The cancer stem cells that drive tumor growth and resist chemotherapies and radiation treatments that kill other cancer cells aren't invincible after all. Researchers reporting online on August 13th in the journal Cell, a Cell Press publication, have discovered the first compound that targets those cancer stem cells directly.
"It wasn't clear it would be possible to find compounds that selectively kill cancer stem cells," said Piyush Gupta of the Massachusetts Institute of Technology (MIT) and the Broad Institute. "We've shown it can be done."
The team including MIT's Robert Weinberg and the Broad Institute's Eric Lander developed a new high-throughput screening method that makes it possible for the first time to systematically look for agents that kill cancer stem cells. That ability had previously eluded researchers due to the rarity of those cells within tumor cell populations and their relative instability in laboratory culture.
In the new study, the researchers manipulated cultured breast cancer cells to greatly enrich for those with the stem-like properties, including increased resistance to standard cancer drugs. They then screened a library of 16,000 natural and commercial chemical compounds for their ability to kill those stem-like cells and not other cancer cells. That screen turned up 32 contenders.
The researchers narrowed that list down to a handful of chemicals that they could readily get in sufficient quantities for further testing on normal cancer stem cells. Of those, one called salinomycin was the clear winner.
Salinomycin reduced the proportion of breast cancer stem cells by more than 100-fold compared to a commonly used chemotherapeutic drug for breast cancer called paclitaxel (aka Taxol™). Salinomycin-treated cells were less able than paclitaxel-treated ones to seed tumors when injected into mice, they report. Salinomycin treatment also slowed the growth of the animals' tumors.
Studies of salinomycin-treated human breast tumors also showed a loss in the activity of genes associated with cancer stem cells.
Exactly how salinomycin's works against cancer stem cells, the researchers don't yet know. As its name suggests, the chemical has antibiotic properties that likely aren't relevant to its newfound cancer stem cell-killing ability. It also disturbs cells' potassium balance.
It remains unclear whether salinomycin itself might find its way to the clinic, Gupta said, since many pharmaceutical steps are involved in the drug discovery process. Nevertheless, the chemical does serve as an immediate tool for manipulating cancer stem cell numbers and observing the effects on cancer's spread and progression.
The findings also highlight a new avenue for the development of cancer therapies, the researchers say.
" To date, rational cancer therapies have been designed to target specific genetic alterations present within tumors," they wrote. "The findings here indicate that a second approach may also prove useful - namely, searching for agents that target specific states of cancer cell differentiation. Accordingly, future therapies could offer greater possibilities for individualized treatment by considering both the genetic alterations and differentiation states present within the cancer cells of a tumor at the time of diagnosis."
They envision a future in which combination therapies might couple more traditional cancer drugs with those designed to hit the cancer stem cells that would otherwise get left behind.
The researchers include Piyush B. Gupta, Massachusetts Institute of Technology, Cambridge, MA, Broad Institute of MIT and Harvard, Cambridge, MA; Tamer T. Onder, Massachusetts Institute of Technology, Cambridge, MA, Whitehead Institute for Biomedical Research, Cambridge, MA; Guozhi Jiang, Massachusetts Institute of Technology, Cambridge, MA, Broad Institute of MIT and Harvard, Cambridge, MA; Kai Tao, Tufts Medical Center, Boston, MA; Charlotte Kuperwasser, Tufts Medical Center, Boston, MA; Robert A. Weinberg, Massachusetts Institute of Technology, Cambridge, MA, Whitehead Institute for Biomedical Research, Cambridge, MA, MIT Ludwig Center for Molecular Oncology, Cambridge, MA; and Eric S. Lander, Massachusetts Institute of Technology, Cambridge, MA, Whitehead Institute for Biomedical Research, Cambridge, MA, Broad Institute of MIT and Harvard, Cambridge, MA, Harvard Medical School, Boston, MA.
Source:
Cathleen Genova
Cell Press
View drug information on Taxol.
пятница, 30 сентября 2011 г.
вторник, 27 сентября 2011 г.
Paradoxical Protein Might Prevent Cancer
One difficulty with fighting cancer cells is that they are similar in many respects to the body's stem cells. By focusing on the differences, researchers at Karolinska Institutet have found a new way of tackling colon cancer. The study is presented in the prestigious journal Cell.
Molecular signal pathways that stimulate the division of stem cells are generally the same as those active in tumour growth. This limits the possibility of treating cancer as the drugs that kill cancer cells also often adversely affect the body's healthy cells, particularly stem cells. A new study from Karolinska Institutet, conducted in collaboration with an international team of scientists led by Professor Jonas FrisГ©n, is now focusing on an exception that can make it possible to treat a form of colon cancer.
The results concern a group of signal proteins called EphB receptors. These proteins stimulate the division of stem cells in the intestine and can contribute to the formation of adenoma (polyps), which are known to carry a risk of cancer. Paradoxically, these same proteins also prevent the adenoma from growing unchecked and becoming cancerous.
The new results show that EphB controls two separate signal pathways, one of which stimulates cell division and the other that curbs the cells' ability to become cancerous. Using this knowledge, the scientists have identified a drug substance called imatinib, which can inhibit the first signal pathway without affecting the other, protective, pathway.
"Imatinib or a similar substance could possibly be used for preventing the development of cancer in people who are in the risk zone for colon cancer instead of intestinal resection," says Maria Genander, one of the researchers involved in the study.
Imatinib has so far proved to inhibit cell division in intestinal tumour cells in vitro and in mice. The substance is a component of the drug Glivec, which is used, amongst other things, in the treatment of certain forms of leukaemia. Whether it can also be used against adenoma and colon cancer in humans remains to be seen. The company that manufactures the drug did not fund the study.
Publication:
Maria Genander, Michael M. Halford, Nan-Jie Xu, Malin Eriksson, Zuoren Yu, Zhaozhu Qiu, Anna Martling, Gedas Greicius, Sonal Thakar, Timothy Catchpole, Michael J. Chumley, Sofia Zdunek, Chenguang Wang, Torbjörn Holm, Stephen P. Goff, Sven Pettersson, Richard G. Pestell, Mark Henkemeyer & Jonas Frisén
Dissociation of EphB2 Signaling Pathways Mediating Progenitor Cell Proliferation and Tumor Suppression
Cell, print issue, 13 Nov 2009
Source: Press Officer Katarina Sternudd
Karolinska Institutet
Molecular signal pathways that stimulate the division of stem cells are generally the same as those active in tumour growth. This limits the possibility of treating cancer as the drugs that kill cancer cells also often adversely affect the body's healthy cells, particularly stem cells. A new study from Karolinska Institutet, conducted in collaboration with an international team of scientists led by Professor Jonas FrisГ©n, is now focusing on an exception that can make it possible to treat a form of colon cancer.
The results concern a group of signal proteins called EphB receptors. These proteins stimulate the division of stem cells in the intestine and can contribute to the formation of adenoma (polyps), which are known to carry a risk of cancer. Paradoxically, these same proteins also prevent the adenoma from growing unchecked and becoming cancerous.
The new results show that EphB controls two separate signal pathways, one of which stimulates cell division and the other that curbs the cells' ability to become cancerous. Using this knowledge, the scientists have identified a drug substance called imatinib, which can inhibit the first signal pathway without affecting the other, protective, pathway.
"Imatinib or a similar substance could possibly be used for preventing the development of cancer in people who are in the risk zone for colon cancer instead of intestinal resection," says Maria Genander, one of the researchers involved in the study.
Imatinib has so far proved to inhibit cell division in intestinal tumour cells in vitro and in mice. The substance is a component of the drug Glivec, which is used, amongst other things, in the treatment of certain forms of leukaemia. Whether it can also be used against adenoma and colon cancer in humans remains to be seen. The company that manufactures the drug did not fund the study.
