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September 5th, 2017

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.

Alterations in Blood-Based miRNA Detected in Veterans Affected with Combat-Related PTSD

Individuals affected with PTSD (post-traumatic stress disorder) demonstrate changes in microRNA (miRNA) molecules associated with gene regulation. A controlled study, involving military personnel on deployment to a combat zone in Afghanistan, provided evidence for the role of blood-based miRNAs as candidate biomarkers for symptoms of PTSD. This may offer an approach towards screening for symptoms of PTSD, and holds promise for understanding other trauma-related psychiatric disorders. Limitations of the study are that it was a small pilot study, and the findings need to be validated, extended, and confirmed. First results were to be presented at the 30th Annual ECNP Conference in Paris (September 2-5). ECNP is the European College of Neuropsychopharmacology. PTSD is a psychiatric disorder that can manifest following exposure to a traumatic event, such as combat, assault, or natural disaster. Among individuals exposed to traumatic events, only a minority of individuals will develop PTSD, while others will show resiliency. Little is known of the mechanisms behind these different responses. The last few years have seen much attention given to whether the modification and expression of genes - epigenetic modifications - might be involved. But there are several practical and ethical challenges in designing a research study on humans undergoing such experiences, meaning that designing relevant study approaches is difficult. The research group from the Netherlands, worked with just over 1,000 Dutch soldiers and the Dutch Ministry of Defense to study changes in biology in relation to changes in presentations of symptoms of PTSD in soldiers who were deployed to combat zone in Afghanistan. In a longitudinal study, the researchers collected blood samples before deployment, as well as 6 months after deployment.

CNPY2 Is Key Initiator of a Pathway of Unfolded Protein Response (UPR); May Be Potential Therapeutic Target in UPR-Related Diseases Such As Metabolic Disorders, Inflammation, and Cancer

The cell's response to unfolded or misfolded proteins could be a cause, rather than a consequence, of metabolic disorders, report researchers at the Medical University of South Carolina (MUSC) in an article published online on September 4, 2017 in Nature Structural & Molecular Biology. The researchers identified a little-known molecule as the trigger for this response. The article is titled “CNPY2 Is a Key Initiator of the PERK–CHOP Pathway of the Unfolded Protein Response.” There are links between protein-folding problems at the cellular level and a range of metabolic disorders, though it is unclear if those problems are causes or manifestations of such disorders. This study provides evidence that problems with protein folding contribute to certain metabolic disorders, according to Zihai Li, MD, PhD, Chair of the Department of Microbiology and Immunology at the MUSC Hollings Cancer Center and principal investigator on the project. Feng Hong, MD, PhD, in the Department of Microbiology and Immunology, is lead author on the paper. "The unfolded protein response in the cell plays important roles in aging and in many diseases, such as cancer, diabetes, and neurodegenerative disease," says Dr. Li. "Our study has uncovered a novel mechanism that triggers this response." When improperly folded molecules are encountered in cells, the unfolded protein response (UPR) is activated within the endoplasmic reticulum (ER). The ER is in charge of molecular quality control, making sure proteins, lipids, and other molecules are folded properly before the cell attempts to use them for metabolic processes. Here, a master protein called grp78 is in contact with three main signaling hubs that make up the control center of the UPR.

New Study in Mice Reveals Biological Origins of a Core Symptom (Memory Deficits) of Schizophrenia

A team of Columbia scientists has found that disruptions to the brain's center for spatial navigation -- its internal GPS -- result in some of the severe memory deficits seen in schizophrenia. The new study in mouse models of the disorder marks the first time that schizophrenia's effects have been observed in the behavior of living animals -- and at the level of individual brain cells -- with such high-resolution, precision and clarity. The findings offer a promising entry point for attacking a near-universal and debilitating symptom of schizophrenia, memory deficits, which has thus far withstood all forms of treatment. The results of this study were published online on September 4, 2017 in Nature Neuroscience. The article is titled “Impaired Hippocampal Place Cell Dynamics in a Mouse Model of 22q11.2 Deletion.” "An almost intractably complex disorder, schizophrenia is nearly impossible to fully treat -- in large part because it acts as two disorders in one," said Joseph Gogos, MD, PhD, a principal investigator at Columbia's Mortimer B. Zuckerman Mind Brain Behavior Institute and the paper's co-senior author. "On one hand, you have paranoia, hallucinations, and delusions; while on the other, you have severe memory deficits. Antipsychotic drugs, which treat the first class of symptoms, are entirely ineffective when dealing with the second. The reasons for this are simple: we do not yet understand what happens in the brains of schizophrenia patients.” Cracking schizophrenia's code must therefore start with deciphering its biological origins, says Dr. Gogos, who is also Professor of Physiology, Cellular Biophysics and Neuroscience at Columbia University Medical Center (CUMC). This has led to a recent focus on the memory impairments that are so common among schizophrenia patients.