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Archive - 2012

February 2nd

Potential New Treatment for Leishmaniasis

Researchers at the University of Dundee in the UK have identified fexinidazole as a possible, much-needed, new treatment for the parasitic disease visceral leishmaniasis. Leishmaniasis is named after William Leishman, a Glasgwegian doctor who served with the British Army in India, and who first identified the parasite in the early 1900s. The disease is the second biggest killer in Africa, Asia, and Latin America after malaria, and affects 500,000 people, killing about 50,000-60,000 patients per year. Current drug treatments for the disease are unsatisfactory for reasons such as high cost, drug resistance, or the need for hospitalization. The disease is caused by the bite of a sand fly. Fexinidazole is already in phase 1 clinical trials for a related disease - African sleeping sickness – but a research team at Dundee, including Dr. Susan Wyllie, Professor Alan Fairlamb, and colleagues, has identified it as having potential in treating leishmaniasis. Their research was published February 1, 2012 in Science Translational Medicine, and was funded by the Wellcome Trust. Tests in mice showed that the drug has a greater than 98% rate of suppressing infection of leishmaniasis, comparable to current treatments such as miltefosine and Pentostam. These and other existing treatment options all suffer from disadvantages; they are not always safe, effective, or easy to administer. The only oral drug, miltefosine, cannot be given to women of child-bearing age due to a substantial risk of birth defects; other drugs are costly and have to be given by injection. Thus, there is a continuing need for safe and cost-effective drugs suitable for use in resource-poor settings. Professor Fairlamb said that fexinidazole has the potential to become a safe and effective oral drug therapy for treating the severest form of visceral leishmaniasis.

January 31st

FDA Approves Cystic Fibrosis Drug for Patients with Rare Mutation

On January 31, 2012, the U.S. Food and Drug Administration approved Kalydeco (ivacaftor) for the treatment of a rare form of cystic fibrosis (CF) in patients ages 6 years and older who have the specific G551D mutation in the cystic fibrosis transmembrane regulator (CFTR) gene. This represents a breakthrough in the field of personalized medicine. CF is a serious genetic disorder affecting the lungs and other organs that ultimately leads to an early death. It is caused by mutations in a gene that encodes the protein CFTR that regulates ion (such as chloride) and water transport in the body. The defect in chloride and water transport results in the formation of thick mucus that builds up in the lungs, digestive tract, and other parts of the body leading to severe respiratory and digestive problems, as well as other complications such as infections and diabetes. CF, which affects about 30,000 people in the United States, is the most common fatal genetic disease in the Caucasian population. About 4 percent of those with CF, or roughly 1,200 people, are believed to have the G551D mutation. “Kalydeco is an excellent example of the promise of personalized medicine – targeted drugs that treat patients with a specific genetic makeup,” said FDA Commissioner Dr. Margaret A. Hamburg. “The unique and mutually beneficial partnership that led to the approval of Kalydeco serves as a great model for what companies and patient groups can achieve if they collaborate on drug development.” The FDA reviewed and approved Kalydeco in approximately three months under the agency’s priority review program that is designed to expedite the review of drugs. The priority review program uses a six-month review, instead of the standard 10 months, for drugs that may offer significant advances in treatment over available therapy.

January 30th

Biological-Clock-Related Mutations Lead to Increased Risk of Type 2 Diabetes

Researchers in Lille and Paris have demonstrated that mutations in the melatonin receptor gene (melatonin or the "hormone of darkness" induces sleep) lead to an almost seven-fold increase in the risk of developing type 2 diabetes. This research, which was published online in Nature Genetics on January 29, 2012, could contribute to the development of new drugs for the treatment or prevention of this metabolic disease. Type 2 diabetes is characterized by excess blood glucose and increased resistance to insulin. It is the most common form of the disease and affects 300 million people in the world, including 3 million in France. This figure should double in the next few years, driven by the obesity epidemic and the disappearance of ancestral lifestyles. It is known that genetic factors, combined with a high-fat, high-sugar diet and lack of exercise, can also contribute to the onset of the disease. Furthermore, several studies have shown that sleeping disorders that affect the duration and quality of sleep are also high risk factors. Shift workers, for example, are at greater risk of developing the disease. No previous research has described any mechanism linking the biological clock to diabetes. The researchers focused their attention on the receptor of a hormone called melatonin, which is produced by the pineal gland as light fades. Melatonin, also known as the hormone of darkness, can be seen as a biological "time-keeper," synchronizing biological rhythms with nightfall. The research teams sequenced the MT2 gene, which encodes a melatonin receptor, in 7,600 diabetics and persons with normal glycemia. They found 40 rare mutations that modify the protein structure of the MT2 melatonin receptor, 14 of which made the receptor in question non-functional.

