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Archive - Mar 11, 2014

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Finding Hiding Place of Human Cytomegalovirus Could Lead to New Treatments

Discovering where a common virus hides in the body has been a long-term quest for scientists. Up to 80 percent of adults harbor the human cytomegalovirus (HCMV), which can cause severe illness and death in people with weakened immune systems. Now, researchers at Wake Forest Baptist Medical Center's Institute for Regenerative Medicine report that stem cells that encircle blood vessels can be a hiding place, suggesting a potential treatment target. In the American Journal of Transplantation (published online on March 4, 2011, ahead of print), senior scientist Graca Almeida-Porada, M.D., Ph.D., professor of regenerative medicine at Wake Forest Baptist, and colleagues report that perivascular stem cells, which are found in bone marrow and surround blood vessels in the body's organs, are a reservoir of HCMV. The virus, which is a member of the herpes family, is unnoticed in healthy people. Half to 80 percent of all adults in the U.S. are infected with HCMV, according to the Centers for Disease Control and Prevention. In people with weakened immune systems, including those with HIV, undergoing chemotherapy, or who are organ or bone marrow transplant recipients, the virus can become re-activated. Once re-activated, HCMV can cause a host of problems – from pneumonia to inflammation of the liver and brain – that are associated with organ rejection and death. "There are anti-viral medications designed to prevent HCMV from re-activating, but HVMC infection remains one of the major complications after both organ and bone marrow transplants," said Dr. Almeida-Porada.

Experimental Drugs for Hepatitis C Offer Hope for Effective Treatment, Fewer Side Effects

Patrizia Cazzaniga had heard the horror stories about early treatments for hepatitis C – multiple daily pills and weekly shots for up to a year, side effects that could be debilitating, and a cure rate of only about 40 percent. According to a March 11, 2014 press release from the University of Texas (UT) Southwestern Medical Center, after a shorter and less intensive treatment with experimental drugs at the UT Southwestern Medical Center that ended in October, Mrs. Cazzaniga is now virus-free three months past treatment. She’s thrilled. “If you don’t get treatment, you can get cancer or cirrhosis. That scared me. Now I feel great, my energy has come back, and I don’t have trouble with my stomach anymore,” said Mrs. Cazzaniga, 57, who took part in one of 10 current clinical trials testing new hepatitis drugs at UT Southwestern. “These new drugs are much more potent and effective,” said Dr. William M. Lee, Professor of Internal Medicine at UT Southwestern and local site investigator for these ongoing national and international drug trials. In the U.S., the Centers for Disease Control and Prevention (CDC) estimates that 4.1 million people carry the hepatitis C virus, with 3.2 million of them chronically infected. Further, CDC data show that about 15,000 Americans infected with the virus die annually from liver disease. About 75 percent of those infected do not know they have hepatitis C, because symptoms may not occur until later stages of the disease. For years, the standard treatment was six ribavirin capsules daily and weekly peginterferon shots. The treatment period was long – nearly a year – and side effects could include body aches, fatigue, headaches, anxiety, or depression.

Researchers Make Insulin-Producing Cells from Gut Cells

Destruction of insulin-producing beta cells in the pancreas is at the heart of type 1 and type 2 diabetes. "We are looking for ways to make new beta cells for these patients to one day replace daily insulin injections," says Ben Stanger, M.D., Ph.D., assistant professor of Medicine in the Division of Gastroenterology, Perelman School of Medicine at the University of Pennsylvania. Transplanting islet cells to restore normal blood sugar levels in patients with severe type 1 diabetes is one approach to treating the disease, and using stem cells to create beta cells is another area of investigation. However, both of these strategies have limitations: transplantable islet cells are in short supply, and stem cell-based approaches have a long way to go before they reach the clinic. "It's a powerful idea that if you have the right combination of transcription factors you can make any cell into any other cell. It's cellular alchemy," comments Dr. Stanger. New research from Dr. Stanger and postdoctoral fellow Yi-Ju Chen, Ph.D., together with a host of colleagues, reported online on March 6, 2014 in an open-access article in Cell Reports, describes how introducing three proteins that control the regulation of DNA in the nucleus -- called transcription factors -- into an immune-deficient mouse turned a specific group of cells in the gut lining into beta-like cells, raising the prospect of using differentiated pancreatic cells as a source for new beta cells. In 2008, the lab of Dr. Stanger's postdoctoral mentor introduced the three beta-cell reprogramming factors -- Pdx1 (P), MafA (M), and Ngn3 (N) -- collectively called PMN – into the acinar cells of the pancreas. Remarkably, this manipulation caused the cells to take on some structural and physiological features of beta cells.

