Neuroscience

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Posts tagged medicine

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Discovery opens door to new drug options for serious diseases Researchers have discovered how oxidative stress can turn to the dark side a cellular protein that’s usually benign, and make it become a powerful, unwanted accomplice in neuronal death. This finding, reported in Proceedings of the National Academy of Sciences, could ultimately lead to new therapeutic approaches to many of the world’s debilitating or fatal diseases. The research explains how one form of oxidative stress called tyrosine nitration can lead to cell death. Through the common link of inflammation, this may relate to health problems ranging from heart disease to chronic pain, spinal injury, cancer, aging, and amyotrophic lateral sclerosis, or Lou Gehrig’s disease. As part of the work, the scientists also identified a specific “chaperone” protein damaged by oxidants, which is getting activated in this spiral of cellular decline and death. This insight will provide a new approach to design therapeutic drugs. The findings were published by scientists from the Linus Pauling Institute at Oregon State University; Maria Clara Franco and Alvaro Estevez, now at the University of Central Florida; and researchers from several other institutions. They culminate a decade of work. “These are very exciting results and could begin a major shift in medicine,” said Joseph Beckman. Beckman is an LPI principal investigator, distinguished professor of biochemistry, and director of the OSU Environmental Health Sciences Center. He also last year received the Discovery Award from the Medical Research Foundation of Oregon, given to the leading medical scientist in the state. “Preventing this process of tyrosine nitration may protect against a wide range of degenerative diseases,” Beckman said. “The study shows that drugs could effectively target oxidatively damaged proteins.” Scientists have known for decades about the general concept of oxidative damage to cells, resulting in neurodegeneration, inflammation and aging. But the latest findings prove that some molecules in a cell are thousands of times more sensitive to attack. In this case, heat shock protein 90, or HSP90, helps monitor and chaperone as many as 200 necessary cell functions. But it can acquire a toxic function after nitration of a single tyrosine residue. “It was difficult to believe that adding one nitro group to one protein will make it toxic enough to kill a motor neuron,” Beckman said. “But nitration of HSP90 was shown to activate a pro-inflammatory receptor called P2X7. This begins a dangerous spiral that eventually leads to the death of motor neurons.” The very specificity of this attack, however, is part of what makes the new findings important. Drugs that could prevent or reduce oxidative attack on these most vulnerable sites in a cell might have value against a wide range of diseases. “Most people think of things like heart disease, cancer, aging, liver disease, even the damage from spinal injury as completely different medical issues,” Beckman said. “To the extent they can often be traced back to inflammatory processes that are caused by oxidative attack and cellular damage, they can be more similar than different. “It could be possible to develop therapies with value against many seemingly different health problems,” Beckman added. Beckman has spent much of his career studying the causes of amyotrophic lateral sclerosis, and this study suggested the processes outlined in this study might be relevant both to that disease and spinal cord injury. One key to this research involved new methods that allowed researchers to genetically engineer nitrotyrosine into HSP90. This allowed scientists to pin down the exact areas of damage, which may be important in the identification of drugs that could affect this process, the researchers said.

Discovery opens door to new drug options for serious diseases

Researchers have discovered how oxidative stress can turn to the dark side a cellular protein that’s usually benign, and make it become a powerful, unwanted accomplice in neuronal death.

This finding, reported in Proceedings of the National Academy of Sciences, could ultimately lead to new therapeutic approaches to many of the world’s debilitating or fatal diseases.

The research explains how one form of oxidative stress called tyrosine nitration can lead to cell death. Through the common link of inflammation, this may relate to health problems ranging from heart disease to chronic pain, spinal injury, cancer, aging, and amyotrophic lateral sclerosis, or Lou Gehrig’s disease.

As part of the work, the scientists also identified a specific “chaperone” protein damaged by oxidants, which is getting activated in this spiral of cellular decline and death. This insight will provide a new approach to design therapeutic drugs.

The findings were published by scientists from the Linus Pauling Institute at Oregon State University; Maria Clara Franco and Alvaro Estevez, now at the University of Central Florida; and researchers from several other institutions. They culminate a decade of work.

“These are very exciting results and could begin a major shift in medicine,” said Joseph Beckman.

Beckman is an LPI principal investigator, distinguished professor of biochemistry, and director of the OSU Environmental Health Sciences Center. He also last year received the Discovery Award from the Medical Research Foundation of Oregon, given to the leading medical scientist in the state.

“Preventing this process of tyrosine nitration may protect against a wide range of degenerative diseases,” Beckman said. “The study shows that drugs could effectively target oxidatively damaged proteins.”

Scientists have known for decades about the general concept of oxidative damage to cells, resulting in neurodegeneration, inflammation and aging. But the latest findings prove that some molecules in a cell are thousands of times more sensitive to attack.

In this case, heat shock protein 90, or HSP90, helps monitor and chaperone as many as 200 necessary cell functions. But it can acquire a toxic function after nitration of a single tyrosine residue.

“It was difficult to believe that adding one nitro group to one protein will make it toxic enough to kill a motor neuron,” Beckman said. “But nitration of HSP90 was shown to activate a pro-inflammatory receptor called P2X7. This begins a dangerous spiral that eventually leads to the death of motor neurons.”

The very specificity of this attack, however, is part of what makes the new findings important. Drugs that could prevent or reduce oxidative attack on these most vulnerable sites in a cell might have value against a wide range of diseases.

“Most people think of things like heart disease, cancer, aging, liver disease, even the damage from spinal injury as completely different medical issues,” Beckman said. “To the extent they can often be traced back to inflammatory processes that are caused by oxidative attack and cellular damage, they can be more similar than different.

“It could be possible to develop therapies with value against many seemingly different health problems,” Beckman added.

Beckman has spent much of his career studying the causes of amyotrophic lateral sclerosis, and this study suggested the processes outlined in this study might be relevant both to that disease and spinal cord injury.

