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Newswise — Everyone knows that tobacco products are bad for your health, and even the new e-cigarettes may have harmful toxins. However, according to research at Texas A&M, it turns out the nicotine itself—when given independently from tobacco—could help protect the brain as it ages, and even ward off Parkinson’s or Alzheimer’s disease. Ursula Winzer-Serhan, PhD, an associate professor at the Texas A&M College of Medicine, and her collaborators found that nicotine’s ability to be neuroprotective may be partly due to its well-known ability to suppress the appetite. Their research is published in the Open Access Journal of Toxicology. Using animal models, Winzer-Serhan and her collaborators added nicotine to the animal’s drinking water. There were three different groups that received nicotine at three different concentrations (low, medium and high) corresponding to occasional, low and medium smokers, respectively, in addition to a control group that did not receive any nicotine. The two groups that received nicotine at low and medium doses didn’t show any levels of the drug in their blood and they experienced no changes in food intake, body weight or number of receptors in the brain where nicotine acts. In contrast, the group getting the highest concentration of nicotine ate less, gained less weight and had more receptors, indicating that at higher doses, the drug gets into the brain where it can impact behavior. However, even at high doses, it didn’t seem to have worrying behavioral side effects like making the individuals more anxious, which the researchers were concerned could happen. “Some people say that nicotine decreases anxiety, which is why people smoke, but others say it increases anxiety,” Winzer-Serhan said. “The last thing you would want in a drug that is given chronically would be a negative change in behavior. Luckily, we didn’t find any evidence of anxiety: Only two measures showed any effect even with high levels of nicotine, and if anything, nicotine made animal models less anxious.” The next step is to test nicotine’s potential anti-aging effects using aged animal models. Although early results indicate that nicotine can keep older individuals from gaining weight like the control group does, Winzer-Serhan hasn’t yet determined whether this lower body mass index translates into less degeneration of the brain. It is also unclear if nicotine’s effects are related only to its ability to suppress appetite, or if there are more mechanisms at work. Because there are still so many unknowns, Winzer-Serhan urges caution. “I want to make it very clear that we’re not encouraging people to smoke,” she said. “Even if these weren’t very preliminary results, smoking results in so many health problems that any possible benefit of the nicotine would be more than cancelled out. However, smoking is only one possible route of administration of the drug, and our work shows that we shouldn’t write-off nicotine completely.” Still, Winzer-Serhan cautions people not to purchase nicotine-containing products just yet. “Although the results are intriguing, we would need large-scale clinical trials before suggesting anyone change their behavior,” she said. “At the end of the day, we haven’t proven that this addictive drug is safe—and it certainly isn’t during childhood or adolescence—or that the benefits outweigh the potential risks.”

Newswise — A team of clinical scientists at the University of Bristol have found a new way to treat high blood pressure (hypertension). The research study, entitled “Unilateral carotid body resection in resistant hypertension: a safety and feasibility trial,” was led by Professor Julian Paton at the University of Bristol, and Dr Angus Nightingale (Cardiology Consultant) at the Bristol Heart Institute, Bristol, and was published recently in the Journal of American College of Cardiology: Basic to Translational Science. The research indicates that the carotid bodies appear to be a cause of high blood pressure, and as such now offer a new target for treatment. The clinical team have shown that removing one carotid body from some patients with high blood pressure caused an immediate and sustained fall in blood pressure. Dr Nightingale said: “The falls in blood pressure we have seen are impressive – more than you would see with pharmacological medication – and demonstrate the exciting potential there now is for targeting the carotid body to treat hypertension.” The carotid bodies “sniff” the levels of oxygen in blood, and when this falls they raise the alarm of a potential emergency by signaling to the brain to increase breathing and blood pressure. The effect is similar to having the thermostat in your home set too high all the time. Professor Paton explained: “Treating the carotid body is a novel approach and a potential game changer as we believe we are reducing one of the main causes for hypertension in many patients. High blood pressure treatment typically tackles the symptoms targeting the end organs such as the heart, kidneys and blood vessels, and not the causes.” “Most importantly, we have developed some unique tests to assess which patients have overactive carotid bodies. This now gives us a way to personalise treatment, which is essential as there are multiple reasons why high blood pressure develops” said Dr Nightingale. The clinical trial demonstrated that the carotid bodies in patients who responded to resection had raised carotid body activity. These patients breathed more at rest and produced exaggerated breathing responses when the oxygen level in their blood was lowered. High blood pressure is the world’s leading