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Archive - Jan 2017

January 17th

Caloric Restriction Improves Health and Survival in Rhesus Monkeys

Settling a persistent scientific controversy, a long-awaited report shows that restricting calories does indeed help rhesus monkeys live longer, healthier lives. A remarkable collaboration between two competing research teams -- one from the University of Wisconsin (UW)-Madison and one from the National Institute on Aging (NIA) -- is the first time the groups worked together to resolve one of the most controversial stories in aging research. The findings by the collaboration -- including Senior Scientist Ricki Colman of the Wisconsin National Primate Research Center and UW-Madison Associate Professor of Medicine Rozalyn Anderson; and NIA Staff Scientist and Nonhuman Primate Core Facility Head Julie Mattison and Senior Investigator and Chief of the Translational Gerontology Branch Rafael de Cabo -- were published online on January 17, 2017) in the journal Nature Communications. The open-access article is titled “Caloric restriction improves health and survival of rhesus monkeys.” In 2009, the UW-Madison study team reported significant benefits in survival and reductions in cancer, cardiovascular disease, and insulin resistance for monkeys that ate less than their peers. In 2012, however, the NIA study team reported no significant improvement in survival, but did find a trend toward improved health. "These conflicting outcomes had cast a shadow of doubt on the translatability of the caloric-restriction paradigm as a means to understand aging and what creates age-related disease vulnerability," says Dr. Anderson, one of the report's corresponding authors. Working together, the competing laboratories analyzed data gathered over many years and including data from almost 200 monkeys from both studies. Now, scientists think they know why the studies showed different results.

Common Heart Drug Repurposed to Treat Rare Soft Tissue Cancer in Europe

A drug that's commonly used to treat high blood pressure is being repurposed for a rare tissue cancer in Europe. The medication, named propranolol, was recently granted Orphan Drug Designation by the European Commission (EC). The designation signifies that the EC supports the use of a drug to treat patients because of its significant benefit to those living with a rare disease -- in this case, soft tissue sarcoma. The cancer affects approximately one quarter of a million people living in Europe, and is generally considered difficult to treat. "People with soft tissue sarcomas have a very poor survival rate," says Brad Bryan, Ph.D., a biomedical scientist at Texas Tech University Health Sciences Center El Paso (TTUHSC El Paso). "Four out of 10 patients with the cancer will die and are in urgent need of new treatment options." Propranolol's ability to treat angiosarcoma, a very lethal form of soft tissue sarcoma, was originally discovered by Dr. Bryan's TTUHSC El Paso lab. In his study, Dr. Bryan used cell lines and animal models to show that propranolol could fight angiosarcoma and remarkably reduce the growth of tumors; the results were published in a 2013 PLOS One paper. Later, in a 2015 JAMA Dermatology article, Dr. Bryan described treating a patient with angiosarcoma -- who only had months left to live -- and bringing the tumor down to undetectable levels. What's more, the treatment had little to no side effects. Several scientists across the world have reported similar results since then, testing propranolol on their own patients with the rare cancer. A 69-year-old woman with metastatic angiosarcoma made a full recovery after being treated with propranolol by Shripad Banavali, M.D., an oncologist at Tata Memorial Center in Mumbai, India and Eddy Pasquier, Ph.D., a researcher at the University of Aix-Marseille.

Malaria Drug Chloroquinone Inhibits Autophagy and Enhances Vemurafenib Treatment of BRAF+ Glioblastoma

