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September 5th, 2017

NIH Awards $2.2 Million to Fund Collaborative Research on the Role of Exosomes in Metastasis

Cancer metastasis - the spread of disease from the original site to a distant organ - remains a major challenge in treating cancer and a main cause of morbidity and mortality. A widely accepted explanation for this process - called "the seed and soil" hypothesis - recognizes the need for the cancer cell or "seed" to travel to a hospitable environment - the "soil.” To understand metastasis, many investigators have focused on the cancer cell- or seed. Yves DeClerck, MD, a pediatrician-scientist at Children's Hospital Los Angeles (CHLA) and co-leader of the Tumor Microenvironment Program at the USC-Norris Comprehensive Cancer Center, has studied this topic for his entire career from a slightly different perspective, concentrating on the "soil" or tumor microenvironment. Because of his recognition as a leader in this area, Dr. DeClerck was recently awarded $2.2 million from the National Cancer Institute, to investigate the microenvironment from a relatively new context. The study will focus on a newly identified type of messenger -- extracellular vesicles released by cancer cells into their environment. These vesicles, called exosomes, are small sacs shed by tumor cells that can contain protein, DNA, RNA and/or lipids. Exosomes are taken in by other cells and can modify the behavior of the receiving cell. According to Dr. DeClerck, healthy cells are typically inhospitable to cancer cells. What causes them to change from foe to friend? "There are different ways that cancer cells communicate with normal cells - causing the change - and one of these ways is through exosomes," said Dr. DeClerck, who is a Professor of Pediatrics and Biochemistry and Molecular Medicine at the Keck School of Medicine of USC. He also holds the Richard Call Family Endowed Chair in Pediatric Research Innovation at CHLA. Dr.

Ducks Reach 22,000 Feet in Migration Flight Over Himalayas

A high-flying duck species reaches altitudes of up to 6,800 meters (22,000 feet) to cross the Himalayas, new research shows. Ruddy shelducks are known to breed north of the Himalayan mountain range, but spend their winters at sea level south of the Tibetan Plateau. They need to fly over the Himalayas in the spring to get back to their breeding grounds, a huge challenge that sees them cross terrain higher than 4,000 meters, where oxygen levels are halved. Scientists from the University of Exeter used satellite tracking to discover that the ducks fly through valleys in the mountain range - avoiding massive peaks like Mount Everest. "This is the first evidence of extreme high-altitude flight in a duck," said lead researcher Dr. Nicole Parr, of the Centre for Ecology and Conservation on the University of Exeter's Penryn Campus in Cornwall, UK. "This species has probably evolved a range of adaptations to be able to cope with flying so high, where oxygen levels are half those at sea level. We don't yet know the nature of these adaptations. "Our research also shows that the ruddy shelduck has a faster climb rate than the bar-headed goose, the only waterfowl known to fly even higher." Dr. Lucy Hawkes, the supervisor of the work at the University of Exeter, had previously tracked bar-headed geese to 7,290 meters altitude near Everest in 2014. They were long thought to be the world's highest-flying bird based on flapping flight (some birds soar higher on thermals), but the new research suggests that the bar-headed geese may not be the only species flying at these high altitudes. However, more research is needed to find out whether ruddy shelducks reach similar heights to bar-headed geese. The scientists used satellite data collected from 15 ruddy shelducks from two populations spending their winter south of the Tibetan Plateau.

