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Archive - 2012

March 13th

Circadian Clocks May Hold Key to Treatment of Bipolar Disorder

Scientists have gained insight into why lithium salts are effective at treating bipolar disorder in what could lead to more targeted therapies with fewer side effects. Bipolar disorder is characterized by alternating states of elevated mood, or mania, and depression. It affects between 1% and 3% of the general population. The extreme 'mood swings' in bipolar disorder have been strongly associated with disruptions in circadian rhythms – the 24-hourly rhythms controlled by our body clocks that govern our day and night activity. For the last 60 years, lithium salt (lithium chloride) has been the mainstay treatment for bipolar disorder, but little research has been carried out to determine whether and how lithium impacts the brain and peripheral body clockwork. "Our study has shown a new and potent effect of lithium in increasing the amplitude, or strength, of the clock rhythms, revealing a novel link between the classic mood-stabilizer, bipolar disorder, and body clocks," said lead researcher Dr. Qing-Jun Meng, in the University of Manchester's Faculty of Life Sciences. "By tracking the dynamics of a key clock protein, we discovered that lithium increased the strength of the clockwork in cells up to three-fold by blocking the actions of an enzyme called glycogen synthase kinase or GSK3. Our findings are important for two reasons: firstly, they offer a novel explanation as to how lithium may be able to stabilize mood swings in bipolar patients; secondly, they open up opportunities to develop new drugs for bipolar disorder that mimic and even enhance the effect lithium has on GSK3 without the side effects lithium salts can cause." These side effects include nausea, acne, thirstiness, muscle weakness, tremor, sedation, and/or confusion.

March 12th

New Findings Have Implications for Treatment and Prevention of Virus-Caused Cancers

New research from the Trudeau Institute, in Saranac Lake, New York, addresses how the human body controls gamma-herpesviruses, a class of viruses thought to cause a variety of cancers. The study, carried out in the laboratory of Dr. Marcia Blackman, awaits publication in The Journal of Immunology. Led by postdoctoral fellow Dr. Mike Freeman, with assistance from other laboratory colleagues, the study describes the role of white blood cells in controlling gamma-herpesvirus infections and has implications for the treatment and prevention of certain cancers. One of the many factors that can contribute to the development of cancer is infection with cancer-causing viruses, among them gamma-herpesviruses like the Epstein-Barr virus and Kaposi's sarcoma-associated herpesvirus. With more than 95 percent of the human population infected with one or both of these viruses, it is important to understand their infection cycles and how immune responses keep them in check in the majority of individuals. Gamma-herpesvirus infections are characterized by two distinct phases. In the initial, active phase, the immune system responds by attacking the virus. The virus, however, has developed a clever mechanism for "sneaking" past the immune response to conceal itself within the body, a process researchers refer to as latent infection. While in hiding, the virus persists in a quiet, inactive state. Occasionally, it can start to reactivate and begin to multiply again, increasing the risk of cancer development. The chance that cancer will develop is greatly increased if the immune system is weakened, such as with immunosuppression following transplantation or as a consequence of other diseases, such as AIDS. Researchers around the globe are asking important questions about the nature of these viruses and working in their labs to answer them.

March 12th

Epstein-Barr-Like Virus Infects and May Cause Cancer in Dogs

More than 90 percent of humans have antibodies to the Epstein-Barr virus (EBV). Best known for causing mononucleosis, or "the kissing disease," the virus has also been implicated in more serious conditions, including Hodgkin's, non-Hodgkin's, and Burkitt's lymphomas. Yet little is known about exactly how EBV triggers these diseases. Now a team of researchers from the University of Pennsylvania School of Veterinary Medicine and Penn's Perelman School of Medicine has the first evidence that an Epstein-Barr-like virus can infect and may also be responsible for causing lymphomas in man's best friend. The findings suggest that domestic dogs possess a similar biology to humans with respect to EBV infection. That could allow scientists to study dogs to help uncover the mechanisms by which EBV leads to cancer in certain people. "There are no large-animal spontaneous models of EBV infection and virus-associated disease, and most studies investigating viral disease are performed in non-human primates, which are very expensive," said Dr. Nicola Mason, senior author of the study and an assistant professor of medicine and pathobiology at Penn Vet. "Discovering that dogs can get infected with this virus like people do may provide us with a long-sought-after model for EBV-associated disease." Dr. Mason's team at Penn Vet included Drs. Shih-Hung Huang, Philip Kozak, Jessica Kim, George Habineza-Ndikuyeze, Charles Meade, Anita Gaurnier-Hausser, and Reema Patel. The team worked closely with Dr. Erle Robertson, professor of microbiology at the Perelman School of Medicine. Their work was published online on March 8, 2012 in the journal Virology. In humans, the Epstein-Barr virus infects B-cells. After an acute phase of infection, of which many people are not even aware, the virus goes into a latent phase.

