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December 26th, 2016

February 11th, 2015

Diabetes Drug Proglitazone Can Stimulate Production of ROS from Mitochonria of WBCs, Meliorating Chronic Granulomatous Disease in Mouse Model

Pioglitazone, a medication approved for treatment of type 2 diabetes, can help bypass genetic defects in chronic granulomatous disease (CJD) to help white blood cells fight bacterial infections, according to researchers at National Jewish Health. Patients with CGD, a rare inherited disorder, lack a functional enzyme, known as NADPH oxidase, which impairs their ability to produce a variety of oxidant molecules, known as reactive oxygen species (ROS), in response to bacterial infection. Normally, ROS destroy bacteria by chemically reacting with their cell walls and other components. As a result of genetic mutation, CGD patients lack this early immune response and suffer ongoing and severe infections, especially of the lungs, liver, skin, and lymph nodes. Pioglitazone, an agonist of the signaling molecule PPAR-gamma, has broad effects on cellular metabolism, which include mimicry of insulin and anti-inflammatory activities. The medication is approved for treatment of type 2 diabetes and is being investigated for use in a variety of other disorders, primarily for its anti-inflammatory properties. Recent findings have suggested that it may also boost the production of ROS. National Jewish Health Professor of Pediatrics, Donna Bratton, M.D., and her colleagues reported in the February 2015 Journal of Allergy and Clinical Immunology that pioglitazone does indeed boost production of ROS in white blood cells by about 30 percent in a mouse model of CGD and in white blood cells from CGD patients. They also found that pioglitazone enhanced the ability of the cells from the CGD mouse model to kill Staphylococcus aureus and Burkholdia cepacia, two pathogens that are difficult to treat and common in CGD.

October 25th, 2014

Mosaic Loss of Y-Chromosome Associated with Shorter Life Span, Increased Risk of Cancer

Age-related mosaic loss of the Y chromosome (LOY) from blood cells, a frequent occurrence among elderly men, is associated with elevated risk of various cancers and earlier death, according to research presented on Tuesday, October 21, at the American Society of Human Genetics (ASHG) 2014 Annual Meeting in San Diego. This finding could help explain why men tend to have a shorter life span and higher rates of sex-unspecific cancers than women, who do not have a Y chromosome, said Lars Forsberg, Ph.D., lead author of the study and a geneticist at Uppsala University in Sweden. LOY, which occurs occasionally as a given man’s blood cells replicate – and thus takes place inconsistently throughout the body – was first reported nearly 50 years ago and remains largely unexplained in both its causes and effects. Recent advances in genetic technology have allowed researchers to use a blood test to detect when only a small fraction of a man’s blood cells have undergone LOY. Dr. Forsberg and colleagues studied blood samples from 1,153 elderly men aged 70 to 84 years, who were followed clinically for up to 40 years. They found that men whose samples showed LOY in a significant fraction of their blood cells lived an average of 5.5 years less than men whose blood was not affected by LOY. In addition, having undergone LOY significantly increased the men’s risk of dying from cancer during the course of the study. These associations remained statistically significant when results were adjusted for men’s age and other health conditions. “Many people think the Y chromosome only contains genes involved in sex determination and sperm production,” said Jan Dumanski, M.D., Ph.D., co-author on the study and a professor at Uppsala University.

September 8th

New, Antibody-Based, Non-Steroidal Treatment for Certain Severe Asthmatics

A team of researchers at McMaster University and St. Joseph's Healthcare Hamilton, both in Canada, have successfully evaluated a new, antibody-based drug for certain patients with severe asthma. The drug – named mepolizumab (image)– can replace traditional, steroid-based treatments for a specific subset of patients, resulting in improved outcomes and reduced side effects. The study and manuscript, published online on September 8, 2014 in the New England Journal of Medicine was led in Canada by Dr. Parameswaran Nair, Staff Respirologist, Firestone Institute for Respiratory Health at St. Joseph's Healthcare Hamilton and Professor of Respirology at the Michael G. DeGroote School of Medicine at McMaster University. Dr. Nair and his colleagues recruited the largest number of participants for this global study. "This new drug is the only therapy that has been proven to be effective in well-established clinical trials to help reduce doses of steroid-based treatments such as prednisone for those with severe asthma," said Dr. Nair, adding that the paper reconfirms the team's observation published in the New England Journal of Medicine in 2009. Patients with severe asthma often require high doses of steroid-based treatments that can significantly impair their quality of life. These high doses can cause debilitating side effects including mood swings, diabetes, bone loss, skin bruising, cataracts, and hypertension. Previous research at the Hamilton institutions has identified specific types of patient with severe asthma who have an overabundance of a particular type of white blood cell (eosinophils) present in their sputum. These patients often suffer from the most severe asthma symptoms and can only be treated through steroid-based medications such as prednisone.