contributor to mortality. In the UK, its cost to the National Health Service is around £2 billion per year, and it remains poorly controlled, triggering heart and renal failure, and strokes. The World Health Organization has identified high blood pressure as the single most important risk factor for the global burden of disease and death. “Although this surgical approach to controlling high blood pressure was successful, we don’t think this will be the solution in the long term. We now need to find a drug that dampens down an overactive carotid body and resets the blood pressure thermostat to a normal level,” Dr Nightingale said. Professor Paton’s team may have found such an alternative. Recent animal studies published last week in Nature Medicine, discovered that the energy molecule adenosine tri-phosphate appears to be responsible. “We are very excited by finding that we can turn down the alarm signals emanating from the carotid body in conditions of hypertension, yet it remains fully operational should an emergency situation occur. The new drug target we found within the carotid body is a receptor for the ATP molecule called the P2X3 receptor” explained Professor Paton. Professor Paton said: “This approach may lead us to the first novel anti-hypertensive treatment strategy in more than 15 years. It has taken almost 10 years of research effort, working with colleagues from the University of Bristol, The University Hospitals Bristol NHS Foundation Trust, Medical University of Gdansk, Poland, the William Harvey Research Institute, London, Dartmouth Medical School, USA, the University of Sao Paulo, Brazil, the University of Auckland, New Zealand, Cibiem Inc., and Afferent Pharmaceuticals. Nor would it have been possible without funding from The British Heart Foundation.” Paper ‘Purinergic receptors in the carotid body as a new drug target for controlling hypertension’ by Julian Paton et al in Journal of American College of Cardiology: Basic to Translational Science.   SEE ORIGINAL STUDY    

Newswise — The increase in illnesses and deaths linked to medication-resistant bacteria has been well-documented by researchers and received extensive public attention in recent years. Now, UCLA-led research shows how these bacteria are making it more difficult to treat a common but severe kidney infection. Pyelonephritis — infection of the kidney usually caused by E. coli bacteria and which can start as a urinary tract infection — causes fever, back pain and vomiting. About half of people infected require hospitalization. If not treated with effective antibiotics, it can cause sepsis and death. In a UCLA-led study based on data from 10 large hospital emergency departments around the country, almost 12 percent of people diagnosed with pyelonephritis had infections resistant to the standard class of antibiotic used in treatment — fluoroquinolone. (Cipro and its generic version ciprofloxacin are commonly used medications in this class.) That’s up from 4 percent in a similar study conducted a decade ago. In some cities, and among some people with certain risk factors — such as international travel or recent hospitalization or treatment with an antibiotic — fluoroquinolone resistance rates exceeded 20 percent. The new study — published in the September issue of Emerging Infectious Diseases — also documents the emergence of infections caused by a specific strain of E. coli that is resistant to additional types of antibiotics, severely limiting treatment options. That strain, dubbed ESBL for the antibiotic-destroying enzymes it produces (extended-spectrum beta-lactamases), was not detected in the previous study. The enzymes were first detected in 1979 and are most often found in developing nations. Currently, there are only a few intravenous antibiotic options to treat ESBL-related infections, and no oral antibiotics that are consistently effective. “This is a very real example of the threat posed by the emergence of new antibiotic-resistant strains of bacteria, which greatly complicates treatment of infection,” said Dr. David Talan, the study’s lead author and a professor in the department of emergency medicine at the David Geffen School of Medicine at UCLA. He is also a professor in the department of medicine, division of infectious diseases. The study included 453 people diagnosed with kidney infection. The study participants were diagnosed between July 2013 and December 2014 in 10 emergency departments at large hospitals around the country, including Olive View–UCLA Medical Center in Sylmar, which is operated by Los Angeles County. Researchers reported that: - The rates of ESBL-related infections varied from 0 percent to more than 20 percent, depending on the location of the emergency room and patient risk factors. - About one in three people infected with ESBL-producing E. coli had no traditional risk factors for antibiotic resistance, suggesting the bacterial strain is now endemic in the United States and healthy people are also at risk. - About three of every four people infected with ESBL-producing E. coli were initially treated with antibiotics ineffective against that particular strain of bacteria, placing them at risk for poor outcomes. Talan and his research colleagues recommended the development of new medications and new guidelines calling for treatment with different types and combinations of antibiotics. They also recommended physicians evaluating treatment options pay close attention to antibiotic resistance rates in their regions and quickly test bacteria samples to determine specific strains. The research was supported by the U.S. Centers for Disease Control and Prevention and by Merck.    

