Syndicate content

Archive - May 2017


May 9th

Potential Biomarker for Glaucoma Damage Identified

Glaucoma, a leading cause of blindness worldwide, is most often diagnosed during a routine eye exam. Over time, elevated pressure inside the eye damages the optic nerve, leading to vision loss. Unfortunately, there's no way to accurately predict which patients might lose vision most rapidly. Now, studying mice, rats, and fluid removed from the eyes of patients with glaucoma, researchers at the Washington University School of Medicine in St. Louis have identified a marker of damage to cells in the eye that potentially could be used to monitor progression of the disease and the effectiveness of treatment. The findings were published online on May 4, 2017 in the journal JCI Insight. The open-access article is titled “GDF15 Is Elevated in Mice Following Retinal Ganglion Cell Death and in Glaucoma Patients.” "There hasn't been a reliable way to predict which patients with glaucoma have a high risk of rapid vision loss," said principal investigator Rajendra S. Apte, MD, PhD, the Paul A. Cibis Distinguished Professor of Ophthalmology and Visual Sciences. "But we've identified a biomarker that seems to correlate with disease severity in patients, and what that marker is measuring is stress to the cells rather than cell death. Other glaucoma tests are measuring cell death, which is not reversible, but if we can identify when cells are under stress, then there's the potential to save those cells to preserve vision." Glaucoma is the second-leading cause of blindness in the world, affecting more than 60 million people. The disease often begins silently, with peripheral vision loss that occurs so gradually that it can go unnoticed. Over time, central vision becomes affected, which can mean substantial damage already has occurred before any aggressive therapy begins.

New Nanotechnology Application for Difficult-to-Treat Cancers

A new treatment combining shock waves with nanoparticles can successfully treat tumors that are difficult to target using conventional chemotherapy. This is the first time this combined therapy has been tested in live animals. The findings of this pre-clinical study, published online on May 9, 2017 in the journal Endocrine-Related Cancer, could lead to the development of more effective therapies for treating life-threatening cancers in the future. The open-access article is titled “Combining Doxorubicin-Nanobubbles and Shockwaves for Anaplastic Thyroid Cancer Treatment: Preclinical Study in a Xenograft Mouse Model.” Nanoparticles can be effective carriers of drugs to the tumor site through the blood stream. The particles contain the chemotherapy drugs and deliver them directly to the tumor, which reduces toxic side effects and enhances the effectiveness of treatments. However, in some cancers drug delivery can be compromised due to the disruption of tumor blood flow. To overcome this problem, researchers led by Dr. Graziella Catalano at the University of Turin (photo) in Italy, designed a treatment that combines extracorporeal shock waves (ESW) and nanobubbles (NBs). ESW are sound-like waves that can be focused with high precision, so that the cancerous cells more readily absorb the drugs. NBs are nanoparticles with a gas core that can be loaded with drugs to be released at the tumor site. The combination of NBs and ESW helps to focus the effects of anti-cancer drugs at the tumor site. In this study, researchers tested this approach on a mouse model of anaplastic thyroid cancer (ATC), a very aggressive, rare, and difficult-to-treat type of cancer. ATC is one of the most lethal cancers - after diagnosis, the average survival rate is just five months.

Precision Medicine Improves Treatment Outcomes for Some Pancreatic Cancer Patients

