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Archive - Aug 2015

August 21st

MSC Exosomes Activate Healing Mechanisms in Fibroblasts from Two-Year-Old Unhealed Ulcer of Patient with Uncontrolled Diabetes

Exosomes derived from mesenchymal stem cells (MSCs) were shown to be effective in stimulating wound-healing mechanisms in vitro for fibroblasts isolated from the edge of a non-healing ulcer in a 59-year-old patient with uncontrolled diabetes. The ulcer had remained unhealed for over two years, despite routine wound care, together with advanced wound care treatments. The MSC exosome work was carried out at the Interdisciplinary Stem Cell Institute (ISCI) at the University of Miami Miller School of Medicine, under the leadership of Joshua M. Hare, M.D., Director of the ISCI at the University of Miami Miller School of Medicine. Dr. Hare’s team found that introducing MSC exosomes could enhance the growth and migration of normal and chronic wound fibroblasts, and induce the development of new blood vessels in vitro. Also important in wound healing is that MSC exosomes appear to induce changes by activation of growth factor signaling cascades. In particular, MSC exosomes were found to activate several signaling pathways important in wound healing (Akt, ERK, and STAT3) and to induce the expression of a number of growth factors [hepatocyte growth factor (HGF), insulin-like growth factor-1 (IGF1), nerve growth factor (NGF), and stromal-derived growth factor-1 (SDF1)]. These findings represent a promising opportunity to gain insight into how MSCs may mediate wound healing. “This study improves our understanding of MSCs and their many functions,” says Dr. Hare. “In the future, exosomes derived from MSCs could be used for wound healing as a safe and effective “off the shelf” product.” “These findings are very exciting and suggest a possible addition to the armamentarium of regenerative medicine.” This work was published online on June 29, 2015 in Stem Cells and Development.

“Possible Cure” for Genetic Obesity; New Obesity-Related Metabolic Pathway Connected with Long-Implicated FTO Gene Region; Single Base Change Can Switch Between Lean and Obese Signatures in Human Pre-Adipocytes

Obesity is one of the biggest public health challenges of the 21st century. Affecting more than 500 million people worldwide, obesity costs at least $200 billion each year in the United States alone, and contributes to potentially fatal disorders such as cardiovascular disease, type 2 diabetes, and cancer. But there may now be a new approach to prevent and even cure obesity, thanks to a study led by researchers at MIT and Harvard Medical School and published online on August 19, 2015 in an open-access article in the New England Journal of Medicine. The article is titled “FTO Obesity Variant Circuitry and Adipocyte Browning in Humans.” “By analyzing the cellular circuitry underlying the strongest genetic association with obesity, the researchers have unveiled a new pathway that controls human metabolism by prompting our adipocytes, or fat cells, to store fat or burn it away. "Obesity has traditionally been seen as the result of an imbalance between the amount of food we eat and how much we exercise, but this view ignores the contribution of genetics to each individual's metabolism," says senior author Dr. Manolis Kellis, a professor of computer science and a member of MIT's Computer Science and Artificial Intelligence Laboratory (CSAIL) and of the Broad Institute. The strongest association with obesity resides in a gene region known as "FTO," which has been the focus of intense scrutiny since its discovery in 2007. However, previous studies have failed to find a mechanism to explain how genetic differences in the region lead to obesity. "Many studies attempted to link the FTO region with brain circuits that control appetite or propensity to exercise," says first author Dr. Melina Claussnitzer, a visiting professor at CSAIL and Instructor in Medicine at Beth Israel Deaconess Medical Center and Harvard Medical School.

August 20th

Profoundly Different Mechanism of Hummingbird Nectar Consumption Discovered; Tongue Acts As Pump, Not Capillary; 50 Years of Nectar-Hummingbird Co-Evolution Research Must Now Be Reconsidered