One key to this research involved new methods that allowed researchers to genetically engineer nitrotyrosine into HSP90. This allowed scientists to pin down the exact areas of damage, which may be important in the identification of drugs that could affect this process, the researchers said.

Filed under cell death tyrosine nitration neurodegenerative diseases oxidants medicine science

72 notes

A proposed link between aging, autism, and oxidation Like any fac­tory, the body burns oxygen to get energy for its var­ious needs. As a result, detri­mental byprod­ucts are released and our cells try to clean up shop with antiox­i­dants. But as we age, this process becomes a losing battle. “Oxi­da­tion inex­orably moves us along toward an oxi­dized state,” said phar­ma­ceu­tical sci­ences pro­fessor Richard Deth. “You have to deal with it progressively.” One option is to slow down the syn­thesis of new pro­teins, a process that requires energy. Indeed, as we age, we pro­duce fewer new pro­teins, which explains why our capacity for learning and healing suffer as we grow old. Since every pro­tein orig­i­nates from instruc­tions in the DNA, pro­tein syn­thesis can be slowed down by turning off par­tic­ular genes. A process called epi­ge­netic reg­u­la­tion accom­plishes the task by adding mol­e­c­ular tags on top of the genome. The pro­tein methio­nine syn­thase reg­u­lates this process. But what reg­u­lates methio­nine syn­thase? Oxidation. “This enzyme is the most easily oxi­dized mol­e­cule in the body,” said Deth, whose research on the sub­ject was recently pub­lished in the journal PLOS ONE. The senior author for the study, Christina Mura­tore, received her doc­torate in phar­ma­ceu­tical sci­ences from North­eastern in 2010. When­ever the body is under oxida­tive stress, Deth explained, methio­nine syn­thase, or MS, stops working. He and his team hypoth­e­sized that MS plays an impor­tant reg­u­la­tory role in aging and that it might be impaired in autism, which Deth has con­nected to unchecked oxida­tive stress in pre­vious research. To examine their hypoth­esis, the researchers looked at post­mortem human brain sam­ples across the lifespan, with sub­jects as young as 28 weeks of fetal devel­op­ment to as old as 84 years. They mea­sured the levels of a mol­e­cule called MS mRNA, which tran­scribes the genetic code for methio­nine syn­thase into actual protein. As the sub­jects aged, their brain tissue showed lower levels of MS mRNA. But, sur­pris­ingly, the levels of the pro­tein itself remained con­stant across the lifespan. Deth and his col­leagues sus­pect that this observed decrease in MS mRNA over our lives may act as a check in the system to save energy that we no longer have in plen­tiful supply and to slow down oxida­tive stress. “One way that the system can guard against too much pro­tein syn­thesis is to restrict the amount of mRNA,” Deth said. The team also com­pared MS pro­tein and mRNA levels between brain tissue sam­ples from autistic and nor­mally devel­oping sub­jects. Autistic brains had markedly less MS mRNA than the con­trol sam­ples but sim­ilar pro­tein levels. Addi­tion­ally, the age-​​dependent trend seen in nor­mally devel­oping brains was not mim­icked among the autistic sample. If decreased MS mRNA does mean decreased pro­tein pro­duc­tion, it’s no big deal for adults who don’t need to make new pro­teins as often. But for the devel­oping brain, new pro­teins are crit­ical. “Your capacity for learning might be pre­ma­turely reduced because meta­bol­i­cally you can’t afford it,” Deth suggested. While the results are pre­lim­i­nary and will ben­efit from repeated studies and more inves­ti­ga­tion, Deth’s find­ings add to a growing body of evi­dence linking both aging and autism to oxida­tive stress.

A proposed link between aging, autism, and oxidation

Like any fac­tory, the body burns oxygen to get energy for its var­ious needs. As a result, detri­mental byprod­ucts are released and our cells try to clean up shop with antiox­i­dants. But as we age, this process becomes a losing battle.

“Oxi­da­tion inex­orably moves us along toward an oxi­dized state,” said phar­ma­ceu­tical sci­ences pro­fessor Richard Deth. “You have to deal with it progressively.”

One option is to slow down the syn­thesis of new pro­teins, a process that requires energy. Indeed, as we age, we pro­duce fewer new pro­teins, which explains why our capacity for learning and healing suffer as we grow old.

Since every pro­tein orig­i­nates from instruc­tions in the DNA, pro­tein syn­thesis can be slowed down by turning off par­tic­ular genes. A process called epi­ge­netic reg­u­la­tion accom­plishes the task by adding mol­e­c­ular tags on top of the genome. The pro­tein methio­nine syn­thase reg­u­lates this process. But what reg­u­lates methio­nine syn­thase? Oxidation.

“This enzyme is the most easily oxi­dized mol­e­cule in the body,” said Deth, whose research on the sub­ject was recently pub­lished in the journal PLOS ONE. The senior author for the study, Christina Mura­tore, received her doc­torate in phar­ma­ceu­tical sci­ences from North­eastern in 2010.

When­ever the body is under oxida­tive stress, Deth explained, methio­nine syn­thase, or MS, stops working. He and his team hypoth­e­sized that MS plays an impor­tant reg­u­la­tory role in aging and that it might be impaired in autism, which Deth has con­nected to unchecked oxida­tive stress in pre­vious research.

To examine their hypoth­esis, the researchers looked at post­mortem human brain sam­ples across the lifespan, with sub­jects as young as 28 weeks of fetal devel­op­ment to as old as 84 years. They mea­sured the levels of a mol­e­cule called MS mRNA, which tran­scribes the genetic code for methio­nine syn­thase into actual protein.

As the sub­jects aged, their brain tissue showed lower levels of MS mRNA. But, sur­pris­ingly, the levels of the pro­tein itself remained con­stant across the lifespan.

Deth and his col­leagues sus­pect that this observed decrease in MS mRNA over our lives may act as a check in the system to save energy that we no longer have in plen­tiful supply and to slow down oxida­tive stress. “One way that the system can guard against too much pro­tein syn­thesis is to restrict the amount of mRNA,” Deth said.