University of Pittsburgh and University of Pittsburgh Medical Center (UPMC) researchers are paving the way for genome-targeted treatments in pancreatic cancer, an especially deadly form of cancer with few existing therapeutic options, according to a pair of recent studies. The first study used genomic profiling to identify targeted therapies that resulted in benefits for patients with pancreatic cancer, including one whose tumor contained a mutation in the anaplastic lymphoma kinase (ALK) gene. In the second study, researchers used existing drugs already treating other types of ALK-mutated cancers to improve outcomes in pancreatic cancer patients with the same genetic alterations. "Together, these two findings begin to capture the promise of precision medicine in pancreatic cancer, which has so far not experienced the same success with targeted treatments as other cancer types," said the senior author of both studies, Nathan Bahary, MD, PhD, Associate Professor of Medicine at Pitt, and Co-Director of the UPMC Pancreatic Cancer Center of Excellence. "The assessment of these actionable alterations is now part of routine pancreatic cancer care at UPMC." As the third-leading cause of cancer deaths in the United States, and with a five-year survival rate of just 8 percent, pancreatic cancer is one of the most lethal forms of the disease. Currently available treatments are largely ineffective, so there is a desperate need for better therapeutic options, explained Dr. Bahary. In the first study, published in the January 2017 issue of Cancer Medicine, first author Mashaal Dhir, MD, an oncologic surgical fellow at UPMC, and colleagues used DNA sequencing to look for gene changes in over 100 patient samples of advanced gastrointestinal cancers, including colorectal and pancreatic tumors.

New Method of Microbial Energy Production Discovered

For all living things to succeed, they must reproduce and have the energy to do so. An organism's ability to extract energy from its surroundings-and to do it better than its competitors-is a key requirement of survival. Until recently it was thought that in all of biology, from microbes to humans, there were only two methods to generate and conserve the energy required for cellular metabolism and survival. Now, researchers have discovered a third method of microbial energy production, called "flavin-based electron bifurcation" (FBEB). This newly found method is actually an ancient form of energy generation and conservation, but is so different from the known processes that it represents a paradigm shift in how scientists think about the way organisms obtain energy. The mechanism of how FBEB works was unknown-that is, until a breakthrough was made by researchers from the Biological Electron Transfer and Catalysis (BETCy) Energy Frontier Research Center, whose members include Cara E. Lubner, David W. Mulder, and Paul W. King from the U.S. Department of Energy's National Renewable Energy Laboratory (NREL). The team examined previously unknown features of the catalytic mechanism, gaining critical, comprehensive insights about the way in which FBEB works. One of the most important findings is how a unique flavin molecule is able to generate two levels of energy from a single precursor compound. One level is used to perform an easy chemical reaction, whereas the other much more energetic one is used to perform more difficult chemistry to form a high-energy compound. In doing so, the two reactions are coupled together so that energy that is normally wasted is conserved in the high-energy compound.

“Juicing” T Cells with Small Molecules Enhances Immune Response Against Melanoma

"Juicing" Th17 cells with FDA-approved small molecule β-catenin and p110δ inhibitors during in vitro expansion for adoptive T cell therapy (ACT) profoundly improves their therapeutic properties, report investigators at the Medical University of South Carolina (MUSC) in an article published online on April 20, 2017 in JCI Insight. The open-access article is titled “β-Catenin and PI3Kδ Inhibition Expands Precursor Th17 Cells with Heightened Stemness and Antitumor Activity.” ACT involves harvesting T cells, rapidly amplifying and/or modifying them in the laboratory to boost their cancer-fighting ability, and then reinfusing them back to the patient to boost anticancer immunity. One challenge for ACT has been that the rapid expansion of T cells in the laboratory can cause them to age and wear out, decreasing their longevity after reinfusion. "Juicing" Th17 cells with the FDA-approved small molecules enhanced their potency, function, and stem-like (less differentiated) quality, suggesting that they would persist better after reinfusion into patients, and also reduced regulatory T cells in the tumor microenvironment, which can blunt the immune response. These findings highlight novel investigative avenues for next-generation immunotherapies, including vaccines, checkpoint modulators, and ACT. "This is exciting because we might be able to overcome some of the delays and disadvantages of rapid expansion in the laboratory," explains senior author Chrystal M. Paulos (photo), PhD, Associate Professor of Immunology and Endowed Peng Chair of Dermatology at MUSC and a member of the MUSC Hollings Cancer Center.

