| Gene Packaging Tells Story Of Cancer Development |
|Resource: Johns Hopkins Kimmel Cancer Center|
Johns Hopkins Kimmel Cancer Center
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GENE PACKAGING TELLS STORY OF CANCER DEVELOPMENT
To decipher how cancer develops, Johns Hopkins Kimmel Cancer Center investigators say researchers must take a closer look at the packaging.
Specifically, their findings in the December 2, 2008, issue of PLoS Biology point to the three dimensional chromatin packaging around genes formed by tight, rosette-like loops of Polycomb group proteins (PcG). The chromatin packaging, a complex combination of DNA and proteins that compress DNA to fit inside cells, provides a repressive hub that keeps genes in a low expression state.
“We think the polycomb proteins combine with abnormal DNA methylation of genes to deactivate tumor suppressor genes and lock cancer cells in a primitive state,” says Stephen B. Baylin, M.D., Virginia and D.K. Ludwig Professor of Oncology and senior author.
Prior to this discovery, investigators studying cancer genes, looked at gene silencing as a linear process across the DNA, as if genes were flat, one dimensional objects. Research did not take into account the way genes are packaged.
To better understand the role of the PcG packaging, the team compared embryonic cells to adult colon cancer cells. The gene studied in the embryonic cells was packaged by PcG proteins, in a low expression state, and had no DNA methylation. When the gene received signals for cells to mature, the PcG loops were disrupted and the gene was highly expressed. However, when the same gene was abnormally DNA methylated, as is the case in adult, mature colon cancer cells, the PcG packaging loops were tighter and there was no gene expression. “These tight loops touch and interact with many gene sites folding it into a structure that shuts off tumor suppressor genes,” says Baylin. However, when the researchers removed DNA methylation from the cancer cells, the loops loosened somewhat, back to the state of an embryonic cell, and some gene expression was restored.
DNA methylation is a normal cellular process, but when it goes awry and genes are improperly methylated, it can shut down important tumor suppressing cell functions.
Demethylating agents, drugs that target and remove abnormal DNA methylation from genes, have been introduced as potential new cancer therapies. For these therapies to be fully effective, Baylin says, researchers may also need to look for agents that disrupt PcG loops.
Working with Baylin on this research were Vijay K. Tiwari, Kelly M. McGarvey, Julien D. F. Licchesi, Joyce E. Ohm, James G. Herman, and Dirk Schübeler.
The research was funded by the National Institutes of Environmental Health Sciences, the National Institutes of Health, and the Novartis Research Foundation.
On the web: www.hopkinskimmelcancercenter.org
|Landmark study defines benefits of early HIV testing and treatment for infected infants || |
|Resource: NIH/National Institute of Allergy and Infectious Diseases |
Testing very young babies for HIV and giving antiretroviral therapy (ART) immediately to those found infected with the virus dramatically prevents illness and death, according to a report in the New England Journal of Medicine. The study found that giving ART to HIV-infected infants beginning at an average age of 7 weeks made them four times less likely to die in the next 48 weeks, compared with postponing ART until signs of illness or a weakened immune system appeared--the standard of care when the study began.
These findings come from the "Children with HIV Early Antiretroviral Therapy" (CHER) study, the first Phase III randomized clinical trial to study the best time to begin ART in infants. Launched in South Africa in July 2005, CHER is sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, and the departments of health of the Western Cape and Gauteng in South Africa.
"HIV devastates the nascent immune systems of infants very quickly, yet too many HIV-infected infants do not get tested for the virus, get tested too late or get tested but lack access to lifesaving antiretroviral drugs," says Anthony S. Fauci, M.D., the director of NIAID. "The results of CHER are a clarion call to scale up widespread early HIV testing of at-risk infants and to make ART immediately accessible to all infants who test positive."
Preliminary results of CHER, released in July 2007, showed that HIV-infected infants were four times less likely to die if given ART immediately after HIV diagnosis (http://www3.niaid.nih.gov/news/newsreleases/2007/cher.htm). This finding helped influence the World Health Organization (WHO) to change its guidelines for treating HIV-infected infants. The new guidelines, issued in April 2008, strongly recommend starting ART in children under age 1 immediately after HIV diagnosis, regardless of their state of health. An NIAID study to identify the best drug regimen for these highly vulnerable children is under way.
"The new WHO guidelines will profoundly improve the survival rate and quality of life of infants born with HIV," says Ed Handelsman, M.D., chief of the Pediatric Medicine Branch in NIAID's Division of AIDS. "We are excited that we know the best time to begin treating HIV-infected infants; the challenge now for the global community is to ensure that all HIV-infected infants who need ART receive it soon enough."
