BreakThrough Digest Medical News |
- Western diet changes gut bacteria and triggers colitis in those at risk
- Clinical trial of human hookworm vaccine begins at Children’s National Medical Center
- New drug-screening method yields long-sought anti-HIV compounds
- New England Journal of Medicine hails new skin cancer drug as ‘greatest advance yet’
| Western diet changes gut bacteria and triggers colitis in those at risk Posted: 13 Jun 2012 02:38 PM PDT Certain saturated fats that are common in the modern Western diet can initiate a chain of events leading to complex immune disorders such as inflammatory bowel diseases (IBD) in people with a genetic predisposition, according to a study to be published early online in the journal Nature.
The finding helps explain why once-rare immune-mediated diseases have become more common in westernized societies in the last half century. It also provides insights into why many individuals who are genetically prone to these diseases are never affected and how certain environmental factors can produce inflammation in individuals already at risk. Researchers at the University of Chicago found that concentrated milk fats, which are abundant in processed and confectionary foods, alter the composition of bacteria in the intestines. These changes can disrupt the delicate truce between the immune system and the complex but largely beneficial mix of bacteria in the intestines. The emergence of harmful bacterial strains in this setting can unleash an unregulated tissue-damaging immune response that can be difficult to switch off. “This is the first plausible mechanism showing step-by-step how Western-style diets contribute to the rapid and ongoing increase in the incidence of inflammatory bowel disease,” said study author Eugene B. Chang, MD, PhD, the Martin Boyer Professor of Medicine at the University of Chicago. “We know how certain genetic differences can increase the risk for these diseases, but moving from elevated risk to the development of disease seems to require a second event which may be encountered because of our changing lifestyle.” The researchers worked with a mouse model that has many of the characteristics of human IBD. Genetically deleting a molecule, interleukin 10, which acts as a brake on the immune system’s response to intestinal bacteria, caused about 20 percent of mice to develop colitis when fed a low-fat diet or a diet high in polyunsaturated fats. But when exposed to a diet high in saturated milk fats, the rate of disease development within six months tripled, increasing to more than 60 percent. In addition, the onset, severity and extent of colitis were much greater than that observed in mice fed low-fat diets. Why would milk fat – a powdered substance that remains when fat has been separated from butter and dehydrated – trigger inflammation when polyunsaturated fat did not? The researchers traced the answer to the gut microbiome, the complex mix of hundreds of bacterial strains that reside in the bowels. The researchers found that an uncommon microbe called Bilophila wadsworthia was preferentially selected in the presence of milk fat. Previous studies had found high levels of B. wadsworthia in patients with appendicitis and other intestinal inflammatory disorders, including inflammatory bowel disease. “That piqued our interest,” Chang said. “These pathobionts, which are usually non-abundant, seem to be quite prominent in these diseases.” Indeed, while Bilophila wadsworthia levels were almost undetectable in mice on a low-fat or unsaturated-fat diet, the bacteria made up about 6 percent of all gut bacteria in mice fed a high milk-fat diet. “Here we show how the trend in consumption of Western-type diets by many societies can potentially tip the mutualistic balance between host and microbe to a state that favors the onset of disease,” Chang said. As its name implies, Bilophila wadsworthia has an affinity for bile, a substance produced by the liver and released into the intestines to help break down ingested fats. Milk fats are particularly difficult to digest and require the liver to secrete a form of bile that is rich in sulfur. B. wadsworthia thrives in the presence of sulfur. So when the bile created to dissolve milk fats reaches the colon, it enables wadsworthia to blossom. “Unfortunately, these can be harmful bacteria,” Chang said. “Presented with a rich source of sulfur, they bloom, and when they do, they are capable of activating the immune system of genetically prone individuals.” The byproducts of B. wadsworthia‘s interaction with bile also can amplify the effect. They serve as “gut mucosal barrier breakers,” said Suzanne Devkota, PhD, a member of Chang’s laboratory and first author of the study. “By increasing the permeability