Fluorescent Fatty Acids Used As Metabolic Tracers in Zebrafish

Studying how our bodies metabolize lipids such as fatty acids, triglycerides, and cholesterol can teach us about cardiovascular disease, diabetes, and other health problems, as well as reveal basic cellular functions. But the process of studying what happens to lipids after they are consumed has been both technologically difficult and expensive to accomplish until now. New work from Carnegie Institution for Science’s Steven Farber, PhD, and his graduate student Vanessa Quinlivan debuts a method using fluorescent tagging to visualize and help measure lipids in real time as they are metabolized by living fish. Their work was published online on March 9, 2017 in the Journal of Lipid Research. The article is titled “An HPLC-CAD/Fluorescence Lipidomics Platform Using Fluorescent Fatty Acids As Metabolic Tracers.” "Lipids play a vital role in cellular function, because they form the membranes that surround each cell and many of the structures inside of it," Quinlivan said. "They are also part of the crucial makeup of hormones such as estrogen and testosterone, which transmit messages between cells." Unlike proteins, the recipes for different lipid-containing molecules are not precisely encoded by DNA sequences. A cell may receive a genetic signal to build a lipid for a certain cellular purpose, but the exact type may not be indicated with a high degree of specificity. Instead, lipid molecules are built from an array of building blocks whose combinations can change depending on the type of food we eat. However, lipid compositions vary between cells and cellular structures within the same organism, so diet isn't the only factor determining which lipids are manufactured.

Soil Microbiome Could Orchestrate Massive Tree Migrations

Warming temperatures are prompting some tree species in the Rocky Mountains to "migrate" to higher elevations in order to survive. Researchers at the University of Tennessee, Knoxville, have discovered that tiny below-ground organisms play a role in this phenomenon -- and could be used to encourage tree migration in order to preserve heat-sensitive species. The scientists’ work shows how these invisible biotic communities create "soil highways" for young trees, meaning they could determine how quickly species march uphill, if at all. The newfound role of the soil microbiome -- the collection of microscopic bacteria, fungi, and archaea that interact with plant roots -- represents a turning point for research aimed at understanding and predicting where important tree species will reside in the future. Just as human microbiome research is rapidly changing our perspectives on human health and behavior, the interactions between trees and their soil microbiomes may dramatically change how we think about the health and behavior of forests. The study was published online on April 28, 2017 in Nature Ecology and Evolution. The article is titled “Divergent Plant–Soil Feedbacks Could Alter Future Elevation Ranges and Ecosystem Dynamics.” The researchers' goal was to better understand how plants will respond as temperatures rise. “One general expectation is that tree ranges will gradually move toward higher elevations as mountain habitats get hotter," said Michael Van Nuland, the project's lead researcher and a doctoral student in UT's Department of Ecology and Evolutionary Biology. "It is easy to see the evidence with photographs that compare current and historical tree lines on mountainsides around the world. Most document that tree lines have ascended in the past century."

Low Oxygen Reverses Mitochondrial Disease in Mice

Thin air can reverse brain damage due to mitochondrial defects in mice, new results show. After a month of breathing air that contains about half the usual amount of oxygen, telltale lesions in the brains of these mice had disappeared, Howard Hughes Medical Institute (HHMI) Investigator Vamsi Mootha (photo), MD, and colleagues reported online on May 8, 2017 in PNAS. The article is titled “Hypoxia Treatment Reverses Neurodegenerative Disease in a Mouse Model of Leigh Syndrome.” "We found, much to our surprise and delight, that we could actually reverse advanced disease," Dr. Mootha says. "I don't think anybody thought that these types of neurological diseases could be reversible." It's a remarkable turnaround -- though the result was seen in mice, not humans. More research is needed before a similar approach could be used to treat people, cautions Dr. Mootha, a mitochondrial biologist at Massachusetts General Hospital in Boston. Still, the findings hint at the promise of low oxygen therapy to prevent, or even reverse, mitochondrial disorders in people. One such disorder is Leigh syndrome, a rare disease that often appears in the first few years of life. The disorder is marked by progressive brain lesions, a loss of motor skills, developmental delays, and a failure to grow. Most forms of the disease have no proven treatments. Yet Dr. Mootha and his team had what seems like a counter-intuitive idea. In 2016, the researchers reported that hypoxia, or oxygen deficiency, actually improves the health of mice genetically engineered to have dysfunctional mitochondria, tiny power-producing organelles. Those results, published in Science, were tantalizing, and also raised a number of questions, such as how long these treated mice actually live, and whether hypoxia treatment needs to be continuous.

