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March 27th, 2011

Scientists Unravel Key Gene Processes Driving Acute Myeloid Leukemia

Researchers have described how the most common gene mutation found in acute myeloid leukemia starts the process of cancer development and how it can cooperate with a well-defined group of other mutations to cause full-blown leukemia. The researchers suggest that three critical steps are required to transform normal blood cells into leukemic ones, each subverting a different cellular process. By charting the route towards cancer, the study identifies processes that might serve as targets for new treatments to halt the cancer's development in its tracks and even reverse it. Acute myeloid leukemia is a rare but devastating disease, which can take hold in a matter of just days or weeks. Every year, 2,000 adults in the UK are diagnosed with acute myeloid leukaemia: only about three in ten adults survive for five years. In recent years researchers have identified a number of genes involved in the development of acute myeloid leukemia. The most common is NPM1, a gene with many known functions. The new research shows that mutation in NPM1 is a key event in the development of a large proportion of cases of acute myeloid leukemia and that it exerts its effect by helping cells to self-renew, a process that can be thought of as the first step towards leukemia. The team also identified two subsequent events that are required to cooperate with NPM1 to drive cells to become cancerous. The new work was published online on March 27, 2011, in Nature Genetics. "We have used targeted gene disruption to look at the way acute myeloid leukemia develops in mice," says Dr George Vassiliou, Consultant Haematologist, cancer researcher and first author on the study from the Wellcome Trust Sanger Institute, "and have found critical steps that take place when the cancer develops.

MS May Involve Previously Unknown Type of Reversible Axonal Degeneration

The immune system recognizes and neutralizes or destroys toxins and foreign pathogens that have gained access to the body. Autoimmune diseases result when the system attacks the body's own tissues instead. One of the most common examples is multiple sclerosis (MS). MS is a serious condition in which nerve-cell projections, or axons, in the brain and the spinal cord are destroyed as a result of misdirected inflammatory reactions. It is often characterized by an unpredictable course, with periods of remission being interrupted by episodes of relapse. A team of researchers led by LMU Munich Professor Martin Kerschensteiner of the Medical Center of the University of Munich and Professor Thomas Misgeld from the Technical University of Munich has now been able to explain how the damage is inflicted. The results reveal that the inflammatory reaction can induce a previously unknown type of axonal degeneration, which they call "focal axonal degeneration" (FAD). In an animal model of MS, this process is reversible if it is recognized and treated early, so the researchers believe that it could serve as a potential target for therapeutic intervention. "Development of an effective treatment will be a long-term project," cautioned Dr. Kerschensteiner. "As yet, we only have a superficial understanding of the underlying molecular mechanisms and, of course, finding effective therapies will require time-consuming screens and extensive trials of drug candidates." The new work was published online on March 27, 2011, in Nature Medicine. Multiple sclerosis is a common and, in many cases seriously disabling, autoimmune disease that can lead to the disturbance or loss of sensory function, voluntary movement, vision and bladder control.

March 25th

Research Sheds Light on Sense of Smell

Researchers seeking to unravel the most ancient yet least understood of the five senses – smell – have discovered a previously unknown step in how odors are detected and processed by the brain. The four-year study, focusing on how mice respond to odors, showed that smells are picked up by the olfactory bulb – the first stop on the way to the brain – then sent to the olfactory cortex for further analysis. But scientists discovered something else – a dialogue between the bulb and the cortex conducted by rapidly firing nerve cells. "It was originally thought that the olfactory bulb filtered and the olfactory cortex made decisions on whether something is, for example, edible," said lead researcher Dr. Diego Restrepo, professor of Cell and Developmental Biology and co-director of the University of Colorado School of Medicine Center for NeuroScience. "Our study says it's not quite like that. You process information on reward in the olfactory bulb, send it to the cortex and there is a dialogue between the two. Then the brain will act." The study was featured on the cover of the March 24, 2011 issue of Neuron. Dr. Restrepo, an expert on the science of taste and smell, said the discovery expands our understanding of how the olfactory system filters and categorizes the thousands of odors that bombard the brain daily. "We know very little about olfaction and we tend to think that it is not very important in humans compared to the other creatures," he said. "But much of what goes on is subtle and we are only beginning to understand it." For example, scientists recently found that when men sniffed the odorless tears of women, their levels of testosterone dropped. And for years it's been known that humans, like animals, secrete pheromones that may subconsciously help them choose a mate.