Publication:
Maria Genander, Michael M. Halford, Nan-Jie Xu, Malin Eriksson, Zuoren Yu, Zhaozhu Qiu, Anna Martling, Gedas Greicius, Sonal Thakar, Timothy Catchpole, Michael J. Chumley, Sofia Zdunek, Chenguang Wang, Torbjörn Holm, Stephen P. Goff, Sven Pettersson, Richard G. Pestell, Mark Henkemeyer & Jonas Frisén
Dissociation of EphB2 Signaling Pathways Mediating Progenitor Cell Proliferation and Tumor Suppression
Cell, print issue, 13 Nov 2009
Source: Press Officer Katarina Sternudd
Karolinska Institutet
суббота, 24 сентября 2011 г.
Anti-inflammatory Effects Of Pomegranate In Rabbits: A Potential Treatment In Humans?
Oral ingestion of pomegranate extract reduces the production of chemicals that cause inflammation suggests a study published in BioMed Central's open access Journal of Inflammation. The findings indicate that pomegranate extract may provide humans with relief of chronic inflammatory conditions.
The group from the Department of Medicine of Case Western Reserve University, Cleveland Ohio, led by Tariq Haqqi, showed that blood samples collected from rabbits fed pomegranate extract inhibited inflammation.
Pomegranate extract is already used as a treatment in alternative medicine for inflammatory conditions, such as arthritis. Although pomegranate extract has antioxidant and anti-inflammatory actions in experiments on isolated tissues, it is not known whether ingestion of it can produce the same anti-inflammatory effects in living systems, either because the active compounds are not absorbed from the gut or because the levels of these compounds in the blood are not high enough.
Pomegranate extract, the equivalent of 175mls of pomegranate juice, was given to rabbits orally. The levels of antioxidants were measured in blood samples obtained after drinking the pomegranate extract and compared to blood samples collected before ingestion of pomegranate extract.
Plasma collected from rabbits following ingestion of pomegranate extract contained significantly higher levels of antioxidants than samples collected before ingestion of pomegranate extract; the extract also significantly reduced the activity of proteins that cause inflammation, specifically cyclooxygenase-2. It also reduced the production of pro-inflammatory compounds produced by cells isolated from cartilage.
The results of this study indicate the beneficial effects of pomegranate extract when ingested. According to Haqqi "the use of dietary nutrients or drugs based on them as an adjunct in the treatment of chronic inflammatory conditions may benefit patients". He adds that, "Current treatment with anti-inflammatory drugs can have serious side effects following long-term use. Further research is needed, however, especially on the absorption of orally ingested substances into the blood."
Notes:
1. Bioavailable Metabolites of Pomegranate (Punica granatum L) Fruit Extract Preferentially Inhibit COX2 Activity ex vivo and IL-1b-induced PGE2 Production in Articular Cartilage Chondrocytes in vitro.
Meenakshi Shukla, Kalpana Gupta, Zafar Rasheed, Khursheed A Khan and Tariq M Haqqi
Journal of Inflammation (in press)
Article available at the journal website: journal-inflammation/
All articles are available free of charge, according to BioMed Central's open access policy.
2. Tariq Haqqi is now with the Department of Pathology, Microbiology & Immunology, School of Medicine, at the University of South Carolina, Columbia.
3. Journal of Inflammation is an Open Access, peer-reviewed online journal on all aspects of research into inflammation.
4. BioMed Central (biomedcentral/) is an independent online publishing house committed to providing immediate access without charge to the peer-reviewed biological and medical research it publishes. This commitment is based on the view that open access to research is essential to the rapid and efficient communication of science.
Source: Charlotte Webber
BioMed Central
The group from the Department of Medicine of Case Western Reserve University, Cleveland Ohio, led by Tariq Haqqi, showed that blood samples collected from rabbits fed pomegranate extract inhibited inflammation.
Pomegranate extract is already used as a treatment in alternative medicine for inflammatory conditions, such as arthritis. Although pomegranate extract has antioxidant and anti-inflammatory actions in experiments on isolated tissues, it is not known whether ingestion of it can produce the same anti-inflammatory effects in living systems, either because the active compounds are not absorbed from the gut or because the levels of these compounds in the blood are not high enough.
Pomegranate extract, the equivalent of 175mls of pomegranate juice, was given to rabbits orally. The levels of antioxidants were measured in blood samples obtained after drinking the pomegranate extract and compared to blood samples collected before ingestion of pomegranate extract.
Plasma collected from rabbits following ingestion of pomegranate extract contained significantly higher levels of antioxidants than samples collected before ingestion of pomegranate extract; the extract also significantly reduced the activity of proteins that cause inflammation, specifically cyclooxygenase-2. It also reduced the production of pro-inflammatory compounds produced by cells isolated from cartilage.
The results of this study indicate the beneficial effects of pomegranate extract when ingested. According to Haqqi "the use of dietary nutrients or drugs based on them as an adjunct in the treatment of chronic inflammatory conditions may benefit patients". He adds that, "Current treatment with anti-inflammatory drugs can have serious side effects following long-term use. Further research is needed, however, especially on the absorption of orally ingested substances into the blood."
Notes:
1. Bioavailable Metabolites of Pomegranate (Punica granatum L) Fruit Extract Preferentially Inhibit COX2 Activity ex vivo and IL-1b-induced PGE2 Production in Articular Cartilage Chondrocytes in vitro.
Meenakshi Shukla, Kalpana Gupta, Zafar Rasheed, Khursheed A Khan and Tariq M Haqqi
Journal of Inflammation (in press)
Article available at the journal website: journal-inflammation/
All articles are available free of charge, according to BioMed Central's open access policy.
2. Tariq Haqqi is now with the Department of Pathology, Microbiology & Immunology, School of Medicine, at the University of South Carolina, Columbia.
3. Journal of Inflammation is an Open Access, peer-reviewed online journal on all aspects of research into inflammation.
4. BioMed Central (biomedcentral/) is an independent online publishing house committed to providing immediate access without charge to the peer-reviewed biological and medical research it publishes. This commitment is based on the view that open access to research is essential to the rapid and efficient communication of science.
Source: Charlotte Webber
BioMed Central
среда, 21 сентября 2011 г.
Study Finds That Blood Test Can Gauge Prostate Cancer Risk
New genomics research has found that a simple blood test can determine which men are likely to develop prostate cancer. Researchers at Wake Forest University School of Medicine and colleagues found that five genetic variants previously associated with prostate cancer risk have a strong cumulative effect.
Reporting in New England Journal of Medicine, researchers found that a man with four of the five variants has an increased risk of 400 to 500 percent compared to men with none of the variants. The researchers then added a family history of prostate cancer to the equation for a total of six risk factors. A man with at least five of the six factors had increased risk of more than 900 percent.
The article was published "Online First" today and will be included in the Feb. 28 print issue.
The scientists say each variant was independently associated with prostate cancer risk and that the variants are fairly common in the population. Together, these five variants and a family history accounted for almost half (46 percent) of prostate cancer patients. The study involved analyzing DNA samples from 2,893 men with prostate cancer and 1,781 healthy individuals of similar ages all participants of a prostate cancer study in Sweden.
"This is significant and could affect clinical care," said senior researcher Jianfeng Xu, M.D., Dr. PH., professor of epidemiology and cancer biology. "The information could substantially improve physicians' ability to assess risk and determine the need for more aggressive screening or even a biopsy."
For example, the test may be especially useful in men with a family history of prostate cancer or those who have a marginally elevated PSA (prostate specific antigen), he said.
The study is also important because it is one of the first to illustrate how a combination of several genes can affect risk of disease. Genomics teams nationwide are currently searching for combinations of genes that may underlie common diseases such as cancer, diabetes and asthma.
Currently, age, race and family history are the three factors associated with increased risk of prostate cancer. Family history is believed to account for about 10 percent of prostate cancer cases. Strikingly, researchers estimated that the five variants combined could account for about 40 percent of cases.
"Our finding provides an opportunity to supplement the well-established risk factors by looking at how many of these variants a man has inherited," said Xu. "It may provide a much better weapon to guide clinicians."
Until last year, no specific genetic variants had been consistently identified as markers for prostate cancer risk. Then, advances in technology allowed researchers to take a more systematic approach to looking at the entire genome. Instead of solely studying genes that they suspected were related to disease susceptibility, they could study the entire genome and look for associations.
