Complement enhances tumour evasion
A seemingly illogical link between activation of immune sensors and the ability of tumours to escape the immune system. The unexpected result reveals a new drug target for cancer treatment.
The complement system comprises a cascade of proteins that act as a fire alarm to alert the immune system to the presence of infection. In a bizarre twist, Lambris and colleagues show that tumour activation of one of the complement proteins – C5 – in fact leads to suppression of the anti-tumour immune response.
The surprising outcome is explained by the observation that the activated protein recruits ‘suppressor’ cells to the site. These act to disarm other immune cells and stop them from killing the tumour. Importantly, the authors show that blocking the activity of C5 slows tumour growth in mice and this treatment is as effective as taxol, a commonly used anti-cancer drug.
Author contact:
John Lambris (University of Pennsylvania, Philadelphia, PA, USA)
Tel: +1 215 746 5765; E-mail: lambris@mail.med.upenn.edu
Monday, September 29, 2008
Glacier acceleration through subsurface ocean warming
The sudden acceleration in 1997 of Jakobshavn Isbræ, one of Greenland’s largest outlet glaciers, was caused by subsurface ocean warming, according to research. The study suggests that ocean temperatures may be more important for glacier flow than previously thought. The prediction of future rapid dynamic responses of other outlet glaciers to climate change may therefore require detailed knowledge of regional ocean dynamics.
David Holland and colleagues present hydrographic data that show a sudden increase in subsurface ocean temperature in 1997 along the entire west coast of Greenland. The arrival of relatively warm water that originated from the Irminger Sea near Iceland could therefore have triggered the increase in the glacier speed. The authors trace these oceanic changes back to changes in the atmospheric circulation in the North Atlantic region.
Author contact:
David Holland (New York University, NY, USA)
Tel: +1 212 998 3245; E-mail: holland@cims.nyu.edu
The sudden acceleration in 1997 of Jakobshavn Isbræ, one of Greenland’s largest outlet glaciers, was caused by subsurface ocean warming, according to research. The study suggests that ocean temperatures may be more important for glacier flow than previously thought. The prediction of future rapid dynamic responses of other outlet glaciers to climate change may therefore require detailed knowledge of regional ocean dynamics.
David Holland and colleagues present hydrographic data that show a sudden increase in subsurface ocean temperature in 1997 along the entire west coast of Greenland. The arrival of relatively warm water that originated from the Irminger Sea near Iceland could therefore have triggered the increase in the glacier speed. The authors trace these oceanic changes back to changes in the atmospheric circulation in the North Atlantic region.
Author contact:
David Holland (New York University, NY, USA)
Tel: +1 212 998 3245; E-mail: holland@cims.nyu.edu
Thwarting tumour invasion
A mechanism used by metastasising tumour cells to invade lung tissue and establish secondary tumours. The research identifies a promising drug target to prevent the spread of cancer.
Primary tumours prepare the lung for invasion by inducing chemokines – chemical factors normally used to recruit immune cells during infection – which guide migration of tumour cells to the secondary site. Hiratsuka and colleagues show that primary tumours also induce lung cells to produce an additional factor, serum amyloid A3 (SAA3). SAA3 accelerates the recruitment of primary tumour cells by switching on genes involved in inflammation and boosting the production of chemokines. Importantly, the team show that blocking SAA3 or its receptor strikingly reduces lung metastasis in mice.
Metastasis is difficult to predict and even harder to treat. The new findings offer researchers vital clues for understanding how cancer cells can establish new tumours at sites quite distant from the original tumour.
Author contact:
Yoshiro Maru (Tokyo Women's Medical University School of Medicine, Japan)
Tel: +81 3 5269 7417; E-mail: ymaru@research.twmu.ac.jp
A mechanism used by metastasising tumour cells to invade lung tissue and establish secondary tumours. The research identifies a promising drug target to prevent the spread of cancer.
Primary tumours prepare the lung for invasion by inducing chemokines – chemical factors normally used to recruit immune cells during infection – which guide migration of tumour cells to the secondary site. Hiratsuka and colleagues show that primary tumours also induce lung cells to produce an additional factor, serum amyloid A3 (SAA3). SAA3 accelerates the recruitment of primary tumour cells by switching on genes involved in inflammation and boosting the production of chemokines. Importantly, the team show that blocking SAA3 or its receptor strikingly reduces lung metastasis in mice.