In a paper titled “Hummingbird Tongues Are Elastic Micropumps,” which is featured as the cover article of the August 22, 2015 print issue of Proceedings of the Royal Society B, Dr. Alejandro Rico Guevara and Dr. Margaret Rubega from the Department of Ecology and Evolutionary Biology and Dr, Tai-Hsi Fan from the School of Engineering, al at the University of Connecticut, say that fluid is actually drawn into the tongue by the elastic expansion of the tongues grooves after they are squeezed flat by the beak. The article was published online, ahead of print, on August 19, 2015. The new data shows that fifty years of research describing how hummingbirds and floral nectar have co-evolved will have to be reconsidered. What is actually taking place, the researcher report, is that during the off-loading of the nectar inside the bill, hummingbirds compress their tongues upon extrusion. The compressed tongue remains flattened until it contacts the nectar surface, after which the tongue reshapes, filling entirely with nectar. The expansive filling mechanism uses the elastic recovery properties of the groove walls to load nectar on the tongue in an order of magnitude that allows the hummingbirds to extract nectar at higher rates than are predicted by capillarity-based foraging models. Observations and measurements were taken from seven countries throughout the Americas where free-living, never handled hummingbirds were feeding at modified transparent feeders simulating nectar volumes and concentrations of hummingbird-pollenated flowers. The researchers measured 96 foraging bouts of 32 local birds belonging to 18 species from seven out the nine main hummingbird clads. In the hundreds of licks studied, the researchers observed capillarity only once, acting on a single tongue groove.

Sloan-Kettering Reports First “Basket” Study, Categorizing Specific Cancer Mutations and Responses to Targeted Drugs, Exclusive of Cancer Origin Site; Described As “First Deliverable of Precision Medicine”

Researchers from the Memorial Sloan Kettering Cancer Center (MSKCC) in New York City have announced results from the first published “basket” study, a new form of clinical trial design that explores responses to drugs based on the specific mutations in patients' tumors rather than the site where their cancer originated. Published in today’s (August 20, 2015 issue of the New England Journal of Medicine, the early phase II study, led by MSKCC Physician-in-Chief and Chief Medical Officer José Baselga, M.D., Ph.D., looked at the effect of vemurafenib (Zelboraf®) in multiple non-melanoma BRAFV600-mutated cancers in 122 patients from 23 centers around the world. The article is titled “Vemurafenib in Multiple Nonmelanoma Cancers with BRAFV600 Mutations.” “Vemurafenib previously has been proven to treat BRAFV600-mutated melanoma. People with lung, colorectal, and ovarian cancers were among those included in the study, as well as people with rare diseases, such as Erdheim-Chester disease. Until this point, the efficacy of vemurafenib in non-melanoma cancers has remained unexplored despite significant therapeutic potential. "This study is the first deliverable of precision medicine. We have proven that histology-independent, biomarker-selected basket studies are feasible and can serve as a tool for developing molecularly targeted cancer therapy," said Dr. Baselga, the study's senior author. "While we can -- and should -- be cautiously optimistic, this is what the future of precision medicine looks like." Basket studies permit the detection of early signals of activity across multiple tumor types simultaneously, while allowing for the possibility that tumor lineage might influence drug sensitivity.

Synthetic DNA Vaccine, for First Time, Induces Protective Immunity to MERS Coronavirus in Non-Human Primates

A novel synthetic DNA vaccine can, for the first time, induce protective immunity against the Middle East Respiratory Syndrome (MERS) coronavirus in animal species, reported researchers from the Perelman School of Medicine at the University of Pennsylvania. David B. Weiner, Ph.D., a Professor of Pathology and Laboratory Medicine, together with colleagues, published their work in the August 19, 2015 issue of Science Translational Medicine (STM). The article is titled “A Synthetic Consensus Anti–Spike Protein DNA Vaccine Induces Protective Immunity Against Middle East Respiratory Syndrome Coronavirus in Nonhuman Primates.” The experimental, preventive vaccine, given six weeks before exposure to the MERS virus, was found to fully protect rhesus macaques from disease. The vaccine also generated potentially protective antibodies in blood drawn from camels, the purported source of MERS transmission in the Middle East. MERS is caused by an emerging human coronavirus, which is distinct from the SARS coronavirus. Since its identification in 2012, MERS has been linked to over 1,300 infections and close to 400 deaths. It has occurred in the Arabian Peninsula, Europe, and in the U.S. The recent 2015 outbreak in South Korea was of great concern as the infection spread from a single patient to infect more than 181 people, resulting in hospital closings, severe economic impact, and more than 30 deaths. During this outbreak rapid human-to-human transmission was documented, with in-hospital transmission the most common route of infection. "The significant recent increase in MERS cases, coupled with the lack of effective antiviral therapies or vaccines to treat or prevent this infection, have raised significant concern," Dr. Weiner said.