Newswise — Cancer treatments that mobilize the body’s immune system to fight the disease have generated a lot of excitement in the past few years. One form of immunotherapy called checkpoint blockade is especially promising. But while checkpoint blockade has had some striking successes, the therapy has almost no effect on some of the most lethal kinds of tumors. Now a group of scientists from the University of Chicago has developed an ingenious way to spur checkpoint blockade into more potent action. The therapy, reported in the Aug. 17 issue of Nature Communications, offers the hope of an effective treatment for intractable metastatic cancers including those of the colon and lung. “Everybody out there working in the cancer space is trying to figure out ways to enhance checkpoint blockade immunotherapy,” said Wenbin Lin, James Franck Professor in Chemistry at UChicago and one of the scientists who conceived the new therapy. “In this work, we were able to achieve that.” The method requires a complex interplay of immune-stimulating nanoparticles comprised of light-sensitive agents and standard chemotherapeutic drugs, both acting together to fortify the checkpoint blockade. Bolstering immunity Checkpoint blockade therapy works by interfering with cancer’s ability to turn off the body’s immune reaction. When cancer cells first develop, the body is able to recognize them as foreign, triggering T-cells to attack and eliminate them. But as malignant cells multiply and form tumors, they release biochemical signals that suppress the immune system and the T-cells no longer function properly. Checkpoint blockade therapy obstructs those signals, makes T-cells see the cancer cells as invaders again, and allows the immune system to do its job. The problem, said Lin, is that if a tumor has been growing for years there are no longer any T-cells inside it to activate, so the therapy fails. “So what we’re trying to do is to come up with ways to recruit T-cells to the tumor,” he said. “And if you have a way to make the T-cells recognize cancer cells, the T-cell will be able to go in there and kill the cancer cells.” The treatment Lin and collaborators invented is a drug cocktail contained in a nanoparticle. The nanoparticles assemble themselves from zinc and a drug called oxaliplatin, which is widely used against advanced-stage metastatic colon cancer. A photosensitizing agent called pyrolipid forms the outer layer. When light is shined on the pyrolipid it generates molecules that can kill cancer. It also activates T-cells that can recognize cancer cells, so the nanoparticles pack a triple punch. Used in concert, the nanoparticles and a checkpoint blockade agent were able to eliminate tumors in a mouse, even when the tumors were widely separated and one of them had received no treatment. The scientists injected a checkpoint blockade drug into the abdomen of a mouse that had two tumors growing at different places on its body, and then injected the nanoparticles into the mouse’s tail vein. They shined light onto one of the tumors to activate the pyrolipid. The other tumor was left untreated. The irradiated tumor disappeared, as would be expected. But, remarkably, the distant, untreated tumor disappeared as well. No irradiation with light meant no T-cells were activated in the second tumor, “so we should not expect that tumor to disappear,” Lin said. “But we believe that this combination is able to activate the immune system to generate the T-cells that will recognize the cancer cells. Then they go around the body and kill the cancer cells in the distant site that has not been irradiated with the light.” Traveling T-cells This ability to activate T-cells in one place and have them travel to disease sites elsewhere in the body could be a powerful tool for treating cancer. Most people who die of cancer do not die from their primary tumor; they die from metastatic disease. When patients have surgery, surgeons don’t know if there are other, smaller lesions elsewhere in the body. “You cannot treat them because you don’t know where to look for them,” Lin said. “If you activate immune cells, they can home in to cancer cells selectively. So you have a better chance of getting rid of these small metastatic tumors throughout the body.” Lin and colleagues have started a company to develop the new therapy and have raised initial funding for clinical trials. “These findings open up new opportunities for using nanoparticles as a platform for combination therapies,” said Yu-Ying He, an associate professor of medicine and dermatology at UChicago who is familiar with the work. “If the mouse models are indicative of human disease, the combination therapy can increase the proportion of patients who respond to therapy without additional adverse side effects and can improve the quality of life for cancer patients."—Carla Reiter Citation: “Core-shell nanoscale coordination polymers combine chemotherapy and photodynamic therapy to potentiate checkpoint blockage cancer immunotherapy,” by Chunbai He, Xiaopin Duan, Nining Guo, Christina Chan, Christopher Poon, Ralph R. Weichselbaum, and Wenbin Lin, Nature Communications, published online Aug. 17, 2016, doi:10.1038/ncomms12499. Funding: National Cancer Institute, University of Chicago Medicine Comprehensive Cancer Center, Cancer Research Foundation, and Ludwig institute for Metastasis Research.