Discovery of Sugar “Warehouse” in Dendritic Cells Could Lead to Improvement of Vaccines and New Approaches to Treatment of Autoimmune Diseases

A surprising discovery that immune cells possess an internal warehouse of glycogen used to activate immune responses could help to increase immune activity in vaccines or suppress immune reactions in autoimmune disease or hyper-inflammatory conditions. Results of the new study were published online in Cell Metabolism and show that the immune responses of dendritic cells are fueled by an intracellular storage of sugar as opposed to external sugar, where prior research has focused. The novel finding adds an important missing piece to the puzzle of how early immune responses are powered from a metabolic standpoint, and provides immunologists with a new area of focus in their ongoing effort to regulate immune activity. "By either enhancing or depleting this sugar warehouse within the cell, the hope would be that we could either influence or dampen immune reactions," says study author Dr. Eyal Amiel, Assistant Professor at the University of Vermont in the Department of Medical Laboratory and Radiation Science in the College of Nursing and Health Sciences. "What we're really in the business of is finding new switches to toggle to that effect and this finding provides us with a new regulatory target that regulates immune activity." The finding gives immunologists a key piece of new information to better understand how the early part of the bioenergetics of a dendritic cell immune response is generated. This is especially significant given the importance of timing when it comes to immune response and the speed at which the switch of inflammation can be either increased or suppressed. "What's surprising is that the intracellular sugar pool is the more important one early on," says Dr. Amiel, who co-authored the paper with Phyu Thwe, a PhD student in Dr. Amiel's lab, and three external researchers.

Height May Be Associated with Risk of Venous Thromboembolism

The taller you are, the more likely you may be to develop blood clots in the veins, according to new research published online on September 5, 2017 in the American Heart Association journal Circulation: Cardiovascular Genetics. The article is titled “Body Height and Incident Risk of Venous Thromboembolism.” In a study of more than two million Swedish siblings, researchers found that the risk of venous thromboembolism - a type of blood clot that starts in a vein - was associated with height, with the lowest risk being in shorter participants. The researchers also found that: for men shorter than 5'3", the risk for venous thromboembolism dropped 65 percent when compared to the men 6'2" or taller; and for women, shorter than 5'1" who were pregnant for the first time, the risk for venous thromboembolism dropped 69 percent, compared to women who were 6 feet or taller. "Height is not something we can do anything about," said lead researcher Bengt Zöller, MD, PhD, Associate Professor at Lund University and Malmö University Hospital in Malmö, Sweden. "However, the height in the population has increased, and continues increasing, which could be contributing to the fact that the incidence of thrombosis has increased." The CDC estimates that venous thromboembolism affects up to 600,000 Americans every year, making it the third leading cause of heart attack and stroke. The most common triggers are surgery, cancer, immobilization and hospitalization. In women, pregnancy and use of hormones like oral contraceptive or estrogen for menopause symptoms are also important triggers. Dr. Zöller said gravity may influence the association between height and venous thromboembolism risk. "It could just be that because taller individuals have longer leg veins there is more surface area where problems can occur," Dr. Zöller said.

Scientists Solve How Thyroid Hormone Prods Red Blood Cell Production

For more than a century, physicians have anecdotally noted that patients with an underactive thyroid--often caused by iodine deficiency--tended to also have anemia. But the link between thyroid hormone and red blood cell production has remained elusive--that is, until two postdoctoral researchers in the lab of Whitehead Institute Founding Member Dr. Harvey Lodish, Dr. Xiaofei Gao and Dr. Hsiang-Ying "Sherry" Lee, decided to investigate. The results were published online on September 1, 2017 in PNAS. The article is titled “"Thyroid Hormone Receptor Beta and NCOA4 Regulate Terminal Erythrocyte Differentiation." During the development of red blood cells, specialized bone marrow stem cells mature through several stages until they finally turn on the genes for hemoglobin and other red blood cell proteins and become mature red blood cells. In order to simulate this process in the lab, researchers have previously found that culturing blood cell progenitors in serum helps them turn on all of the proper proteins to take the final step and become a red blood cell. Drs. Gao and Lee, now Principal Investigators at China’s Westlake Institute for Advanced Study and Peking University, respectively, wondered if something in the serum was key to flipping the switch to becoming a mature red blood cell. To narrow down which of the molecules in the serum might be the trigger, Drs. Gao and Lee ran the serum through a standard laboratory filter that many of us use every day for our tap water: charcoal. Long known for removing odors from the air and flavors from water, charcoal attracts and retains hydrophobic molecules. Drs. Gao and Lee noticed that once filtered, the serum no longer supported red blood cell production; they deduced that one of the hydrophobic molecules trapped by charcoal is the key to the final step of red blood cell maturation.