of the bowel, they enhance immune-cell infiltration, and that can induce tissue damage.” Much of the recent progress in understanding the biology of inflammatory bowel disease has focused on gene variants that can increase risk, beginning with the discovery in 2001 of Nod2 by researchers at the University of Chicago. But the new study puts the focus on changing environmental factors that might trigger the disease in high-risk patients. “Right now we can’t do much about correcting genes that predispose individuals to increased risk for these diseases,” Chang said, “and while we could encourage people to change their diets, this is seldom effective and always difficult.” “However, the balance between host and microbes can be altered back to a healthy state to prevent or treat these diseases,” he added. “In essence, the gut microbiome can be ‘re-shaped’ in sustainable and predictable ways that restore a healthy relationship between host and microbes, without significantly affecting the lifestyles of individuals who are genetically prone to these diseases. We are testing that right now.” ### The National Institutes of Health, the Gastrointestinal Research Foundation, the Crohn’s & Colitis Foundation of America, the Peter D. and Carol Goldman Foundation, and the Leona M. and Harry B. Helmsley Charitable Trust supported this research. Additional authors include Yunwei Wang, Mark Musch, Vanessa Leone, Hannah Fehlner-Peach, Anuradha Nadimpalli and Bana Jabri from the University of Chicago, and Dionysios Antonopoulos from the Institute for Genomics and Systems Biology at Argonne National Laboratory. |
| Clinical trial of human hookworm vaccine begins at Children’s National Medical Center Posted: 12 Jun 2012 09:00 PM PDT Today, the Sabin Vaccine Institute, in partnership with the George Washington University and the Children’s National Medical Center, began vaccinating participants for a Phase 1 clinical trial of a novel human hookworm vaccine. The trial will investigate the Na-GST-1 antigen developed by the Sabin Vaccine Institute Product Development Partnership (Sabin PDP) to prevent hookworm infections in endemic areas.
“This trial signifies the great progress global health leaders are making to help combat diseases of poverty,” said Dr. Peter Hotez, president of the Sabin Vaccine Institute and director of the Sabin Vaccine Institute and Texas Children’s Hospital Center for Vaccine Development. “This trial helps advance our goal to develop a safe, efficacious and low-cost vaccine to reduce the global burden of human hookworm, which infects nearly 600 million people worldwide.” Dr. Hotez is also the founding dean of the National School of Tropical Medicine at Baylor College of Medicine. This study will help to quickly determine the optimal vaccine formulation for future clinical testing of the Na-GST-1 antigen. A critical component of the vaccine being tested is a novel adjuvant developed by the Infectious Disease Research Institute (IDRI) of Seattle, Washington. The adjuvant, GLA-AF, could potentially help to stimulate the immune system for an improved specific antibody response to the vaccine antigen. “We hope that this trial will offer us the breakthrough we need to ultimately stop transmission of this parasite, especially among the world’s poorest,” said Dr. Jeff Bethony, Associate Professor of Microbiology, Immunology and Tropical Medicine at the George Washington University. The clinical trial is based at the Children’s National Medical Center in Washington, D.C. The trial will enroll 72 healthy adults between the ages of 18 and 45 residing within the Washington, DC metropolitan area. Each volunteer will receive three injections over four months. The researchers will then follow each volunteer for 12 additional months, monitoring the vaccine’s safety and analyzing the recipients’ immune responses. A concurrent trial of the Na-GST-1 antigen began in November 2011 in Brazil, an area with a high hookworm disease burden in endemic regions. The Brazil trial is being conducted by a team based at the Oswaldo Cruz Foundation (FIOCRUZ) of the Brazilian Ministry of Health, a member of the Sabin PDP. “By conducting clinical trials in both Brazil and here in the United States, we will be able to rapidly determine the best formulation of the Na-GST-1 vaccine to advance into future vaccine trials in children, the population most at risk of hookworm disease. At the same time, we will help improve biotechnology capacity in an endemic country,” said Dr. David Diemert, Principal Investigator of both clinical trials and an Associate Research Professor at the George Washington University. Hookworm is a soil-transmitted helminth infection caused by the intestinal parasites Necator americanus and Ancylostoma