Revolutionary Sepsis-Treatment Device Optimized by Wyss Institute/Harvard Scientists in Effort to Speed Clinical Adoption of Life-Saving Additional Approach to Curing Deadly Sepsis; Engineered FcMBL Protein Is Key

In 2014, a team of sciencitsts from the Wyss Institute for Biologically Inspired Engineering at Harvard University described the development of a new device to treat sepsis that works by mimicking our spleen. It cleanses pathogens and toxins from blood circulating through a dialysis-like circuit. Now, the Wyss Institute team has developed an improved device that synergizes with conventional antibiotic therapies and has been streamlined to better position it for near-term translation to the clinic. The improved design is described in the October 2015 issue (volume 67) of Biomaterials and is available online now. Sepsis is a common, and frequently fatal, medical complication that can occur when a person's body attempts to fight off serious infection. Resulting widespread inflammation can cause organs to shut down, blood pressure to drop, and the heart to weaken. This can lead to septic shock, and more than 30 percent of septic patients in the United States eventually die. In most cases, the pathogen responsible for triggering the septic condition is never pinpointed, so clinicians blindly prescribe an antibiotic course in a blanket attempt to stave off infectious bacteria and halt the body's dangerous inflammatory response. But sepsis can be caused by a wide-ranging variety of pathogens that are not susceptible to antibiotics, including viruses, fungi, and parasites. What's more, even when antibiotics are effective at killing invading bacteria, the dead pathogens fragment and release toxins into the patient's bloodstream.

August 19th

First Genome-Wide Annotation of Long, Primary miRNA Transcripts Suggests Complex Regulatory Mechanisms

MicroRNAs are short, noncoding RNAs that play critical roles in regulating gene expression in normal physiology and disease. Despite having tightly controlled expression levels, little is known about how miRNAs themselves are regulated because their genes are poorly defined. In a study published online on August 19, 2015 in Genome Research, researchers devised a strategy for genome-wide annotation of primary miRNA transcripts, providing extensive new annotations in human and mouse, and shedding light on mechanisms of regulation of microRNA gene expression. The article is titled “Genome-Wide Annotation of MicroRNA Primary Transcript Structures Reveals Novel Regulatory Mechanisms.” Although mature miRNAs are only ~22 nucleotides, their transcripts are up to hundreds of kilobases long. Primary miRNA transcripts, or pri-miRNAs, are quickly processed into mature miRNAs from hairpin structures located in the exons or introns of pri-miRNA transcripts. Because processing occurs very quickly, standard methods such as RT-PCR or RNA sequencing detect full-length pri-miRNAs with poor sensitivity. Many miRNA genes, therefore, lack annotated features such as a promoter or splice sites, hindering progress in understanding their transcriptional and post-transcriptional regulation. To overcome this, researchers from the University of Texas Southwestern Medical Center and Johns Hopkins University stabilized pri-miRNAs by expressing a dominant negative form of DROSHA, the RNase III enzyme responsible for pri-miRNA cleavage, in a variety of human and mouse cell lines. By deeply sequencing nuclear RNAs and applying the computational tool StringTie to assemble transcripts, the researchers were able to annotate 69% of human miRNAs and 75% of mouse miRNAs.

Wild Honey Bees Evolve Rapidly to Overcome New Disease; Dopamine Receptor Gene (Aversion Learning & Grooming) and Numerous Developmental Genes Altered; Bees Are Also Smaller and Wings Are Different