The CHER study team, lead by Avy Violari, FCPaed, and Mark F. Cotton, MMed PhD, recruited and enrolled 377 infants between 6 and 12 weeks of age who had confirmed HIV infection but normal immune system development. Originally, the infants were randomly assigned to one of three regimens: start ART immediately and continue for 40 weeks; start ART immediately and continue for 96 weeks; or defer ART until signs of clinical or immunological progression to AIDS appeared. The ART regimen consists of ritonavir-boosted lopinavir, zidovudine and lamivudine, provided by GlaxoSmithKline PLC of Britain and the South African Department of Health. CHER is being conducted at two locations in South Africa: the Perinatal HIV Research Unit of the University of Witwatersrand; and the Children's Infectious Diseases Clinical Research Unit of Tygerberg Children's Hospital and Stellenbosch University. These sites are collaborating with the Medical Research Council Clinical Trials Unit in London.
In June 2007, a data and safety monitoring board (DSMB) overseeing CHER found that the babies who received immediate ART were four times less likely to die than the babies whose treatment was deferred. This was true even though 66 percent of those in the deferred treatment arm had met the criteria for ART during the first 32 weeks of the trial and already had begun treatment. Consequently, the DSMB recommended, and NIAID agreed, to assess all the children in the deferred-treatment arm for potential initiation of ART.
The study measured the effectiveness of the treatment strategies by counting the number of babies who died or whose immune systems were not protected by the original ART regimen. After a median of 48 weeks, 10 of 252 infants (4 percent) in the immediate-treatment arms had died, as had 20 of 125 (16 percent) infants in the deferred-treatment arm. Thus, immediate ART reduced deaths by 75 percent. As a secondary measure of success or failure, CHER counted the number of infants who developed HIV-related disease. Such disease developed in 16 babies (6.3 percent) in the immediate-treatment arms and 32 babies (26 percent) in the deferred-treatment arm. Thus, the infants who received treatment immediately were more than four times less likely to develop HIV-related disease.
NIAID conducts and supports research--at NIH, throughout the United States, and worldwide--to study the causes of infectious and immune-mediated diseases, and to develop better means of preventing, diagnosing and treating these illnesses. News releases, fact sheets and other NIAID-related materials are available on the NIAID Web site at http://www.niaid.nih.gov.
The National Institutes of Health (NIH)--The Nation's Medical Research Agency--includes 27 Institutes and Centers and is a component of the U. S. Department of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical and translational medical research, and it investigates the causes, treatments and cures for both common and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov.
Reference: A Violari et al. Early antiretroviral therapy reduces mortality in HIV-infected infants: evidence from the CHER trial. New England Journal of Medicine DOI 10.1056/NEJMoa0800971 (2008).
News releases, fact sheets and other NIAID-related materials are available on the NIAID Web site at http://www.niaid.nih.gov.
Release Date: Nov. 12, 2008
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The Next Step in Health Care: Telemedicine
Researchers broadcast live surgery using Internet2
Imagine a scenario where doctors from different hospitals can collaborate on a surgery without having to actually be in the operating room. What if doctors in remote locations could receive immediate expert support from top specialists in hospitals around the world?
This environment could soon become a reality thanks to research by a multi-university partnership that is testing the live broadcast of surgeries using the advanced networking consortium Internet2.
Rochester Institute of Technology is collaborating with a team led by the University of Puerto Rico School of Medicine that recently tested technology, which allows for the transmission of high quality, real time video to multiple locations. Using a secure, high-speed network, an endoscopic surgery at the University of Puerto Rico was broadcast to multiple locations in the United States. The experiment also included a multipoint videoconference that was connected to the video stream, allowing for live interaction between participants.
Results from the test were presented at a meeting of the collaboration special interest group at the fall 2008 Internet2 member meeting in New Orleans.
“The University of Puerto Rico has been performing this type of transmission between two sites for more than a year, but we are now able to utilize a combination of technologies that allows us to transmit to multiple sites simultaneously,” notes José Conde, director of the Center for Information Architecture in Research at the University of Puerto Rico Medical Sciences Campus.
“Being isolated geographically from major research centers, we need to use information technology to foster research collaborations with scientists around the world,” Conde adds.
“Previous efforts in telemedicine have been hampered by the quality of the video stream produced and the potential for network interruptions,” says Gurcharan Khanna, director of research computing at RIT and a member of the research team. “This test demonstrates that by using the speed and advanced protocols support provided by the Internet2 network, we have the potential to develop real-time, remote consultation and diagnosis during surgery, taking telemedicine to the next level.”