After her brain cancer became resistant to chemotherapy and then to targeted treatments, 26-year-old Lisa Rosendahl's doctors gave her only a few months to live. Now, a paper published online on January 17,2016 in the journal eLife describes a new drug combination that has stabilized Rosendahl's disease and increased both the quantity and quality of her life: adding the anti-malaria drug chloroquine to her treatment stopped an essential process that Rosendahl's cancer cells had been using to resist therapy, re-sensitizing her cancer to the targeted treatment that had previously stopped working. Along with Rosendahl, two other brain cancer patients were treated with the combination (vemurafenib and chloroquinone) and both showed similar, dramatic improvement. The eLife article is titled “Autophagy Inhibition Overcomes Multiple Mechanisms of Resistance to BRAF Inhibition in Brain Tumors.” "When I was 21 they found a large mass in my brain and I had it resected right away. They tested it for cancer and it came back positive," Lisa says. "Lisa is a young adult with a very strong will to live. But it was a high-risk, aggressive glioblastoma and by the time we started this work, she had already tried everything. For that population, survival rates are dismal. Miraculously, she had a response to this combination. Four weeks later, she could stand and had improved use of her arms, legs and hands," says paper first author Jean Mulcahy-Levy (photo), M.D., investigator at the University of Colorado Cancer Center and pediatric oncologist at Children's Hospital Colorado. The science behind the innovative, off-label use of this malaria drug, chloroquine, was in large part built in the lab of Andrew Thorburn, Ph.D., Deputy Director of the CU Cancer Center, where Mulcahy-Levy worked as a postdoctoral fellow, starting in 2009. Dr.

TGen Identifies Compound with Potential Utility in Treatment of Glioblastoma

A study led by scientists at the Translational Genomics Research Institute (TGen) in Arizona has identified "a potent inhibitory compound" in the elusive hunt for an improved treatment against glioblastoma, the most common and deadly type of adult brain cancer. Aurintricarboxylic acid (ATA) is a chemical compound that in laboratory tests was shown to block the chemical cascade that otherwise allows glioblastoma cells to invade normal brain tissue and resist both chemo and radiation therapy, according to a TGen-led report published online on January 17, 2017 in the scientific journal Oncotarget. The article is titled “Identification of Aurintricarboxylic Acid As a Selective Inhibitor of the TWEAK-Fn14 Signaling Pathway in Glioblastoma Cells.” "The findings of this study could represent a breakthrough in our efforts to find an effective long-term treatment against glioblastoma multiforme (GBM)," said Dr. Harshil Dhruv, an Assistant Professor in TGen's Cancer and Cell Biology Division, and a lead author of the study. Initial treatment of glioblastoma consists of surgical removal of the tumor, radiation, and chemotherapy using the drug temozolomide (TMZ). However, the proclivity of glioblastoma to invade adjacent brain tissue prevents the surgical removal of all tumor cells. Plus, invasive glioblastoma cells show resistance to TMZ, resulting in the cancer's eventual return and the patient's death, often within a year. Despite recent advances, the median survival of glioblastoma patients is only 15 months, and survival statistics have not significantly improved over the past three decades. More than 16,000 Americans die each year of brain and other nervous system cancers. "We simply must find a better way of treating patients with glioblastoma," said Dr. Michael Berens, TGen Deputy Director and one of the study co-authors.

Researchers Zero-In on Role of Cholesterol in Cells

Scientists have long puzzled over cholesterol. It's biologically necessary; it's observably harmful - and nobody knows what it's doing where it's most abundant in cells: in the cell membrane. Now, for the first time, chemists at the University of Illinois at Chicago (UIC) have used a path-breaking optical imaging technique to pinpoint cholesterol's location and movement within the membrane. They made the surprising finding that, in addition to its many other biological roles, cholesterol is a signaling molecule that transmits messages across the cell membrane. The finding was reported online on December 26, 2016 in Nature Chemical Biology. The article is titled “Orthogonal Lipid Sensors Identify Transbilayer Asymmetry of Plasma Membrane Cholesterol.” "Cholesterol is a lipid that gets bad press because of its association with cardiovascular disease," says Wonhwa Cho, Ph.D., Professor of Chemistry at UIC, who led the research. "It's been very well studied, but not much is known about its cellular function. What is its role? Is it a bad lipid? Absolutely not - for example, the brain is about half lipid, and cholesterol is the richest lipid in the brain," he said. A cholesterol deficiency can cause several diseases, and the substance is the starting material for making the body's dozen or so steroid hormones. Dr. Cho's earlier studies showed cholesterol interacts with many regulatory molecules - mostly cellular proteins - but it was never thought to be one. "We knew it could play an important role in cell regulation - for example, in proliferation or development," he said. "We know that high-fat diets, which boost cholesterol levels, have been linked to an elevated incidence of cancer. How, is not fully understood," Dr. Cho said.