Through these searches, several research teams identified five genetic locations associated with risk of developing prostate cancer: three on chromosome 8q24, one on chromosome 17q12 and one on 17q24.3.
Each variant alone was associated with moderate risk, but the effect wasn't considered significant enough to justify testing individuals. The current study was the first to evaluate whether there is a cumulative effect from having multiple variants.
"When we considered the variants together we discovered their potential for predicting individual risk," said Xu. "Because of the cumulative effects of these risk variants and family history, for the first time associations found through genome-wide screening appear to be useful in clinical practice."
The researchers said further study is needed to determine how their findings of genetic testing may complement PSA (prostate-specific antigen) testing. The researchers found that the risk associated with the genetic variants is independent of PSA results.
"This suggests that a subset of men deemed to have a low risk of prostate cancer based on their PSA levels may in fact be at significantly elevated risk due to inheriting one or more of the genetic variants," said S. Lilly Zheng, M.D., associate professor of internal medicine and the first author of the paper.
Genetic testing of these five variants will soon be offered at a CLIA (Clinical Laboratory Improvement Amendments)-certified laboratory at Wake Forest University School of Medicine.
Co-researchers include senior author Henrik Gronberg, M.D., Ph.D. professor at the Karolinska Institutet in Stockholm, Sweden, and William B. Isaacs, Ph.D, professor at Johns Hopkins Medical Institutions in Baltimore, Md.
Wake Forest University Baptist Medical Center is an academic health system comprised of North Carolina Baptist Hospital and Wake Forest University Health Sciences, which operates the university's School of Medicine. U.S. News & World Report ranks Wake Forest University School of Medicine 18th in family medicine, 20th in geriatrics, 25th in primary care and 41st in research among the nation's medical schools. It ranks 35th in research funding by the National Institutes of Health. Almost 150 members of the medical school faculty are listed in Best Doctors in America.
Wake Forest University Baptist Medical Center
Medical Center Blvd.
Winston-Salem, NC 27157-1015
United States
www1.wfubmc
Reporting in New England Journal of Medicine, researchers found that a man with four of the five variants has an increased risk of 400 to 500 percent compared to men with none of the variants. The researchers then added a family history of prostate cancer to the equation for a total of six risk factors. A man with at least five of the six factors had increased risk of more than 900 percent.
The article was published "Online First" today and will be included in the Feb. 28 print issue.
The scientists say each variant was independently associated with prostate cancer risk and that the variants are fairly common in the population. Together, these five variants and a family history accounted for almost half (46 percent) of prostate cancer patients. The study involved analyzing DNA samples from 2,893 men with prostate cancer and 1,781 healthy individuals of similar ages all participants of a prostate cancer study in Sweden.
"This is significant and could affect clinical care," said senior researcher Jianfeng Xu, M.D., Dr. PH., professor of epidemiology and cancer biology. "The information could substantially improve physicians' ability to assess risk and determine the need for more aggressive screening or even a biopsy."
For example, the test may be especially useful in men with a family history of prostate cancer or those who have a marginally elevated PSA (prostate specific antigen), he said.
The study is also important because it is one of the first to illustrate how a combination of several genes can affect risk of disease. Genomics teams nationwide are currently searching for combinations of genes that may underlie common diseases such as cancer, diabetes and asthma.
Currently, age, race and family history are the three factors associated with increased risk of prostate cancer. Family history is believed to account for about 10 percent of prostate cancer cases. Strikingly, researchers estimated that the five variants combined could account for about 40 percent of cases.
"Our finding provides an opportunity to supplement the well-established risk factors by looking at how many of these variants a man has inherited," said Xu. "It may provide a much better weapon to guide clinicians."
Until last year, no specific genetic variants had been consistently identified as markers for prostate cancer risk. Then, advances in technology allowed researchers to take a more systematic approach to looking at the entire genome. Instead of solely studying genes that they suspected were related to disease susceptibility, they could study the entire genome and look for associations.
Through these searches, several research teams identified five genetic locations associated with risk of developing prostate cancer: three on chromosome 8q24, one on chromosome 17q12 and one on 17q24.3.
Each variant alone was associated with moderate risk, but the effect wasn't considered significant enough to justify testing individuals. The current study was the first to evaluate whether there is a cumulative effect from having multiple variants.
"When we considered the variants together we discovered their potential for predicting individual risk," said Xu. "Because of the cumulative effects of these risk variants and family history, for the first time associations found through genome-wide screening appear to be useful in clinical practice."
The researchers said further study is needed to determine how their findings of genetic testing may complement PSA (prostate-specific antigen) testing. The researchers found that the risk associated with the genetic variants is independent of PSA results.
"This suggests that a subset of men deemed to have a low risk of prostate cancer based on their PSA levels may in fact be at significantly elevated risk due to inheriting one or more of the genetic variants," said S. Lilly Zheng, M.D., associate professor of internal medicine and the first author of the paper.
Genetic testing of these five variants will soon be offered at a CLIA (Clinical Laboratory Improvement Amendments)-certified laboratory at Wake Forest University School of Medicine.
Co-researchers include senior author Henrik Gronberg, M.D., Ph.D. professor at the Karolinska Institutet in Stockholm, Sweden, and William B. Isaacs, Ph.D, professor at Johns Hopkins Medical Institutions in Baltimore, Md.
Wake Forest University Baptist Medical Center is an academic health system comprised of North Carolina Baptist Hospital and Wake Forest University Health Sciences, which operates the university's School of Medicine. U.S. News & World Report ranks Wake Forest University School of Medicine 18th in family medicine, 20th in geriatrics, 25th in primary care and 41st in research among the nation's medical schools. It ranks 35th in research funding by the National Institutes of Health. Almost 150 members of the medical school faculty are listed in Best Doctors in America.
Wake Forest University Baptist Medical Center
Medical Center Blvd.
Winston-Salem, NC 27157-1015
United States
www1.wfubmc
воскресенье, 18 сентября 2011 г.
Strategic Approach To Early-Detection Of Pancreatic Cancer Biomarkers
A cancer scientist from Johns Hopkins has convinced an international group of colleagues to delay their race to find new cancer biomarkers and instead begin a 7,000-hour slog through a compendium of 50,000 scientific articles already published to assemble, decode and analyze the molecules that might herald the furtive presence of pancreatic cancer.
With limited resources available for the exhaustive and expensive testing that needs to be done before any candidate can be considered a bona fide biomarker of clinical value, it's important to take stock of the big picture and strategize, says Akhilesh Pandey, M.D., Ph.D., an associate professor in the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, and founder and director of the Institute of Bioinformatics in Bangalore, India.
Having mined the literature to amass 2,516 potential biomarkers of pancreatic cancer, Pandey and his team published their compendium on April 6 in PLoS Medicine. They systematically cataloged the genes and proteins that are overexpressed in pancreatic cancer patients, then characterized and compared these biomarker candidates in terms of how worthy each is of further study.
More than 200 genes are shortlisted because they were reported in four or more published studies to be overexpressed - meaning that the proteins they make are in higher abundance in people with pancreatic cancer than in people without the disease. This qualifies them as "excellent candidates" for the further studies that are needed to validate them as sensitive and specific biomarkers, note the authors.
Pandey says he was motivated by the fact that even leading cancer investigators had no real idea about how many candidate biomarkers for pancreatic cancer had already been identified, much less how they stacked up against each other in terms of clinical value in detecting early stages of the disease. Such biomarkers are highly valued because they gallop Paul Revere-like through the bloodstream and can signal early warnings of clinically invisible cancers and other diseases.
"Curation and databases are not very sexy concepts," says Pandey. "But we can't keep doing the exciting new discovery stuff and never take the time to catalog our results and share them."
Taking pancreatic cancer biomarkers to prove the value of such a strategic "big picture" approach, Pandey says it could serve as a basis for other disease-marker research.
"For the first time with pancreatic cancer - and potentially with any cancer - we have a handle on the number of candidates already identified and a real sense of how big an army we should send on the mission of further testing them," says Pandey.