New Results Could Lead to More Effective Drug Discovery for Cystic Fibrosis

A recent study led by Dr. Gergely Lukacs, a professor at McGill University's Faculty of Medicine, Department of Physiology, and published in the January 20, 2012 issue of Cell, has shown that restoring normal function to the mutant gene product responsible for cystic fibrosis (CF) requires correcting two distinct structural defects. This finding could point to more effective therapeutic strategies for CF in the future. CF, a fatal genetic disease that affects aqpproximately 60,000 people worldwide, is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR), a membrane protein involved in ion and water transport across the cell surface. As such, CF is characterized by impaired chloride secretion, causing the accumulation of viscous mucus that may cause multiple organ dysfunctions, including recurrent lung infection. The most common mutation in CFTR, known as deltaF508, is caused by a single amino acid deletion and results in a misfolded version of CFTR that is retained within the cell and quickly degrades rather than being trafficked to the cell membrane where it would function as a chloride channel. In 2005, Dr. Lukacs and his lab suggested that the deltaF508 mutation effect is not restricted to the domain (the nucleotide binding domain 1, or NBD1, one of five building blocks of CFTR) where the deltaF508 is located. Specifically, his team found that the mutation destabilizes the NBD1 as well as the NBD2 architecture, suggesting that domain-domain interaction plays a critical role in both normal and pathological CFTR folding. Building on his team's previous work and using computer-generated models of CFTR, Dr. Lukacs and his team set out to determine whether it was possible to correct both NBD1 stability and the domain-domain interaction defect.

March 11th

Gorilla Genome Sequenced

Researchers have completed the genome sequence for the gorilla – the last genus of the living great apes to have its genome decoded. The work was published online on March 7, 2012 in Nature. While confirming that our closest relative is the chimpanzee, the research team showed that much of the human genome more closely resembles the gorilla genome than it does the chimpanzee genome. This is the first time scientists have been able to compare the genomes of all four living great apes: humans, chimpanzees, gorillas, and orang-utans. This study provides a unique perspective on our own origins and is an important resource for research into human evolution and biology, as well as for gorilla biology and conservation. "The gorilla genome is important because it sheds light on the time when our ancestors diverged from our closest evolutionary cousins. It also lets us explore the similarities and differences between our genes and those of gorilla, the largest living primate," says Dr. Aylwyn Scally, first author from the Wellcome Trust Sanger Institute. "Using DNA from Kamilah, a female western lowland gorilla, we assembled a gorilla genome sequence and compared it with the genomes of the other great apes. We also sampled DNA sequences from other gorillas in order to explore genetic differences between gorilla species." The team searched more than 11,000 genes in human, chimpanzee, and gorilla for genetic changes important in evolution. Humans and chimpanzees are genetically closest to each other over most of the genome, but the team found many places where this is not the case. 15% of the human genome is closer to the gorilla genome than it is to chimpanzee, and 15% of the chimpanzee genome is closer to the gorilla than to human.

March 7th

Possible New Treatment for Acute Lymphoblastic Leukemia (ALL)

A team of researchers at Case Western Reserve University School of Medicine has developed the first "theranostic" agent for the treatment of acute lymphoblastic leukemia (ALL). ALL is the most common type of childhood cancer, with approximately 5,000 new cases diagnosed each year in the United States. The findings provide insight into pediatric oncology that specifically focuses on the development of so-called "theranostic" agents-- a treatment platform that combines a selective diagnostic test with targeted therapy based on the test results. Discovery of this new class of drugs is the first step towards new diagnostic markers and therapeutic approaches in treatments with anti-cancer agents of numerous other cancers in addition to ALL. "This discovery takes a chemical biology approach to target ALL. Our nucleosides represent a new class of theranostic agents that provide an original approach to achieving personalized treatments against pediatric leukemia," says Dr. Anthony J. Berdis, assistant professor of pharmacology at Case Western Reserve School of Medicine. "We've developed a non-natural nucleoside that specifically targets this form of childhood leukemia. The combination of therapeutic and diagnostic activities will provide more selective and more expedient ways to treat patients by optimizing the dosages needed to kill the cancer cells without affecting normal cells. This selectivity should minimize the development of adverse side effects typically associated with conventional anti-cancer nucleosides," says Dr. Berdis. Using an enzyme implicated in the disease, terminal deoxynucleotidyl transferase (TdT) which serves as a biomarker and is overexpressed in 90 percent of ALL patients, Dr. Berdis and his team designed a new selective anti-cancer agent against ALL.

February 27th

Study of New Cell May Lead to New Treatments for Asthma, Other Allergies

A collaboration between scientists at Trinity College Dublin (TCD) and in the United Kingdom has identified new processes that lead to the development of a novel cell (the nuocyte) implicated in allergies. The discovery has the potential to spawn new strategies to treat asthma and other allergic diseases. The research findings were published in the March 2012 issue of Nature Immunology. The work was performed by Professor Padraic Fallon, Science Foundation Ireland Stokes Professor of Translational Immunology of TCD's School of Medicine, Dr. Andrew McKenzie of the Medical Research Council Laboratory for Molecular Biology in Cambridge, UK, and colleagues. The number of people with allergic disease, such as asthma and atopic dermatitis, is increasing globally with Irish children having the fourth highest incidence of asthma in the world. A major area of research in developing new strategies to treat allergic diseases is directed towards increasing understanding of the processes and cells involved in causing allergic inflammation. Professor Fallon and colleagues previously discovered a new white blood cell (the nuocyte) that initiates the early generation of the immune responses that can lead to asthma or other allergic conditions. In the current study, a new pathway for the development of nuocytes was identified and a transcription factor, RORalpha, was shown to be critical for both the generation of nuocytes and of allergic-like inflammation. This new finding identifies targets for allergic diseases that could be developed into new therapeutic strategies. [Press release] [Nature Immunology abstract]