Newswise — A UC Santa Barbara researcher studying how the brain uses perception of the environment to guide action has a new understanding of the neural circuits responsible for transforming sensation into movement. “Mapping perception to a future action seems simple,” UCSB neuroscientist Michael Goard. “We do it all the time when we see a traffic light and use that information to guide our later motor action. However, how these associations are mapped across time in the brain is not well understood.” In a new paper, published in the journal eLife, Goard and colleagues at the Massachusetts Institute of Technology make progress in mapping brain activity in mice during simple but fundamental cognitive tasks. Although a mouse’s brain is much smaller than a human’s, remarkable structural similarities exist. The mouse brain is composed of about 75 million nerve cells or neurons, which are wired together in complex networks that unerlie sophisticated behaviors. The researchers used large-scale calcium imaging to measure the responses of individual neurons in multiple areas of the brain while mice performed a delayed response task. First, they trained mice to respond to visual stimuli — drifting bars — by either licking or withholding licking, depending on whether the bars moved vertically or horizontally. While the mice performed the task, the investigators recorded neural activity from multiple brain regions thought to be involved — including visual, parietal and frontal motor cortices. Using a powerful laser-scanning microscope, the team was able to detect the signals from calcium indicators expressed in the neurons well below the brain’s surface. Neurons normally have very low concentrations of intracellular calcium, but when they become active, calcium levels rise, increasing the fluorescence of the indicator and enabling measurement of neuron activity. In this way, the scientists were able to see which neurons were active while the mice performed the delayed response task. “As expected, we found many neurons that responded only during the visual stimulus or the licking action, but we also found a lot of neurons that responded during other parts of the task,” said Goard, an assistant professor in UCSB’s Department of Psychological & Brain Sciences and Department of Molecular, Cellular and Developmental Biology. “In the frontal motor cortex, we found quite a few neurons that were active during the delay period between the visual stimulus and motor response. This led us to several new interpretations of the role that different brain regions were playing during performance of the task.” Based on the neural activity in the different brain areas, Goard and his team then used optogenetics — a method of manipulating the nerve cells with light — to inactivate neurons in a temporally precise manner to identify those that function during different parts of the task. This allowed them to figure out which areas were necessary for performing the task. For example, the team determined that the visual and parietal areas are involved in perceiving the stimulus and transforming that into a motor plan, but only the frontal motor cortex is necessary for maintaining the motor plan over the delay period. “Using this general approach, we hope to map the essential regions for different types of cognitive tasks,” Goard explained. “We are particularly interested in how mice maintain specific types of memories across distributed brain regions.” SEE ORIGINAL STUDY    

Newswise — PHILADELPHIA— Few effective treatments have been approved to treat ovarian cancer, the deadliest of all cancers affecting the female reproductive system. Now, new research from The Wistar Institute demonstrates how a drug already in clinical trials could be used to boost anti-tumor immunity and cause T-cells to target the cancer directly while minimizing side effects. The results were published in the journal Cell Reports. There has been considerable interest in the programmed cell death-1 (PD-1) protein and its ligand (PD-L1) because the interaction between the two inhibits important T-cell activity aimed at stopping tumor growth. PD-L1 is expressed on the surface of both cancer cells and immune cells across many different cancer types. Antibody-based drugs that specifically halt this interaction have shown promising results, though patients have experienced immune-related side effects as a result. “We wanted to explore anti-PD-L1 therapies specifically for ovarian cancer, but we also wanted to determine if other drugs that did not cause these negative anti-PD-L1 antibody-related side effects could be used to target this cancer-promoting pathway,” said Rugang Zhang, Ph.D., professor and co-program leader in the Gene Expression and Regulation program at The Wistar Institute and lead author of the study. Zhang and his team decided to screen for small molecule inhibitors that could be used as a treatment option. Small molecule inhibitors are a preferable form of cancer treatment because they block cancer progression by targeting cells that have proteins or mutations associated with cancer while sparing normal, healthy cells. The researchers found that a class of drugs known as bromodomain and extraterminal domain (BET) inhibitors were particularly effective at suppressing PD-L1 activity when they studied the drug in epithelial ovarian cancer cell lines. Multiple BET inhibitors are in various stages of clinical trials for different types of cancer. They are able to suppress inflammatory responses, and they may be able to do so without affecting the anti-tumor immune response. In this study, they used an experimental BET inhibitor called JQ1. Even though BET