Pandey's ultimate goal is to ferret out the best protein biomarker for pancreatic cancer - a molecule that reveals itself in an accessible bodily fluid and therefore can be detected with ease and accuracy - just like the protein biomarker that's made early on by a developing fetus and is exploited by at-home pregnancy tests.
The "gold standard" pancreatic cancer biomarker would possess both high sensitivity and specificity for early diagnosis. Cancer, at its most basic, is an abnormal population of cells that produce specific molecules - biomarkers - which healthy, cancer-free bodies do not. Cancer also tends to be incipient, Pandey says.
The ideal biomarker would allow for easy diagnosis when a cancer is still young, before it spreads to other organs. It could also help clinicians make informed decisions about treatments and better predict of outcomes, Pandey says: "Biomarkers could tell us who should undergo surgery, who should get chemotherapy, and in which people a cancer is likely to recur."
Biomarker discovery is an exploding area of research, Pandey says, yielding ever-increasing amounts of data - more than any one person can hope to keep track of, unless it's all strategically collected for widespread study.
"We want to initiate a trend by proving the importance of collection and cataloging," Pandey says, "which are exercises that many might view as tedious."
The team's next step is to create a searchable Web database that is universally available and free.
Notes:
The research was supported in part by the Lustgarten Foundation for Pancreatic Cancer Research.
Authors of the paper, in addition to Pandey, are H.C. Harsha and Arivusudar Marimuthu of the Institute of Bioinformatics, Bangalore, India; Manipal University, Karnataka, India; and McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University. Also, Kumaran Kandasamy, Suresh Mathivanan, and Manoj Kashyap of the Institute of Bioinformatics, Bangalore, India, and the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University. Prathibha Ranganathan, Sandhya Rani, Subhashri Ramabadran, Sashikanth Gollapudi, Lavanya Balakrishman, Sutopa B. Dwivedi, Deepthi Telikicherla, Lakshmi Dhevi N. Selvan, and Renu Goel, of the Institute of Bioinformatics, Bangalore, India; Robert Vizza of The Lustgarten Foundation for Pancreatic Cancer Research, New York; Robert J. Mayer and James A. DeCaprio of the Dana-Farber Cancer Institute, Boston; Sudhir Srivastava of the Cancer Biomarkers Research Group, NIH; Samir M. Hanash of the Fred Hutchinson Cancer Research Center, Seattle; and Ralph H. Hruban of the Departments of Pathology and Oncology at the Sol Goldman Pancreatic Cancer Institute, Johns Hopkins.
Source:
Maryalice Yakutchik
Johns Hopkins Medical Institutions
With limited resources available for the exhaustive and expensive testing that needs to be done before any candidate can be considered a bona fide biomarker of clinical value, it's important to take stock of the big picture and strategize, says Akhilesh Pandey, M.D., Ph.D., an associate professor in the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, and founder and director of the Institute of Bioinformatics in Bangalore, India.
Having mined the literature to amass 2,516 potential biomarkers of pancreatic cancer, Pandey and his team published their compendium on April 6 in PLoS Medicine. They systematically cataloged the genes and proteins that are overexpressed in pancreatic cancer patients, then characterized and compared these biomarker candidates in terms of how worthy each is of further study.
More than 200 genes are shortlisted because they were reported in four or more published studies to be overexpressed - meaning that the proteins they make are in higher abundance in people with pancreatic cancer than in people without the disease. This qualifies them as "excellent candidates" for the further studies that are needed to validate them as sensitive and specific biomarkers, note the authors.
Pandey says he was motivated by the fact that even leading cancer investigators had no real idea about how many candidate biomarkers for pancreatic cancer had already been identified, much less how they stacked up against each other in terms of clinical value in detecting early stages of the disease. Such biomarkers are highly valued because they gallop Paul Revere-like through the bloodstream and can signal early warnings of clinically invisible cancers and other diseases.
"Curation and databases are not very sexy concepts," says Pandey. "But we can't keep doing the exciting new discovery stuff and never take the time to catalog our results and share them."
Taking pancreatic cancer biomarkers to prove the value of such a strategic "big picture" approach, Pandey says it could serve as a basis for other disease-marker research.
"For the first time with pancreatic cancer - and potentially with any cancer - we have a handle on the number of candidates already identified and a real sense of how big an army we should send on the mission of further testing them," says Pandey.
Pandey's ultimate goal is to ferret out the best protein biomarker for pancreatic cancer - a molecule that reveals itself in an accessible bodily fluid and therefore can be detected with ease and accuracy - just like the protein biomarker that's made early on by a developing fetus and is exploited by at-home pregnancy tests.
The "gold standard" pancreatic cancer biomarker would possess both high sensitivity and specificity for early diagnosis. Cancer, at its most basic, is an abnormal population of cells that produce specific molecules - biomarkers - which healthy, cancer-free bodies do not. Cancer also tends to be incipient, Pandey says.
The ideal biomarker would allow for easy diagnosis when a cancer is still young, before it spreads to other organs. It could also help clinicians make informed decisions about treatments and better predict of outcomes, Pandey says: "Biomarkers could tell us who should undergo surgery, who should get chemotherapy, and in which people a cancer is likely to recur."
Biomarker discovery is an exploding area of research, Pandey says, yielding ever-increasing amounts of data - more than any one person can hope to keep track of, unless it's all strategically collected for widespread study.
"We want to initiate a trend by proving the importance of collection and cataloging," Pandey says, "which are exercises that many might view as tedious."
The team's next step is to create a searchable Web database that is universally available and free.
Notes:
The research was supported in part by the Lustgarten Foundation for Pancreatic Cancer Research.
Authors of the paper, in addition to Pandey, are H.C. Harsha and Arivusudar Marimuthu of the Institute of Bioinformatics, Bangalore, India; Manipal University, Karnataka, India; and McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University. Also, Kumaran Kandasamy, Suresh Mathivanan, and Manoj Kashyap of the Institute of Bioinformatics, Bangalore, India, and the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University. Prathibha Ranganathan, Sandhya Rani, Subhashri Ramabadran, Sashikanth Gollapudi, Lavanya Balakrishman, Sutopa B. Dwivedi, Deepthi Telikicherla, Lakshmi Dhevi N. Selvan, and Renu Goel, of the Institute of Bioinformatics, Bangalore, India; Robert Vizza of The Lustgarten Foundation for Pancreatic Cancer Research, New York; Robert J. Mayer and James A. DeCaprio of the Dana-Farber Cancer Institute, Boston; Sudhir Srivastava of the Cancer Biomarkers Research Group, NIH; Samir M. Hanash of the Fred Hutchinson Cancer Research Center, Seattle; and Ralph H. Hruban of the Departments of Pathology and Oncology at the Sol Goldman Pancreatic Cancer Institute, Johns Hopkins.
Source:
Maryalice Yakutchik
Johns Hopkins Medical Institutions
четверг, 15 сентября 2011 г.
Canada's New Government Invests $583 Million In The Next Generation Of Canadian Researchers
Dr. Colin Carrie, Parliamentary Secretary to the Honourable Maxime Bernier, Minister of Industry and Minister responsible for the Natural Sciences and Engineering Research Council of Canada (NSERC), and Dr. Suzanne Fortier, President of NSERC, have announced the results of the 2007 Grants and Scholarships awards, which will see $583 million disbursed to 10,000 professors and students across Canada.
As a result of the current competition, some 3,300 professors from across Canada will receive $458.8 million in Discovery Grants to support their research in the natural sciences and engineering. (These awards are normally paid out over five years.)
In addition, 2,402 young university researchers - 2,148 at the graduate level and 254 at the postdoctoral level - will receive $99.2 million to pursue their studies in these fields, while 4,296 undergraduate students will receive Undergraduate Student Research Awards worth a total of $19.3 million to give them hands-on research experience in a laboratory.
"Our newly released science and technology strategy - Mobilizing Science and Technology to Canada's Advantage - recognizes the importance of doing more to turn ideas into innovations that provide solutions to our environmental, health and other important challenges, and to improve Canada's economic competitiveness," said Parliamentary Secretary Carrie. "These awards will help ensure that this country's best and brightest professors and students can continue their work and their contribution to the prosperity and well-being of all Canadians."