The team also com­pared MS pro­tein and mRNA levels between brain tissue sam­ples from autistic and nor­mally devel­oping sub­jects. Autistic brains had markedly less MS mRNA than the con­trol sam­ples but sim­ilar pro­tein levels. Addi­tion­ally, the age-​​dependent trend seen in nor­mally devel­oping brains was not mim­icked among the autistic sample.

If decreased MS mRNA does mean decreased pro­tein pro­duc­tion, it’s no big deal for adults who don’t need to make new pro­teins as often. But for the devel­oping brain, new pro­teins are crit­ical. “Your capacity for learning might be pre­ma­turely reduced because meta­bol­i­cally you can’t afford it,” Deth suggested.

While the results are pre­lim­i­nary and will ben­efit from repeated studies and more inves­ti­ga­tion, Deth’s find­ings add to a growing body of evi­dence linking both aging and autism to oxida­tive stress.

Filed under brain oxidation autism brain tissue lifespan antioxidants protein synthesis aging medicine science

80 notes

Adding to the list of disease-causing proteins in brain disorders A multi-institution group of researchers has found new candidate disease proteins for neurodegenerative disorders. James Shorter, Ph.D., assistant professor of Biochemistry and Biophysics at the Perelman School of Medicine, University of Pennsylvania, Paul Taylor, M.D., PhD, St. Jude Children’s Research Hospital, and colleagues describe in an advanced online publication of Nature that mutations in prion-like segments of two RNA-binding proteins are associated with a rare inherited degeneration disorder affecting muscle, brain, motor neurons and bone (called multisystem proteinopathy) and one case of the familial form of amyotrophic lateral sclerosis (ALS). "This study uses a variety of scientific approaches to provide powerful evidence that unregulated polymerization of proteins involved in RNA metabolism may contribute to ALS and related diseases," said Amelie Gubitz, Ph.D., a program director at the National Institute of Neurological Disorders and Stroke (NINDS). ALS, or Lou Gehrig’s disease, is a universally fatal neurodegenerative disease. Previous studies found that mutations in two related RNA-binding proteins, TDP-43 and FUS, cause some forms of ALS, but more proteins were suspected of causing other forms of the disease. TDP-43 and FUS regulate how the genetic code is translated for the assembly of proteins. There are over 200 human RNA-binding proteins, including FUS and TDP-43, raising the possibility that additional RNA-binding proteins might contribute to ALS pathology. Computer algorithms, based on protein sequences, designed to identify yeast prions predict that around 250 human proteins, including several RNA-binding proteins associated with neurodegenerative disease, harbor a distinctive prion-like segment. These segments are essential for the assembly of certain protein complexes. But, the interplay between human prion-like segments and disease is not well understood. Using yeast as a model organism, co-author Aaron Gitler, while at Penn in 2011, surveyed 133 of 200-plus candidate human RNA-binding proteins to predict new ALS disease genes, other than TDP-43 and FUS. They further winnowed the candidates to about 10 proteins with prion-like segments, and selected two candidates, TAF15 and EWSR1, for further study. Both TAF15 and EWSR1 aggregated in the test tube and were toxic in yeast. Remarkably, they also uncovered TAF15 and EWSR1 mutations in ALS patients that were not found in healthy individuals. Based on these findings, they proposed that RNA-binding proteins with prion-like segments might contribute very broadly to the pathology of ALS and related brain disorders. Characterizing the Top-Ten Taylor, Gitler, Shorter, and others continued to characterize the top-ten human RNA-binding proteins with prion-like segments. The Nature study describes that two more of the top-ten candidates, called hnRNPA1 and hnRNPA2B1, are mutated and cause familial cases of brain disease. The mutations in hnRNPA1 and hnRNPA2B1 were present in two families with an extremely rare inherited degeneration affecting muscle, brain, motor neuron, and bone and another from a person with familial ALS. Mutations in these two proteins fell in the prion-like segments and coincided with “sticky” regions in the proteins, making these regions more prone to assemble into self-organizing fibrils. The normal form of the proteins shows a natural tendency to assemble into fibrils, which is exacerbated by the disease mutations. "The mutations accelerate the formation of the fibrils that recruit normal protein to form more fibrils," noted co-first author Emily Scarborough, from Penn. This dysregulated assembly likely contributes to disease. Indeed, the disease mutations also promote excess incorporation of the proteins into stress granules within a cell and the formation of clumps in the cells of animal models of human neurodegenerative disease. "Neurodegenerative disease could ensue from unregulated fibril formation initiated spontaneously by environmental stress or another factor that regulates a protein’s assembly," says Scarborough. "This paper reflects an amazing collaborative effort and provides a great example of how understanding the underlying pure protein biochemistry can help explain how genetic mutations might cause pathology and disease," says Shorter. "The findings confirm a strong prediction that the disease-causing mutations make the prion-like segment ‘stickier’ and more prone to clump," added co-first author Zamia Diaz, also from Penn. Diseases associated with fibrils forming from prion-like domains in proteins frequently show “spreading” pathology, in which cellular degeneration via inclusions starts in one center of the brain and “spreads” to neighboring tissue. Although not directly addressed in the Nature study, the findings suggest that cell-to-cell transmission of a self-templating protein could contribute to the spreading pathology that is characteristic of these diseases. "Related proteins with prion-like domains must be considered candidates for initiating and perhaps propagating similar pathologies in muscle, brain, motor neurons, and bone," concluded Shorter.

Adding to the list of disease-causing proteins in brain disorders

A multi-institution group of researchers has found new candidate disease proteins for neurodegenerative disorders. James Shorter, Ph.D., assistant professor of Biochemistry and Biophysics at the Perelman School of Medicine, University of Pennsylvania, Paul Taylor, M.D., PhD, St. Jude Children’s Research Hospital, and colleagues describe in an advanced online publication of Nature that mutations in prion-like segments of two RNA-binding proteins are associated with a rare inherited degeneration disorder affecting muscle, brain, motor neurons and bone (called multisystem proteinopathy) and one case of the familial form of amyotrophic lateral sclerosis (ALS).