The researchers utilized a 30-megabit-per-second broadcast quality video stream, which produces high quality images, and configured it to be transmitted via multicast using Microsoft Research’s ConferenceXP system. This level of real time video was not possible in the past due to slower and lower quality computer networks. The team also utilized a Polycom videoconferencing system to connect all parties.
The team will next conduct additional tests with different surgical procedures and an expanded number of remote locations. The researchers’ goal is to transfer the technology for use in medical education and actual diagnostic applications.
“Today, physicians often need to travel to both examine patients and conduct consultations,” says Khanna. “Given the growing capacity of Internet technologies, the development of live remote consultation with high quality video could revolutionize medicine and greatly enhance the care patients can receive while reducing overall costs to the health care system.”
The research is being funded through a grant from the National Center for Research Resources at the National Institutes of Health to the University of Puerto Rico. The team also includes Johns Hopkins Hospital, the University of Michigan School of Medicine and the Office of High-Performance Computing at the National Library of Medicine. For more information about the project visit http://rc.rit.edu/endo.html or http://rcmi.rcm.upr.edu.##
|New Findings on the Role of Inflammation in Prevention of Coronary Heart Disease || |
Resource: National Institutes of Health News
Statement from Elizabeth G. Nabel, M.D., Director, National Heart, Lung, and Blood Institute on New Findings on the Role of Inflammation in Prevention of Coronary Heart Disease
This year, about 450,000 Americans will die of coronary heart disease — the leading cause of death for both men and women. Although we have made great strides in preventing and treating heart disease, we continue to explore the complex mechanisms involved in cardiovascular disease, and we are eager to refine risk assessment tools and preventive strategies to reduce the incidence of heart attack and stroke.
New results from three studies being presented at the American Heart Association (AHA) Scientific Sessions in New Orleans and published in scientific journals today provide the strongest evidence to date that a simple blood test for high-sensitivity C-reactive protein (hsCRP) is a useful marker for cardiovascular disease. Importantly, a much-anticipated study demonstrates for the first time that hsCRP levels in the blood can be used to guide treatment decisions to effectively lower the risk of heart attacks, stroke, and death. Together, these studies show great promise in helping clinicians better identify and treat individuals at risk for cardiovascular disease – potentially saving millions more lives.
For years, growing evidence has suggested that inflammation plays a strong role in developing cardiovascular disease, especially atherosclerosis, or hardening of the arteries. HsCRP is one of the most widely studied markers of inflammation in cardiovascular disease.
But, whether measuring hsCRP adds any measurable value for predicting risk for cardiovascular disease independent of traditional risk factors, such as age, blood cholesterol levels, blood pressure, diabetes, and smoking has been a topic of great debate. Further, it has been uncertain whether hsCRP levels can be used to improve treatment decisions.
Two studies supported by the National Heart, Lung, and Blood Institute (NHLBI) show that adding hsCRP levels to assess risk of a first heart attack or stroke in middle-aged or older adults improves accuracy over the traditional assessment tools by between 5 percent and 14 percent. The information proved to be especially valuable in reclassifying the risk of heart disease and stroke among individuals considered to be at intermediate risk (10 percent to 20 percent risk of having a heart attack within 10 years) by traditional methods.
Using data from the 3006 participants in NHLBI's Framingham Heart Offspring Study, Peter W. F. Wilson, M.D., of Emory University in Atlanta and colleagues from NHLBI, Boston University, and Tufts USDA Nutrition Center in Boston found that using hsCRP levels to assess risk provided a more accurate risk assessment over traditional risk scores among people otherwise considered at intermediate risk. The researchers suggest a two-stepped approach to assessing risk — using traditional risk scores first, then adding hsCRP levels to those found to be at intermediate risk — to guide clinical decisions. These results are published online today in Circulation Cardiovascular Quality and Outcomes.
In the second study, researchers used data from 10,724 men in the Physicians Health Study-II to prospectively develop the Reynolds Risk Score for Men, which adds hsCRP levels and parental history of early heart disease to traditional risk factors to assess men's risk. The new assessment tool was significantly more accurate than traditional risk factors alone in the study population. The report, by Paul Ridker, MD, of Brigham and Women's Hospital and Harvard Medical School in Boston, and colleagues, is published online in the journal Circulation today and will be presented Tuesday at the AHA Scientific Sessions. Previous work in the NHLBI-funded Women’s Health Study led to the development of a comparable Reynolds Risk Score for women last year.
