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
четверг, 29 сентября 2011 г.
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
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