"This study uses a variety of scientific approaches to provide powerful evidence that unregulated polymerization of proteins involved in RNA metabolism may contribute to ALS and related diseases," said Amelie Gubitz, Ph.D., a program director at the National Institute of Neurological Disorders and Stroke (NINDS).

ALS, or Lou Gehrig’s disease, is a universally fatal neurodegenerative disease. Previous studies found that mutations in two related RNA-binding proteins, TDP-43 and FUS, cause some forms of ALS, but more proteins were suspected of causing other forms of the disease. TDP-43 and FUS regulate how the genetic code is translated for the assembly of proteins.

There are over 200 human RNA-binding proteins, including FUS and TDP-43, raising the possibility that additional RNA-binding proteins might contribute to ALS pathology. Computer algorithms, based on protein sequences, designed to identify yeast prions predict that around 250 human proteins, including several RNA-binding proteins associated with neurodegenerative disease, harbor a distinctive prion-like segment. These segments are essential for the assembly of certain protein complexes. But, the interplay between human prion-like segments and disease is not well understood.

Using yeast as a model organism, co-author Aaron Gitler, while at Penn in 2011, surveyed 133 of 200-plus candidate human RNA-binding proteins to predict new ALS disease genes, other than TDP-43 and FUS. They further winnowed the candidates to about 10 proteins with prion-like segments, and selected two candidates, TAF15 and EWSR1, for further study. Both TAF15 and EWSR1 aggregated in the test tube and were toxic in yeast.

Remarkably, they also uncovered TAF15 and EWSR1 mutations in ALS patients that were not found in healthy individuals. Based on these findings, they proposed that RNA-binding proteins with prion-like segments might contribute very broadly to the pathology of ALS and related brain disorders.

Characterizing the Top-Ten

Taylor, Gitler, Shorter, and others continued to characterize the top-ten human RNA-binding proteins with prion-like segments. The Nature study describes that two more of the top-ten candidates, called hnRNPA1 and hnRNPA2B1, are mutated and cause familial cases of brain disease. The mutations in hnRNPA1 and hnRNPA2B1 were present in two families with an extremely rare inherited degeneration affecting muscle, brain, motor neuron, and bone and another from a person with familial ALS.

Mutations in these two proteins fell in the prion-like segments and coincided with “sticky” regions in the proteins, making these regions more prone to assemble into self-organizing fibrils. The normal form of the proteins shows a natural tendency to assemble into fibrils, which is exacerbated by the disease mutations.

"The mutations accelerate the formation of the fibrils that recruit normal protein to form more fibrils," noted co-first author Emily Scarborough, from Penn. This dysregulated assembly likely contributes to disease. Indeed, the disease mutations also promote excess incorporation of the proteins into stress granules within a cell and the formation of clumps in the cells of animal models of human neurodegenerative disease.

"Neurodegenerative disease could ensue from unregulated fibril formation initiated spontaneously by environmental stress or another factor that regulates a protein’s assembly," says Scarborough.

"This paper reflects an amazing collaborative effort and provides a great example of how understanding the underlying pure protein biochemistry can help explain how genetic mutations might cause pathology and disease," says Shorter.

"The findings confirm a strong prediction that the disease-causing mutations make the prion-like segment ‘stickier’ and more prone to clump," added co-first author Zamia Diaz, also from Penn.

Diseases associated with fibrils forming from prion-like domains in proteins frequently show “spreading” pathology, in which cellular degeneration via inclusions starts in one center of the brain and “spreads” to neighboring tissue. Although not directly addressed in the Nature study, the findings suggest that cell-to-cell transmission of a self-templating protein could contribute to the spreading pathology that is characteristic of these diseases.

"Related proteins with prion-like domains must be considered candidates for initiating and perhaps propagating similar pathologies in muscle, brain, motor neurons, and bone," concluded Shorter.

Filed under neurodegenerative diseases motor neurons proteins Lou Gehrig's disease RNA metabolism medicine science

60 notes

New chemical probe provides tool to investigate role of malignant brain tumor domains In an article published as the cover story of the March 2013 issue of Nature Chemical Biology, Lindsey James, PhD, research assistant professor in the lab of Stephen Frye, Fred Eshelman Distinguished Professor in the UNC School of Pharmacy and member of the UNC Lineberger Comprehensive Cancer Center, announced the discovery of a chemical probe that can be used to investigate the L3MBTL3 methyl-lysine reader domain. The probe, named UNC1215, will provide researchers with a powerful tool to investigate the function of malignant brain tumor (MBT) domain proteins in biology and disease. “Before this there were no known chemical probes for the more than 200 domains in the human genome that recognize methyl lysine. In that regard, it is a first in class compound. The goal is to use the chemical probe to understand the biology of the proteins that it targets,” said Dr. James. Chromatin regulatory pathways play a fundamental role in gene expression and disease development, especially in the case of cancer. While many chemical probes work through the inhibition of enzyme activity, L3MBTL3 functions as a mediator of protein-to-protein interactions, which have been historically difficult to target with small, drug-like molecules.The researchers found three to four further disease subtypes within TN tumors, with more than 75 percent of the tumors falling into the basal-like subtype. Further research is needed to identify the distinct biomarkers shared by the expanded subtypes of TN cancers. The ultimate goal will be to target the individual biomarkers of these subtypes and create therapies that target their individual biology, according to Dr. Perou. “Many people believe that protein-protein interactions are difficult to target. Often they have a large surface area, so it is hard for small molecules to go in and intervene,” said Dr. James. Almost 40 percent of the genes that drive cancer can be mapped to dysfunction within signaling pathways. In the last five years, chemical probe development has allowed researchers to make fundamental observations of the role of these pathways in cancer development, as well as pointing to potential targets for new therapies. Each of the complex interactions within the signaling pathways represents a potential point where a therapy can be applied, and the probes allow researchers to interact with these processes at the molecular level and observe the overall effect of their perturbation on the disease state. In a 2008 Nature Chemical Biology commentary, Dr. Frye outlined the qualities that make a good chemical probe. To Frye, a good chemical probe must be highly selective to enable specific questions to be asked and it must function as well in a cell as in the test tube, providing clear quantitative data with a well understood mechanism of action in either situation. It also must be available to all academic researchers without restrictions on its use, a criteria that the L3MBTL3 probe fulfills through the Frye lab’s commitment to provide researchers with the probe free of charge on request and UNC1215 is already available through commercial vendors as well.