Research Refutes Popular Hypothesis of Multiple Sclerosis Triggering Mechanism

Millions of adults suffer from the incurable disease multiple sclerosis (MS). It is relatively certain that MS is an autoimmune disease in which the body's own defense cells attack the myelin in the brain and spinal cord. Myelin enwraps the nerve cells and is important for their function of transmitting stimuli as electrical signals. There are numerous unconfirmed hypotheses on the development of MS, one of which has now been refuted by the neuroimmunologists in their current research: The death of oligodendrocytes, as the cells that produce the myelin sheath are called, does not trigger MS. With their research, published February 26, 2012 in Nature Neuroscience, the scientists disprove the so-called "neurodegenerative hypothesis," which was based on observations that certain patients exhibited characteristic myelin damage without a discernable immune attack. In the popular hypothesis, the scientists assume that MS-triggering myelin damage occurs without the involvement of the immune system. In this scenario, the immune response against myelin would be the result – and not the cause – of this pathogenic process. The aim of the current research project was to confirm or disprove this hypothesis based on a new mouse model. Using genetic tricks, the researchers induced myelin defects without alerting the immune defense. "At the beginning of our study, we found myelin damage that strongly resembled the previous observations in MS patients," explains Dr. Burkhard Becher, a professor at the University of Zurich. "However, not once were we able to observe an MS-like autoimmune disease." In order to ascertain whether an active immune defense causes the disease based on a combination of an infection and myelin damage, the researchers conducted a variety of further experiments – without success.

February 23rd

Human Y Chromosome Not Headed to Extinction

If you were to discover that a fundamental component of human biology has survived virtually intact for the past 25 million years, you'd probably be quite confident in saying that it is here to stay. Such is the case for a team of Whitehead Institute scientists, whose latest research on the evolution of the human Y chromosome confirms that the Y—despite arguments to the contrary—has a long, healthy future ahead of it. Proponents of the so-called “rotting Y” theory have been predicting the eventual extinction of the Y chromosome since it was first discovered that the Y has lost hundreds of genes over the past 300 million years. The rotting Y theorists have assumed this trend is ongoing, concluding that inevitably, the Y will one day be utterly devoid of its genetic content. Over the past decade, Whitehead Institute Director Dr. David Page and his lab have steadily been churning out research that should have permanently debunked the rotting Y theory, but to no avail. "For the past 10 years, the one dominant storyline in public discourse about the Y is that it is disappearing," says Dr. Page. "Putting aside the question of whether this ever had a sound scientific basis, the story went viral—fast—and has stayed viral. I can't give a talk without being asked about the disappearing Y. This idea has been so pervasive that it has kept us from moving on to address the really important questions about the Y." To Dr. Page, this latest research represents checkmate in the chess match he's been drawn into against the "rotting Y" theorists. Members of his lab have dealt their fatal blow by sequencing the Y chromosome of the rhesus macaque—an Old World monkey whose evolutionary path diverged from that of humans some 25 million years ago—and comparing it with the sequences of the human and chimpanzee Y chromosomes.

February 22nd

Study Suggests Novel Genetic Model of Skin Cancer

The University of Kentucky (UK) has announced that Dr. Daret St. Clair, the James Graham Brown Endowed Chair and professor of toxicology, has published the first comprehensive study that provides insight into the relationship between two types of suppressors in cancerous tumors. The results will enhance the understanding of transcriptional mechanisms in carcinogenesis. The study was supported by a National Cancer Institute research grant and was published in the November 1, 2011 issue of Cancer Research. Dr. St. Clair and her team generated transgenic mice expressing a luciferase reporter gene under the control of human MnSOD promoter-enhancer elements and investigated the changes of MnSOD transcription using the 7,12-dimethylbenz(a)anthracene (DMBA)/12-O-tetradecanoylphorbol-l3-acetate (TPA) multistage skin carcinogenesis model. Manganese superoxide dismutase (MnSOD) plays a critical role in the survival of aerobic life, and its abnormal expression has been implicated in carcinogenesis and tumor resistance to therapy. Despite extensive studies in MnSOD regulation and its role in cancer, when and how the alteration of MnSOD expression occurs during the process of tumor development in vivo are unknown. The current results show that MnSOD expression was suppressed at a very early stage, but increased at late stages of skin carcinogenesis. The suppression and subsequent restoration of MnSOD expression were mediated by two transcription factors, Sp1 and p53. Exposure to DMBA and TPA activated p53 and decreased MnSOD expression via p53-mediated suppression of Sp1 binding to the MnSOD promoter in normal appearing skin and benign papillomas. In squamous cell carcinomas, Sp1 binding increased due to loss of functional p53. Dr. St.