The third hsCRP study results released today are from JUPITER (the Justification for Use of statins in Prevention: an Intervention Trial Evaluating Rosuvastatin), an international randomized clinical trial to test the effectiveness of treating individuals with high levels of hsCRP. Dr. Ridker and his colleagues demonstrate for the first time that a strategy of treatment decisions based upon hsCRP levels in otherwise healthy individuals significantly improves outcomes.
The study of 17,802 apparently healthy men and women was stopped early on March 30 after about 2 years because of the strong positive results. The researchers found that a daily dose of a commonly used statin, rosuvastatin (Crestor), reduced the risk of heart attack, stroke, and death by nearly half (44 percent) in individuals with high levels of hsCRP (2.0 mg/L or higher) but with normal or low levels of LDL (130mg/dL or lower). The treatment reduced LDL cholesterol by 50 percent and hsCRP by 37 percent. Supported by AstraZeneca, U.S., the study was presented today at the AHA Scientific Sessions and appears online in the New England Journal of Medicine (November 20, 2008, print issue).
These studies expand our understanding of the role of inflammation in detecting early signs of cardiovascular disease and identifying adults who are at risk for heart attack or stroke. These findings suggest that adding hsCRP levels to traditional risk factors could identify millions more adults for whom treatment with statins appears to lower the risk of heart attack.
Many clinicians now offer hsCRP testing to their patients, but until now the value of hsCRP levels to treatment decisions, especially in adults with desirable cholesterol levels, was unclear. As with any medical discovery, however, broadly adopting a new approach to detect or treat a condition should first be critically tested, preferably through large-scale event-based randomized clinical trials like JUPITER, and proven to bear greater benefits than risks, including costs.
As part of the NHLBI strategic plan, we have engaged an expert panel to review and update the scientific evidence regarding the assessment and management of cardiovascular risk factors. Today’s findings will be part of the rigorous scientific review to distill the scientific evidence and generate an evidence-based, comprehensive, set of clinical guidelines for primary care practitioners to help adult patients reduce their risk for cardiovascular disease.
In the meantime, however, we must not lose sight of the essential truth of what we already know to prevent heart disease: Cholesterol still counts, and we have proven ways to lower it and lessen its impact. The value of following a heart-healthy eating plan, being physically active, maintaining a healthy weight, and not smoking cannot be overestimated. And, statins can significantly reduce the risk of heart attack in those at high risk.
Let us continue to use our current knowledge as well as apply new discoveries based on solid evidence to take action for the betterment of individual and public health. Resources: What is Coronary Artery Disease?, http://www.nhlbi.nih.gov/health/dci/Diseases/Cad/CAD_WhatIs.html NHLBI Workshop Report, July 10-11, 2006: C-Reactive Protein: Basic and Clinical Research Needs, http://www.nhlbi.nih.gov/meetings/workshops/crp/report.htm
Part of the National Institutes of Health, the National Heart, Lung, and Blood Institute plans, conducts, and supports research related to the causes, prevention, diagnosis, and treatment of heart, blood vessel, lung, and blood diseases; and sleep disorders. The Institute also administers national health education campaigns on women and heart disease, healthy weight for children, and other topics. NHLBI press releases and other materials are available online at www.nhlbi.nih.gov.
The National Institutes of Health (NIH) — The Nation's Medical Research Agency — includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical and translational medical research, and it investigates the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.
National Institutes of Health. (2008). Statement from Elizabeth G. Nabel, M.D., Director, National Heart, Lung, and Blood Institute on new findings on the role of inflammation in prevention of coronary heart disease. Retrieved November 16, 2008, from http://www.nih.gov/news/health/nov2008/nhlbi-10.htm
Resource: MIT News Office
Untangling DNA regulation:
Biologists theorize role for DNA packaging in stem cell development
MIT biologists have discovered that the organization of DNA's packing material plays a critical role in directing stem cells to become different types of adult cells.
The work, to be published in the journal Cell on Nov. 14, could also shed light on the possible role of DNA packaging in cancer development.
Led by Laurie Boyer, assistant professor of biology at MIT, the researchers examined the role of chromatin -- the structure that forms when DNA is wound around a core of proteins called histones.
"We're particularly interested in how chromatin structure influences gene expression and ultimately cell fate," Boyer said. "We hope the studies we are doing can lead to better understanding of development as well as certain diseases."
It has been theorized that cancer cells may overexpress genes involved in early embryonic development, allowing them to proliferate unchecked and regress from adult tissue cells to a stem cell-like state.