New chemical probe provides tool to investigate role of malignant brain tumor domains

In an article published as the cover story of the March 2013 issue of Nature Chemical Biology, Lindsey James, PhD, research assistant professor in the lab of Stephen Frye, Fred Eshelman Distinguished Professor in the UNC School of Pharmacy and member of the UNC Lineberger Comprehensive Cancer Center, announced the discovery of a chemical probe that can be used to investigate the L3MBTL3 methyl-lysine reader domain. The probe, named UNC1215, will provide researchers with a powerful tool to investigate the function of malignant brain tumor (MBT) domain proteins in biology and disease.

“Before this there were no known chemical probes for the more than 200 domains in the human genome that recognize methyl lysine. In that regard, it is a first in class compound. The goal is to use the chemical probe to understand the biology of the proteins that it targets,” said Dr. James.

Chromatin regulatory pathways play a fundamental role in gene expression and disease development, especially in the case of cancer. While many chemical probes work through the inhibition of enzyme activity, L3MBTL3 functions as a mediator of protein-to-protein interactions, which have been historically difficult to target with small, drug-like molecules.The researchers found three to four further disease subtypes within TN tumors, with more than 75 percent of the tumors falling into the basal-like subtype. Further research is needed to identify the distinct biomarkers shared by the expanded subtypes of TN cancers. The ultimate goal will be to target the individual biomarkers of these subtypes and create therapies that target their individual biology, according to Dr. Perou.

“Many people believe that protein-protein interactions are difficult to target. Often they have a large surface area, so it is hard for small molecules to go in and intervene,” said Dr. James.

Almost 40 percent of the genes that drive cancer can be mapped to dysfunction within signaling pathways. In the last five years, chemical probe development has allowed researchers to make fundamental observations of the role of these pathways in cancer development, as well as pointing to potential targets for new therapies. Each of the complex interactions within the signaling pathways represents a potential point where a therapy can be applied, and the probes allow researchers to interact with these processes at the molecular level and observe the overall effect of their perturbation on the disease state.

In a 2008 Nature Chemical Biology commentary, Dr. Frye outlined the qualities that make a good chemical probe. To Frye, a good chemical probe must be highly selective to enable specific questions to be asked and it must function as well in a cell as in the test tube, providing clear quantitative data with a well understood mechanism of action in either situation. It also must be available to all academic researchers without restrictions on its use, a criteria that the L3MBTL3 probe fulfills through the Frye lab’s commitment to provide researchers with the probe free of charge on request and UNC1215 is already available through commercial vendors as well.

Filed under brain tumor brain cancer gene expression proteins medicine neuroscience science

13 notes

Choosing Wisely: AAN Cites Five Things to Question In 2012, the AAN joined the Choosing Wisely campaign, a project initiated by the American Board of Internal Medicine (ABIM) Foundation to promote appropriate medical decision-making and the stewardship of health care resources. The campaign is designed to help consumers and physicians engage in conversations about the overuse of particular tests, procedures, and treatments and to help patients make smart and effective care choices. In February 2013, the AAN participated in a news conference with the ABIM Foundation and Consumer Reports, where medical specialties announced their lists of the top five questionable tests and procedures each selected for patients and physicians to consider. Read AAN’s Five Things Physicians and Patients Should Question The AAN’s complete recommendations were published online ahead of print in the February 21, 2013, issue of Neurology®. How Neurology Tests and Procedures Were identified The AAN established a Choosing Wisely Working Group to develop its list of recommendations. Members of this group were selected to broadly represent varying practice settings and neurological subspecialties. Neurologists with expertise in evidence-based medicine and a broad range of subspecialty disciplines were also included. The working group solicited recommendations from AAN members, which were then rated based upon their judgments of harm and benefit that would result based upon compliance with the recommendation. Based on committee voting and a literature review, candidate recommendations were sent to relevant AAN sections, committees, specialty societies and patient advocacy groups for review and comment. The working group reviewed this feedback and voted on the final top five recommendations, which were approved by the AAN Practice Committee and Board of Directors.

Choosing Wisely: AAN Cites Five Things to Question

In 2012, the AAN joined the Choosing Wisely campaign, a project initiated by the American Board of Internal Medicine (ABIM) Foundation to promote appropriate medical decision-making and the stewardship of health care resources. The campaign is designed to help consumers and physicians engage in conversations about the overuse of particular tests, procedures, and treatments and to help patients make smart and effective care choices.

In February 2013, the AAN participated in a news conference with the ABIM Foundation and Consumer Reports, where medical specialties announced their lists of the top five questionable tests and procedures each selected for patients and physicians to consider.

Read AAN’s Five Things Physicians and Patients Should Question

The AAN’s complete recommendations were published online ahead of print in the February 21, 2013, issue of Neurology®.

How Neurology Tests and Procedures Were identified

The AAN established a Choosing Wisely Working Group to develop its list of recommendations. Members of this group were selected to broadly represent varying practice settings and neurological subspecialties. Neurologists with expertise in evidence-based medicine and a broad range of subspecialty disciplines were also included. The working group solicited recommendations from AAN members, which were then rated based upon their judgments of harm and benefit that would result based upon compliance with the recommendation. Based on committee voting and a literature review, candidate recommendations were sent to relevant AAN sections, committees, specialty societies and patient advocacy groups for review and comment. The working group reviewed this feedback and voted on the final top five recommendations, which were approved by the AAN Practice Committee and Board of Directors.