September 4th

Researcher Awarded $1.9 Million to Study Exosome-Based Approach to Battling Neuroblastoma

Muller Fabbri (photo), MD, PhD, of the Children’s Center for Cancer and Blood Diseases at Children’s Hospital Los Angeles (CHLA), has been awarded $1.9 million by the National Cancer Institute of the NIH to further his research on neuroblastoma – the third most common type of childhood cancer. The research will focus on a completely new strategy targeting immune cells that contribute to disease progression with a goal toward the development of more potent immunotherapies to improve the outcomes for children with this disease. Neuroblastoma (NB) is a type of solid tumor that starts in immature nerve cells of the sympathetic nervous system. While NB is one of the most common types of pediatric cancer, it is still very rare. Out of the 13,000 children who are diagnosed with cancer each year, only about 650-700 are diagnosed with NB. The disease primarily occurs in children younger than age 10 and is most common in infants and very young children. “My research project is based on the fact that sometimes cancer cells are able to hijack the immune system and use it to their advantage,” said Dr. Fabbri. “The cancer cells release a signal that can be captured by the immune cell and consequently the immune cells stop fighting the cancer and actually help the cancer grow.” As principal investigator of the project, Dr. Fabbri will study how microRNAs contained in the exosomes of immune cells known as tumor-associated macrophages (TAMs) contribute to disease progression and result in the development of NB resistance to chemotherapy. His goal is to identify new molecular targets to prevent and overcome the development of cancer resistance to treatment, which is the main obstacle in the treatment of NB and other types of cancers.

Study Suggests Simple Way to Predict Preterm Births: Test of Cervical Mucus May Reveal Pregnant Women’s Risk of Going into Labor Too Early

Up to 18 percent of babies born worldwide arrive before they are full-term, defined as 37 weeks of gestation. About 1 million of those babies do not survive, and those who do can face developmental problems such as impaired vision or hearing, defects in the heart or lungs, or cognitive impairments. Currently there is no reliable way to predict whether a woman with a normal pregnancy will go into labor before 37 weeks. However, a study from MIT offers a new approach to evaluating this risk, by analyzing the properties of cervical mucus. The researchers found that cervical mucus from women who delivered their babies before 37 weeks was very different from that of women who delivered later. This type of analysis could offer an easy way to calculate the risk of early labor, potentially allowing doctors to try to intervene earlier to prevent preterm births. “Our prediction is that we might be able to identify risk for preterm birth ahead of time, before labor sets in,” says Katharina Ribbeck (photo), PhD, an Associate Professor of Biological Engineering at MIT and the senior author of the study. “Diagnostic tools for this are missing.” Dr. Ribbeck worked on the study with Dr. Michael House, an Associate Professor at Tufts University School of Medicine. MIT postdoc Dr. Kathryn Smith-Dupont is the first author of the paper, which was published in the September 4, 2017 issue of Scientific Reports. The open-access article is titled “Probing the Potential of Mucus Permeability to Signify Preterm Birth Risk.” Dr. Ribbeck’s lab at MIT investigates the distinctive chemical and mechanical properties of mucus, and how those properties help mucus to perform many critical roles as part of the body’s first line of defense against infection. Several years ago, Dr.