duodenale. Although people living in most middle and upper income countries are largely free from the suffering caused by hookworm, the infection remains widespread in tropical and sub-tropical climates of Africa, Asia and Latin America. Left untreated, hookworm infection causes severe intestinal blood loss leading to iron-deficiency anemia and protein malnutrition, which in turn can result in impaired physical and cognitive development in children. ### Established in 2000 with funding from the Bill & Melinda Gates Foundation and with additional support from the Dutch Ministry of Foreign Affairs, the Brazilian Ministry of Health, the George Washington University, and the Children’s National Clinical and Translational Science Insititute, the Sabin PDP is the first and only program that aims to reduce the prevalence of human hookworm infection by developing the world’s first vaccine targeting the disease. To learn more about the clinical trial being conducted at the Children’s National Medical Center, please visit www.sabin.org. About Sabin Vaccine Institute
Sabin Vaccine Institute is a non-profit, 501(c)(3) organization of scientists, researchers, and advocates dedicated to reducing needless human suffering caused by vaccine preventable and neglected tropical diseases. Sabin works with governments, leading public and private organizations, and academic institutions to provide solutions for some of the world’s most pervasive health challenges. Since its founding in 1993 in honor of the oral polio vaccine developer, Dr. Albert B. Sabin, the Institute has been at the forefront of efforts to control, treat, and eliminate these diseases by developing new vaccines, advocating use of existing vaccines, and promoting increased access to affordable medical treatments. For more information please visit www.sabin.org. About Sabin’s PDP
The Sabin PDP is focused on developing vaccines targeting neglected tropical diseases and the world’s first and only vaccine initiative targeting human hookworm infection. This product development partnership (PDP) engages partners in academia, industry, government and civil society to fill an important market gap by collaborating with world class research and development institutions to create ultra low-cost vaccines for poor and underserved populations. Other PDP members include Texas Children’s Hospital, Baylor College of Medicine, the George Washington University, the Oswaldo Cruz Foundation (FIOCRUZ), the London School of Hygiene and Tropical Medicine (UK), the James Cook University (Australia), Instituto Butantan (Brazil) and the Institute of Parasite Diseases of the Chinese Centers for Disease Control and Prevention (China). About the School of Medicine and Health Sciences
Founded in 1825, the GW School of Medicine and Health Sciences (SMHS) was the first medical school in the nation’s capital and is the 11th oldest in the country. Working together in our nation’s capital, with integrity and resolve, the GW SMHS is committed to improving the health and well-being of our local, national and global communities. www.smhs.gwumc.edu About Children’s National Medical Center
Children’s National Medical Center in Washington, DC, has been serving the nation’s children since 1870. Home to Children’s Research Institute and the Sheikh Zayed Institute for Pediatric Surgical Innovation, Children’s National is consistently ranked among the top pediatric hospitals by U.S.News & World Report and the Leapfrog Group. Children’s National is a Magnet® designated hospital. With 303 beds and eight regional outpatient centers, Children’s National is the only exclusive provider of acute pediatric services in the Washington metropolitan area. For more information, visit ChildrensNational.org, or follow us on Facebook and Twitter. About Clinical and Translational Science Institute-Children’s National:
The Clinical and Translational Science Institute at Children’s National is a joint effort by Children’s National Medical Center and The George Washington University Medical Center with several goals:
For more information, visit www.ctsicn.org. The project described is supported by Award Number UL1RR031988/UL1TR000075 from the NIH National Center for Advancing Translational Sciences. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Contact: Johanna Harvey |
| New drug-screening method yields long-sought anti-HIV compounds Posted: 12 Jun 2012 09:00 PM PDT Scientists at The Scripps Research Institute have used a powerful new chemical-screening method to find compounds that inhibit the activity of human immunodeficiency virus (HIV), the virus that causes AIDS. Unlike existing anti-HIV drugs, the compounds bind to a protein called “nucelocapsid,” which is unlikely to mutate into drug-resistant forms.
