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Archive - Apr 2013

Date

April 30th

Two Types of Blood Vessel Stem Cells Identified—May Point to Disease Therapies

Many diseases – obesity, Type 2 diabetes, and muscular dystrophy, for example – are associated with fat accumulation in muscle. In essence, fat replacement causes the muscles to weaken and degenerate. Scientists at Wake Forest Baptist Medical Center have discovered the biological mechanism involved in this process, which could point the way to potential therapies. The findings were published online on April 27, 2013 in Stem Cells and Development. The Wake Forest Baptist researchers proved that pericytes, stem cells associated with blood vessels, contain two sub-types with completely different roles: Type 1, which form only fat cells, and Type 2, which form only muscle cells. "We found that Type 1 contributes to fat accumulation in the skeletal muscle under pathogenic conditions, while Type 2 helps in forming muscle," said Osvaldo Delbono, M.D., Ph.D., professor of internal medicine at Wake Forest Baptist and senior author of the study. "This is important because now we have the potential to develop therapies that can block the activity of Type 1 pericytes to form fat or activate Type 2 pericytes to regenerate muscle." In the study, the researchers were able to identify the subtypes through genetic and molecular labeling methods. Using an in vitro model, they showed that Type 1 pericytes form fat while Type 2 pericytes form muscle. To test their theory in an animal model, the scientists first injected Type 2 cells into injured muscle in healthy young mice to determine if the muscle would regenerate to repair the damage; it did. When Type 1 cells were injected, the mice did not form muscle.

Zebrafish Study Suggests Vitamin B2 May Be Antidote to Cyanide Poisoning

With the remains of a recent lottery winner having been exhumed for investigation of foul play related to cyanide poisoning, future winners might wonder what they can do to avoid the same fate. A new report in May 2013 issue of The FASEB Journal involving studies in zebrafish suggests that riboflavin, also known as vitamin B2, may mitigate the toxic effects of this infamous poison. In addition, the report shows that zebrafish are a viable model for investigating the effects of cyanide on humans. As with any research involving animal models, these findings are preliminary until thoroughly tested in clinical trials. Anyone who suspects cyanide poisoning should not attempt to use riboflavin as an antidote, and instead should contact local poison control centers or emergency health services immediately."We are encouraged to see that many of the effects of cyanide on zebrafish mirror the effects on humans," said Randall Peterson, Ph.D., the senior author of the study and a research at the Harvard Medical School. "Hopefully, the cyanide biomarkers and antidotes we discover with the help of zebrafish can one day improve our ability to diagnose and treat humans affected by cyanide poisoning." To make this discovery, scientists exposed zebrafish to cyanide and measured the effects on their behavior, heart rate, and survival. The chemical changes that occurred were measured using a mass spectrometer. The effects in zebrafish were then compared to the effects of cyanide on rabbits and humans. Many of the effects in zebrafish matched those seen in rabbits and humans, confirming that the zebrafish could be used as a model of human cyanide exposure.

How Does Early Pregnancy Reduce Breast Cancer Risk?

Being pregnant while young is known to protect women against breast cancer. But why? Research published online on April 29, 2013 in BioMed Central's open access journal Breast Cancer Research finds that Wnt/Notch signaling ratio is decreased in the breast tissue of mice that have given birth, compared to virgin mice of the same age. Early pregnancy is protective against breast cancer in humans and in rodents. In humans having a child before the age of 20 decreases risk of breast cancer by half. Using microarray analysis researchers from Basel discovered that genes involved in the immune system and differentiation were up-regulated after pregnancy, while the activity of genes coding for growth factors was reduced. The activity of one particular gene, Wnt4, was also down-regulated after pregnancy. The protein from this gene (Wnt4) is a feminizing protein - absence of this protein propels a fetus towards developing as a boy. Wnt and Notch are opposing components of a system which controls cellular fate within an organism and when the team looked at Notch they found that genes regulated by Notch were up-regulated, Notch-stimulating proteins were up-regulated, and Notch-inhibiting proteins were down-regulated. Wnt/Notch signaling ratio was permanently altered in the basal stem/progenitor cells of mammary tissue of mice by pregnancy. Dr. Mohamed Bentires-Alj from the Friedrich Miescher Institute for Biomedical Research, who led this study explained, "The down-regulation of Wnt is the opposite of that seen in many cancers, and this tightened control of Wnt/Notch after pregnancy may be preventing the runaway growth present in cancer." [Press release] [Breast Cancer Research article]

Zone in with Zon: Highlights of Molecular Medicine Tri-Conference 2013

Dr. Gerald Zon’s latest blog post in “Zone in with Zon—What’s Trending in Nucleic Acid Research,” (http://zon.trilinkbiotech.com/) was posted on April 28, 2013 and features Dr. Zon’s key takeaways from the Molecular Medicine Tri-Conference 2013 held in February in San Francisco. Among the conference highlights for Dr. Zon were the “democratization” of diagnostics, the clinical impact of next-generation sequencing, and the emerging use of smartphone technology in point-of-care diagnostics. Dr. Zon is an eminent nucleic acid chemist and Director of Business Development at TriLink BioTechnologies in San Diego, California. [Zon blog post]