This year also sees the introduction of the Discovery Accelerator Supplements, a new NSERC initiative to foster research excellence. With a total of $6 million in new funding, this initiative will provide significant supplements to a select group of researchers in order to boost their productivity at a critical juncture in their careers.
"These new grants target 50 outstanding researchers. Based on their success and accomplishments so far, we believe they are poised to make real breakthroughs in their fields, and we believe it is critically important to support them financially at this time," observed Dr. Fortier.
NSERC is a federal agency whose role is to make investments in people, discovery and innovation for the benefit of all Canadians. The agency invests in people by supporting some 23,000 university students and postdoctoral fellows in their advanced studies. NSERC promotes discovery by funding more than 11,000 university professors every year and helps make innovation happen by encouraging about 1,300 Canadian companies to invest in university research and training. Over the past 10 years, NSERC has invested $6 billion in basic research, university-industry projects, and the training of Canada's next generation of scientists and engineers.
For more information, contact:
Isabelle Fontaine
Office of the Honourable Maxime Bernier
Minister of Industry
Background Information
The 15 universities receiving the largest allocation of NSERC grants and scholarships this year are:
University of Toronto: $65.8 million
University of British Columbia: $46.4 million
McGill University: $38.6 million
University of Alberta: $31.9 million
University of Waterloo: $29.9 million
The University of Western Ontario: $21.2 million
Universite de Montreal: $19.7 million
University of Calgary: $18.5 million
Dalhousie University: $18.0 million
Universite de Sherbrooke: $17.8 million
Universite Laval: $17.6 million
McMaster University: $17.3 million
Queen's University: $16.0 million
University of Ottawa: $15.7 million
University of Manitoba: $14.0 million
Contact: Michael Dwyer
Natural Sciences and Engineering Research Council
As a result of the current competition, some 3,300 professors from across Canada will receive $458.8 million in Discovery Grants to support their research in the natural sciences and engineering. (These awards are normally paid out over five years.)
In addition, 2,402 young university researchers - 2,148 at the graduate level and 254 at the postdoctoral level - will receive $99.2 million to pursue their studies in these fields, while 4,296 undergraduate students will receive Undergraduate Student Research Awards worth a total of $19.3 million to give them hands-on research experience in a laboratory.
"Our newly released science and technology strategy - Mobilizing Science and Technology to Canada's Advantage - recognizes the importance of doing more to turn ideas into innovations that provide solutions to our environmental, health and other important challenges, and to improve Canada's economic competitiveness," said Parliamentary Secretary Carrie. "These awards will help ensure that this country's best and brightest professors and students can continue their work and their contribution to the prosperity and well-being of all Canadians."
This year also sees the introduction of the Discovery Accelerator Supplements, a new NSERC initiative to foster research excellence. With a total of $6 million in new funding, this initiative will provide significant supplements to a select group of researchers in order to boost their productivity at a critical juncture in their careers.
"These new grants target 50 outstanding researchers. Based on their success and accomplishments so far, we believe they are poised to make real breakthroughs in their fields, and we believe it is critically important to support them financially at this time," observed Dr. Fortier.
NSERC is a federal agency whose role is to make investments in people, discovery and innovation for the benefit of all Canadians. The agency invests in people by supporting some 23,000 university students and postdoctoral fellows in their advanced studies. NSERC promotes discovery by funding more than 11,000 university professors every year and helps make innovation happen by encouraging about 1,300 Canadian companies to invest in university research and training. Over the past 10 years, NSERC has invested $6 billion in basic research, university-industry projects, and the training of Canada's next generation of scientists and engineers.
For more information, contact:
Isabelle Fontaine
Office of the Honourable Maxime Bernier
Minister of Industry
Background Information
The 15 universities receiving the largest allocation of NSERC grants and scholarships this year are:
University of Toronto: $65.8 million
University of British Columbia: $46.4 million
McGill University: $38.6 million
University of Alberta: $31.9 million
University of Waterloo: $29.9 million
The University of Western Ontario: $21.2 million
Universite de Montreal: $19.7 million
University of Calgary: $18.5 million
Dalhousie University: $18.0 million
Universite de Sherbrooke: $17.8 million
Universite Laval: $17.6 million
McMaster University: $17.3 million
Queen's University: $16.0 million
University of Ottawa: $15.7 million
University of Manitoba: $14.0 million
Contact: Michael Dwyer
Natural Sciences and Engineering Research Council
понедельник, 12 сентября 2011 г.
Only Two Genes Make The Difference Between Herbaceous Plants And Trees
Scientists from VIB at Ghent University have succeeded in converting annual plants into perennials. They discovered that the deactivation of two genes in annuals led to the formation of structures that converted the plant into a perennial. This was most likely an important mechanism in plant evolution, initiating the formation of trees.
Annuals and perennials
Annual crops grow, blossom and die within one year. Perennials overwinter and grow again the following year. The life strategy of many annuals consists of rapid growth following germination and rapid transition to flower and seed formation, thus preventing the loss of energy needed to create permanent structures. They germinate quickly after the winter so that they come out before other plants, thus eliminating the need to compete for food and light. The trick is basically to make as many seeds as possible in as short a time as possible.
Perennials have more evolved life strategies for surviving in poor conditions. They compose perennial structures such as overwintering buds, bulbs or tubers. These structures contain groups with cells that are not yet specialised, but which can later be converted when required into new organs such as stalks and leaves.
The flowering of annuals
Annual crops consume all the non-specialised cells in developing their flowers. Thus the appearance of the flower signals means the end of the plant. But fortunately they have left seeds that sense - after winter - that the moment has come to start up. Plants are able to register the lengthening of the days. With the advent of longer days in the spring, a signal is sent from the leaves to the growth tops to activate a limited number of blooming-induction genes.
Deactivating two genes
VIB researchers, such as Siegbert Melzer in Tom Beeckman's group, have studied two such flower-inducing genes. They have deactivated them in thale cress (Arabidopsis thaliana), a typical annual. The VIB researchers found that mutant plants can no longer induce flowering, but they can continue to grow vegetatively or come into flower much later. Melzer had found that modified crops did not use up their store of non-specialised cells, enabling perennial growth. They can therefore continue to grow for a very long time.
As with real perennials these plants show secondary growth with wood formation creating shrub-like Arabidopsis plants.
Raising the veil of evolution
Researchers have been fascinated for a long time by the evolution of herbaceous to woody structures. This research clearly shows only two genes are in fact necessary in this process. This has probably been going on throughout the evolution of plants. Furthermore it is not inconceivable this happened independently on multiple occasions.
Relevant scientific publication
The research appears in the leading journal Nature Genetics (Siegbert Melzer et al., Flowering-time genes modulate meristem determinacy and growth form in Arabidopsis thaliana).
Funding
This research was financed by VIB, UGent, IWT, FWO.
Tom Beeckman is in charge of the Root Development research group in the VIB Plant Systems Biology department, UGent - under the management of Dirk InzГ©. Click here for more information.
VIB is a non-profit research institute in life sciences. Approximately 1100 scientists and technicians perform basic research into the molecular mechanisms that are responsible for the functioning of the human body, plants and micro-organisms. By means of a strong partnership with four Flemish universities - UGent, K.U.Leuven, Universiteit Antwerpen and Vrije Universiteit Brussel - and a robust investment programme, VIB bundles the strengths of 65 research groups into one institute. Their research aims at fundamentally pushing out the boundaries of our knowledge. With its technology transfer activities VIB aims to convert research results into products for the consumer and the patient. VIB develops and disseminates a broad range of scientifically based information on all aspects of biotechnology. More information on vib.be.
The Universiteit Gent (UGent) is one of the largest Dutch-speaking universities, with more than 30,000 students. The course options include almost all academic courses that are offered in Flanders.
The UGent prides itself on being an open, socially engaged and pluralistic university with an international perspective. More information on ugent.be.