Metastasis is difficult to predict and even harder to treat. The new findings offer researchers vital clues for understanding how cancer cells can establish new tumours at sites quite distant from the original tumour.
Author contact:
Yoshiro Maru (Tokyo Women's Medical University School of Medicine, Japan)
Tel: +81 3 5269 7417; E-mail: ymaru@research.twmu.ac.jp
Risk factor for narcolepsy
A genetic variant that predisposes to narcolepsy has been identified, according to a study. Narcolepsy is characterized by excessive daytime sleepiness, impaired vision, and muscle weakness that may lead to collapse. It occurs in approximately 1 in 2,500 individuals in the United States and Europe, but is at least 4 times more frequent in Japanese.
Katsushi Tokunaga and colleagues carried out a genome-wide association of Japanese individuals, and found one variant to be significantly associated with risk of narcolepsy. They also found support for the association in Koreans, but not in individuals of European or African descent, probably because the frequency of the risk variant is much lower in the latter two populations.
The risk variant is located between the genes CPT1B and CHKB, each of which is a reasonable candidate to have a role in the disorder. The gene CPT1B encodes an enzyme involved in fatty acid oxidation, which has been implicated in sleep regulation. CHKB encodes an enzyme that catalyzes the production of one of the major components of cellular membranes, which is a precursor to a molecule that has been linked to the sleep-wake cycle.
Author contact:
Katsushi Tokunaga (University of Tokyo, Japan)
Tel: +81 3 5841 3692; E-mail: tokunaga@m.u-tokyo.ac.jp
A genetic variant that predisposes to narcolepsy has been identified, according to a study. Narcolepsy is characterized by excessive daytime sleepiness, impaired vision, and muscle weakness that may lead to collapse. It occurs in approximately 1 in 2,500 individuals in the United States and Europe, but is at least 4 times more frequent in Japanese.
Katsushi Tokunaga and colleagues carried out a genome-wide association of Japanese individuals, and found one variant to be significantly associated with risk of narcolepsy. They also found support for the association in Koreans, but not in individuals of European or African descent, probably because the frequency of the risk variant is much lower in the latter two populations.
The risk variant is located between the genes CPT1B and CHKB, each of which is a reasonable candidate to have a role in the disorder. The gene CPT1B encodes an enzyme involved in fatty acid oxidation, which has been implicated in sleep regulation. CHKB encodes an enzyme that catalyzes the production of one of the major components of cellular membranes, which is a precursor to a molecule that has been linked to the sleep-wake cycle.
Author contact:
Katsushi Tokunaga (University of Tokyo, Japan)
Tel: +81 3 5841 3692; E-mail: tokunaga@m.u-tokyo.ac.jp
Friday, September 26, 2008
Researchers Develop New Model for Cystic Fibrosis
In a first, researchers at the University of Iowa and the University of Missouri (MU) have developed a pig model for cystic fibrosis (CF) that appears to closely mimic the disease in human infants. The striking similarities between disease manifestations in the CF piglets and human newborns with CF suggest that this new model will help improve understanding of the disease and may also speed discovery of new treatments. The study is published in the Sept. 26 issue of Science.
CF is a common hereditary disease that affects multiple organ systems, including the intestines, pancreas, and lung. Mice with CF-causing mutations have helped researchers learn more about this disease, however, differences in physiology and biology mean that mice with CF mutations do not develop many of the typical symptoms that affect humans with CF.
"Lack of a better model has hampered our ability to answer long-standing questions in CF," explained Christopher Rogers, Ph.D., a former postdoctoral fellow in internal medicine at the UI Roy J. and Lucille A. Carver College of Medicine, and one of the study's lead authors. "The CF pig provides a unique opportunity to study one of the most common genetic diseases, and we hope to translate this new knowledge into better therapies and preventions."
In addition to Rogers, co-lead authors of the study were David Stoltz, M.D., Ph.D., UI assistant professor of internal medicine, and David Meyerholz, D.V.M., Ph.D., UI assistant professor of pathology.
The senior study author was Michael Welsh, M.D., UI professor of internal medicine and molecular physiology and biophysics, who holds the Roy J. Carver Chair of Internal Medicine and Physiology and Biophysics. Welsh also is a Howard Hughes Medical Institute investigator.