Such regression could be partly mediated by changes in chromatin. This packaging is believed to help control DNA transcription because the more tightly wound the chromatin is, the less accessible DNA is to be transcribed.
The new study focused on a variant type of histone known as H2AZ, which other researchers have recently identified as a protein of interest in cancer.
While H2AZ is ubiquitously expressed in many cell types including adult cells, it is known to be essential for normal embryonic development. The new research reveals why: The variant histones are found near the promoter regions of a particular set of genes that are important for development.
The same genes are also regulated by a group of proteins known as Polycomb group (PcG) proteins, which act as gene silencers.
"It suggests that this histone variant -- along with the Polycomb group proteins -- may act as some kind of regulatory switch that mediates cell fate transitions," Boyer said. "We hypothesize that they're working together, and that allows these genes to be silent yet poised for activation in stem cells."
In future studies, Boyer's team plans to look at patterns of H2AZ distribution in cancerous cells.
Lead authors of the paper are Whitehead Institute postdoctoral associates Menno Creyghton and Styliani Markoulaki. Other authors are Whitehead postdoctoral associates Stuart Levine and Jacob Hanna; graduate student Michael Lodato; Ky Sha, a postdoctoral associate in biology; Richard Young, professor of biology; and Rudolf Jaenisch, professor of biology and member of the Whitehead Institute.
The research was funded by the Dutch Cancer Foundation, the Helen Hay Whitney Foundation, the National Institutes of Health and Genzyme Corp.
MIT News Office. (2008). Untangling DNA regulation: Biologists theorize role for DNA packaging in stem cell development. Retrieved November 15, 2008, from http://web.mit.edu/newsoffice/2008/stemcell-1106.html
WHO - 10 Facts on the Global Burden of Disease
Resource: WHO - World Health Organization 2008
Around 10 million children under the age of five die each year
Almost all of these children could survive with access to simple and affordable interventions. WHO is working with governments and partners worldwide to deliver integrated, effective care and strengthen health systems, both of which are crucial to reduce child deaths.
Cardiovascular diseases are the leading causes of death in the world
Cardiovascular diseases are diseases of the heart and blood vessels that can cause heart attacks and stroke. At least 80% of premature deaths from cardiovascular heart disease and strokes could be prevented through a healthy diet, regular physical activity and avoiding the use of tobacco.
HIV/AIDS is the leading cause of adult death in Africa
Despite substantial progress in the prevention and treatment of HIV/AIDS mortality remains high. A lack of access to health services limits survival. Obstacles for better care include weak health care systems and shortages of human resources.
Population aging is contributing to the rise in cancer and heart disease
The increasing proportion of older people in the global population is contributing to the increase of age-associated chronic diseases, particularly in developing countries. Care-givers, health systems and societies need to be ready to cope with the growing needs of the elderly in every part of the world.
Lung cancer is the most common cause of death from cancer in the world
Tobacco use is the single largest preventable cause of cancer in the world. In developing countries, smoking is responsible for more than 80% of all lung cancers.
Complications of pregnancy account for almost 15 % of deaths in women of reproductive age worldwide
More than half a million women die from preventable complications during pregnancy or childbirth. WHO works to improve maternal health by assisting countries to improve care before, during and after childbirth.
Mental disorders such as depression are among the 20 leading causes of disability worldwide
Depression affects around 120 million people worldwide and this number is projected to increase. Fewer than 25% of those affected have access to adequate treatment and health care.
Hearing loss, vision problems and mental disorders are the most common causes of disability
These disorders can affect people's lives and livelihoods, but many are easily treatable (e.g. hearing loss and cataracts). Statistics vary between higher- and lower-income countries but high overall rates of these disorders underline the need for wider access to interventions that help people live productively.
Road traffic injuries are projected to rise from the ninth leading cause of death globally in 2004, to the fifth in 2030
More than 3500 people die from road traffic crashes every day and millions are injured or disabled for life. WHO works to increase awareness of this preventable cause of death by promoting road safety practices such as wearing helmets and seat-belts, and not speeding or driving under the influence of alcohol.
Under-nutrition is the underlying cause of death for at least 30% of all children under age five
Almost 20 million children worldwide are severely malnourished. Inadequate breastfeeding, inappropriate food and a lack of access to highly nutritious foods contribute to the problem. Common childhood diseases affect a child's ability to eat or absorb the necessary nutrients from food.
World Health Organization (2008). 10 facts on the burden of global disease. Retrieved November 15, 2008, from http://www.who.int/features/factfiles/global_burden/facts/en/index.html