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April 26th, 2011

Targeted Topical Treatment May Prevent Melanoma

While the incidence of melanoma continues to increase despite the use of sunscreen and skin screenings, a topical compound called ISC-4 may prevent melanoma lesion formation, according to Penn State College of Medicine researchers. "The steady increase in melanoma incidence suggests that additional preventive approaches are needed to complement these existing strategies," said Dr. Gavin Robertson, professor of pharmacology, pathology, dermatology, and surgery, and director of the Penn State Hershey Melanoma Center. Researchers targeted the protein Akt3, which plays a central role in 70 percent of melanoma by preventing cell death and has the potential to prevent early stages of melanoma. "The Akt3 signaling pathway is deregulated in the majority of melanomas, making it a promising target which, if inhibited, could correct the apoptotic -- or cell death -- defect in melanocytic lesions, thereby preventing this disease," Dr. Robertson said. Isothiocyantes were identified as inhibitors of Akt3. These are naturally occurring compounds found in cruciferous vegetables like broccoli and brussels sprouts that have anticancer properties. Unfortunately, previous research showed these compounds have low chemotherapy potency on melanoma cells because high concentrations are needed to be effective. To create a more potent version, Penn State Hershey Melanoma Center researchers previously developed isoselenocyanates (e.g., ISC-4), by replacing sulfur with selenium. Researchers have now found that repeated topical application of ISC-4 can reduce tumor cell expansion in laboratory-generated human skin by 80 to 90 percent and decrease tumor development in mice skin by about 80 percent. The research also showed that the use of the compound is safe.

Brain Protein May Be Useful Target in Colorectal Cancer

Tumor progression is usually ensured by more than one proliferative mechanism. When one of these is shut down by a specifically targeted drug, other mechanisms may emerge. While these events may lead to treatment failure, they may also become an opportunity for researchers to identify novel targets to be further explored. In a paper recently published online in the journal Oncology (Vol. 79, pages 430-439, 2011), Dr. Rafael Roesler and colleagues describe a novel potential drug target in colorectal cancer. Colorectal cancer (CRC) is the fourth most common cancer in men and the third in women worldwide. It is a frequent cancer, with more than 1 million new cases every year and a poor survival rate. Rapid increases in CRC incidence have been observed mainly in emerging economies. These increases are attributed to changes in diet, life style, and patterns of physical activity. In Western countries, only 55% of the patients are alive 5 years after diagnosis, with most patients dying from metastatic disease. Although a number of treatment options are available for CRC patients, including surgery, chemotherapy, and biologic therapies targeting two different mechanisms—angiogenesis (drug: bevacizumab) and epidermal growth factor receptors (drugs: cetuximab and panitumumab)—new treatment options are required to improve survival rates. The search for novel targets led Dr. Roesler at the Federal University of Rio Grande do Sul (UFRGS) Brazil, Dr. Gilberto Schwartsmann, and graduate student Caroline Brunetto de Farias, among others, to investigate whether a brain-derived protein known to be involved in tumor growth, metastasis, and drug resistance in a number of cancers, including some non-neurological cancers, could also be found in CRC. The team led by Dr.

RAD Technology May Simplify Genome Sequencing

Take millions of puzzle pieces containing partial words and put them back together into full words, sentences, paragraphs and chapters until the book these random parts came from is rebuilt. That daunting process in not unlike sequencing an organism's genome, says University of Oregon biologist Dr. Eric A. Johnson, a member of the UO Institute of Molecular Biology. His lab developed a patent-pending technology for discovering differences between genomes called restriction-site associated DNA markers, or RAD. They have now shown that RAD can also be used to help put a genome sequence together. The original RAD technique, unveiled in 2005, led to the UO spinoff company Floragenex, which uses the technology in plant genetics. More recently, Dr. Johnson and UO colleague Dr. William A. Cresko used it to identify genetic differences in threespine stickleback, a fish, which evolved separately after environmental conditions had isolated some of the saltwater fish into freshwater habitats. Now, after three years of research, adapting the technology along the way as sequencing tools advanced, Dr. Johnson, Dr. Cresko, and three UO colleagues provide a proof-of-principle paper published online on April 13, 2011, in PLoS One. The NIH-funded research documents that the new method, called RAD paired-end contigs, works and provides accurate sequencing results. "The RAD sequence is a placeholder that identifies one small region of a genome," Dr. Johnson said. "We showed that this technique lets us gather together appropriate nearby sequences and piece them together." In just seconds, a section is completed, he said. In a matter of hours, he added, an entire genome's sequence emerges. Using the book analogy, Dr.