CF occurs when a person inherits two mutated copies of the CFTR gene leading to loss of ion channel function that adversely affects many organs. To create the CF pigs, the researchers used gene targeting to disrupt one copy of the normal gene in pig cells. They then cloned these altered cells to produce pigs with only one good copy of the gene. Like human CF-carriers, these animals did not show disease symptoms. The pigs were then bred naturally, and about one in four of the piglets were born with two disrupted copies of the gene.
The researchers established that piglets lacking CFTR have the abnormal ion channel activity that is a hallmark of CF disease. They also showed that the CF piglets develop the same disease characteristics that are commonly seen in newborn humans with CF, including a bowel obstruction known as meconium ileus, which often is the first sign of CF in humans. The pigs also have an abnormal pancreas, liver, and gall bladder, similar to CF patients.
"Thus far, the clinical, physiological and age-related appearance of disease in the pigs, as well as the organs involved, mimic CF seen in people," Stoltz said.
A primary cause of death and disability in patients with CF is lung disease. However, many questions remain about how infection and inflammation leads to lung damage. In the study, the lungs of the newborn CF pigs appeared similar to the lungs of their normal littermates and had no sign of infection or inflammation, possibly shedding some initial insight on the process. As the CF pigs mature and are exposed to airborne bacteria and viruses, the researchers hope to learn more about how and why lung disease develops in patients with CF.
"Researchers can now begin to study the disease progression as it is happening, something not possible in humans," Meyerholz said.
The research team included UI scientists from internal medicine, pediatrics, surgery and periodontics. In addition, Randall Prather, Ph.D., the distinguished professor of reproductive biology at MU College of Agriculture, Food and Natural Resources, and his colleagues were part of the research team.
The study was funded in part by grants from the National Heart, Lung, and Blood Institute and National Institute of Diabetes and Digestive and Kidney Disease of the National Institutes of Health, Food for the 21st Century and the Cystic Fibrosis Foundation.
In a first, researchers at the University of Iowa and the University of Missouri (MU) have developed a pig model for cystic fibrosis (CF) that appears to closely mimic the disease in human infants. The striking similarities between disease manifestations in the CF piglets and human newborns with CF suggest that this new model will help improve understanding of the disease and may also speed discovery of new treatments. The study is published in the Sept. 26 issue of Science.
CF is a common hereditary disease that affects multiple organ systems, including the intestines, pancreas, and lung. Mice with CF-causing mutations have helped researchers learn more about this disease, however, differences in physiology and biology mean that mice with CF mutations do not develop many of the typical symptoms that affect humans with CF.
"Lack of a better model has hampered our ability to answer long-standing questions in CF," explained Christopher Rogers, Ph.D., a former postdoctoral fellow in internal medicine at the UI Roy J. and Lucille A. Carver College of Medicine, and one of the study's lead authors. "The CF pig provides a unique opportunity to study one of the most common genetic diseases, and we hope to translate this new knowledge into better therapies and preventions."
In addition to Rogers, co-lead authors of the study were David Stoltz, M.D., Ph.D., UI assistant professor of internal medicine, and David Meyerholz, D.V.M., Ph.D., UI assistant professor of pathology.
The senior study author was Michael Welsh, M.D., UI professor of internal medicine and molecular physiology and biophysics, who holds the Roy J. Carver Chair of Internal Medicine and Physiology and Biophysics. Welsh also is a Howard Hughes Medical Institute investigator.
CF occurs when a person inherits two mutated copies of the CFTR gene leading to loss of ion channel function that adversely affects many organs. To create the CF pigs, the researchers used gene targeting to disrupt one copy of the normal gene in pig cells. They then cloned these altered cells to produce pigs with only one good copy of the gene. Like human CF-carriers, these animals did not show disease symptoms. The pigs were then bred naturally, and about one in four of the piglets were born with two disrupted copies of the gene.
The researchers established that piglets lacking CFTR have the abnormal ion channel activity that is a hallmark of CF disease. They also showed that the CF piglets develop the same disease characteristics that are commonly seen in newborn humans with CF, including a bowel obstruction known as meconium ileus, which often is the first sign of CF in humans. The pigs also have an abnormal pancreas, liver, and gall bladder, similar to CF patients.
"Thus far, the clinical, physiological and age-related appearance of disease in the pigs, as well as the organs involved, mimic CF seen in people," Stoltz said.
A primary cause of death and disability in patients with CF is lung disease. However, many questions remain about how infection and inflammation leads to lung damage. In the study, the lungs of the newborn CF pigs appeared similar to the lungs of their normal littermates and had no sign of infection or inflammation, possibly shedding some initial insight on the process. As the CF pigs mature and are exposed to airborne bacteria and viruses, the researchers hope to learn more about how and why lung disease develops in patients with CF.