Plant MicroRNAs in Larval Food Regulate Caste Development in Honey Bees

Bee larvae develop into workers, in part, because their diet of pollen and honey, called beebread, is rich in plant regulatory molecules called microRNAs, which delay development and keep their ovaries inactive. Xi Chen of Nanjing University in China, and colleagues, report these results online on August 31, 2017 in PLOS Genetics. The open-access article is titled “Plant microRNAs in Larval Food Regulate Honeybee Caste Development.” Researchers have long known that diet plays an important role in the complex process that determines whether a honeybee larva will become a worker or a queen. While the workers primarily consume beebread, the queens feast on royal jelly secreted by the glands of nurse bees. Beebread contains much higher levels of plant microRNAs than royal jelly, so researchers decided to investigate if these molecules, which regulate gene expression in plants, could also impact honeybee caste development. They found that honeybees raised in the lab on simulated beebread supplemented with plant microRNAs developed more slowly and had a smaller body and smaller ovaries than larvae raised without the supplements. The plant microRNAs also had a similar effect on fruit fly larvae, even though fruit flies are not social insects. Further experiments showed that one of the most common plant microRNAs in beebread targets the TOR gene in honeybees, which helps determine caste. The study shows that there is more to the story of honeybee caste formation than the traditional focus on royal jelly and identifies a previously unknown function of plant microRNAs in fine-tuning larval development. The work is a powerful example of the effects of cross-kingdom microRNAs and how these interactions can affect a species' development and evolution.

Liquid Biopsy Detects Tumor-Specific DNA and Protein Markers for Early-Stage Pancreatic Cancer, Hopkins Scientists Report

Johns Hopkins scientists and colleagues say they have developed a blood test that spots tumor-specific DNA and protein biomarkers for early-stage pancreatic cancer. The combined "liquid biopsy" identified the markers in the blood of 221 patients with the early-stage disease. The results, published online the week of Septtember 4, 2017 in PNAS, show that detection of markers from both DNA and protein products of DNA was twice as accurate at identifying the disease as detection of DNA alone. Such liquid biopsies aim to fish out DNA molecules specific for cancer amid a wide sea of normal DNA circulating in the blood. Tumors tend to shed their mutated DNA into the bloodstream, making it possible for scientists to use genomic sequencing tools to sift through the blood and find such cancer-linked DNA. Most early-stage pancreatic cancers are found incidentally during an imaging scan and generally cause no symptoms. But the disease is most often found late, when it's far advanced and resection, or surgery, is not the first treatment option, says Jin He, MD, Assistant Professor of Surgery at the Johns Hopkins University School of Medicine. "In the past 30 years, we haven't made much progress in identifying people with resectable cancers," says Dr. He. "If this test's performance is validated in larger studies, it could be used to identify patients with early, asymptomatic pancreatic cancer." While their test is not ready to be used outside of a research setting, the scientists say, mutated DNA of the type that is shed from tumors and found in blood is "exquisitely specific" for cancer.

Adipose Tissue May Affect Cancer Development in Multiple Ways, Review Concludes

In a comprehensive review, scientists report that adipose tissue, or fat, may influence the development of cancer in diverse ways, depending on the type of fat and the location in the body. The review was published in the September 2017 issue of Cancer Prevention Research, a journal of the American Association for Cancer Research (AACR). The article is titled “Signals from the Adipose Microenvironment and the Obesity-Cancer Link—A Systematic Review.” The senior author of the review is Cornelia M. Ulrich, PhD, Senior Director of Population Sciences at the Huntsman Cancer Institute at the University of Utah in Salt Lake City. "Obesity is increasing dramatically worldwide, and is now also recognized as one of the major risk factors for cancer, with 16 different types of cancer linked to obesity," Dr. Ulrich said. "We urgently need to identify the specific mechanisms that link obesity to cancer." Dr. Ulrich explained that previous research has shown several ways that fat contributes to carcinogenesis. For example, obesity increases the risk of inflammation, which has long been associated with cancer. Also, obesity is believed to affect cancer cell metabolism and immune clearance, all of which can contribute to the growth and spread of tumors, she said. The relationship between fat and carcinogenesis also depends upon "crosstalk," or the ways cells react when the same signal is shared by more than one signaling pathway in two different cell types, Dr. Ulrich explained. Identifying ways to interrupt the crosstalk could help researchers identify new cancer prevention strategies. In this study, Dr.