Cancer Cells Take Direct Route Not Random Walk When Metastasizing

Because of results seen in flat lab dishes, biologists have believed that cancers cells move through the body in a slow, aimless fashion, resembling an intoxicated person who cannot walk three steps in a straight line. This pattern, called a random walk, may hold true for cells traveling across two-dimensional lab containers, but Johns Hopkins researchers have discovered that for cells moving through three-dimensional spaces within the body, the “random walk” model doesn’t hold true. This finding, reported in the March 4, 2014 online Early Edition of PNAS, is important because it should lead to more accurate results for scientists studying how cancer spreads through the body, often leading to a grim prognosis. To address this dimensional disagreement, the study’s authors have produced a new mathematical formula that they say better reflects the behavior of cells migrating through 3D environments. The research was supervised by Dr. Denis Wirtz, the university’s Theophilus H. Smoot Professor, with appointments in the departments of Chemical and Biomolecular Engineering, Pathology and Oncology within Johns Hopkins’ Whiting School of Engineering and School of Medicine. Dr. Wirtz said the discovery reinforces the current shift toward studying how cells move within three dimensions. His lab team has conducted earlier studies showing that that cells in 2D and 3D environments behave differently, which affects how cancer migrates within the body. “Cancer cells that break away from a primary tumor will seek out blood vessels and lymph nodes to escape and metastasize to distant organs,” Dr. Wirtz said. “For a long time, researchers have believed that these cells make their way to these blood vessels through random walks. In this study, we found out that they do not.

Gene Therapy for Lysosomal Storage Disease

Several young children suffering from a severe degenerative genetic disease received injections of therapeutic genes packaged within a noninfectious viral delivery vector. Safety, tolerability, and efficacy results from this early stage clinical trial are reported in Human Gene Therapy. Dr. Marc Tardieu, Université Paris-Sud and INSERM, and a team of international researchers administered the adeno-associated viral (AAV) vector carrying a normal copy of the N-sulfoglycosamine sulfohydrolase (SGSH) gene into the brains of four children affected by mucopolysaccharidosis type IIIA (MPSIIIA), an inherited lysosomal storage disease in which the SGSH gene is defective. The AAV vector also delivered a sulfatase-modifying factor (SUMF1), needed to activate the SGSH protein. In addition to measures of toxicity, adverse events, and tolerability, the researchers evaluated the children for brain shrinkage (a characteristic of MPSIIIA) and for changes in behavior, attention, sleep, and cognitive benefit. They describe their findings in the article "Intracerebral administration of AAV rh.10 carrying human SGSH and SUMF1 cDNAs in children with MPSIIIA disease: results of a phase I/II trial." "This is an important new approach for treating CNS manifestations of lysosomal storage diseases that could be applied across a wide array of disorders," says James M. Wilson, M.D., Ph.D., Editor-in-Chief of Human Gene Therapy, and Director of the Gene Therapy Program, Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia.

Potential New Heart Attack Drug with Minimal or No Side Effects

Melbourne, Australia scientists are a step closer to creating a new drug to stop a heart attack in its tracks and reduce the damage caused, without any side effects. The Monash University research, published online in the early edition of PNAS, offers new hope to thousands of people who experience heart attacks and heart failure – one of the major causes of death worldwide. Professors Arthur Christopoulos and Peter Scammells from the Monash Institute of Pharmaceutical Sciences (MIPS) led a team of scientists combining molecular pharmacology and medicinal chemistry to reveal new insights into a specific protein belonging to the family of G-protein-coupled receptors (GPCRs). After successfully combining two molecules, the researchers are a step closer to creating a brand new class of drug that is more targeted and could possess minimal side effects. GPCRs play a role in virtually every biological process and most diseases, including, cardiovascular disease, obesity and diabetes, neuropsychiatric disorders, inflammation, and cancer. Almost half of all current medications available use GPCRs to achieve their therapeutic effect. Current GPCR drugs work either by fully activating or completely blocking receptors, treating the protein like a simple “on-off” switch. This new research discovered alternative recognition sites on GPCRs that can be targeted by drugs to fine-tune the behavior of the protein, basically converting the “on-off” switch into a “dimmer switch”. Professor Christopoulos said it was this insight that enabled the new breakthrough. “When a heart attack strikes, heart cells die because of a lack of oxygen and nutrients.

New Tool to Study Kinase Activities at Heart of Many Diseases and Metastasis

Researchers at the University of North Carolina (UNC) School of Medicine have devised a new biochemical technique that will allow them and other scientists to delve much more deeply than ever before into the specific cellular circuitry that keeps us healthy or causes disease. The method – developed in the lab of Klaus Hahn, Ph.D., and described online on March 9, 2014 in the journal Nature Chemical Biology – helps researchers study how specific proteins called kinases interact to trigger a specific cellular behavior, such as how a cell moves. These kinase interactions are extraordinarily complex, and their interactions remain largely unknown. But researchers do know that kinases are crucial operators in disease. "I dare you to find a disease in which kinases are not involved," said Dr. Hahn, senior author of the study and the Thurman Distinguished Professor of Pharmacology. "These kinase processes have been very difficult to fully understand, but we all know they're very important." For years, scientists have been able to tweak a kinase to see what would happen – such as causing cell death or cell movement or cellular signaling. But these experiments can only scratch the surface when it comes to understanding the cascade of kinase interactions that lead to a cellular behavior. Nor have these experiments been able to show the timing of rapid events. That's important, Dr. Hahn said, because when a protein is activated has a lot to do with how the cell will respond. Drug developers haven't been able to take this into account, which is likely one reason why some drugs that target proteins don't work as well as scientists had hoped.