April 24th

Blocking Cytokine May Be Key to Treatment of Multiple Sclerosis

Reporting online on April 24, 2011, in Nature Immunology, Jefferson Medical College neuroscientists have identified a driving force behind autoimmune diseases such as multiple sclerosis (MS), and suggest that blocking this cell-signaling molecule is the first step in developing new treatments to eradicate these diseases. Researchers led by Dr. Abdolmohamad Rostami, Professor and Chairman of the Department of Neurology at Jefferson Medical College of Thomas Jefferson University, found that GM-CSF, which stands for granulocyte-macrophage colony-stimulating factor, appears to be the key culprit in the onset of MS, because without it, T helper 17 (Th17) cells did not induce the MS-like disease in an experimental animal model. Th17 cells have been shown to play an important pathogenic role in humans and experimental models of autoimmune diseases, but the mechanisms behind this have remained elusive until now. "There was no connection between GM-CSF and Th17 cells before," said Dr. Rostami. "What we have shown in this paper is that GM-CSF derived from Th17 cells is important in the cell-signaling process that leads to inflammation in the central nervous system. Now we know how the Th17 cells work and a better understanding of this mechanism and biology leads to new therapeutics," he added. The results suggest that blocking GM-CSF activity may be a successful therapeutic strategy in MS, one of the most common neurological diseases affecting young adults, and other autoimmune diseases, said Dr. Rostami, who is also the Chair of Neurology at Thomas Jefferson University Hospital. These findings identify the interleukin-23 (IL-23)/ Th17/GM-CSF axis as the major pathway in pathogenesis of autoimmune central nervous system inflammation and likely other autoimmune diseases.

April 21st

New Hope for Treatment of Shingles

Researchers at the University of Georgia and Yale University have discovered a compound with the potential to be more effective than existing agents in treating the very painful blisters known as shingles—a condition that affects up to 30 percent of Americans, mostly elderly, and for which no specific treatment exists. Most adults remember the fever, itchy blisters, and possibly tiny scars they experienced as children when they had chickenpox, which is caused by the varicella-zoster virus, or VZV. Unfortunately, that memory can come back—with a vengeance—when they are older. The VZV virus from childhood chickenpox hides in the nerves, emerging most frequently in adults over the age of 60 as a blistering rash on one side of the body. The rate of complications, including nerve pain that can persist for months or years after the shingles attack is gone, also increases with age. The novel and effective anti-shingles agent called L-BHDA may change that. Rights to the shingles treatment have been licensed to Bukwang Pharmaceutical Company for preclinical investigations by the University of Georgia Research Foundation, Inc. and Yale University. "We need new options for medications with increased potency and specificity that can treat VZV, including strains that may be resistant to existing drugs," said medicinal chemist Dr. Chung (David) Chu, Distinguished Research Professor of Pharmaceutical and Biomedical Sciences at UGA, one of the inventors of L-BHDA. A collaboration between Dr. Chu and co-inventor Dr. Yung-Chi (Tommy) Cheng, the Henry Bronson Professor of Pharmacology at Yale, has resulted in an extensive portfolio of antiviral compounds that target such diseases as HIV, shingles, hepatitis, and cancers. Dr.

Mechanism of B Cell Differentiation Clarified

An article in the April 19, 2011 issue of Science Signaling by researchers at the RIKEN Research Center for Allergy and Immunology (RCAI) in Japan, and colleagues, has clarified for the first time the mechanism governing differentiation of B cells into antibody-producing plasma cells. The finding establishes a role for the extracellular signal-regulated kinase (ERK) signaling pathway in B cell differentiation, a key step toward the development of B cell-targeted drugs for treatment of autoimmune diseases and allergies. As the only cells in the body that produce antibodies, B cells play an essential role in the immune system's defense against bacteria and viruses. Differentiation of B cells into antibody-producing plasma cells is central to this role, initiating the production of antibodies whose targeted binding mechanism enables the immune system to identify and neutralize foreign objects. The mechanism underlying this differentiation process, however, remains unknown. To better understand this mechanism, the research group focused on the signaling of the extracellular signal-regulated kinases (ERK), intracellular signaling molecules known to play an important role in the cell cycle and survival of immune cells. Hoping to glean insights into the role of ERKs in B cell differentiation into plasma cells, the researchers generated mice deficient in two different ERKs, ERK1 and ERK2, and studied the effect of this deficiency on the fate of B cells. What they found confirmed that ERKs are in fact essential to B cell differentiation: B cells in mice without these key molecules were unable to form plasma cells.

April 20th

New Insight into Survival Strategy of Sleeping Sickness Parasite

Fresh insight into the survival strategy of the parasite that causes sleeping sickness could help inform new treatments for the disease. Scientists have found that the parasite, which can transform itself into either of two physical forms, has developed a careful balance between these. One of these types ensures infection in the bloodstream of a victim, and the other type is taken up by the tsetse fly and spread to another person or animal. The parasite maintains a trade-off between maintaining enough parasites to beat off the immune response and cause infection, and ensuring sufficient parasites to enable the spread of the disease. Researchers at the University of Edinburgh, who carried out the study, used a combination of biological and mathematical techniques to show how the parasite balances production of each of the forms as it causes an infection. Their results enable fresh understanding of how the parasite reacts to its surroundings to ensure its survival in the short term as well as the long-term spread of the disease. Sleeping sickness, which is spread by the bite of the tsetse fly, affects some 30,000 people in sub-Saharan Africa. Many millions more are considered to be at risk. The disease affects people and animals and without treatment is considered fatal. The research, funded by the Wellcome Trust, was published in the April 21, 2011 issue of the journal Cell Host & Microbe. Professor Keith Matthews of the University of Edinburgh, who led the study, said: "Sleeping sickness parasites alter their form in order to ensure their survival and spread.