Histone Mutations Associated with Aggressive Childhood Brain Tumors

Researchers studying a rare, lethal childhood tumor of the brainstem discovered that nearly 80 percent of the tumors have mutations in genes not previously tied to cancer. Early evidence suggests the alterations play a unique role in other aggressive pediatric brain tumors as well. The findings from the St. Jude Children's Research Hospital – Washington University Pediatric Cancer Genome Project (PCGP) offer important insight into a poorly understood tumor that kills more than 90 percent of affected patients within two years. The tumor, diffuse intrinsic pontine glioma (DIPG), is found almost exclusively in children and accounts for 10 to 15 percent of pediatric tumors of the brain and central nervous system. "We are hopeful that identifying these mutations will lead us to new selective therapeutic targets, which are particularly important since this tumor cannot be treated surgically and still lacks effective therapies," said Dr. Suzanne Baker, co-leader of the St. Jude Neurobiology and Brain Tumor Program and a member of the St. Jude Department of Developmental Neurobiology. She is a corresponding author of the study published in the January 29, 2012 online edition of Nature Genetics. DIPG is an extremely invasive tumor that occurs in the brainstem, which is at the base of the skull and controls such vital functions as breathing and heart rate. DIPG cannot be cured by surgery and is accurately diagnosed by non-invasive imaging. As a result, DIPG is rarely biopsied in the U.S. and little is known about it. Cancer occurs when normal gene activity is disrupted, allowing for the unchecked cell growth and spread that makes cancer so lethal.

Genetic Breakthrough in Pediatric Brain Cancer

An international research team led by the Research Institute of the McGill University Health Centre (RI MUHC) in Montreal, Canada has made a major genetic breakthrough that could change the way pediatric cancers are treated in the future. The researchers identified two genetic mutations responsible for up to 40 per cent of glioblastomas in children - a fatal cancer of the brain that is unresponsive to chemotherapy and radiotherapy treatment. The mutations were found to be involved in DNA regulation, which could explain the resistance to traditional treatments, and may have significant implications on the treatment of other cancers. The study was published online on January 29, 2012 in Nature. Another article, by a different research team, independently reported related findings online on January 29, 2012 in Nature Genetics (see separate article in BioQuick News, “Histone Mutations Associated with Aggressive Childhood Brain Tumors”). Using the knowledge and advanced technology of the team from the McGill University and Génome Québec Innovation Centre, the researchers identified two mutations in an important gene known as the histone H3.3 gene. This gene, one of the guardians of our genetic heritage, is key to modulating the expression of our genes. "These mutations prevent the cells from differentiating normally and help protect the genetic information of the tumor, making it less sensitive to radiotherapy and chemotherapy," says Dr. Nada Jabado, hematologist-oncologist at The Montreal Children's Hospital of the MUHC and principal investigator of the study. "This research helps explain the ineffectiveness of conventional treatments against cancer in children and adolescents – we've been failing to hit the right spot," says Dr. Jabado, who is also an Associate Professor of Pediatrics at McGill University.

January 27th

Probe of Mysterious Protein Involved in Diabetes, Cancer, and Aging

Like a magician employing sleight of hand, the protein mitoNEET -- a mysterious but important player in diabetes, cancer and aging -- draws the eye with a flurry of movement in one location while the subtle, more crucial action takes place somewhere else. Using a combination of laboratory experiments and computer modeling, scientists from Rice University and the University of California, San Diego (UCSD) have deciphered part of mitoNEET's movements to gain a better understanding of how it handles its potentially toxic payload of iron and sulfur. Their research was published online on January 23, 2012 in PNAS. "We scrutinize proteins with an unconventional approach," said Dr. José Onuchic, Rice's Harry C. and Olga K. Wiess Professor of Physics and Astronomy and co-director of the Center for Theoretical Biological Physics. "We use biophysics to probe biology rather than the other way around. Using computational theory, we find structures that are possible -- regardless of whether they've already been observed experimentally -- and we ask ourselves whether these structures might be biologically significant." Study co-leader Dr. Patricia Jennings, professor of chemistry and biochemistry at UCSD, who has collaborated with Dr. Onuchic for 15 years, said they save a great deal of time by using structural biophysics to guide their experiments on a wide variety of targets. For example, Dr. Jennings' laboratory determined less than five years ago that mitoNEET contained a novel folded structure. Since then, her lab has been using insights gained from static and dynamic snapshots of the protein to guide biological and biochemical studies. "I think people forget that proteins are machines with moving parts," said study lead author Elizabeth Baxter, a UCSD graduate student who works under the guidance of both Drs. Onuchic and Jennings.

Discovery May Aid Fight Againt Cholera

A team of biologists at the University of York in the UK has made an important advance in our understanding of the way cholera attacks the body. The discovery could help scientists target treatments for the globally significant intestinal disease which kills more than 100,000 people every year. The disease is caused by the bacterium Vibrio cholerae, which is able to colonize the intestine usually after consumption of contaminated water or food. Once infection is established, the bacterium secretes a toxin that causes watery diarrhea and ultimately death if not treated rapidly. Colonization of the intestine is difficult for incoming bacteria as they have to be highly competitive to gain a foothold among the trillions of other bacteria already present in situ. Scientists at York, led by Dr Gavin Thomas in the University’s Department of Biology, have investigated one of the important routes that V. cholera takes to gain this foothold. To be able to grow in the intestine, the bacterium harvests and then eats a sugar, called sialic acid, that is present on the surface of our gut cells. Collaborators of the York group at the University of Delaware, USA, led by Professor Fidelma Boyd, had shown previously that eating sialic acid was important for the survival of V. cholerae in animal models, but the mechanism by which the bacteria recognize and take up the sialic was unknown. The York research demonstrates that the pathogen uses a particular kind of transporter called a TRAP transporter to recognize sialic acid and take it up into the bacterial cell. The transporter has particular properties that are suited to scavenging the small amount of available sialic acid. The research also provided some important basic information about how TRAP transporters work in general. Dr.