August 29th

Good to Bad and Bad to Good--“Tour de Force” by Nobel Prize Winner and MIT Team Reverses Emotional Associations of Memories--Possible Applications in Mental Illness

Most memories have some kind of emotion associated with them: recalling the week you just spent at the beach probably makes you feel happy, while reflecting on being bullied provokes more negative feelings. A new study by MIT neuroscientists reveals the brain circuit that controls how memories become linked with positive or negative emotions. Furthermore, the researchers found that they could reverse the emotional association of specific memories by manipulating brain cells with optogenetics — a technique that uses light to control neuron activity. The findings, described online on August 27, 2014 in Nature, demonstrated that a neuronal circuit connecting the hippocampus and the amygdala plays a critical role in associating emotion with memory. This circuit could offer a target for new drugs to help treat conditions such as post-traumatic stress disorder, the researchers say. “In the future, one may be able to develop methods that help people to remember positive memories more strongly than negative ones,” says Dr. Susumu Tonegawa (image), the Picower Professor of Biology and Neuroscience, director of the RIKEN-MIT Center for Neural Circuit Genetics at MIT’s Picower Institute for Learning and Memory, and senior author of the paper. Dr. Tonegawa won the Nobel Prize for Physiology or Medicine in 1987 for his discovery of the genetic mechanism that produces antibody diversity. The paper’s lead authors are Dr. Roger Redondo, a Howard Hughes Medical Institute postdoc at MIT, and Joshua Kim, a graduate student in MIT’s Department of Biology. Memories are made of many elements, which are stored in different parts of the brain.

Engineered Molecule May Protect Brain from Detrimental Effects Linked to Diabetes

Researchers at the Hebrew University of Jerusalem have created a molecule that could potentially lower diabetic patients' higher risk of developing dementia or Alzheimer's disease. Recent studies indicate that high levels of sugar in the blood in diabetics and non-diabetics are a risk factor for the development of dementia, impaired cognition, and a decline of brain function. Diabetics have also been found to have twice the risk of developing Alzheimer's disease compared to non-diabetics. Now, researchers from the Hebrew University of Jerusalem have found a potential neuro-inflammatory pathway that could be responsible for the increases of diabetics' risk of Alzheimer's and dementia. They also reveal a potential treatment to reverse this process. The research group led by Professor Daphne Atlas, of the Department of Biological Chemistry in the Alexander Silberman Institute of Life Sciences at the Hebrew University, experimented with diabetic rats to examine the mechanism of action that may be responsible for changes in the brain due to high sugar levels. The researchers found that diabetic rats displayed high activity of enzymes called MAPK kinases, which are involved in facilitating cellular responses to a variety of stimuli, leading to inflammatory activity in brain cells and the early death of cells. The study shows that the diabetic rats given a daily injection of the sugar-lowering drug rosiglitazone for a month enjoyed a significant decrease in MAPK enzyme activity accompanied by a decrease in the inflammatory processes in the brain. According to the authors, this finding represents the first unequivocal evidence of a functional link between high blood sugar and the activation of this specific inflammatory pathway in the brain.

August 19th, 2013

Novel Chinese Herbal Medicine Improves Spinal Cord Injury Outcomes in Rats

A new study, published online on June 12, 2013 in Restorative Neurology and Neuroscience, demonstrates that the Chinese herbal medicine Ji-Sui-Kang (JSK), given systemically for three weeks after injury in rats, improved locomotor function, reduced tissue damage, and preserved the structure of neural cells compared to control rats. The report also includes data showing that JSK may first act to reduce inflammation and cell apoptosis and death, and boost local oxygen supply while, later on, it appears to restore function and promote tissue regeneration. Although Chinese herbal medicines have traditionally been used for a variety of ailments, the rationale for their use relies more on anecdotal evidence than the results of modern-day controlled experiments. "A number of anecdotal reports from Chinese medicine practitioners indicate that treatment with a novel herbal formulation, JSK, for periods of one week or three months improved functional recovery," explains co-lead investigator Shucui Jiang, M.D., Ph.D., head of the Hamilton NeuroRestorative Group at McMaster University in Hamilton, Ontario, Canada. "Our present study provides an important and necessary foundation for further studies of JSK." In this study, rats began JSK treatment immediately after undergoing spinal cord injury. Within 7 days, hindlimb locomotor function was significantly better in JSK-treated rats compared to those receiving only saline. JSK-treated rats continued to have better motor function than controls throughout the 21-day test period and treated animals appeared to support their weight better and have more coordinated movements.