Filed under headache EEG migraines neurologic symptoms physician-patient communication medicine

52 notes

Cell discovery could hold key to causes of inherited diseases

Fresh insights into the protective seal that surrounds the DNA of our cells could help develop treatments for inherited muscle, brain, bone and skin disorders.

Researchers have discovered that the proteins within this coating – known as the nuclear envelope – vary greatly between cells in different organs of the body.

This variation means that certain disease causing proteins will interact with the proteins in the protective seal to cause illness in some organs, but not others.

Until now scientists had thought that all proteins within the nuclear envelope were the same in every type of organ.

In particular the finding may provide insights into a rare muscle disease, Emery-Dreifuss muscular dystrophy.

This condition causes muscle wastage and heart problems, affects only muscles, even though it is caused by a defect in a nuclear envelope protein found in every cell in the body.

Scientists say that the envelope proteins they have identified as being specific to muscle may interact with the defective nuclear envelope protein that causes Emery-Dreifuss muscular dystrophy, to give rise to the disease.

In a similar way, this may help to explain other heritable diseases that only affect certain parts of the body despite the defective proteins being present in every cell. The study also identified nuclear envelope proteins specific to liver and blood.

Some of these also interact with proteins in all cells that are responsible for other nuclear envelope diseases, ranging from brain and fat to skin diseases, and so may help explain why things go wrong.

Dr Eric Schirmer, of the University of Edinburgh’s Wellcome Trust Centre for Cell Biology, who led the study said: “Nobody could have imagined what we found.

The fact that most proteins in the nuclear envelope would be specific for certain tissue types is a very exciting development. This may finally enable us to understand this ever-growing spectrum of inherited diseases as well as new aspects of tissue-specific gene regulation.”

The findings build on previous research that showed proteins in the nuclear envelope are linked to more than 20 heritable diseases.

(Source: eurekalert.org)

Filed under muscular dystrophy envelope protein brain disorders inherited diseases medicine science

120 notes

New FDA-Approved Clot Removal Devices Show Promise for Treating Stroke Patients

Specialists at Stony Brook Medicine’s Cerebrovascular and Stroke Center (CVC) are treating patients with a new generation of blood clot removal devices that show promise in successfully revascularizing stroke patients, including those with large vessel blockages. The Solitaire Flow Restoration Device and the Trevo device, approved by Food and Drug Administration (FDA) in 2012 to treat stroke caused by the sudden obstruction of a brain blood vessel (acute ischemic stroke) showed improved results over a previous standard and first generation clot-removal device in clinical trials. 

“We have had excellent outcomes using these new devices,” said David Fiorella, M.D., Ph.D., a Professor of Clinical Neurological Surgery and Radiology at Stony Brook University School of Medicine and Co-Director of the CVC. “In acute ischemic stroke, ‘time is brain,’ and in some cases just minutes matter. Therefore, restoring blood flow in an effective and timely manner is critical to the survival and recovery of stroke patients. These new devices enable us to quickly restore blood flow and retrieve the clot in most patients,” said Dr. Fiorella, who has performed some 30 procedures on stroke patients using the new devices. 

“These blot clot removal devices are an important new component of our armamentarium against stroke” said Henry Woo, MD, Professor of Neurological Surgery and Radiology and Co-Director of the CVC, who has also used both devices in patient procedures. “Our center provides endovascular treatment for acute stroke 24/7, and by having the latest technologies to remove brain blood clots, and the expertise to perform endovascular procedures, our Center remains on the cutting-edge against this life-threatening condition.”

Recent results of clinical trials reported in The New England Journal of Medicine (February 2013) about the use of first generation of blood clot removal devices in the endovascular treatment of acute ischemic stroke revealed that endovascular treatment does not result in better patient outcomes compared to standard drug treatments. Dr. Fiorella contends that while these trial results are important in the search for the best treatment protocols for acute ischemic stroke, the new devices and techniques are markedly better than those used to treat the majority of patients in these trials and may yet prove to be the most effective approach in select patients. Further research trials are being conducted at Stony Brook to investigate the efficacy of these newer, better devices in acute ischemic stroke. 

The new devices that Stony Brook cerebrovascular specialists use to perform revascularization are expandable wire-mesh systems that collapse and are delivered into the brain blood vessels through small flexible tubes (microcatheters) which are guided from the groin to the brain. The devices open at the site of the clot, displacing the occlusion and immediately restoring blood flow to the brain. When the devices are withdrawn from the blood vessel, they take the clot with them, allowing the clot to be removed from the blood vessel.

Filed under stroke blood clots blood vessels clot-removal device blood flow medicine neuroscience science

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Students invited to take cocaine for London university’s research A London university has offered its students the chance to take part in a clinical trial of cocaine in a bid to understand how the Class A drug affects the body. King’s College London has sent an email to hundreds of undergraduates inviting them to “take part in a clinical study involving nasal administration of cocaine”. Students who use drugs recreationally will not be allowed to participate, nor those studying medicine or dentistry. Those who are accepted will be given “reasonable financial compensation” for the time and expenses incurred. The email explains the study will mean that: “After cocaine administration, repeated biological samples (blood, urine, hair, sweat, oral fluid) will be taken to compare and investigate how cocaine and its metabolites are spread through the human body.” Participants will not be able to cut or dye their hair for 120 days during the study follow-up period as scientists investigate a wide range of physical effects on the body. The project, which has been approved by London Westminster Research Ethics Committee, will be supervised by the clinical toxicology department at St Thomas’ Hospital. A spokesman for King’s said: “This is an important scientific study to investigate how cocaine and its metabolites are spread through the human body. “All the relevant ethical approvals were received for this study. The study will be conducted under the highest level of medical supervision in a dedicated clinical research suite. Further information about the NHS ethical approval process, which was followed, is available on our website.” The email has already attracted online comments and jokes from students. The university has a reputation for research into the use and effects of illegal drugs, including studies into the genetic causes of addiction and papers on whether certain substances should be legalised. An estimated 700,000 people in Britain took cocaine last year, making it the second most popular drug after cannabis.