HIV Integration Requires Use of Host DNA-Repair Pathway

The human immunodeficiency virus (HIV), the cause of AIDS, makes use of the base excision repair pathway when inserting its DNA into the host-cell genome, according to a new study led by researchers at the Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute. Crippling the repair pathway prevents the virus from completing this critical step in the retrovirus's life cycle. The findings offer potential new targets for novel anti-HIV drugs that may not lead as quickly to viral resistance as current drugs, the researchers say. "HIV continues to develop resistance to current therapies," says first author Dr. Kristine Yoder, assistant professor of molecular virology, immunology, and medical genetics. "But the proteins we talk about in this paper are made by the cell, so drugs that target them might not lead to resistance as quickly as drugs that target viral proteins. And while targeting host proteins does have the potential for side effects, studies of mice suggest that targeting some of these genes may not lead to significant side effects." The paper was published online on March 23, 2011, in the journal PLoS ONE. Cells normally use base excision repair to fix oxidative damage to DNA caused by reactive molecules such as hydrogen peroxide and oxygen radicals, which form during energy production and other metabolic processes. For this study, Dr. Yoder and her colleagues investigated the role of the repair pathway in the virus insertion process by engineering four strains of mouse fibroblast cells that each lacked a component of the pathway. Specifically, they deleted genes for three glycosylase enzymes – Ogg1, Myh, and Neil1 – and one polymerase gene, Pol-beta.

Neural-Like Stem Cells Found in Pig Blood

A group of scientists at Marshall University in West Virginia is conducting research that may someday lead to new treatments for repair of the central nervous system. Dr. Elmer M. Price, who heads the research team and is chairman of Marshall’s Department of Biological Sciences, said his group has identified and analyzed unique adult animal stem cells that can turn into neurons. Dr. Price said the neurons they found appear to have many of the qualities desired for cells being used in development of therapies for slowly progressing, degenerative conditions like Parkinson’s disease, Huntington’s disease and multiple sclerosis, and for damage due to stroke or spinal cord injury. According to Dr. Price, what makes the discovery especially interesting is that the source of these neural stem cells is adult blood, a readily available and safe source. Unlike embryonic stem cells, which have a tendency to cause cancer when transplanted for therapy, adult stems like those identified in Dr. Price’s lab are found in the bodies of all living animals and do not appear to be carcinogenic. “Neural stem cells are usually found in specific regions of the brain, but our observation of neural-like stem cells in blood raises the potential that this may prove to be a source of cells for therapies aimed at neurological disorders,” Dr. Price added. So far, the group at Marshall has been able to isolate the unique neural cells from pig blood. Price said pigs are often used as models of human diseases due to their anatomical and physiological similarities to humans. In the future, his lab will work to isolate similar cells from human blood, paving the way for patients to perhaps one day be treated with stem cells derived from their own blood.

March 25th

FDA Approves BMS Drug for Late-Stage Melanoma

The U.S. Food and Drug Administration today (March 25, 2011) approved Yervoy (ipilimumab) to treat patients with late-stage (metastatic) melanoma, the most dangerous type of skin cancer. Melanoma is the leading cause of death from skin disease. An estimated 68,130 new cases of melanoma were diagnosed in the United States during 2010 and about 8,700 people died from the disease, according to the National Cancer Institute. “Late-stage melanoma is devastating, with very few treatment options for patients, none of which previously prolonged a patient’s life,” said Dr. Richard Pazdur, director of the Office of Oncology Drug Products in the FDA’s Center for Drug Evaluation and Research. "Yervoy is the first therapy approved by the FDA to clearly demonstrate that patients with metastatic melanoma live longer by taking this treatment." Yervoy is a monoclonal antibody that blocks a molecule known as cytotoxic T-lymphocyte antigen or CTLA-4. CTLA-4 may play a role in slowing down or turning off the body’s immune system, affecting its ability to fight off cancerous cells. Yervoy may work by allowing the body’s immune system to recognize, target, and attack cells in melanoma tumors. The drug is administered intravenously. Yervoy’s safety and effectiveness were established in a single international study of 676 patients with melanoma. All patients in the study had stopped responding to other FDA-approved or commonly used treatments for melanoma. In addition, participants had disease that had spread or that could not be surgically removed. The study was designed to measure overall survival, the length of time from when this treatment started until a patient's death. The randomly assigned patients received Yervoy plus an experimental tumor vaccine called gp100, Yervoy alone, or the vaccine alone.

Existing Asthma Drug May Prove Useful in Treating Alzheimer’s

A drug used to treat asthma has been shown, in a transgenic mouse model, to help reduce the formation of amyloid beta, a peptide in the brain that is implicated in the development of Alzheimer's disease, according to researchers at Temple University's School of Medicine. The researchers published their findings, "Pharmacologic Blockade of 5-Lipoxygenase Improves the Amyloidotic Phenotype of an AD Transgenic Mouse Model," in the American Journal of Pathology. In previous studies, the Temple researchers discovered that 5-lipoxygenase, an enzyme long known to exist in the brain, controls the activation state of gamma secretase, another enzyme that is necessary and responsible for the final production of amyloid beta. When produced in excess, amyloid beta causes neuronal death and forms plaques in the brain. The amount of these amyloid plaques in the brain is used as a measurement of the severity of Alzheimer's. In the current study, led by Dr. Domenico Praticò, an associate professor of pharmacology in Temple's School of Medicine, the researchers tested the drug Zileuton, an inhibitor of 5-lipoxygenase typically used to treat asthma, in a transgenic mouse model of Alzheimer's disease. At the end of the treatment they found that this drug, by blocking the 5-lipoxygenase, reduced gamma secretase's production of amyloid beta and the subsequent build up of amyloid plaques in the brain by more than 50 percent. Dr. Praticò said that gamma secretase is present throughout the body and, despite its role in the development of amyloid plaques, plays a significant role in numerous important functions. Direct inhibitors of gamma secretase are known, he said, but blocking the enzyme completely may cause problems such as the development of cancer.