January 16th

Potentially Reversible Changes in Gene Control “Prime'” Pancreatic Cancer Cells to Spread

A multicenter team of researchers reports that a full genomic analysis of tumor samples from a small number of people who died of pancreatic cancer suggests that chemical changes to DNA that do not affect the DNA sequence itself yet control how it operates confer survival advantages on subsets of pancreatic cancer cells. Those advantages, the researchers say, let such cancer cells thrive in organs like the liver and lungs, which receive a sugar-rich blood supply. In a summary of the study, published online on January 16, 2017 in the journal Nature Genetics, the research teams also report evidence that an experimental drug -- not approved for human use -- can reverse these "epigenetic" changes to block tumor formation in lab-grown pancreatic cancer cells. The article is titled “Epigenomic Reprogramming During Pancreatic Cancer Progression Links Anabolic Glucose Metabolism to Distant Metastasis.” These findings may lead to more effective treatment strategies against metastatic pancreatic cancer, which is universally lethal. "What we found astonished us," says study leader Andrew Feinberg, M.D., Bloomberg Distinguished Professor of Epigenetics at The Johns Hopkins University and a Johns Hopkins Kimmel Cancer Center member. "Changes in genes' regulation -- not in the DNA sequence of genes themselves -- were the driving force behind successful metastases in our experiments, and, as far as we know, this is the first genomewide experimental evidence for this phenomenon." Metastasis, or cancer spread by the formation of tumors at new sites, is generally what makes cancers deadly because surgery and other treatments are unlikely to find and destroy every cancer cell. That is particularly true, Dr. Feinberg says, for pancreatic cancer, which usually goes undetected until after it has spread.

January 14th

Harvard Scientists Create Novel Multiregional Brain-on-a-Chip

Harvard University researchers have developed a multiregional brain-on-a-chip that models the connectivity between three distinct regions of the brain. The in vitro model was used to extensively characterize the differences between neurons from different regions of the brain and to mimic the system’s connectivity. The Harvard work was reported online on December 28, 2017 in The Journal of Neurophysiology. The article is titled “Neurons Derived from Different Brain Regions Are Inherently Different in Vitro: A Novel Multiregional Brain-On-A-Chip. “The brain is so much more than individual neurons,” said Ben Maoz, Ph.D., co-first author of the paper and postdoctoral fellow in the Disease Biophysics Group in the Harvard John A. Paulson School of Engineering and Applied Sciences (SEAS). “It’s about the different types of cells and the connectivity between different regions of the brain. When modeling the brain, you need to be able to recapitulate that connectivity because there are many different diseases that attack those connections. “Roughly twenty-six percent of the U.S. healthcare budget is spent on neurological and psychiatric disorders,” said Kit Parker (photo), Ph.D., the Tarr Family Professor of Bioengineering and Applied Physics Building at SEAS and Core Faculty Member of the Wyss Institute for Biologically Inspired Engineering at Harvard University. “Tools to support the development of therapeutics to alleviate the suffering of these patients is not only the human thing to do, it is the best means of reducing this cost." The Harvard work was reported online on December 28, 2017 in The Journal of Neurophysiology. The article is titled “Neurons Derived from Different Brain Regions Are Inherently Different in Vitro: A Novel Multiregional Brain-On-A-Chip.