An international research team has some good news for the struggling honeybee, and the millions of people who depend on them to pollinate crops and other plants. These valuable pollinators have faced widespread colony losses over the past decade, largely due to the spread of a predatory mite called Varroa destructor. But the bees might not be in as dire a state as it seems, according to research recently published in Nature Communications. Researchers found a population of wild bees from around Ithaca, New York, which is as strong today as ever, despite the mites invading the region in the mid-1990s. “They took a hit, but they recovered,” said Dr. Alexander Mikheyev, a professor at the Okinawa Institute of Science and Technology Graduate University (OIST) in Japan and lead paper author. The research was published online on August 9, 2015 in an open-access article in Nature Communications. The article is titled “Museum Samples Reveal Rapid Evolution by Wild Honey Bees Exposed to a Novel Parasite.” “The population appears to have developed genetic resistance.” Dr. Mikheyev and his collaborators at OIST and Cornell University studied the population genetics of the wild colony by comparing the DNA of specimens collected in 1977 with bees collected from the same forest in 2010. To conduct the study, they developed a new DNA analysis tool that works especially well for degraded DNA stored in museum samples. Such a study is extremely rare, especially with bees. Few people collect them, and even fewer collect in a way that is good enough for a population level study. Luckily, Cornell Professor Tom Seeley worked in this area during his Ph.D., and deposited his samples in the Cornell University Insect Collection.

August 18th

Early, Out-of-Sequence Exposure to Inflammatory Cytokines Paralyzes CD4 T-Cells; Surprising Finding May Engender More Effective Cancer Immunotherapies, Better Drugs for Autoimmune Conditions, New Ways to Speed Sepsis Recovery

In a discovery that is likely to rewrite immunology text books, researchers at the University of California (UC) Davis have found that early exposure to inflammatory cytokines, such as interleukin 2, can "paralyze" CD4 T cells, immune components that help orchestrate the body's response to pathogens and other invaders. This mechanism may act as a firewall, shutting down the immune response before it gets out of hand. However, from a clinical standpoint, this discovery could lead to more effective cancer immunotherapies, better drugs for autoimmune conditions, and new ways to expedite recovery from sepsis. The research was published in the August 18, 2015 issue of the journal Immunity. The article is titled “Out-of-Sequence Signal 3 Paralyzes Primary CD4+ T-Cell-Dependent Immunity.” "There's a three-signal process to activate T cells, of which each component is essential for proper activation," said first author Dr. Gail Sckisel, a post-doctoral fellow. "But no one had really looked at what happens if they are delivered out of sequence. If the third signal - cytokines - is given prematurely, it basically paralyzes CD4 T cells." To be activated, T cells must first recognize an antigen, receive appropriate co-stimulatory signals, and then encounter inflammatory cytokines to expand the immune response. Until now, no one realized that sending the third signal early - as is done with some immunotherapies - could actually hamper overall immunity. "These stimulatory immunotherapies are designed to activate the immune system," said Dr. Sckisel, "but considering how T cells respond, that approach could damage a patient's ability to fight off pathogens.

Combination of Two Serum Biomarkers (Diacetyl Spermine & Pro-SFTPB) Can Identify 80% of Early-Stage Lung Cancer (NSCLC)

Despite decades of warnings about smoking, lung cancer is still the second-most common cancer and the leading cause of death from cancer in the U.S. Patients are often diagnosed only when their disease is already at an advanced stage and difficult to treat. Researchers at the West Coast Metabolomics Center at the University of California (UC) Davis are trying to change that, by identifying biomarkers that could be the basis of early tests for lung cancer. "Early diagnosis is the key to fighting lung cancer," said Dr. Oliver Fiehn, Director of the Metabolomics Center and a Professor of Molecular and Cellular Biology at UC Davis. Lung cancer can be diagnosed early with regular low-dose CT (computed tomography) scans of people at risk. But these tests are very expensive, and also involve exposing patients to X-ray radiation. Instead, Dr. Fiehn, project scientist Dr. William Wikoff, and colleagues set out to look for biomarkers of developing lung cancer in blood from patients. Dr. Fiehn's lab specializes in "metabolomics," an approach that involves analyzing all the biochemical products of metabolism in cells and tissues at the same time. Like other "-omics" approaches, it's made possible by new technology and computing power, and it's opening up new ways to understand living processes. To find early biomarkers for lung cancer, the team needed to look at blood samples collected from people who developed the disease, months or years before they were diagnosed. Fortunately, the researchers were able to access samples stored from the CARET clinical trial. The CARET study, which ran from 1985 until it was halted in 1996, attempted to test whether doses of antioxidant vitamins could prevent cancer in heavy smokers and other people at high risk.