when statin doses are increased, or physical activity is added. The results of a new study may offer another note of caution for high-dose statin patients. Working with primary human satellite cell cultures, researchers have found that statins at higher doses may affect the ability of the skeletal muscles - which allow the body to move - to repair and regenerate themselves.
The study is entitled "Simvastatin Reduces Human Primary Satellite Cell Proliferation in Culture." It was conducted by Anna Thalacker-Mercer, Melissa Baker, Chris Calderon and Marcas Bamman, University of Alabama at Birmingham. They will discuss their findings at the American Physiological Society (APS; The-APS) conference, The Integrative Biology of Exercise V. The meeting is being held September 24-27, 2008 in Hilton Head, SC.
The Study
Statins have been reported to have adverse effects on skeletal muscle in both human and animal models causing cramping and fatigue and potentially myopathy. Relatively little is known regarding the effect of statins on the muscle progenitor cells (i.e., satellite cells (SC)) which play a key role in skeletal muscle repair and regeneration following exercise or injury. SC remain in a quiescent state until stimulated to proliferate. Statins are known to have antiproliferative effects in other cell types and therefore may inhibit or effect this critical step in muscle repair. Thus it is important to understand the influence of statins on SC function which may further affect the overall health and physiology of human skeletal muscle..
The study examined the proliferative capacity of human satellite cells in culture, which were exposed, to a lipophilic statin: simvastatin. The aim of the study was to determine SC viability during proliferation when treated with statins which may be indicative of the ability of SCs to undergo mitosis (i.e. divide to make new cells).
The research team used primary cell lines isolated from quadriceps muscle biopsies. SC were mixed and grown for 48 hours with several concentrations of statin: 0.0, 0 plus the solvent DMSO (control), 0.05, 0.1, 1.0, 10, or 100ВµM. The MTS assay was utilized to measure cell viability/reproducibility.
Additionally the investigators determined the effects of varying concentrations of simvastatin on SCs in different states (i.e., undergoing differentiation or differentiated into myotubes).
Key Findings
The researchers found the following:
There was a dose dependent decrease in the viability of the satellite cells at 1.0, 10 and 100ВµM concentrations of simvastatin. At approximately 5.0 ВµM concentration the viability of the proliferating cells was reduced by 50% (equivalent to the availability of simvastatin in circulation from a 40 milligram dose per day used in some patients). Specifically, the higher end concentrations led to reduced SC proliferation, which would likely negatively affect the muscle's ability to heal and/or repair itself.
There was no change in the viability of satellite cells at concentrations of 0.05 or 0.1ВµM.
Cell viability was reduced by approximately half in differentiating cells and myotubes with concentrations of 1.0 and 5.0 ВµM, respectively.
Next Steps
According to Dr. Thalacker-Mercer, a member of the research team, "While these are preliminary data and more research is necessary, the results indicate serious adverse effects of statins that may alter the ability of skeletal muscle to repair and regenerate due to the anti-proliferative effects of statins."
Looking ahead, she added, "We are very interested in these effects in the older population. It is possible that older adults may not be able to distinguish between muscle pain related to a statin effect or an effect of aging and therefore adverse effects of statins in older adults may be under-reported. Therefore, our next step is to examine statins among older adults."
Physiology is the study of how molecules, cells, tissues and organs function to create health or disease. The American Physiological Society (APS; The-APS/press) has been an integral part of this discovery process since it was established in 1887.
The APS Conference, The Integrative Biology of Exercise V, is being held September 24-27, 2008 in Hilton Head, SC.
Source: Donna Krupa
American Physiological Society
The study is entitled "Simvastatin Reduces Human Primary Satellite Cell Proliferation in Culture." It was conducted by Anna Thalacker-Mercer, Melissa Baker, Chris Calderon and Marcas Bamman, University of Alabama at Birmingham. They will discuss their findings at the American Physiological Society (APS; The-APS) conference, The Integrative Biology of Exercise V. The meeting is being held September 24-27, 2008 in Hilton Head, SC.
The Study
Statins have been reported to have adverse effects on skeletal muscle in both human and animal models causing cramping and fatigue and potentially myopathy. Relatively little is known regarding the effect of statins on the muscle progenitor cells (i.e., satellite cells (SC)) which play a key role in skeletal muscle repair and regeneration following exercise or injury. SC remain in a quiescent state until stimulated to proliferate. Statins are known to have antiproliferative effects in other cell types and therefore may inhibit or effect this critical step in muscle repair. Thus it is important to understand the influence of statins on SC function which may further affect the overall health and physiology of human skeletal muscle..
The study examined the proliferative capacity of human satellite cells in culture, which were exposed, to a lipophilic statin: simvastatin. The aim of the study was to determine SC viability during proliferation when treated with statins which may be indicative of the ability of SCs to undergo mitosis (i.e. divide to make new cells).
The research team used primary cell lines isolated from quadriceps muscle biopsies. SC were mixed and grown for 48 hours with several concentrations of statin: 0.0, 0 plus the solvent DMSO (control), 0.05, 0.1, 1.0, 10, or 100ВµM. The MTS assay was utilized to measure cell viability/reproducibility.