inhibitors do not specifically target PD-L1, the researchers were able to determine why this class of drugs is so effective. They showed that bromodomain-containing protein 4 (BRD4), one of the members of the BET family that is inhibited by these drugs, is a critical regulator of PD-L1 expression. The BRD4 gene is often amplified in ovarian cancer and may serve as a valuable biomarker to determine which ovarian cancer patients could benefit the most from receiving treatment with BET inhibitors. “Targeting PD-L1 appears to be an effective strategy for combating a variety of human cancers,” said Hengrui Zhu, Ph.D., a postdoctoral fellow in the Zhang lab and first author of the study. “With BET inhibitors, we believe we have found a powerful new addition to available therapeutic strategies for ovarian cancer.” This work was supported by the National Institutes of Health/National Cancer Institute R01 grants CA160331, CA163377, CA202919 and K99CA194318, U.S. Department of Defense grants OC140632P1 and OC150446, an Ovarian Cancer Research Fund (OCRF) program project and The Jayne Koskinas & Ted Giovanis Breast Cancer Research Consortium at Wistar. Zhu is an OCRF Ann Schreiber Mentored Investigator. Support for shared resources used in this study was provided by Cancer Center Support Grant (CCSG) CA010815 to The Wistar Institute. The Structure Genomics Consortium provided the panel of small molecule inhibitors that target epigenetic regulators used in this study. Co-authors of this study from The Wistar Institute include Fee Bengsch, Nikolaos Svoronos, Melanie Rutkowski, Benjamin Bitler, Michael Allegrezza, Yuhki Yokoyama, Andrew Kossenkov, and José Conejo-Garcia. James Bradner from Dana-Faber Cancer Institute was also a co-author of this study. ###

Newswise — A computer model developed by scientists at the University of Chicago shows that small increases in transmission rates of the seasonal influenza A virus (H3N2) can lead to rapid evolution of new strains that spread globally through human populations. The results of this analysis, published September 13, 2016 in the Proceedings of the Royal Society B, reinforce the idea that surveillance for developing new, seasonal vaccines should be focused on areas of east, south and southeast Asia where population size and community dynamics can increase transmission of endemic strains of the flu. “The transmissibility is a feature of the pathogen, but it's also a feature of the host population,” said Sarah Cobey, PhD, assistant professor of ecology and evolution at the University of Chicago and senior author of the study. “So a host population that potentially has more crowding, larger classroom sizes for children, or even certain types of social contact networks, potentially sustains higher transmission rates for the same virus or pathogen.” There are four influenza strains that circulate in the human population: A/H3N2, A/H1N1, and two B variants. These viruses spread seasonally each year because of a phenomenon known as antigenic drift: They evolve just enough to evade human immune systems, but not enough to develop into completely new versions of the virus. The H3N2 subtype causes the most disease each year. Genetic sequencing shows that from 2000 to 2010, 87 percent of the most successful, globally-spreading strains of H3N2 originated in east, south and southeast Asia. Cobey and her colleagues, lead author Frank Wen from the University of Chicago and Trevor Bedford of the Fred Hutchinson Cancer Research Center, developed a computer model to simulate conditions in these areas. The team used the model to test several hypotheses about why antigenically new, seasonal flu strains tend to emerge from this part of the world, including: • Seasonality: 85 percent of Asia’s population lives in tropical or subtropical regions with no distinct winter, allowing continuous transmission of endemic flu strains and more opportunities for evolution of new strains. • Host population size: This area contains more than half of the world’s population. The sheer number of people could contribute a larger fraction of strains that spread globally.• Host population turnover: Birth rates have historically been higher in these areas than other temperate regions. This may contribute to a larger number of infants and young children who are more susceptible to the flu.• Initial conditions: H3N2 first emerged in Hong Kong in 1968. One hypothesis states that this gives the viral population an evolutionary head start, thus new epidemics will almost always begin in the area.• Transmission rates: Differences in the transmission rate of a given virus, or the expected number of secondary cases caused by a single infection, can affect the evolution of new strains. Cobey and her colleagues simulated climate conditions, population dynamics and patterns of flu epidemics in these regions and found that only the transmission rate had a significant effect on the evolution of new strains that had the potential to spread globally. A transmission rate 17-28 percent higher in one region could explain historically observed patterns of flu epidemics. “We basically find that increasing the transmission rate just a little bit greatly accelerates the rate at which antigenically novel strains can displace one another,” Cobey said. Understanding how and why seasonal flu tends to originate in these areas reinforces the need for surveillance to identify new strains, not just in the affected parts of Asia, but other parts of the world with high-density populations, like west Africa. It also highlights how public health efforts to limit the spread of flu, namely widespread vaccination, can also limit the emergence of new strains. Cobey said that while the team’s analysis focused initially on flu, it can also apply to any fast-evolving, human transmissible viruses like enteroviruses and colds. “They spread from continent to continent over a pretty short time scale, so it will be exciting to see if we find similar patterns down the road once we have better surveillance of all these viruses,” she said. The study, “Explaining the geographic origins of seasonal influenza A (H3N2)” was supported by the National Institutes of Health. ###