Students invited to take cocaine for London university’s research

A London university has offered its students the chance to take part in a clinical trial of cocaine in a bid to understand how the Class A drug affects the body.

King’s College London has sent an email to hundreds of undergraduates inviting them to “take part in a clinical study involving nasal administration of cocaine”.

Students who use drugs recreationally will not be allowed to participate, nor those studying medicine or dentistry. Those who are accepted will be given “reasonable financial compensation” for the time and expenses incurred. The email explains the study will mean that: “After cocaine administration, repeated biological samples (blood, urine, hair, sweat, oral fluid) will be taken to compare and investigate how cocaine and its metabolites are spread through the human body.”

Participants will not be able to cut or dye their hair for 120 days during the study follow-up period as scientists investigate a wide range of physical effects on the body.

The project, which has been approved by London Westminster Research Ethics Committee, will be supervised by the clinical toxicology department at St Thomas’ Hospital.

A spokesman for King’s said: “This is an important scientific study to investigate how cocaine and its metabolites are spread through the human body.

“All the relevant ethical approvals were received for this study. The study will be conducted under the highest level of medical supervision in a dedicated clinical research suite. Further information about the NHS ethical approval process, which was followed, is available on our website.”

The email has already attracted online comments and jokes from students. The university has a reputation for research into the use and effects of illegal drugs, including studies into the genetic causes of addiction and papers on whether certain substances should be legalised.

An estimated 700,000 people in Britain took cocaine last year, making it the second most popular drug after cannabis.

Filed under cocaine recreational drug use stimulants research medicine science

228 notes

Bioengineers print ears that look and act like the real thing Cornell bioengineers and physicians have created an artificial ear that looks and acts like a natural ear, giving new hope to thousands of children born with a congenital deformity called microtia. In a study published online Feb. 20 in PLOS One, Cornell biomedical engineers and Weill Cornell Medical College physicians described how 3-D printing and injectable gels made of living cells can fashion ears that are practically identical to a human ear. Over a three-month period, these flexible ears grew cartilage to replace the collagen that was used to mold them. "This is such a win-win for both medicine and basic science, demonstrating what we can achieve when we work together," said co-lead author Lawrence Bonassar, associate professor of biomedical engineering. The novel ear may be the solution reconstructive surgeons have long wished for to help children born with ear deformity, said co-lead author Dr. Jason Spector, director of the Laboratory for Bioregenerative Medicine and Surgery and associate professor of plastic surgery at Weill Cornell. "A bioengineered ear replacement like this would also help individuals who have lost part or all of their external ear in an accident or from cancer," Spector said. Replacement ears are usually constructed with materials that have a Styrofoam-like consistency, or sometimes, surgeons build ears from a patient’s harvested rib. This option is challenging and painful for children, and the ears rarely look completely natural or perform well, Spector said. To make the ears, Bonassar and colleagues started with a digitized 3-D image of a human subject’s ear and converted the image into a digitized “solid” ear using a 3-D printer to assemble a mold. They injected the mold with collagen derived from rat tails, and then added 250 million cartilage cells from the ears of cows. This Cornell-developed, high-density gel is similar to the consistency of Jell-O when the mold is removed. The collagen served as a scaffold upon which cartilage could grow. The process is also fast, Bonassar added: “It takes half a day to design the mold, a day or so to print it, 30 minutes to inject the gel, and we can remove the ear 15 minutes later. We trim the ear and then let it culture for several days in nourishing cell culture media before it is implanted.” The incidence of microtia, which is when the external ear is not fully developed, varies from almost 1 to more than 4 per 10,000 births each year. Many children born with microtia have an intact inner ear, but experience hearing loss due to the missing external structure. Bonassar and Spector have been collaborating on bioengineered human replacement parts since 2007. Bonassar has also worked with Weill Cornell neurological surgeon Dr. Roger Härtl on bioengineered disc replacements using some of the same techniques demonstrated in the PLOS One study. The researchers specifically work on replacement human structures that are primarily made of cartilage — joints, trachea, spine, nose — because cartilage does not need to be vascularized with a blood supply in order to survive. They are now looking at ways to expand populations of human ear cartilage cells in the laboratory so that these cells can be used in the mold, instead of cow cartilage. "Using human cells, specifically those from the same patient, would reduce any possibility of rejection," Spector said. He added that the best time to implant a bioengineered ear on a child would be when they are about 5 or 6 years old. At that age, ears are 80 percent of their adult size. If all future safety and efficacy tests work out, it might be possible to try the first human implant of a Cornell bioengineered ear in as little as three years, Spector said.

Bioengineers print ears that look and act like the real thing

Cornell bioengineers and physicians have created an artificial ear that looks and acts like a natural ear, giving new hope to thousands of children born with a congenital deformity called microtia.

In a study published online Feb. 20 in PLOS One, Cornell biomedical engineers and Weill Cornell Medical College physicians described how 3-D printing and injectable gels made of living cells can fashion ears that are practically identical to a human ear. Over a three-month period, these flexible ears grew cartilage to replace the collagen that was used to mold them.

"This is such a win-win for both medicine and basic science, demonstrating what we can achieve when we work together," said co-lead author Lawrence Bonassar, associate professor of biomedical engineering.

The novel ear may be the solution reconstructive surgeons have long wished for to help children born with ear deformity, said co-lead author Dr. Jason Spector, director of the Laboratory for Bioregenerative Medicine and Surgery and associate professor of plastic surgery at Weill Cornell.