Researchers ID Possible Powerful New Colon Cancer Marker

A research team at the University of Colorado Cancer Center has identified an enzyme that could be used to diagnose colon cancer earlier. It is possible that this enzyme also could be a key to stopping the cancer. Colon cancer is the third most common cancer in Americans, with a one in 20 chance of developing it, according to the American Cancer Society. This enzyme biomarker could help physicians identify more colon cancers and do so at earlier stages when the cancer is more successfully treated. The research was led by Dr. Vasilis Vasiliou, professor of molecular toxicology at the University of Colorado School of Pharmacy, and published in the February 11, 2011 issue of Biochemical and Biophysical Research Communications. Dr. Vasiliou’s laboratory specializes in understanding the role of enzymes called aldehyde dehydrogenases in drug metabolism, metabolic diseases, cancer, and normal and cancer stem cells. Dr. Vasiliou’s team studied colon cancers from 40 patients and found a form of aldehyde dehydrogenase known as ALDH1B1 present in every colon cancer cell in 39 out of the 40 cases. The enzyme, which is normally found only in stem cells, was detected at extraordinarily high levels. “Other potential colon cancer biomarkers have been identified in the past, but none thus far are present in such a high percent of the cancer cells and virtually none are overexpressed like this one,” says Dr. David Orlicky, associate professor of pathology at the CU medical school and a member of the research team. This finding is particularly timely as it was recommended recently at the Human Genome 2011 annual meeting that a chemical analysis for biomarkers should always accompany genotyping in early detection of colon cancer, said Dr. Vasiliou, who attended the meeting in Dubai.

Clue to Mechanism by Which Certain Gene Mutations Cause Familial Parkinson’s

Researchers at the Mount Sinai School of Medicine and collaborating institutions have discovered a way that mutations in a gene called LRRK2 may cause the most common inherited form of Parkinson's disease. The study, published online on March 1, 2011, in the journal PLoS ONE, shows that upon specific modification called phosphorylation, LRRK2 protein binds to a family of proteins called 14-3-3, which has a regulatory function inside cells. When there is a mutation in LRRK2, 14-3-3 is impaired, leading to Parkinson's. This finding explains how mutations lead to the development of Parkinson's, providing a new diagnostic and drug target for the disease. Using one-of-a-kind mouse models developed at the Mount Sinai School of Medicine, Dr. Zhenyu Yue, Associate Professor of Neurology and Neuroscience, and his colleagues, found that several common Parkinson's disease mutations—including one called G2019S—disturb the specific phosphorylation of LRRK2. This impairs 14-3-3 binding to varying degrees, depending on the type of mutation. "We knew that the LRRK2 mutation triggers a cellular response resulting in Parkinson's disease, but we did not know what processes the mutation disrupted," said Dr. Yue. "Now that we know that phosphorylation is disturbed, causing 14-3-3 binding to be impaired, we have a new idea for diagnostic analysis and a new target for drug development." Dr. Yue's team also identified a potential enzyme called protein kinase A (PKA), responsible for the phosphorylation of LRRK2. Although the exact cellular functions disrupted by these changes are unclear, the study provides a starting point for understanding brain signaling that contributes to the disease.

Potential Non-Insulin Treatment of Type 1 Diabetes Investigated

Researchers at the University of Texas Southwestern Medical Center have discovered a hormone pathway that potentially could lead to new ways of treating type 1 diabetes independent of insulin, long thought to be the sole regulator of carbohydrates in the liver. Results of this new study are published in the March 25, 2011 issue of Science. Another hormone, fibroblast growth factor 19 (FGF19), has insulin-like characteristics beyond its role in bile acid synthesis. Unlike insulin, however, FGF19 does not cause excess glucose to turn to fat, suggesting that its activation could lead to new treatments for diabetes or obesity. “The fundamental discovery is that there is a pathway that exists that is required for the body, after a meal, to store glucose in the liver and drive protein synthesis. That pathway is independent of insulin,” said Dr. David Mangelsdorf, chairman of pharmacology at UT Southwestern. Naturally elevating this pathway, therefore, could lead to new diabetes treatments outside of insulin therapy. The standard treatment for type 1 diabetes, which affects about 1 million people in the U.S., involves taking insulin multiple times a day to metabolize blood sugar. Dr. Mangelsdorf and Dr. Steven Kliewer, professor of molecular biology and pharmacology at UT Southwestern, are co-senior authors of the study. Dr. Kliewer has been studying the hormone FGF19 since he discovered its involvement in metabolism about eight years ago. Fibroblast growth factors control nutrient metabolism and are released upon bile acid uptake into the small intestine. Bile acids, produced by the liver, break down fats in the body. In this work, researchers studied mice lacking FGF15 – the rodent FGF19 hormone equivalent. These mice, after eating, could not properly maintain blood concentrations of glucose and normal amounts of liver glycogen.