Close Relative of Arabidopsis Has Much Bigger Genome

It would appear reasonable to assume that two closely related plant species would have similar genetic blueprints. However, scientists from the Max Planck Institute for Developmental Biology in Tübingen, working in cooperation with an international research team have now decoded, for the first time, the entire genome of the lyre-leaved rock cress (Arabidopsis lyrata), a close relative of the thale cress (Arabidopsis thaliana), a model plant used by geneticists. They discovered that the genome of the lyre-leaved rock cress is fifty percent bigger than that of the thale cress. Moreover, these changes arose over a very short period in evolutionary terms. This new high-quality genome analysis will provide a basis for further detailed comparative studies on the function, ecology and evolution of the plant genus Arabidopsis. Genome size among the different species of the plant kingdom varies significantly. At the upper end of the currently known spectrum, scientists have identified the herb Paris or true-lover’s knot (Paris quadrifolia), whose genome is a good thousand times longer than that of the carnivorous plants from the genus Genlisea. However, these plants are so distantly related that it is almost impossible to identify the evolutionary forces at work in the individual species. Therefore, researchers from Dr. Detlef Weigel’s Department of Molecular Biology at the Max Planck Institute for Developmental Biology in Tübingen working in cooperation with an international research team selected for their genome study a species closely related to the thale cress (Arabidopsis thaliana), probably the most widely studied flowering plant in genetics. The species in question was lyre-leaved rock cress (Arabidopsis lyrata) which, unlike thale cress, is unable to self-fertilize.

Placenta Synthesizes Serotonin for Developing Fetus

Research at the Keck School of Medicine of the University of Southern California's (USC) Zilkha Neurogenetic Institute shows for the first time that the human placenta plays an active role in synthesizing serotonin, paving the way to new treatment strategies that could mitigate health impacts such as cardiovascular disease and mental illness. The groundbreaking findings, conducted with researchers from Vanderbilt University as part of a Silvio Conte Center of Excellence grant from the National Institute of Mental Health, offer conclusive evidence that the placenta provides serotonin to the fetal forebrain, not through the mother's blood supply, as theorized for the past 60 years. The research was published in Nature on April 21, 2011. "Our research indicates that the placenta actually synthesizes serotonin, and the serotonin is released from the placenta into the fetal bloodstream where it can reach the fetal brain," said lead author Dr. Alexandre Bonnin. "The placenta was seen as a passive organ, but we now know that it has significant synthetic capabilities and has a much more critical role in developmental programming of the fetus than previously thought.” Dr. Bonnin's work with Dr. Pat Levitt, director of the Zilkha Neurogenetic Institute and corresponding author on the paper, included the invention of a unique technology known as a "placentometer" that monitors substances that pass through the mouse placenta from mother to fetus. This technology can incorporate genetic models of human disease, and could lead to targeted therapies that treat the mother without affecting the fetus, or vice versa. "The findings by Dr.

April 20th

Nutlin-3a Activates p53, Stimulates Apoptosis in Glioblastoma Cells

Researchers of Apoptosis and Cancer Group of the Bellvitge Biomedical Research Institute (IDIBELL) have found that a small molecule, Nutlin-3a, an antagonist of MDM2 protein, stimulates the signaling pathway of another protein, p53. In this way, it induces cell death and senescence (loss of proliferative capacity) in brain cancer, a fact that slows the cancer’s growth. These results open the door for MDM2 agonists as new treatments for glioblastomas. The study was published online on April 5, 2011, in the journal PLOS One. Glioblastoma multiforme is the most common brain tumor in adults and the most aggressive. Despite efforts on new treatments and technological innovation in neurosurgery, radiation therapy, and clinical trials of new therapeutic agents, most patients die two years after diagnosis. Dr. Avelina Tortosa, IDIBELL and University of Barcelona (UB) researcher, coordinator of the study, explained that one objective of her group is "to find substances that sensitize tumor cells to radiotherapy for more efficient treatments.” There is evidence that several genetic alterations promote the growth, invasion, and resistance to stimuli that induce programmed cell death (apoptosis). Along these lines, the pilot project TCGA (The Cancer Genome Atlas) has sequenced the genome of up to 25 glioblastomas noting that 14% of patients have an increased expression of MDM2 and 35% had alterations in p53 expression (apoptosis-inducing). That's why research is now focused on the development of new therapeutic strategies that target the apoptosis in gliomas. The aim of this study was to investigate the antitumor activity of Nutlin-3a in cell lines and primary cultures of glioblastoma.