“Most of the nucleocapsid-inhibiting compounds that have been identified to date are very toxic, but our screening method identified inhibitors that are less toxic and thus more likely to lead to useful drugs,” said Scripps Research Associate Professor Bruce Torbett. Torbett is the senior author of the new report, which appears in the June 14, 2012 print issue of the Journal of Medicinal Chemistry. HIV’s nucleocapsid protein binds to the viral genome to package and protect it, and plays a key role in the assembly of new virus copies, as well as in the reverse transcription of the viral genome into DNA. It has long been a target of HIV drug developers because it grabs hold of the viral genome using protein structures?known as zinc knuckles?that can’t change much without losing their functionality. It thus is thought to have little room to mutate into drug-resistant forms, in contrast with other HIV proteins. Screening Out Toxicity
However, despite almost two decades of research, there are still no FDA-approved drugs that target HIV’s nucleocapsid protein and its zinc knuckle structures. One reason is that similar structures exist on many healthy cellular proteins; thus compounds that target them are apt to have unwanted side effects. “When researchers have targeted these nucleocapsid zinc knuckles in the past, they’ve usually ended up producing toxicity,” Torbett said. To increase the chances of finding safe compounds, Torbett and his colleagues?postdoctoral researcher Sebastian Breuer, the study’s first author, and Max Chang and Jinyun Yuan, also postdoctoral researchers?began with the Maybridge HitFinder Collection, a library of 14,400 chemical compounds from which many broadly toxic molecules have already been excluded. The Scripps Research Molecular Screening Center maintains the latest robotic equipment for quickly applying chemical tests to such libraries. With the help of screening expert Scripps Research Professor Hugh Rosen, Screening Center Staff Scientist Steven Brown, and Research Assistant Jacqueline Lohse, Breuer applied a special combination of screening tests to the Maybridge library to rapidly zero in on effective and safe nucleocapsid-inhibiting compounds. The first screening test employed a technique known as fluorescence polarization to measure the ability of each compound in the library to displace the binding of the viral genome to the nucleocapsid protein. (The study focused on the virus type HIV-1, which accounts for the vast majority of HIV infections outside West Africa.) The second test, using differential scanning fluorimetry, was applied to the 101 compounds that passed the first test; it identified those that perform the displacement by binding strongly to the nucleocapsid protein rather than to the viral genome. After eliminating the weaker and more toxic candidates with further tests, Breuer, Torbett, and their colleagues ended up with 10 compounds. Detailed analyses of these yielded two that were sufficiently powerful at inhibiting viral infectivity in cell culture tests, without being unacceptably toxic. “We went very quickly from having a concept to having these two inhibitors with demonstrated anti-HIV activity in cells,” said Torbett. Searching for the ‘Sweet Spot’
With his Scripps Research colleagues M. G. Finn and Valery Fokin, Torbett now plans to evaluate compounds that are closely related to the two inhibitors to see if the scientists can find any that are even more safe and effective. Torbett and colleagues also plan to apply the same combination-screening method to larger compound libraries to identify entirely new nucleocapsid-inhibiting compounds. To gain a better understanding of how these inhibitors work, Torbett is also collaborating with Scripps Research structural biologists, including David Stout and Arthur Olson, and virologist John Elder to perform X-ray crystallography studies of the inhibitors in combination with the HIV nucleocapsid protein. “The overall goal here is to find a ‘sweet spot’ on the nucleocapsid protein that can be targeted effectively by a small-molecule drug without causing toxicity,” Torbett said. ### The study was supported by grants from the National Institutes of Health’s National Institute of General Medical Sciences, National Institute of Allergy and Infection Diseases, and National Heart, Lung and Blood Institute, as well as the California HIV/AIDS Research Program. Contact: Mika Ono |
| New England Journal of Medicine hails new skin cancer drug as ‘greatest advance yet’ Posted: 11 Jun 2012 09:00 PM PDT Vismodegib, a new skin cancer drug for patients with advanced basal cell carcinoma tested by TGen, Virginia G. Piper Cancer Center at Scottsdale Healthcare and Mayo Clinic, is hailed as “the greatest advance in therapy yet seen” for advanced basal cell carcinoma in an editorial in the New England Journal of Medicine.