Additionally the investigators determined the effects of varying concentrations of simvastatin on SCs in different states (i.e., undergoing differentiation or differentiated into myotubes).
Key Findings
The researchers found the following:
There was a dose dependent decrease in the viability of the satellite cells at 1.0, 10 and 100ВµM concentrations of simvastatin. At approximately 5.0 ВµM concentration the viability of the proliferating cells was reduced by 50% (equivalent to the availability of simvastatin in circulation from a 40 milligram dose per day used in some patients). Specifically, the higher end concentrations led to reduced SC proliferation, which would likely negatively affect the muscle's ability to heal and/or repair itself.
There was no change in the viability of satellite cells at concentrations of 0.05 or 0.1ВµM.
Cell viability was reduced by approximately half in differentiating cells and myotubes with concentrations of 1.0 and 5.0 ВµM, respectively.
Next Steps
According to Dr. Thalacker-Mercer, a member of the research team, "While these are preliminary data and more research is necessary, the results indicate serious adverse effects of statins that may alter the ability of skeletal muscle to repair and regenerate due to the anti-proliferative effects of statins."
Looking ahead, she added, "We are very interested in these effects in the older population. It is possible that older adults may not be able to distinguish between muscle pain related to a statin effect or an effect of aging and therefore adverse effects of statins in older adults may be under-reported. Therefore, our next step is to examine statins among older adults."
Physiology is the study of how molecules, cells, tissues and organs function to create health or disease. The American Physiological Society (APS; The-APS/press) has been an integral part of this discovery process since it was established in 1887.
The APS Conference, The Integrative Biology of Exercise V, is being held September 24-27, 2008 in Hilton Head, SC.
Source: Donna Krupa
American Physiological Society
понедельник, 15 августа 2011 г.
Liposome finding implies electrical effect on cell development
Experiments with liposomes - cell-like "water balloons" composed of artificially created phospholipid bilayers similar to
natural cell membranes - have revealed unexpected behavior in the presence of electrical fields that may provide a
paradigm-shifting change in science's understanding of biomembrane function in operating living systems.
Arizona State University chemists Mark Hayes and Michele Pysher have found that liposomes have a tendency to form tube-like
extensions in their membranes through the influence of local electrical fields. In particular, the surprising finding of such
electrically caused bionanotubule formation may reveal a previously unknown process involved in the development of structures
like axons and dendrites in nerve cells.
Hayes will present the results of the experiments at a 2 p.m. March 15 session entitled "Colloids in Complex Fluids" at the
American Chemical Society meeting in San Diego.
In the experiments, the researchers placed liposomes in a droplet of water and applied very low electric fields (5-10 volts
per centimeter), much lower than the fields present in operating neurons (a fraction of a volt but operating over a very
short distance--less than a micron--to produce a field up to one thousand times stronger). In images achieved through optical
and scanning electron microscopy, microtubules were observed to immediately form and extend from the phospholipid balloon,
like a seed putting forth a stalk or root.
Hayes believes that the phenomena may have significant implications for both cellular biology and for nanotechnology. "This
finding might not only be important in its application to understanding life processes, but it has a potentially exciting
practical application in the fabrication of bionanotubes," he said.
Source: Mark Hayes, 480-965-2566; 480-620-0193 (cell)
Images/video: bionanotubes.homestead
Contact: James Hathaway
hathawayasu
480-965-6375
Arizona State University
asu/asunews
natural cell membranes - have revealed unexpected behavior in the presence of electrical fields that may provide a
paradigm-shifting change in science's understanding of biomembrane function in operating living systems.
Arizona State University chemists Mark Hayes and Michele Pysher have found that liposomes have a tendency to form tube-like
extensions in their membranes through the influence of local electrical fields. In particular, the surprising finding of such
electrically caused bionanotubule formation may reveal a previously unknown process involved in the development of structures
like axons and dendrites in nerve cells.
Hayes will present the results of the experiments at a 2 p.m. March 15 session entitled "Colloids in Complex Fluids" at the
American Chemical Society meeting in San Diego.
In the experiments, the researchers placed liposomes in a droplet of water and applied very low electric fields (5-10 volts
per centimeter), much lower than the fields present in operating neurons (a fraction of a volt but operating over a very
short distance--less than a micron--to produce a field up to one thousand times stronger). In images achieved through optical
and scanning electron microscopy, microtubules were observed to immediately form and extend from the phospholipid balloon,
like a seed putting forth a stalk or root.
Hayes believes that the phenomena may have significant implications for both cellular biology and for nanotechnology. "This
finding might not only be important in its application to understanding life processes, but it has a potentially exciting
practical application in the fabrication of bionanotubes," he said.
Source: Mark Hayes, 480-965-2566; 480-620-0193 (cell)
Images/video: bionanotubes.homestead
Contact: James Hathaway
hathawayasu
480-965-6375
Arizona State University
asu/asunews
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