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Archive - Mar 27, 2017

Study Links Shorter Telomeres & Mutation-Associated Heart Disease (CAVD); Results May Enable Better Mouse Models for Study of Mutation-Associated Human Disease

Scientists at the Gladstone Institutes in San Francisco have discovered a key mechanism that protects mice from developing a human disease of aging, and begins to explain the wide spectrum of disease severity often seen in humans. Both aspects center on the critical role of telomeres, protective caps on the ends of chromosomes that erode with age. Erosion of telomeres has long been associated with diseases of aging, but how telomere length affects human disease has remained largely a mystery. Now, scientists find that shortening telomeres in mice carrying a human genetic mutation linked to heart disease results in a deadly buildup of calcium in heart valves and vessels. This innovative model allows the researchers to test viable new drugs for this disease, and it provides a potential solution to studying other human disorders of aging in mice. Calcific aortic valve disease (CAVD) causes calcium to accumulate in heart valves and vessels until they harden like bone. It can only be treated by replacing the valve through heart surgery and is the third leading cause of heart disease, affecting 3 percent of adults over the age of 75. CAVD develops with age, and it can be caused by a mutation in one of two copies of the NOTCH1 gene. Humans typically have two copies of each gene. When one copy is lost, the remaining gene may not produce enough of its protein to sustain normal function. While reducing protein levels by half often causes disease in humans, mice with the same change are frequently protected from disease, but scientists have been unsure why. In the new study, published online on March 27, 2017 in the Journal of Clinical Investigation, the Gladstone scientists linked telomere length to risk for, or resistance to, these types of diseases.

Cellular Uptake of Exosomes Appears Size-Dependent; Smaller Exosomes Taken Up More Quickly by Target Cells

Size really does matter when it comes to the mechanisms that cells use to communicate with each other, according to pioneering new nanobiotechnology research that has important implications for the diagnosis and treatment of disease. An international team of scientists has made major strides in understanding “exosomes”– tiny biological structures (or ‘vesicles’) that are believed to be used, at least in part, by cells in the body to transfer information. The researchers believe the findings could be significant for several fields of medical science, from personalizing medical treatments to better understanding the growth and spread of cancerous tumors. Exosomes can be packed with proteins and RNA. They can be generated by one cell, taken up by another, and then trigger a specific response in the second cell. To date, scientific research has focused on the content of exosomes, but a new study led by scientists at the University of Lincoln, UK, focused instead on the size of exosomes and how this affects the way they work. Led by Dr. Enrico Ferrari, a specialist in nanobiotechnology, the research team discovered that the smaller the exosomes are, the easier it is for target cells to pick them up. This makes communication between cells much faster. The study examined exosomes taken from a patient with a high-grade glioma (rapidly growing brain tumor). The researchers had previously found that some stem cells within the patient’s brain were producing exosomes that were responsible for supporting cancer cells and making them more aggressive. The scientists’ latest work suggests that the level of aggression in a tumor could be determined by the size of the exosomes produced by the cancerous cells – for example the smaller the exosomes, the faster the cells can communicate and reproduce, and the more quickly the cancer develops.

Mutation Detection Via DNA Sequencing Could Lead to Earlier Liver Cancer Diagnosis; New Technique Can Reveal Exposure to Aflatoxin, a Potent Carcinogen, Before Tumors Develop.

In many parts of the world, including Southeast Asia and sub-Saharan Africa, exposure to a fungal product called aflatoxin is believed to cause up to 80 percent of liver cancer cases. This fungus is often found in corn, peanuts, and other crops that are dietary staples in those regions. MIT researchers have now developed a way to determine, by sequencing DNA of liver cells, whether those cells have been exposed to aflatoxin. This profile of mutations could be used to predict whether someone has a high risk of developing liver cancer, potentially many years before tumors actually appear. “What we’re doing is creating a fingerprint,” says John Essigmann, Ph.D., the William R. and Betsy P. Leitch Professor of Biological Engineering and Chemistry at MIT. “It’s really a measure of prior exposure to something that causes cancer.” This approach could also be used to generate profiles for other common carcinogens, says Dr. Essigmann, who is the senior author of a paper describing the findings in the Proceedings of the National Academy of Sciences the week of March 27, 2017. The paper’s lead author is MIT postdoc Supawadee Chawanthayatham. Other MIT authors are technical assistant Charles Valentine, research scientists Bogdan Fedeles and Robert Croy, BioMicro Center Director Stuart Levine, postdoc Stephen Slocum, and Professor of Biological Engineering Emeritus Gerald Wogan. University of Washington researchers Edward Fox and Lawrence Loeb are also authors of the study. As Dr. Essigmann’s lab has previously reported, exposure to aflatoxin usually results in a genetic mutation that converts the DNA base guanine to thymine.