April 28th

Mapping of Cancer Cell Fuel Pumps Paves Way for New Drugs

For the first time, researchers at Karolinska Institutet in Sweden have managed to obtain detailed images of the way in which the transport protein GLUT transports sugars into cells. Because tumors are highly dependent on the transportation of nutrients in order to be able to grow rapidly, the researchers are hoping that the study, published in Nature Structural & Molecular Biology, will form the basis for new strategies to fight cancer cells. In order to be able to fuel their rapid growth, cancer tumors depend on transporter proteins to work at high speed to introduce sugars and other nutrients that are required for the cell's metabolism. One possible treatment strategy would therefore be to block some of the transporters in the cell membrane which operate as fuel pumps, thus starving out and killing the cancer cells. One important group of membrane transporters is the GLUT family, which introduces glucose and other sugars into the cell. Glucose is one of the most important energy sources for cancer cells and GLUT transporters have been shown to play a key role in tumor growth in many different types of cancer. In the current study, researchers from Karolinska Institutet have performed a detailed study of the way in which suger transport is executed by the protein XylE, from the Escherichia coli bacterium, whose function and structure is very similar to GLUT transporters in humans. For the first time, the researchers have described the way in which the protein's structure changes between two different conformations when it binds and transports a sugar molecule. "In showing details of the molecular structure of the region that binds the sugar, our study opens up the opportunities to more efficiently develop new substances that may inhibit GLUT transporters", says Dr.

Gilead Drug Induces Loss of Infected Cells in Chimp Model of Hepatitis B

A novel drug developed by Gilead Sciences and tested in an animal model at the Texas Biomedical Research Institute in San Antonio suppresses hepatitis B virus infection by stimulating the immune system and inducing loss of infected cells. In a study conducted at Texas Biomed's Southwest National Primate Research Center, researchers found that the immune modulator GS-9620, which targets a receptor on immune cells, reduced both the virus levels and the number of infected liver cells in chimpanzees chronically infected with hepatitis B virus (HBV). Chimpanzees are the only species other than humans that can be infected by HBV. Therefore, the results from this study were critical in moving the drug forward to human clinical trials which are now in progress. The new report, co-authored by scientists from Texas Biomed and Gilead Sciences, was published online on February 14, 2013 in Gastroenterology. Gilead researchers had previously demonstrated that the same therapy could induce a cure of hepatitis infection in woodchucks that were chronically infected with a virus similar to human HBV. "This is an important proof-of-concept study demonstrating that the therapy stimulates the immune system to suppress the virus and eliminate infected liver cells," said co-author Robert E. Lanford, Ph.D., of Texas Biomed. "One of the key observations was that the therapy continued to suppress virus levels for months after therapy was stopped.” The current therapy for HBV infection targets the virus and works very well at suppressing viral replication and delaying progression of liver disease, but it is a lifelong therapy that does not provide a cure. "This GS-9620 therapy represents the first conceptually new treatment for HBV in more than a decade, and combining it with the existing antiviral therapy could be transformative in dealing with this disease," stated Dr.

April 27th

Hitting “Reset” in Protein Synthesis Restores Myelination in Model of Charcot-Marie-Tooth Disease

A potential new treatment strategy for patients with Charcot-Marie-Tooth disease is on the horizon, thanks to research by neuroscientists now at the University at Buffalo’s (UB’s) Hunter James Kelly Research Institute and their colleagues in Italy and England. The institute is the research arm of the Hunter's Hope Foundation, established in 1997 by Jim Kelly, Buffalo Bills Hall of Fame quarterback, and his wife, Jill, after their infant son Hunter was diagnosed with Krabbe leukodystrophy, an inherited fatal disorder of the nervous system. Hunter died in 2005 at the age of eight. The institute conducts research on myelin and its related diseases with the goal of developing new ways of understanding and treating conditions such as Krabbe disease and other leukodystrophies. Charcot-Marie-Tooth or CMT disease, which affects the peripheral nerves, is among the most common of hereditary neurological disorders; it is a disease of myelin and it results from misfolded proteins in cells that produce myelin. The new findings were published online on April 1, 2013 in The Journal of Experimental Medicine. They may have relevance for other diseases that result from misfolded proteins, including Alzheimer’s disease, Parkinson’s, multiple sclerosis, Type 1 diabetes, cancer, and mad cow disease. The paper shows that missteps in translational homeostasis, the process of regulating new protein production so that cells maintain a precise balance between lipids and proteins, may be how some genetic mutations in CMT cause neuropathy. CMT neuropathies are common, hereditary, and progressive; in severe cases, patients end up in wheelchairs. These diseases significantly affect quality of life but not longevity, taking a major toll on patients, families, and society, the researchers note.