Newswise — PHILADELPHIA – Individual cells within a tumor are not all the same. This may sound like a modern medical truism, but it wasn’t very long ago that oncologists assumed that taking a single biopsy from a patient’s tumor would be an accurate reflection of the physiological and genetic make-up of the entire mass. Researchers have come to realize that cancer is a disease driven by the same “survival of the fitter” forces that Darwin proposed drove the evolution of life on Earth. In the case of tumors, however, individual cells are constantly evolving as a tumor’s stage advances. Mobile cancer cells causing metastasis are a deadly outcome of this process. Tumors also differ among patients with the same type of cancer, so how is a physician able to prescribe a tailored regimen for the patient? To start to address this conundrum, an interdisciplinary team from the Perelman School of Medicine and the Wharton School at the University of Pennsylvania developed Canopy, an approach to infer the evolutionary track of tumor cells by surveying two types of mutations – somatic copy number alterations and single-nucleotide alterations – derived from multiple samples taken from a single patient. They demonstrated the approach on samples from leukemia and ovarian cancer, along with samples from a human breast cancer cell line. Overall, the evolution of a tumor involves the accumulation of mutations of all types collectively influencing the fitness of tumor cells. The team, Yuchao Jiang, a doctoral student in the Genomics and Computational Biology program, Yu Qiu, PhD, a postdoctoral researcher in the lab of coauthor Andy Minn, MD, PhD, an assistant professor of Radiation Oncology, and Nancy R Zhang, PhD, an associate professor of Statistics in the Wharton School, published their findings online in the early edition of the Proceedings of the National Academy of Sciences. “The make-up of a tumor for a given patient is often a mixture of multiple distinct cell populations that differ in genetic make-up, gene expression, and physiology,” Jiang said. “This heterogeneity contributes to failures of targeted therapies and to drug resistance based on old thinking that tumors are homogenous masses.” However, Canopy takes these differences into account because it uses data from multiple slices of the same tumor in space and time, as opposed to sampling in one spot at one time point, the way it is currently done in most sequencing studies. Canopy is an open-source software so oncologists will be able to use it to identify potential biomarkers for different cancer cell populations within tumor specimens that are associated with drug resistance and invasive malignancy, among other characteristics. “Data input for Canopy from the clinic would come from tissue samples from the same patient - from normal tissue and from different places on the tumor and at different times,” Jiang said. “Canopy can then be used to infer the evolutionary history of the tumor to better understand how the tumor evolved and to find potential biomarkers.” The goal for Canopy is to help new patients at an early stage, using biomarkers to ascertain a correct diagnosis and prognosis. The team also used animal models to refine their understanding of a metastasis model for breast cancer. After injecting human breast cancer cells into mice they observed where the primary breast cancer cells metastasized -- lung, bone, or other tissues. The site-specific metastatic samples, as well as the primary cancer cell lines were sequenced by whole-exome sequencing, from which somatic single-nucleotide alterations and copy number mutations were profiled. The relationships reconstructed by Canopy showed that, compared to the primary breast cancer cell lines, the metastatic samples from different organs had distinct genotypic patterns. Canopy identified metastasis-site-specific mutations for this specific malignant breast cancer cell line. The concept behind this proof-of-concept study can be applied to larger studies with the goal of identifying genomic changes that serve as prognostic markers for the development of distant metastasis. By assigning mutation types to different parts of a tumor’s “evolutionary tree,” oncologists will be able to predict the site and severity of metastasis, and potentially, better courses of treatment. Applying Canopy to a larger cohort of samples is one of the team’s future directions. In addition, says Zhang, recent advances in single-cell sequencing make possible the study of tumors at the single-cell level. However, reliable simultaneous profiling of copy number and single nucleotide mutations by single-cell sequencing is still in its infancy. “Our work shows that traditional bulk sequencing can lead to accurate tumor subclone identification, if the researcher is willing to sequence multiple slices of the tissue,” she said. “Bulk tissue sequencing can play an important part in our understanding of tumor heterogeneity, and in the coming years, experimental designs that combine bulk tissue sampling and single cell analysis need to be better explored.” This work was funded by the NIH (R01-HG006137) and the PA Breast Cancer Coalition.