Study Compares Radiologic Imaging to Histopathology for Diagnosis of Calciphylaxis, an Oft-Fatal Condition Seen in Stage 5 Kidney Disease

Dermatologist and BioQuick News Science & Medicine Advisory Board Member (http://www.bioquicknews.com/node/34) Charles Halasz (photo), M.D., has had an article published online on March 9, 2017 in the Journal of the American Academy of Dermatology. The article is titled “Calciphylaxis: Comparison of Radiologic Imaging and Histopathology.” Dr. Halasz, Associate Professor of Dermatology at Columbia University, New York, and colleagues, sought to investigate whether radiologic imaging might offer any benefit over histopathology in the diagnosis of calciphylaxis. The current gold standard for diagnosis of calciphylaxis is a skin biopsy specimen demonstrating calcification of small-caliber arteries or arterioles. Calciphylaxis, or calcific uremic arteriolopathy (CUA), is a syndrome of calcification of small arteriolar blood vessels, with blood clots, and skin necrosis (https://en.wikipedia.org/wiki/Calciphylaxis). It is seen mostly in patients with stage 5 chronic kidney disease, but can occur in the absence of kidney failure. It results in chronic non-healing wounds and is often fatal. Here, the physicians sought to compare diameters of calcified vessels seen in skin biopsy specimens and radiology images of patients with calciphylaxis. They conducted a retrospective study of patients, with known calciphylaxis from 2009 to 2016 at a community hospital, who had both skin biopsy specimens and radiology images taken as part of their routine care. Vascular calcification was compared in skin biopsy specimens and radiology images. Seven patients were identified. Small-vessel calcification as fine as 0.1 to 0.3 mm was identified on plain films in 3 patients; 0.1 to 0.2 mm by mammography in 3 patients, and 0.1 to 0.2 mm by computed tomography imaging in 1 patient, nearly as fine a resolution as on histopathology.

Rapid Blood Test to Diagnose & Quantitate Severity of Active TB Infection

Tuberculosis (TB), once better known as consumption for the way its victims wasted away, has a long and deadly history, with estimates indicating it may have killed more people than any other bacterial pathogen. Studies have discovered evidence of TB’s human impact going back to as early as 8,000 BCE, and estimates suggest that it has killed a billion people over the past two centuries. Now, a group of scientists from Arizona, Texas, and Washington, D.C. has teamed up to develop the first rapid blood test to diagnose and quantitate the severity of active TB cases. Led by Tony Hu (photo), Ph.D., a researcher at Arizona State University's Biodesign Institute, eight research groups, including the Houston Methodist Research Institute and scientists at the NIH, are harnessing the new field of nanomedicine to improve worldwide TB control. "In the current frontlines of TB testing, coughed-up sputum, blood culture tests, invasive lung and lymph biopsies, or spinal taps are the only way to diagnose TB," said Dr. Hu, a scientist in the Biodesign Institute's Virginia G. Piper Center for Personalized Diagnostics. "The results can give false negatives, and these tests are further constrained because they can take days to weeks to get the results." Despite $6.6 billion spent for international TB care and prevention efforts, TB remains a major risk to human health, particularly for the developing world and people with HIV infections. Making matters worse, TB bacteria can lurk dormant in a person's lung tissue, often for decades, before spontaneously producing full-blown TB disease that can then spread to others. Currently, the World Health Organization (WHO) estimates that up to one-third of the world's population may have such dormant TB infections.