New Vaccine Approach to Cancer Reported

Scientists at Trinity College Dublin (TCD), Ireland, have developed a new vaccine to treat cancer at the pre-clinical level. The research team led by Professor Kingston Mills, Professor of Experimental Immunology at TCD discovered a new approach for treating the disease based on manipulating the immune response to malignant tumors. The discovery has been patented and there are plans to develop the vaccine for clinical use for cancer patients. The first cancer vaccine Sipuleucel-T (Provenge™) was licensed last year for use in prostate cancer patients unresponsive to hormone treatment. Unfortunately, this cell-based vaccine only improves patient survival by an average of 4.1 months. Vaccines for infectious diseases are highly effective at generating immune responses that prevent infection with bacteria or viruses. The immune system can also protect us against tumors and, in theory, a vaccine approach should be effective against cancer. In practice, this has proven very difficult because, unlike infectious diseases, tumors are derived from normal human cells, and are not made up of foreign substances or antigens capable of triggering an immune response. The tumors instead produce molecules that suppress the efficacy of the immune system. They generate regulatory cells that inhibit the immune response that could potentially clear the tumors. Professor Mills' group has developed a novel vaccine and immunotherapeutic approach that can overcome these obstacles and has the potential to significantly improve on existing technologies. The therapy is based on a combination of molecules that manipulates the immune response to curb the regulatory arm while enhancing the protective arm, allowing the induction of specialist white blood cells called killer T cells to target and eliminate the tumors.

January 26th

Rotational Motion Plays Key Role in Development of Glandular Tissues

In a study that holds major implications for breast cancer research as well as basic cell biology, scientists with the U.S. Department of Energy (DOE)’s Lawrence Berkeley National Laboratory (Berkeley Lab) have discovered a rotational motion that plays a critical role in the ability of breast cells to form the spherical structures in the mammary gland known as acini. This rotation, which the researchers call “CAMo,” for coherent angular motion, is necessary for the cells to form spheres. Without CAMo, the cells do not form spheres, which can lead to random motion, loss of structure, and malignancy. “What is most exciting to me about this stunning discovery is that it may finally give us a handle by which to discover the physical laws of cellular motion as they apply to biology,” says Dr. Mina Bissell, a leading authority on breast cancer and Distinguished Scientist with Berkeley Lab’s Life Sciences Division. Dr. Bissell is a corresponding author of a paper describing this work in PNAS, along with Dr. Kandice Tanner, a post-doctoral physicist in Dr. Bissell’s research group. The PNAS paper was published online on January 25, 2012. Healthy human epithelial cells in breast and other glandular tissue form either sphere-shaped acini or tube-shaped ducts. The cell and tissue polarity (function-enabling spatial orientations of cellular and tissue structures) that comes with the formation of acini is essential for the health and well-being of the breast. Loss of this polarity as a result of cells not forming spheres is one of the earliest signs of malignancy. However, despite all that is known about cell morphogenesis, the fundamental question as to how epithelial cells are able to assemble into spheres that are similar in size and shape to organs in vivo has until now been a mystery.

January 24th

Promising New Target Identified for Anti-Hepatitis C Therapy

A molecule embedded in the membrane of human liver cells that aids in cholesterol absorption also allows the entry of hepatitis C virus, the first step in hepatitis C infection, according to research at the University of Illinois at Chicago (UIC) College of Medicine. The cholesterol receptor offers a promising new target for anti-viral therapy, for which an approved drug may already exist, say the researchers, whose findings were reported online on January 8, 2012 in Nature Medicine. An estimated 4.1 million Americans are infected with hepatitis C virus (HCV), which attacks the liver and leads to inflammation, according to the National Institutes of Health. Most people have no symptoms initially and may not know they have the infection until liver damage shows up decades later during routine medical tests. Previous studies showed that cholesterol was somehow involved in HCV infection. The UIC researchers suspected that a receptor called NPC1L1 (Niemann-Pick C1–like 1) cholesterol absorption receptor, known to help maintain cholesterol balance, might also be transporting the virus into the cell. The receptor is common in the gut of many species -- but is found on liver cells only in humans and chimpanzees, says Dr. Susan Uprichard, assistant professor in medicine and microbiology and immunology and principal investigator in the study. These primates, she said, are the only animals that can be infected by HCV. Dr. Uprichard and her coworkers showed that knocking down or blocking access to the NPC1L1 receptor prevented the virus from entering and infecting cells. Dr. Bruno Sainz, Jr., UIC postdoctoral research associate in medicine and first author of the paper, said that because the receptor is involved in cholesterol metabolism it was already well-studied.