Newswise — Therapeutics for Alzheimer’s disease are most likely to work if started early in the disease’s course, when amyloid plaques accumulate in the brain but memory is still intact. In their quest to recruit subjects in this preclinical disease state, clinicians must test people for AD risk factors such as brain amyloid accumulation or ApoE genotype, and then disclose that information to them so they can enroll in a trial. At the Alzheimer's Association International Conference, researchers presented early findings regarding the ethical, psychological, and societal impacts of such disclosure, and laid out their plans for the best ways to deliver the information. Cancer risk disclosure is more advanced, and guides their way. Beyond clinical trials, having smart disclosure procedures in place will be crucial if an AD therapy is approved, as then scores of people will want to get tested to head off the disease. Jessica Shugartexamines the dilemma. About UsFounded in 1996, Alzforum is a news and information resource website dedicated to helping researchers accelerate discovery and advance development of diagnostics and treatments for Alzheimer’s disease and related disorders. Our site expands the traditional mode of scientific communication by reporting the latest scientific findings and industry news with insightful analysis that puts breaking news into context. We advance research by developing open-access databases of curated, highly specific scientific content to visualize and facilitate the exploration of complex data. Alzforum is a platform to disseminate the evolving knowledge around basic, translational, and clinical research in the field of AD. Alzforum is supported by a team with backgrounds in science, journalism, information technology, design, and data science. Together with a distinguished Scientific Advisory Board, and the active participation of a global network of scientists, we strive to produce unbiased content to a rigorous editorial standard. Alzforum is operated by the Biomedical Research Forum (BRF) LLC. BRF is a wholly owned subsidiary of FMR LLC. FMR LLC and its affiliates invest broadly in many companies, including life sciences and pharmaceutical companies. Alzforum does not endorse any specific product or scientific approach.

Newswise — BOSTON — A new analysis of 100 million Medicare records from U.S. adults aged 65 and older reveals rising healthcare costs for infections associated with opportunistic premise plumbing pathogens—disease-causing bacteria, such as Legionella—which can live inside drinking water distribution systems, including household and hospital water pipes. A team led by researchers from the Friedman School of Nutrition Science and Policy at Tufts University and Tufts University School of Medicine found that between 1991 and 2006, more than 617,000 hospitalizations related to three common plumbing pathogens resulted in around $9 billion in Medicare payments—an average of $600 million a year. The costs may now exceed $2 billion for 80,000 cases per year, write the study authors. Antibiotic resistance, which can be exacerbated by aging public water infrastructure, was present in between one and two percent of hospitalizations and increased the cost per case by between 10 to 40 percent. “Premise plumbing pathogens can be found in drinking water, showers, hot tubs, medical instruments, kitchens, swimming pools—almost any premise where people use public water. The observed upward trend in associated infections is likely to continue, and aging water distribution systems might soon be an additional reservoir of costly multidrug resistance,” said lead study author Elena Naumova, Ph.D., professor at the Friedman School and Director of the Initiative for the Forecasting and Modeling of Infectious Disease at Tufts University. “This is a clear call for deepened dialogue between researchers, government agencies, citizens, and policy makers, so that we can improve data sharing and find sustainable solutions to reduce the public health risks posed by these bacteria.” The study was published in the Journal of Public Health Policy on Sept. 12. State and federal oversight has ensured generally safe and good quality public drinking water in the U.S. However, premise plumbing systems—the pipes and fixtures in homes and buildings that transport water after delivery by public water utilities—are largely unregulated, which can lead to inconsistent monitoring and reporting of potentially harmful deficiencies. This is highlighted by the ongoing crisis in Flint, Michigan, where a water source change, aging pipes, and lack of corrosion control not only exposed thousands of children to elevated lead levels in drinking water, but is also thought to have triggered an outbreak of Legionnaire’s disease that led to 10 deaths. Opportunistic premise plumbing pathogens, such as the bacteria that causes Legionnaire’s disease, Legionella pneumophila, can thrive in low-nutrient conditions and grow as biofilms on the inner surfaces of pipes. Biofilms allow these pathogens to resist disinfectants and environmental stressors, and aid in the spread of antibiotic resistance and virulent genes. As water distribution systems age, their susceptibility to contamination increases. However, few large-scale studies have examined the economic and public health burden of these bacteria. To investigate, Naumova and her colleagues analyzed 100 million medical claims from 1991 through 2006 from the US Centers for Medicare and Medicaid Services, which provides exhaustive coverage of Medicare beneficiaries aged 65 and older. The team focused on hospitalizations related to three opportunistic premise plumbing pathogens: Legionella pneumophila, Mycobacterium avium, and Pseudomonas aeruginosa, which can cause a range of serious respiratory, systemic, or localized infections, particularly in vulnerable populations such as the elderly or immunocompromised individuals. Based on clinical diagnostic codes, reported cases for all three infections totaled 617,291, with the majority due to pneumonia caused by Pseudomonas and related bacteria (560,504). Legionnaire’s disease and Mycobacteria infections accounted for 7,933 and 48,854 