"Researchers can now begin to study the disease progression as it is happening, something not possible in humans," Meyerholz said.
The research team included UI scientists from internal medicine, pediatrics, surgery and periodontics. In addition, Randall Prather, Ph.D., the distinguished professor of reproductive biology at MU College of Agriculture, Food and Natural Resources, and his colleagues were part of the research team.
The study was funded in part by grants from the National Heart, Lung, and Blood Institute and National Institute of Diabetes and Digestive and Kidney Disease of the National Institutes of Health, Food for the 21st Century and the Cystic Fibrosis Foundation.
Gene Variant Boosts Risk of Fatty Liver Disease
Researchers at UT Southwestern Medical Center have found that individuals who carry a specific form of the gene PNPLA3 have more fat in their livers and a greater risk of developing liver inflammation.
They also found that Hispanics are more likely to carry the gene variant responsible for higher liver-fat content than African-Americans and Caucasians.
The new findings, published online today in the journal Nature Genetics, provide a gene-based explanation for the results of a 2004 UT Southwestern-led study that determined that the propensity to develop nonalcoholic fatty liver disease differs among ethnic groups, with a higher percentage of Hispanics developing the disorder than African-Americans or Caucasians.
“A single variation in the PNPLA3 gene was strongly associated with hepatic fat content, even after adjusting for other factors, such as obesity, diabetes status and alcohol intake,” said senior study author Dr. Helen Hobbs, director of the Eugene McDermott Center for Human Growth and Development and an investigator for the Howard Hughes Medical Institute at UT Southwestern.
“Sequence variations in this gene explain much of the increased propensity of Hispanics to accumulate excess liver fat,” she said.
Nonalcoholic fatty liver disease (NAFLD) is the most common form of liver disease in Western countries, and its incidence is growing. Previous UT Southwestern research has shown that it may affect as many as one-third of adults in America.
“The gene variations we have identified might provide a way to predict who is most at risk for developing fatty liver disease and liver injury in response to environmental stresses such as obesity or infection,” said Dr. Jonathan Cohen, professor of internal medicine in the McDermott Center and one of the authors of the study.
NAFLD results from the accumulation of triglycerides in the liver and is associated with metabolic disorders such as insulin resistance, obesity, diabetes and high cholesterol – many of the conditions that contribute to heart disease. It can also lead to liver inflammation, cirrhosis and liver cancer. Approximately 10 percent of liver transplants performed in the U.S. are for cirrhosis related to NAFLD, according to the researchers.
Treatments for NAFLD include weight loss, exercise, reducing alcohol intake and improved diabetes control.
“Knowing who is at increased risk of developing liver disease could aid physicians in encouraging their patients to make lifestyle changes or take other preventive measures to help mitigate their underlying genetic risk for the disorder,” said Dr. Cohen, holder of the C. Vincent Prothro Distinguished Chair in Human Nutrition Research.
The new findings come out of the Dallas Heart Study, an 8-year-old groundbreaking investigation of cardiovascular disease that involves a large multiethnic group of participants. The $12 million study investigates the links between genetics, lifestyle and the risks for heart disease.
As part of the Dallas Heart Study, more than 3,500 individuals from Dallas County provided blood samples in 2000 for DNA isolation and other tests. Each participant also underwent multiple body scans with magnetic resonance imaging and computed tomography to examine the heart and other organs. Along with discovering new genetic ties to differences in blood levels of cholesterol and triglycerides, the researchers have used this information to identify new drug targets for the prevention and treatment of heart disease.
Data-gathering for the new study on fatty liver disease took advantage of a unique aspect of the Dallas Heart Study. Researchers with the study were the first to analyze hepatic fat in a large population using a technique called proton magnetic resonance spectroscopy – the most sensitive and quantitative noninvasive imaging technique available to measure the amount of fat in the liver. With this technique, they screened more than 2,100 individuals across multiple ethnicities. They then correlated that data with DNA tests from the same people and found the link to the PNPLA3 gene.
The next step in the research is to investigate how the various forms of the PNPLA3 gene affect lipid metabolism.