Universiteit Gent
Annuals and perennials
Annual crops grow, blossom and die within one year. Perennials overwinter and grow again the following year. The life strategy of many annuals consists of rapid growth following germination and rapid transition to flower and seed formation, thus preventing the loss of energy needed to create permanent structures. They germinate quickly after the winter so that they come out before other plants, thus eliminating the need to compete for food and light. The trick is basically to make as many seeds as possible in as short a time as possible.
Perennials have more evolved life strategies for surviving in poor conditions. They compose perennial structures such as overwintering buds, bulbs or tubers. These structures contain groups with cells that are not yet specialised, but which can later be converted when required into new organs such as stalks and leaves.
The flowering of annuals
Annual crops consume all the non-specialised cells in developing their flowers. Thus the appearance of the flower signals means the end of the plant. But fortunately they have left seeds that sense - after winter - that the moment has come to start up. Plants are able to register the lengthening of the days. With the advent of longer days in the spring, a signal is sent from the leaves to the growth tops to activate a limited number of blooming-induction genes.
Deactivating two genes
VIB researchers, such as Siegbert Melzer in Tom Beeckman's group, have studied two such flower-inducing genes. They have deactivated them in thale cress (Arabidopsis thaliana), a typical annual. The VIB researchers found that mutant plants can no longer induce flowering, but they can continue to grow vegetatively or come into flower much later. Melzer had found that modified crops did not use up their store of non-specialised cells, enabling perennial growth. They can therefore continue to grow for a very long time.
As with real perennials these plants show secondary growth with wood formation creating shrub-like Arabidopsis plants.
Raising the veil of evolution
Researchers have been fascinated for a long time by the evolution of herbaceous to woody structures. This research clearly shows only two genes are in fact necessary in this process. This has probably been going on throughout the evolution of plants. Furthermore it is not inconceivable this happened independently on multiple occasions.
Relevant scientific publication
The research appears in the leading journal Nature Genetics (Siegbert Melzer et al., Flowering-time genes modulate meristem determinacy and growth form in Arabidopsis thaliana).
Funding
This research was financed by VIB, UGent, IWT, FWO.
Tom Beeckman is in charge of the Root Development research group in the VIB Plant Systems Biology department, UGent - under the management of Dirk InzГ©. Click here for more information.
VIB is a non-profit research institute in life sciences. Approximately 1100 scientists and technicians perform basic research into the molecular mechanisms that are responsible for the functioning of the human body, plants and micro-organisms. By means of a strong partnership with four Flemish universities - UGent, K.U.Leuven, Universiteit Antwerpen and Vrije Universiteit Brussel - and a robust investment programme, VIB bundles the strengths of 65 research groups into one institute. Their research aims at fundamentally pushing out the boundaries of our knowledge. With its technology transfer activities VIB aims to convert research results into products for the consumer and the patient. VIB develops and disseminates a broad range of scientifically based information on all aspects of biotechnology. More information on vib.be.
The Universiteit Gent (UGent) is one of the largest Dutch-speaking universities, with more than 30,000 students. The course options include almost all academic courses that are offered in Flanders.
The UGent prides itself on being an open, socially engaged and pluralistic university with an international perspective. More information on ugent.be.
Universiteit Gent
пятница, 9 сентября 2011 г.
New Protocol Quickly And Efficiently Differentiates Human Embryonic Stem Cells Into Committed Neural Precursor Cells
Investigators at the Burnham Institute for Medical Research (Burnham) have developed a protocol to rapidly differentiate human embryonic stem cells (hESCs) into neural progenitor cells that may be ideal for transplantation. The research, conducted by Alexei Terskikh, Ph.D., and colleagues, outlines a method to create these committed neural precursor cells (C-NPCs) that is replicable, does not produce mutations in the cells and could be useful for clinical applications. The research was published on March 13 in the journal Cell Death and Differentiation.
When the C-NPCs created using the Terskikh protocol were transplanted into mice, they became active neurons and integrated into the cortex and olfactory bulb. The transplanted cells did not generate tumor outgrowth.
"The uniform conversion of embryonic stem cells into neural progenitors is the first step in the development of cell-based therapies for neurodegenerative disorders or spinal injuries," said Dr. Terskikh. "Many of the methods used to generate neural precursor cells for research in the lab would never work in therapeutic applications. This protocol is very well suited for clinical application because it is robust, controllable and reproducible."
Dr. Terskikh notes that the extensive passaging (moving cells from plate to plate) required by some protocols to expand the numbers of neural precursor cells limits the plasticity of the cells, can introduce mutations and may lead to the expression of oncogenes. The Terskikh protocol avoids this by using efficient conversion of hESCs into primary neuroepithelial cells without the extensive passaging.
The scientists were able to rapidly neuralize the hESCs by culturing them in small clusters in a liquid suspension. The cells developed the characteristic "rosettes" seen in neuroepithelial cells. The C-NPCs were then cultured in monolayers. Immunochemical and RT-PCR analysis of the cells demonstrated that they were uniformly C-NPCs. Whole-genome analysis confirmed this finding. Immunostaining and imaging showed that the cells could be differentiated into three distinct types of neural cells. The team then demonstrated that the C-NPCs differentiated into neurons after transplantation into the brains of neonatal mice.
Notes:
This research received funding from the National Institutes of Health and the California Institute for Regenerative Medicine.
About Burnham Institute for Medical Research
Burnham Institute for Medical Research is dedicated to revealing the fundamental molecular causes of disease and devising the innovative therapies of tomorrow. Burnham, with operations in California and Florida, is one of the fastest-growing research institutes in the country. The Institute ranks among the top-four institutions nationally for NIH grant funding and among the top-25 organizations worldwide for its research impact. Burnham utilizes a unique, collaborative approach to medical research and has established major research programs in cancer, neurodegeneration, diabetes, infectious and inflammatory and childhood diseases. The Institute is known for its world-class capabilities in stem cell research and drug discovery technologies. Burnham is a nonprofit, public benefit corporation.
Source:
Josh Baxt
Burnham Institute
When the C-NPCs created using the Terskikh protocol were transplanted into mice, they became active neurons and integrated into the cortex and olfactory bulb. The transplanted cells did not generate tumor outgrowth.
"The uniform conversion of embryonic stem cells into neural progenitors is the first step in the development of cell-based therapies for neurodegenerative disorders or spinal injuries," said Dr. Terskikh. "Many of the methods used to generate neural precursor cells for research in the lab would never work in therapeutic applications. This protocol is very well suited for clinical application because it is robust, controllable and reproducible."
Dr. Terskikh notes that the extensive passaging (moving cells from plate to plate) required by some protocols to expand the numbers of neural precursor cells limits the plasticity of the cells, can introduce mutations and may lead to the expression of oncogenes. The Terskikh protocol avoids this by using efficient conversion of hESCs into primary neuroepithelial cells without the extensive passaging.
The scientists were able to rapidly neuralize the hESCs by culturing them in small clusters in a liquid suspension. The cells developed the characteristic "rosettes" seen in neuroepithelial cells. The C-NPCs were then cultured in monolayers. Immunochemical and RT-PCR analysis of the cells demonstrated that they were uniformly C-NPCs. Whole-genome analysis confirmed this finding. Immunostaining and imaging showed that the cells could be differentiated into three distinct types of neural cells. The team then demonstrated that the C-NPCs differentiated into neurons after transplantation into the brains of neonatal mice.
Notes:
This research received funding from the National Institutes of Health and the California Institute for Regenerative Medicine.
About Burnham Institute for Medical Research
Burnham Institute for Medical Research is dedicated to revealing the fundamental molecular causes of disease and devising the innovative therapies of tomorrow. Burnham, with operations in California and Florida, is one of the fastest-growing research institutes in the country. The Institute ranks among the top-four institutions nationally for NIH grant funding and among the top-25 organizations worldwide for its research impact. Burnham utilizes a unique, collaborative approach to medical research and has established major research programs in cancer, neurodegeneration, diabetes, infectious and inflammatory and childhood diseases. The Institute is known for its world-class capabilities in stem cell research and drug discovery technologies. Burnham is a nonprofit, public benefit corporation.