Vismodegib (marketed under the name Erivedge) was administered for the first time in the world on Jan. 23, 2007 in a Phase I clinical trial at Virginia G. Piper Cancer Center Clinical Trials at Scottsdale Healthcare, a partnership with the Translational Genomics Research Institute (TGen). This is the first drug tested under the Scottsdale Healthcare-TGen partnership to receive FDA approval, and is the first to receive FDA approval to treat inoperable basal cell carcinoma. Successful early trial results led to additional study sponsored by Genentech. The successful Phase I study at Virginia G. Piper Cancer Center Clinical Trials at Scottsdale Healthcare, headed by Scottsdale Healthcare Chief Scientific Officer and TGen Physician-In-Chief Daniel Von Hoff, M.D, led to a broader study, published June 7 by the New England Journal of Medicine. “The first patient put on this drug had advanced basal cell cancer, so we suspected that the tumor had the mutation this drug is targeted against,” said Ramesh K. Ramanathan, M.D., Medical Director at Virginia G. Piper Cancer Center Clinical Trials and Clinical Professor and Deputy Director of the Clinical Translational Research Division at TGen. “And our partnership with Dr. Ronald Korn and his team who did advanced PET imaging helped to really demonstrate the drug’s efficacy for Genentech to continue pursuing the additional study.” The follow-up study, a Phase 2 clinical trial of basal cell carcinoma (BCC), was headed by Dr. Aleksandar Sekulic, Assistant Professor of Dermatology for the Mayo Clinic in Arizona, and an Assistant Professor in TGen’s Integrated Cancer Genomics Division. This Phase 2 study provided the efficacy data for vismodegib that led to its approval by the U.S. Food and Drug Administration (FDA) on Jan. 30, 2012. “As a result of a strong collaboration between the Valley institutions, clinical development of this new medication, from the first clinical trial to the FDA approval, was led by the Valley researchers,” said Dr. Sekulic, M.D and Ph.D., whose study found that vismodegib shrank advanced basal cell carcinoma tumors in 43 percent of patients with locally advanced disease and in 30 percent of patients whose disease spread to other organs. The drug blocks the Hedgehog signaling pathway and was approved for treatment of locally advanced and metastatic basal cell carcinomas. Additional research noted encouraging results for patients with inherited genetic susceptibility for development of large numbers of BCC tumors, known as basal cell nevus syndrome. “The availability of vismodegib and similar medications will really change the way we treat the patients with advanced forms of BCC, who had very limited options to date. In addition, this drug will likely offer a life-changing treatment for patients with basal cell nevus syndrome. It is possible that the drug may also be of benefit in treatment of earlier stages of BCC, and this is currently being evaluated in several clinical trials,” Dr. Sekulic said. “It is a landmark day for patients with basal cell carcinoma and all those involved in their care,” said the NEJM editorial. However the editors cautioned that additional study of Hedgehog pathway inhibitors like vismodegib warrant further study so a larger number of patients may benefit. FDA approval in five years is a remarkable achievement because clinical trials typically progress through three phases and can take up to 15 years to successfully complete, according to Mark Slater, Ph.D., Vice President of Research at Scottsdale Healthcare. Most instances of basal cell cancer can be effectively treated, but in some cases, the cancer cells spread and develop an aggressive form of the cancer that does not respond to standard surgical treatment. “For a small percentage of patients, basal cell carcinoma can progress to inoperable life-threatening, locally advanced or metastatic tumors. Vismodegib, taken as a once a day pill, represents an opportunity to improve quality of life for these patients,” said Dr. Glen Weiss, Director of Thoracic Oncology at Virginia G. Piper Cancer Center Clinical Trials and Clinical Associate Professor of TGen’s Cancer and Cell Biology Division. San Francisco-based Genentech developed vismodegib. Successful results of early clinical trials at the Virginia G. Piper Cancer Center at Scottsdale Healthcare, Johns Hopkins University and Karmanos Cancer Institute were published in the Sept. 17, 2009, New England Journal of Medicine and led to interest in increased access to the drug. ### Individuals seeking information about eligibility to participate in clinical trials at the Virginia G. Piper Cancer Center at Scottsdale Healthcare may contact the cancer care coordinator at 480-323-1339; toll free at 1-877-273-3713 or via email at clinicaltrials@shc.org. About the Virginia G. Piper Cancer Center at Scottsdale Healthcare
The Virginia G. Piper Cancer Center at Scottsdale Healthcare in Scottsdale, Ariz. offers comprehensive cancer treatment and research through Phase I clinical trials, diagnosis, prevention and support services in collaboration with leading scientific researchers and community oncologists. Scottsdale Healthcare is the nonprofit parent organization of the Virginia G. Piper Cancer Center at Scottsdale Healthcare, Scottsdale Healthcare Research Institute, Scottsdale Healthcare Osborn Medical Center, Scottsdale Healthcare Shea Medical Center and Scottsdale Healthcare Thompson Peak Hospital. For more information, visit www.shc.org. Press Contact: About Mayo Clinic
Mayo Clinic is a nonprofit worldwide leader in medical care, research and education for people from all walks of life. For more information, visit MayoClinic.com or MayoClinic.org/news. Media Contact About TGen
The Translational Genomics Research Institute (TGen) is a Phoenix, Arizona-based non-profit organization dedicated to conducting groundbreaking research with life changing results. Research at TGen is focused on helping patients with diseases such as cancer, neurological disorders and diabetes. TGen is on the cutting edge of translational research where investigators are able to unravel the genetic components of common and complex diseases. Working with collaborators in the scientific and medical communities, TGen believes it can make a substantial contribution to the efficiency and effectiveness of the translational process. For more information, visit: www.tgen.org. Contact: Steve Yozwiak |
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