June 22nd

Alzheimer's-Disease-Associated Protein Controls Movement in Mice

Researchers in Berlin and Munich, Germany and Oxford, United Kingdom, have revealed that a protein well known for its role in Alzheimer's disease controls spindle development in muscle and leads to impaired movement in mice when the protein is absent or treated with inhibitors. The results, which were published online on June 21, 2013 in an open-access article in The EMBO Journal, suggest that drugs under development to target the beta-secretase-1 protein, which may be potential treatments for Alzheimer's disease, might produce unwanted side effects related to defective movement. Alzheimer's disease is the most common form of dementia found in older adults. The World Health Organization estimates that approximately 18 million people worldwide have Alzheimer's disease. The number of people affected by the disease may increase to 34 million by 2025. Scientists know that the protein beta-secretase-1 or Bace1, a protease enzyme that breaks down proteins into smaller molecules, is involved in Alzheimer's disease. Bace1 cleaves the amyloid precursor protein and generates the damaging Abeta peptides that accumulate as plaques in the brain leading to disease. Now scientists have revealed in more detail how Bace1 works. "Our results show that mice that lack Bace1 proteins or are treated with inhibitors of the enzyme have difficulties in coordination and walking and also show reduced muscle strength," remarked Dr. Carmen Birchmeier, one of the authors of the paper, Professor at the Max-Delbrück-Center for Molecular Medicine in Berlin, Germany, and an EMBO Member. "In addition, we were able to show that the combined activities of Bace1 and another protein, neuregulin-1 or Nrg1, are needed to sustain the muscle spindles in mice and to maintain motor coordination." Muscle spindles are sensory organs that are found throughout the muscles of vertebrates.

May 5th

Genetics of Pulmonary Fibrosis

Researchers from the University of Colorado Denver and colleagues have carried out a genome-wide association study to identify susceptibility loci for fibrotic idiopathic pneumonia. Their results sugget that genes involved in host defense, cell-cell adhesion, and DNA repair contribute to risk for this disease. Specifically, the scientists confirmed association with TERT at 5p15, MUC5B at 11p15, and the 3q26 region near TERC. In addition, they identified seven newly associated loci: FAM13A at 4q22, DSP at 6p24, OBFC1 at 10q24, ATP11A at 13q34,DPP9 at 19p13, and chromosomal regions 7q22 and 15q14-15. The results of this study were published online in Nature Genetics on April 14, 2013. [Nature Genetics abstract]

Why Dense Breasts Predispose to Metastasis in Breast Cancer

Researchers at Washington University School of Medicine in St. Louis have discovered why breast cancer patients with dense breasts are more likely than others to develop aggressive tumors that spread. The finding opens the door to drug treatments that may prevent metastasis. It has long been known that women with denser breasts are at higher risk for breast cancer. This greater density is caused by an excess of a structural protein called collagen. "We have shown how increased collagen in the breasts could increase the chances of breast tumors spreading and becoming more invasive," says Gregory D. Longmore, M.D., professor of medicine. "It doesn't explain why women with dense breasts get cancer in the first place. But once they do, the pathway that we describe is relevant in causing their cancers to be more aggressive and more likely to spread." The results were published online on May 5, 2013 in Nature Cell Biology. Working in mouse models of breast cancer and with breast tumor samples from patients, Dr. Longmore and his colleagues showed that a protein that sits on the surface of tumor cells, called DDR2, binds to collagen and activates a multi-step pathway that encourages tumor cells to spread. "We had no idea DDR2 would do this," says Dr. Longmore, also professor of cell biology and physiology. "The functions of DDR2 are not well understood, and it has not been implicated in cancer -- and certainly not in breast cancer -- until now.” At the opposite end of the chain of events initiated by DDR2 is a protein called SNAIL1, which has long been associated with breast cancer metastasis. Dr. Longmore and his colleagues found that DDR2 is one factor helping to maintain high levels of SNAIL1 inside a tumor cell's nucleus, a necessary state for a tumor cell to spread.