Source:
Josh Baxt
Burnham Institute
вторник, 6 сентября 2011 г.
Brain Protein Reduces Alzheimer's Plaques In Mice
Increasing levels of a protein that helps the brain use cholesterol may slow the development of Alzheimer's disease changes in the brain, according to researchers studying a mouse model of the disease at Washington University School of Medicine in St. Louis.
Elevated levels of the protein ABCA1 sharply reduced buildup of brain plaques that are a hallmark of Alzheimer's disease, according to senior author David M. Holtzman, M.D., the Andrew and Gretchen Jones Professor and chair of the Department of Neurology at the School of Medicine and neurologist-in-chief at Barnes-Jewish Hospital.
The study, appearing this month in The Journal of Clinical Investigation, highlights a new possibility for potential Alzheimer's treatment: altering the brain's use of lipids, a class of fat-soluble compounds that includes cholesterol.
"It's becoming clear that ABCA1 may be a good drug target for Alzheimer's therapies," Holtzman says. "There are known drugs that can increase ABCA1 levels, and with some further development of this or similar classes of drugs and additional insights into how ABCA1 slows down plaque deposition, there may be a way to create a new approach to Alzheimer's treatment."
Discovered in 2001, ABCA1 is a naturally occurring enzyme already under study for its potential to treat heart disease. Lipids like cholesterol aren't soluble, so to be transported through the bloodstream and into and out of cells and organs, they have to be associated with molecules known as apolipoproteins. ABCA1 facilitates this process, which is known as lipidation.
In the circulatory system, ABCA1 lipidates HDL with cholesterol to form fully functioning HDL, the "good" cholesterol thought to decrease risk of heart disease. Cardiovascular researchers are testing drugs that increase ABCA1 levels, hoping eventually to use them to prevent or alleviate atherosclerosis.
Holtzman was intrigued by the connection between ABCA1 and lipidation because a primary risk factor for Alzheimer's disease is an apolipoprotein known as apoE. Different genetic forms of apoE are linked to significant changes in an individual's risk of developing late-onset Alzheimer's disease.
In earlier research, Holtzman's lab revealed that ABCA1 also lipidates good cholesterol in the brain. When they utilized mice lacking the gene for ABCA1 and bred them to mouse model of Alzheimer's disease, the animals developed a much great number of the brain plaques that are characteristic of the disease.
For the new experiment, Holtzman laboratory members Suzanne Wahrle, an M.D./Ph.D. student, and Hong Jiang, a senior research technician, created a line of mice genetically altered to make unusually high levels of ABCA1 in the brain. When they crossbred that line with their Alzheimer's disease mouse model, they found mice with high ABCA1 levels built up plaques in their brains much more slowly and to a much lesser extent than those with normal ABCA1 levels.
The work showed that ABCA1 is facilitating the lipidation of HDL and apoE. Holtzman theorizes that this allows apoE to better scavenge amyloid beta, the main ingredient of plaques, from the brain in a way that decreases the chances that plaques will begin to form. An earlier experiment by other scientists showed that lipidated apoE binds more tightly to soluble amyloid beta than non-lipidated apoE. But further research is needed to prove this theory.
A class of drugs is already available that increases ABCA1 levels: LXR (liver X receptor) agonists. However, Holtzman notes, these drugs need to be fine-tuned to avoid an undesirable side effect that increases fat buildup in the liver.
Holtzman is conducting additional studies to clarify the details of the relationship between ABCA1, apoE and amyloid beta.
Wahrle SE, Jiang H, Parsadanian M, Kim J, Li A, Knoten A, Jain S, Hirsch-Reinshagen V, Wellington CL, Bales KR, Paul SM, Holtzman DM. Overexpression of ABCA1 reduces amyloid deposition in the PDAPP mouse model of Alzheimer's disease. Journal of Clinical Investigation, February 2008 (online January 17)
Funding from the National Institutes of Health, the O'Brien Center for Kidney Disease Research, Eli Lilly and Co, the Canadian Institutes of Health Research and the American Health Assistance Foundation supported this research.
Washington University School of Medicine's 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children's hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked fourth in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children's hospitals, the School of Medicine is linked to BJC HealthCare.
Washington University in St. Louis
One Brookings Dr., Campus Box 1070
St. Louis, MO 63130
United States
wustl
Elevated levels of the protein ABCA1 sharply reduced buildup of brain plaques that are a hallmark of Alzheimer's disease, according to senior author David M. Holtzman, M.D., the Andrew and Gretchen Jones Professor and chair of the Department of Neurology at the School of Medicine and neurologist-in-chief at Barnes-Jewish Hospital.
The study, appearing this month in The Journal of Clinical Investigation, highlights a new possibility for potential Alzheimer's treatment: altering the brain's use of lipids, a class of fat-soluble compounds that includes cholesterol.
"It's becoming clear that ABCA1 may be a good drug target for Alzheimer's therapies," Holtzman says. "There are known drugs that can increase ABCA1 levels, and with some further development of this or similar classes of drugs and additional insights into how ABCA1 slows down plaque deposition, there may be a way to create a new approach to Alzheimer's treatment."
Discovered in 2001, ABCA1 is a naturally occurring enzyme already under study for its potential to treat heart disease. Lipids like cholesterol aren't soluble, so to be transported through the bloodstream and into and out of cells and organs, they have to be associated with molecules known as apolipoproteins. ABCA1 facilitates this process, which is known as lipidation.
In the circulatory system, ABCA1 lipidates HDL with cholesterol to form fully functioning HDL, the "good" cholesterol thought to decrease risk of heart disease. Cardiovascular researchers are testing drugs that increase ABCA1 levels, hoping eventually to use them to prevent or alleviate atherosclerosis.
Holtzman was intrigued by the connection between ABCA1 and lipidation because a primary risk factor for Alzheimer's disease is an apolipoprotein known as apoE. Different genetic forms of apoE are linked to significant changes in an individual's risk of developing late-onset Alzheimer's disease.
In earlier research, Holtzman's lab revealed that ABCA1 also lipidates good cholesterol in the brain. When they utilized mice lacking the gene for ABCA1 and bred them to mouse model of Alzheimer's disease, the animals developed a much great number of the brain plaques that are characteristic of the disease.
For the new experiment, Holtzman laboratory members Suzanne Wahrle, an M.D./Ph.D. student, and Hong Jiang, a senior research technician, created a line of mice genetically altered to make unusually high levels of ABCA1 in the brain. When they crossbred that line with their Alzheimer's disease mouse model, they found mice with high ABCA1 levels built up plaques in their brains much more slowly and to a much lesser extent than those with normal ABCA1 levels.
The work showed that ABCA1 is facilitating the lipidation of HDL and apoE. Holtzman theorizes that this allows apoE to better scavenge amyloid beta, the main ingredient of plaques, from the brain in a way that decreases the chances that plaques will begin to form. An earlier experiment by other scientists showed that lipidated apoE binds more tightly to soluble amyloid beta than non-lipidated apoE. But further research is needed to prove this theory.
A class of drugs is already available that increases ABCA1 levels: LXR (liver X receptor) agonists. However, Holtzman notes, these drugs need to be fine-tuned to avoid an undesirable side effect that increases fat buildup in the liver.
Holtzman is conducting additional studies to clarify the details of the relationship between ABCA1, apoE and amyloid beta.
Wahrle SE, Jiang H, Parsadanian M, Kim J, Li A, Knoten A, Jain S, Hirsch-Reinshagen V, Wellington CL, Bales KR, Paul SM, Holtzman DM. Overexpression of ABCA1 reduces amyloid deposition in the PDAPP mouse model of Alzheimer's disease. Journal of Clinical Investigation, February 2008 (online January 17)
Funding from the National Institutes of Health, the O'Brien Center for Kidney Disease Research, Eli Lilly and Co, the Canadian Institutes of Health Research and the American Health Assistance Foundation supported this research.
Washington University School of Medicine's 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children's hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked fourth in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children's hospitals, the School of Medicine is linked to BJC HealthCare.