Algorithm Will Guide Treatment of Genetic Childhood Kidney Disease (ARPKD)

A collaborative team of physician-scientists at the Medical College of Wisconsin (MCW) and the Children's Hospital of Wisconsin Research Institute has developed a new evidence-based, clinical algorithm to help physicians treat complex patients with autosomal recessive polycystic kidney disease (ARPKD). Their invited review article, written by Grzegorz Telega, M.D., associate professor of pediatrics (gastroenterology and hepatology) at MCW and program director of hepatology at Children's Hospital of Wisconsin; David Cronin, II, M.D., Ph.D., professor of surgery and member of the new Transplantation Institute; and Ellis D. Avner, M.D. professor of pediatrics (nephrology) and physiology at MCW, and director of the Multidisciplinary Childhood PKD Program (MCPP) at Children's Hospital of Wisconsin Research Institute, was published online on April 17, 2013 in Pediatric Transplantation. ARPKD is a rare genetic disorder that causes progressive disease of the kidneys and liver. Of the patients with ARPKD who survive the first year of life, more than 85 percent will reach their tenth birthday. However, despite dramatic improvements in overall survival and quality of life, nearly 50 percent of those survivors develop end-stage kidney disease during that time. Based on a comprehensive analysis of published medical literature, unique insights generated from the MCPP (established in 2005 and the only such program in the U.S.) and more than 50 years of clinical experience by the authors in treating complex problems in ARPKD patients, an algorithm was developed to guide patient therapy. Of particular note, the authors recommend an innovative approach for a subgroup of ARPKD patients with severe kidney and liver disease: simultaneous kidney and liver transplantation.

April 24th

New Findings Challenge Traditional View of Transcription

Like musicians in an orchestra who have the same musical score but start and finish playing at different intervals, cells with the same genes start and finish transcribing them at different points in the genome. For the first time, researchers at the European Molecular Biology Laboratory (EMBL) have described the striking diversity of messenger RNAs (mRNAs) that such start and end variation produces, even from the simple genome of yeast cells. Their findings, published online on April 24, 2013 in Nature, shed new light on the importance of mRNA boundaries in determining the functional potential of genes. Hundreds of thousands of unique mRNA transcripts are generated from a genome of only about 8,000 genes, even with the same genome sequence and environmental condition. “We knew that transcription could lead to a certain amount of diversity, but we were not expecting it to be so vast,” explains Dr. Lars Steinmetz, who led the project. “Based on this diversity, we would expect that no yeast cell has the same set of messenger RNA molecules as its neighbor.” The traditional understanding of transcription was that mRNA boundaries were relatively fixed. While it has long been known that certain parts of mRNAs can be selectively “spliced” out, this phenomenon is very rare in baker's yeast, meaning that the textbook one gene - one mRNA transcript relationship should hold. Recent studies have suggested that things aren't quite that simple, inspiring the EMBL scientists to create a new technique to capture both the start and end points of single mRNA molecules. They have now discovered that each gene can be transcribed into dozens or even hundreds of unique mRNA molecules, each with different boundaries. This suggests that not only transcript abundance, but also transcript boundaries, should be considered when assessing gene function.

International Study Finds 14 New Genetic Links to Juvenile Arthritis

Researchers report in Nature Genetics that they have increased the number of confirmed genes linked to juvenile idiopathic arthritis (JIA) from 3 to 17 – a finding that will clarify how JIA fits into the spectrum of autoimmune disorders and help identify potential treatment targets. Published online on April 21, 2013, the study involves an international research team that analyzed 2,816 JIA cases recruited from more than 40 pediatric rheumatology clinics. It was the largest collaborative patient population of JIA to date, including patient DNA samples from across the United States, Germany, and the United Kingdom, according to Susan Thompson, Ph.D., a researcher in the Division of Rheumatology at Cincinnati Children's Hospital Medical Center who was a leader for the study. "These findings will help us understand how the long suspected genetic contributions to JIA are driving the disease process, with the ultimate goal being earlier and improved diagnosis and treatment," Dr. Thompson said. JIA is the most common rheumatic disease of childhood that involves several different but related forms. Affecting some 50,000 children in the US, the actual cause of the disease remains unknown. JIA is considered an autoimmune disorder, in which the body's immune system mounts an attack against its own healthy tissues. JIA can be treated with medications and physical therapy, but the disease can persist for many patients into adulthood. Prior to the current study only three genes were associated with known JIA risk, although scientists have suspected the likelihood that more genes are involved. The research team used what is known as the Immunochip array to measure variation in the genes (DNA) coding for components of the immune system for 2,816 JIA patients in the study.