Other researchers from the McDermott Center involved with the study were lead author Dr. Stefano Romeo, a postdoctoral research fellow; Dr. Alexander Pertsemlidis, assistant professor; Dr. Chao Xing, assistant professor of clinical sciences; and Julia Kozlitina, a graduate student participating in a joint program between Southern Methodist University and UT Southwestern. Researchers from Perlegen Sciences, Lawrence Berkeley National Laboratory and the UT Health Science Center at Houston also were involved.
The research was funded by the Donald W. Reynolds Foundation, the National Institutes of Health and the Department of Energy.
Researchers at UT Southwestern Medical Center have found that individuals who carry a specific form of the gene PNPLA3 have more fat in their livers and a greater risk of developing liver inflammation.
They also found that Hispanics are more likely to carry the gene variant responsible for higher liver-fat content than African-Americans and Caucasians.
The new findings, published online today in the journal Nature Genetics, provide a gene-based explanation for the results of a 2004 UT Southwestern-led study that determined that the propensity to develop nonalcoholic fatty liver disease differs among ethnic groups, with a higher percentage of Hispanics developing the disorder than African-Americans or Caucasians.
“A single variation in the PNPLA3 gene was strongly associated with hepatic fat content, even after adjusting for other factors, such as obesity, diabetes status and alcohol intake,” said senior study author Dr. Helen Hobbs, director of the Eugene McDermott Center for Human Growth and Development and an investigator for the Howard Hughes Medical Institute at UT Southwestern.
“Sequence variations in this gene explain much of the increased propensity of Hispanics to accumulate excess liver fat,” she said.
Nonalcoholic fatty liver disease (NAFLD) is the most common form of liver disease in Western countries, and its incidence is growing. Previous UT Southwestern research has shown that it may affect as many as one-third of adults in America.
“The gene variations we have identified might provide a way to predict who is most at risk for developing fatty liver disease and liver injury in response to environmental stresses such as obesity or infection,” said Dr. Jonathan Cohen, professor of internal medicine in the McDermott Center and one of the authors of the study.
NAFLD results from the accumulation of triglycerides in the liver and is associated with metabolic disorders such as insulin resistance, obesity, diabetes and high cholesterol – many of the conditions that contribute to heart disease. It can also lead to liver inflammation, cirrhosis and liver cancer. Approximately 10 percent of liver transplants performed in the U.S. are for cirrhosis related to NAFLD, according to the researchers.
Treatments for NAFLD include weight loss, exercise, reducing alcohol intake and improved diabetes control.
“Knowing who is at increased risk of developing liver disease could aid physicians in encouraging their patients to make lifestyle changes or take other preventive measures to help mitigate their underlying genetic risk for the disorder,” said Dr. Cohen, holder of the C. Vincent Prothro Distinguished Chair in Human Nutrition Research.
The new findings come out of the Dallas Heart Study, an 8-year-old groundbreaking investigation of cardiovascular disease that involves a large multiethnic group of participants. The $12 million study investigates the links between genetics, lifestyle and the risks for heart disease.
As part of the Dallas Heart Study, more than 3,500 individuals from Dallas County provided blood samples in 2000 for DNA isolation and other tests. Each participant also underwent multiple body scans with magnetic resonance imaging and computed tomography to examine the heart and other organs. Along with discovering new genetic ties to differences in blood levels of cholesterol and triglycerides, the researchers have used this information to identify new drug targets for the prevention and treatment of heart disease.
Data-gathering for the new study on fatty liver disease took advantage of a unique aspect of the Dallas Heart Study. Researchers with the study were the first to analyze hepatic fat in a large population using a technique called proton magnetic resonance spectroscopy – the most sensitive and quantitative noninvasive imaging technique available to measure the amount of fat in the liver. With this technique, they screened more than 2,100 individuals across multiple ethnicities. They then correlated that data with DNA tests from the same people and found the link to the PNPLA3 gene.
The next step in the research is to investigate how the various forms of the PNPLA3 gene affect lipid metabolism.
Other researchers from the McDermott Center involved with the study were lead author Dr. Stefano Romeo, a postdoctoral research fellow; Dr. Alexander Pertsemlidis, assistant professor; Dr. Chao Xing, assistant professor of clinical sciences; and Julia Kozlitina, a graduate student participating in a joint program between Southern Methodist University and UT Southwestern. Researchers from Perlegen Sciences, Lawrence Berkeley National Laboratory and the UT Health Science Center at Houston also were involved.
The research was funded by the Donald W. Reynolds Foundation, the National Institutes of Health and the Department of Energy.
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