Washington University in St. Louis
One Brookings Dr., Campus Box 1070
St. Louis, MO 63130
United States
wustl
суббота, 3 сентября 2011 г.
Using Probes To Control Chemistry - Molecule By Molecule
Using probes originally designed to detect and image topographical features on surfaces, scientists at the U.S. Department of Energy's Brookhaven National Laboratory have demonstrated the ability to initiate and spatially localize chemical reactions on the submicron scale. They have been able to reliably manipulate chemistry on a very, very small scale in contrast to normal beaker-type reactions carried out in bulk. Such "site-selective" chemistry, taken down to the molecule-by-molecule level, could lead to new ways to etch small-scale electronic circuits, the development of extremely sensitive chemical sensors, as well as a better understanding and control of chemical reactions such as those used to convert sunlight into electricity in solar cells.
"Atomic force microscopy (AFM) uses probes that are analogous to the stylus on an old-style record player," says Brookhaven Lab materials scientist Stanislaus S. Wong. However, as opposed to "feeling" the nature of slight variations of pits within record grooves, AFM probes normally detect intermolecular interactions, related to changes in surface chemistry. "What we've demonstrated in our work is the ability to alter the AFM probe so it can be used not just passively, to sense chemistry, but actively, to initiate or control chemical reactions on a surface," Wong said.
In their proof-of-principle experiment, Wong's group attached titanium dioxide nanoparticles to the end of a conventional AFM probe and used it to photocatalytically oxidize selected sites on a thin film of photoreactive dye -- a model for understanding photocatalysis in solar cells. Mandakini Kanungo, a postdoctoral researcher in Wong's lab, will describe this work in a talk at the 231st national meeting of the American Chemical Society (ACS) in Atlanta, Georgia, on Thursday, March 30, 2006.
In the experiment, oxidized and unaffected areas of the dye were often separated by a mere 0.1 microns (millionths of a meter). The hope is to increase the spatial resolution of the technique to affect changes molecule by molecule, or at the one-nanometer (billionths of a meter) scale, Wong says.
Being able to control chemistry at this level has many potential applications. First, it gives the scientists deeper insight into the kinetics of reactions at the molecular level when, for example, a catalyst triggers the in situ oxidation of a chemical in the presence of light. This reaction is important toward understanding how to convert sunlight into useable forms of energy such as electricity. A "close-up" view of the chemistry will allow scientists to experiment with different types of catalyst particles, sizes and shapes of particles, and other characteristics to see precisely how these changes affect the kinetics and other dynamic properties associated with the photocatalytic process. This work could ultimately lead to the design of more efficient catalysts and more efficient solar cells.
In another application, Wong says, "You can use the AFM tip almost like an ultrafine pencil to draw out areas that you would like to react. This creates nanometer-scale 'lines' that are different from the chemistry of surrounding areas on the substrate." In essence, he says, you can etch out such "lines of reactivity," using chemistry to "draw," for example, nanoscale circuits. Such small-scale circuits could further shrink the scale of electronic devices, as well as increase the efficiency and/or speed of data storage and retrieval.
One important benefit of this technique is that it is environmentally friendly, Wong says, using no electric current or potentially harmful reaction conditions. Furthermore, the technique has such high specificity that it offers the potential for single-molecule detection and analysis -- a benefit with possible applications in refined chemical sensor technology. Such sensors might be able to detect as little as a single molecule of a potentially hazardous material released, for example, in a terror attack.
To learn more about the technique, recent results, and potential applications, attend Kanungo's ACS talk on Thursday, March 30, 2006 at 2:30 p.m. in Room B213 of the Georgia World Congress Center.
This research was funded by the Office of Basic Energy Sciences within the U.S. Department of Energy's Office of Science.
One of ten national laboratories overseen and primarily funded by the Office of Science of the U.S. Department of Energy (DOE), Brookhaven National Laboratory conducts research in the physical, biomedical, and environmental sciences, as well as in energy technologies and national security. Brookhaven Lab also builds and operates major scientific facilities available to university, industry and government researchers. Brookhaven is operated and managed for DOE's Office of Science by Brookhaven Science Associates, a limited-liability company founded by the Research Foundation of State University of New York on behalf of Stony Brook University, the largest academic user of Laboratory facilities, and Battelle, a nonprofit, applied science and technology organization. Visit Brookhaven Lab's electronic newsroom for links, news archives, graphics, and more: bnl/newsroom
Contact: Karen McNulty Walsh
kmcnultybnl
DOE/Brookhaven National Laboratory
"Atomic force microscopy (AFM) uses probes that are analogous to the stylus on an old-style record player," says Brookhaven Lab materials scientist Stanislaus S. Wong. However, as opposed to "feeling" the nature of slight variations of pits within record grooves, AFM probes normally detect intermolecular interactions, related to changes in surface chemistry. "What we've demonstrated in our work is the ability to alter the AFM probe so it can be used not just passively, to sense chemistry, but actively, to initiate or control chemical reactions on a surface," Wong said.
In their proof-of-principle experiment, Wong's group attached titanium dioxide nanoparticles to the end of a conventional AFM probe and used it to photocatalytically oxidize selected sites on a thin film of photoreactive dye -- a model for understanding photocatalysis in solar cells. Mandakini Kanungo, a postdoctoral researcher in Wong's lab, will describe this work in a talk at the 231st national meeting of the American Chemical Society (ACS) in Atlanta, Georgia, on Thursday, March 30, 2006.
In the experiment, oxidized and unaffected areas of the dye were often separated by a mere 0.1 microns (millionths of a meter). The hope is to increase the spatial resolution of the technique to affect changes molecule by molecule, or at the one-nanometer (billionths of a meter) scale, Wong says.
Being able to control chemistry at this level has many potential applications. First, it gives the scientists deeper insight into the kinetics of reactions at the molecular level when, for example, a catalyst triggers the in situ oxidation of a chemical in the presence of light. This reaction is important toward understanding how to convert sunlight into useable forms of energy such as electricity. A "close-up" view of the chemistry will allow scientists to experiment with different types of catalyst particles, sizes and shapes of particles, and other characteristics to see precisely how these changes affect the kinetics and other dynamic properties associated with the photocatalytic process. This work could ultimately lead to the design of more efficient catalysts and more efficient solar cells.
In another application, Wong says, "You can use the AFM tip almost like an ultrafine pencil to draw out areas that you would like to react. This creates nanometer-scale 'lines' that are different from the chemistry of surrounding areas on the substrate." In essence, he says, you can etch out such "lines of reactivity," using chemistry to "draw," for example, nanoscale circuits. Such small-scale circuits could further shrink the scale of electronic devices, as well as increase the efficiency and/or speed of data storage and retrieval.
One important benefit of this technique is that it is environmentally friendly, Wong says, using no electric current or potentially harmful reaction conditions. Furthermore, the technique has such high specificity that it offers the potential for single-molecule detection and analysis -- a benefit with possible applications in refined chemical sensor technology. Such sensors might be able to detect as little as a single molecule of a potentially hazardous material released, for example, in a terror attack.
To learn more about the technique, recent results, and potential applications, attend Kanungo's ACS talk on Thursday, March 30, 2006 at 2:30 p.m. in Room B213 of the Georgia World Congress Center.
This research was funded by the Office of Basic Energy Sciences within the U.S. Department of Energy's Office of Science.
One of ten national laboratories overseen and primarily funded by the Office of Science of the U.S. Department of Energy (DOE), Brookhaven National Laboratory conducts research in the physical, biomedical, and environmental sciences, as well as in energy technologies and national security. Brookhaven Lab also builds and operates major scientific facilities available to university, industry and government researchers. Brookhaven is operated and managed for DOE's Office of Science by Brookhaven Science Associates, a limited-liability company founded by the Research Foundation of State University of New York on behalf of Stony Brook University, the largest academic user of Laboratory facilities, and Battelle, a nonprofit, applied science and technology organization. Visit Brookhaven Lab's electronic newsroom for links, news archives, graphics, and more: bnl/newsroom
Contact: Karen McNulty Walsh
kmcnultybnl
DOE/Brookhaven National Laboratory
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