Molecular Mechanism Underlying Lithium’s Effectiveness in Treating Bipolar Disorder Revealed

An international collaborative study led by researchers at the Sanford Burnham Prebys Medical Discovery Institute (SBP), with major participation from Yokohama School of Medicine, Harvard Medical School, and UC San Diego, has identified the molecular mechanism behind lithium's effectiveness in treating bipolar disorder patients. The study, published recently in PNAS, utilized human induced pluripotent stem cells (hiPS cells) to map lithium's response pathway, enabling the larger pathogenesis of bipolar disorder to be identified. These results are the first to explain the molecular basis of the disease, and may support the development of a diagnostic test for the disorder, as well as predict the likelihood of patient response to lithium treatment. It may also provide the basis to discover new drugs that are safer and more effective than lithium. Bipolar disorder is a mental health condition causing extreme mood swings that include emotional highs (mania or hypomania) and lows (depression) and affects approximately 5.7 million adults in the U.S. Lithium is the first treatment explored after bipolar symptoms, but it has significant limitations. Only approximately one-third of patients respond to lithium treatment, and its effect is only found through a trial-and-error process that takes months--and sometimes years--of prescribing the drug and monitoring for response. Side effects of lithium treatment can be significant, including nausea, muscle tremors, emotional numbing, irregular heartbeat, weight gain, and birth defects, and many patients choose to stop taking the medicine as a result.

Cell Factory Claims Milestone in Development of EV-Based Treatment of Drug-Resistant Epilepsy in Children; Full Results Will Be Presented at ISEV 2017 Meeting in Toronto May 18-21

Esperite`s biotech subsidiary The Cell Factory develops the extracellular vesicles (EVs) biologic drug (CF-MEV-117) for treatment of drug-resistant epilepsy in children. In a May 5, 2017 press release, Espertite announced that a consortium sponsored by The Cell Factory has achieved an important milestone in the CF-MEV-117 drug development, confirming an anti-inflammatory and immunosuppressive activity of the CF-MEV-117 in a dose response manner. Full results will be presented during the International Society for Extracellular Vesicles (ISEV) meeting in Toronto, Canada fromMay 18-21, 2017. The Cell Factory, a company subsiadiery of the Esperite Group, in collaboration with Bambino Gesù Children`s Hospital in Rome, Mario Negri Institute for Pharmacological Research in Milan, and Women`s and Children`s Health Department of the University of Padua is developing the EV drug candidate (CF-MEV-117) for treatment of drug-resistant epilepsy in children. The consortium is investigating the immunomodulatory properties of EVs derived from mesenchymal stem cells (MSCs) in several in vitro and in vivo models. It has been previously demonstrated by independent research groups that inhibitory effects of MSCs on human leukocytes are mediated by secreted EVs. Subsequently, it was demonstrated by Cell Factory partners that MSC-derived EVs were responsible for inhibition of B-cell proliferation and differentiation and for activation of T-cell apoptosis (Budoni et al., 2013; Del Fattore et al., 2015). These results have been recently confirmed with the CF-MEV-117 drug candidate manufactured by The Cell Factory. Preclinical and clinical study demonstrate that brain inflammation could be responsible for severe epileptic seizures. Pro-inflammatory molecules secreted by the stimulated glial cells are responsible for a status epilepticus.