cases respectively. On average, each hospitalization represented $45,840 in Medicare charges and $14,920 in payments. Antibiotic resistance, recorded in a little under two percent of cases, increased the average costs to $60,870 in Medicare charges and $16,690 in payments per case. Over the past decade, the US Centers for Disease Control and Prevention reported a substantial increase in incidence of opportunistic premise plumbing pathogens, with Pseudomonas alone accounting for 51,000 hospitalizations per year with more than 6,000 multi-drug resistant infections in 2011. The annual costs for these pathogens may now exceed a total of $2 billion for more than 80,000 cases per year, as increased antibiotic resistance leads to greater hospital charges, longer lengths of stay, and increased risk of complications. Antibiotic resistance is likely underreported, and this number is a conservative estimate for the Medicare population based on the study findings and reported data on hospitalization costs per case, says Naumova. “While public drinking water is safe, it is clearly more safe if you are healthy than if you have medical conditions that enhance your vulnerability to infections. The risk of becoming ill from drinking water is much less than the risk of becoming ill from food, but it is not zero,” said last author Jeffrey K. Griffiths, M.D., professor of public health and community medicine at Tufts University School of Medicine. Griffiths is also former chair of the Drinking Water Committee for the US Environmental Protection Agency’s Science Advisory Board. “These infections can cause a lot of illness and cost us a lot of money, and targeted disinfection of premise piping could save us from these consequences.” The authors caution that their data cannot draw conclusions about the percentage of infections directly caused by contaminated water. The link between aging water distribution systems and drug resistance is highly plausible, but has yet to be firmly established, say the authors. However, this study highlights the need for improved surveillance systems and targeted investigations of water-related outbreaks in order to determine the direct link between water contamination and drug-resistant infection. A 2010 report from the national Waterborne Disease and Outbreak Surveillance System, a partnership between the Centers for Disease Control, the Council of State and Territorial Epidemiologists, and the U.S. Environmental Protection Agency, urged serious attention to be paid to the growing proportion of outbreaks associated with premise plumbing deficiencies in public water systems. However, budgets for state and federal water regulators have decreased. In 2013, the Association of State Drinking Water Administrators reported that "federal officials had slashed drinking-water grants, 17 states had cut drinking-water budgets by more than a fifth, and 27 had cut spending on full-time employees," with "serious implications for states’ ability to protect public health.” “The Flint Water Crisis revealed many unsolved social, environmental, and public health problems for US drinking water,” Naumova said. “Unfortunately, water testing for pathogens is not done routinely; furthermore, most water tests are not accessible, are too complicated, or are too costly. Well-controlled, experimental studies of the influence of microbial ecology, disinfectant type, pipe materials, and water age, on opportunistic pathogen occurrence and persistence are needed in order to establish their relationships to drug resistance.” ## Additional authors on this study are Alexander Liss, M.B.A., Ph.D., postdoctoral fellow in the Department of Civil and Environmental Engineering in the School of Engineering at Tufts University, Jyotsna S. Jagai, M.S., M.P.H., Ph.D., assistant professor in the Division of Environmental and Occupational Health Sciences at the University of Illinois at Chicago, Irmgard Behlau, M.D., research assistant professor in the Department of Molecular Biology and Microbiology at Tufts University School of Medicine. This study was in part supported by awards from the National Institute of Environmental Health Sciences (ES013171) and the National Institute of Allergy and Infectious Diseases (AI062627 and AI050032), both of the National Institutes of Health. Naumova, EN, Liss, A, Jagai, JS, Behlau, I, Griffiths, JK, “Hospitalizations due to selected infections caused by opportunistic premise plumbing pathogens (OPPP) and reported drug resistance in the United States older adult population in 1991-2006,” Journal of Public Health Policy. 2016. About the Friedman School of Nutrition Science and PolicyThe Gerald J. and Dorothy R. Friedman School of Nutrition Science and Policy at Tufts University is the only independent school of nutrition in the United States. The school's eight degree programs – which focus on questions relating to nutrition and chronic diseases, molecular nutrition, agriculture and sustainability, food security, humanitarian assistance, public health nutrition, and food policy and economics – are renowned for the application of scientific research to national and international policy.About Tufts University School of Medicine and the Sackler School of Graduate Biomedical SciencesTufts University School of Medicine and the Sackler School of Graduate Biomedical Sciences are international leaders in medical and population health education and advanced research. Tufts University School of Medicine emphasizes rigorous fundamentals in a dynamic learning environment to educate physicians, scientists, and public health professionals to become leaders in their fields. The School of Medicine and the Sackler School are renowned for excellence in education in general medicine, the biomedical sciences, and public health, as well as for innovative research at the cellular, molecular, and population health level. The School of Medicine is affiliated with six major teaching hospitals and more than 30 health care facilities. Tufts University School of Medicine and the Sackler School undertake research that is consistently rated among the highest in the nation for its effect on the advancement of medical and prevention science.