"A bioengineered ear replacement like this would also help individuals who have lost part or all of their external ear in an accident or from cancer," Spector said.

Replacement ears are usually constructed with materials that have a Styrofoam-like consistency, or sometimes, surgeons build ears from a patient’s harvested rib. This option is challenging and painful for children, and the ears rarely look completely natural or perform well, Spector said.

To make the ears, Bonassar and colleagues started with a digitized 3-D image of a human subject’s ear and converted the image into a digitized “solid” ear using a 3-D printer to assemble a mold.

They injected the mold with collagen derived from rat tails, and then added 250 million cartilage cells from the ears of cows. This Cornell-developed, high-density gel is similar to the consistency of Jell-O when the mold is removed. The collagen served as a scaffold upon which cartilage could grow.

The process is also fast, Bonassar added: “It takes half a day to design the mold, a day or so to print it, 30 minutes to inject the gel, and we can remove the ear 15 minutes later. We trim the ear and then let it culture for several days in nourishing cell culture media before it is implanted.”

The incidence of microtia, which is when the external ear is not fully developed, varies from almost 1 to more than 4 per 10,000 births each year. Many children born with microtia have an intact inner ear, but experience hearing loss due to the missing external structure.

Bonassar and Spector have been collaborating on bioengineered human replacement parts since 2007. Bonassar has also worked with Weill Cornell neurological surgeon Dr. Roger Härtl on bioengineered disc replacements using some of the same techniques demonstrated in the PLOS One study.

The researchers specifically work on replacement human structures that are primarily made of cartilage — joints, trachea, spine, nose — because cartilage does not need to be vascularized with a blood supply in order to survive.

They are now looking at ways to expand populations of human ear cartilage cells in the laboratory so that these cells can be used in the mold, instead of cow cartilage.

"Using human cells, specifically those from the same patient, would reduce any possibility of rejection," Spector said.

He added that the best time to implant a bioengineered ear on a child would be when they are about 5 or 6 years old. At that age, ears are 80 percent of their adult size.

If all future safety and efficacy tests work out, it might be possible to try the first human implant of a Cornell bioengineered ear in as little as three years, Spector said.

Filed under microtia artificial ear ear replacement implants cartilage medicine neuroscience science

129 notes

Circadian clock linked to obesity, diabetes and heart attacks Disruption in the body’s circadian rhythm can lead not only to obesity, but can also increase the risk of diabetes and heart disease. That is the conclusion of the first study to show definitively that insulin activity is controlled by the body’s circadian biological clock. The study, which was published on Feb. 21 in the journal Current Biology, helps explain why not only what you eat, but when you eat, matters. The research was conducted by a team of Vanderbilt scientists directed by Professor of Biological Sciences Carl Johnson and Professors of Molecular Physiology and Biophysics Owen McGuinness and David Wasserman. “Our study confirms that it is not only what you eat and how much you eat that is important for a healthy lifestyle, but when you eat is also very important,” said postdoctoral fellow Shu-qun Shi, who performed the experiment with research assistant Tasneem Ansari in the Vanderbilt University Medical Center’s Mouse Metabolic Phenotyping Center. In recent years, a number of studies in both mice and men have found a variety of links between the operation of the body’s biological clock and various aspects of its metabolism, the physical and chemical processes that provide energy and produce, maintain and destroy tissue. It was generally assumed that these variations were caused in response to insulin, which is one of the most potent metabolic hormones. However, no one had actually determined that insulin action follows a 24-hour cycle or what happens when the body’s circadian clock is disrupted. Because they are nocturnal, mice have a circadian rhythm that is the mirror image of that of humans: They are active during the night and sleep during the day. Otherwise, scientists have found that the internal timekeeping system of the two species operate in nearly the same way at the molecular level. Most types of cells contain their own molecular clocks, all of which are controlled by a master circadian clock in the suprachiasmatic nucleus in the brain. “People have suspected that our cells’ response to insulin had a circadian cycle, but we are the first to have actually measured it,” said McGuinness. “The master clock in the central nervous system drives the cycle and insulin response follows.”

Circadian clock linked to obesity, diabetes and heart attacks

Disruption in the body’s circadian rhythm can lead not only to obesity, but can also increase the risk of diabetes and heart disease.

That is the conclusion of the first study to show definitively that insulin activity is controlled by the body’s circadian biological clock. The study, which was published on Feb. 21 in the journal Current Biology, helps explain why not only what you eat, but when you eat, matters.

The research was conducted by a team of Vanderbilt scientists directed by Professor of Biological Sciences Carl Johnson and Professors of Molecular Physiology and Biophysics Owen McGuinness and David Wasserman.

“Our study confirms that it is not only what you eat and how much you eat that is important for a healthy lifestyle, but when you eat is also very important,” said postdoctoral fellow Shu-qun Shi, who performed the experiment with research assistant Tasneem Ansari in the Vanderbilt University Medical Center’s Mouse Metabolic Phenotyping Center.

In recent years, a number of studies in both mice and men have found a variety of links between the operation of the body’s biological clock and various aspects of its metabolism, the physical and chemical processes that provide energy and produce, maintain and destroy tissue. It was generally assumed that these variations were caused in response to insulin, which is one of the most potent metabolic hormones. However, no one had actually determined that insulin action follows a 24-hour cycle or what happens when the body’s circadian clock is disrupted.

Because they are nocturnal, mice have a circadian rhythm that is the mirror image of that of humans: They are active during the night and sleep during the day. Otherwise, scientists have found that the internal timekeeping system of the two species operate in nearly the same way at the molecular level. Most types of cells contain their own molecular clocks, all of which are controlled by a master circadian clock in the suprachiasmatic nucleus in the brain.

“People have suspected that our cells’ response to insulin had a circadian cycle, but we are the first to have actually measured it,” said McGuinness. “The master clock in the central nervous system drives the cycle and insulin response follows.”

Filed under circadian clock biological clock suprachiasmatic nucleus insulin insulin resistance obesity medicine science

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