Researchers Create First Model of Genetically Induced Obesity in Fruit Flies

Why do people become obese? Poor dietary choices and overeating seem like clear causes, but what is at the root of these behaviors? Significantly overweight people may be genetically predisposed to be affected disproportionately when faced with the ready availability of calorie-laden treats. It appears, in others words, that some people’s genes place them at particular risk of gaining more weight than others in the modern food landscape. Scientists at Cold Spring Harbor Laboratory (CSHL) report in the January 10, 2017 issue of Cell Metabolism that they have created the first model of genetically induced obesity in fruit flies. The model can be used to study ways to dodge adverse health effects triggered by the perfect storm of genetic predisposition to obesity and calorie-rich, nutrient-poor diets. The Cell Metabolism article is titled “A Leptin Analog Locally Produced in the Brain Acts Via a Conserved Neural Circuit to Modulate Obesity-Linked Behaviors in Drosophila” Lead investigator Jen Beshel, Ph.D., who conducted the experiments while performing postdoctoral research in the laboratories of Yi Zhong, Ph.D. and Josh Dubnau, Ph.D., explains that a hormone in the fly, called unpaired 1, performs the same function as the hormone leptin in people: After its release from cells, it docks with receptors in the brain to tell the body to stop eating. Leptin is the famous dispatcher of what scientists call the “satiety” signal—the one that tells you you’re full. The idea of therapeutically administering leptin to obese people to overcome a genetically induced failure of leptin signaling emerged from research in mice first conducted at Rockefeller University in the 1990s. Dr. Beshel’s research breaks new ground.

Salmonella-Based Treatment Improves Survival Rate in 20% of Glioblastomas in Animal Model

Biomedical engineers at Duke University have recruited an unlikely ally in the fight against the deadliest form of brain cancer -- a strain of salmonella that usually causes food poisoning. Clinicians sorely need new treatment approaches for glioblastoma, the most aggressive form of brain cancer. The blood-brain barrier -- a protective sheath separating brain tissue from its blood vessels -- makes it difficult to attack the disease with drugs. It's also difficult to completely remove through surgery, as even tiny remnants inevitably spawn new tumors. Even with the best care currently available, median survival time is a dire 15 months, and only 10 percent of patients survive five years once diagnosed. The Duke team decided to pursue an aggressive treatment option to match its opponent, turning to the bacterium Salmonella typhimurium. With a few genetic tweaks, the engineers turned the bacterium into a cancer-seeking missile that produces self-destruct orders deep within tumors. Tests in rat models with extreme cases of the disease showed a remarkable 20 percent survival rate over 100 days -- roughly equivalent to 10 human years -- with the tumors going into complete remission. The results were presented online on December 15, 2016, in the journal Molecular Therapy - Oncolytics. The article is titled “Bacterial Carriers for Glioblastoma Therapy.” "Because glioblastoma is so aggressive and difficult to treat, any change in the median survival rate is a big deal," said Jonathan Lyon, a Ph.D. student working with Ravi Bellamkonda, Ph.D., Vinik Dean of Duke's Pratt School of Engineering, whose laboratory is currently transitioning to Duke from Georgia Tech, where much of the work was completed.

January 13th

Arabica Coffee Genome Sequenced

The first public genome sequence for Coffea arabica, the species responsible for more than 70 percent of global coffee production, was released today by researchers at the University of California (UC) Davis. Funding for the sequencing was provided by Suntory group, an international food and beverage company based in Tokyo. Now available for immediate use by scientists and plant breeders around the world, the new genome sequence has been posted to Phytozome.net, the public database for comparative plant genomics coordinated by the U.S. Department of Energy's Joint Genome Institute (JGI). Details of the sequence will be presented Sunday, January 15, 2017 at the Plant and Animal Genome Conference in San Diego. Sequencing of the C. arabica genome is particularly meaningful for California, where coffee plants are being grown commercially for the first time in the continental United States and a specialty-coffee industry is emerging. "This new genome sequence for Coffea arabica contains information crucial for developing high-quality, disease-resistant coffee varieties that can adapt to the climate changes that are expected to threaten global coffee production in the next 30 years," said Juan Medrano, Ph.D., a geneticist in the UC Davis College of Agricultural and Environmental Sciences and co-researcher on the sequencing effort. "We hope that the C. arabica sequence will eventually benefit everyone involved with coffee -- from coffee farmers, whose livelihoods are threatened by devastating diseases like coffee leaf rust, to coffee processors and consumers around the world," he said. The sequencing was conducted through a collaboration among Dr. Medrano, plant scientists Dr. Allen Van Deynze and Dr. Dario Cantu, and postdoctoral research scholar Dr. Amanda Hulse-Kemp, all from UC Davis.