Newswise — DURHAM, N.C. -- Scientists at the Duke Cancer Institute have identified a molecular key that breast cancer cells use to invade bone marrow in mice, where they may be protected from chemotherapy or hormonal therapies that could otherwise eradicate them. Through years of experiments in mice, the scientists have found ways to outmaneuver this stealth tactic by not only preventing breast cancer cells from entering the bone marrow, but also by flushing cancer cells out into the blood stream where they could be targeted for destruction. The findings provide insight into one of the most devastating tendencies of some breast cancers -- the ability to return after seemingly being vanquished. The researchers hope the findings, if replicated in additional animal and human tests, could eventually lead to new therapies for treating breast cancer. “Clinical studies have found that breast cancer can be caught early and treated, and patients can have no signs of disease,” said Dorothy A. Sipkins, M.D., Ph.D., associate professor in the division of hematological malignancies and cellular therapy at Duke. “And then five, 10 or even 15 years later, a patient can relapse. Most often, the site of the metastasized cancer is in the bone.” In an article published online May 25 in Science Translational Medicine, the researchers describe how cells from breast cancers that are hormone receptor-positive roam through the blood and tissues of mice. They’re hunting for specific blood vessels in bone marrow that contain the molecule E-selectin. With a key -- molecules on their surface that bind to E-selectin -- the cancer cells enter the spongy tissue inside bones, often lying dormant for years. Hormone receptor-positive breast cancers are the most common type of breast cancer, according to the American Society of Clinical Oncology, and grow by exploiting the body’s estrogen or progesterone. In human patients, these dormant cells can resurge later and create metastatic cancer relapse, for which there is no cure, said Sipkins, who is the paper’s senior author. Biopsies of bone marrow in human breast cancer patients have shown that even at very early stages of the cancer, roaming cancer cells, or micrometastases, are making their way out of the breast and into the bone marrow, Sipkins said. “Now we know how they are getting in,” she said. “We also identified an important mechanism that allows them to remain anchored in the bone marrow. In the mouse, our findings could offer new strategies to intervene at the molecular level before dormant cells can take hold and cause relapse.” One strategy is finding a way to inhibit E-selectin, which could limit the cancer’s ability to travel into the bone and resurge as metastatic cancer, she said. The scientists used an E-selectin inhibitor called GMI-1271, which is currently in human clinical trials. They found the compound successfully prevented the breast cancer cells from entering the bone marrow in mice. Because microscopic metastases can spread to the bone marrow before patients are even diagnosed with breast cancer, the researchers also tested a strategy that appears to kick dormant breast cancer cells out of their safe house in the bone marrow and back into circulation. They gave the mice plerixafor, an agent used in human bone marrow donors to push stem cells into the bloodstream for harvesting. The drug was able to force dormant breast cancer cells out of the bone tissue into the bloodstream. The researchers hypothesize that flushing these dormant cancer cells back into the bloodstream might give the immune system, chemotherapy or hormonal therapy another opportunity at killing them off, Sipkins said. She and colleagues hope to investigate that approach further. “We are hopeful that by understanding how these breast cancer cells migrate through the body and what their life cycle is, we can discover ways to make them more vulnerable and treatable,” Sipkins said. “Our hope is to move forward with additional studies in mice to better understand our approach before moving on to studies in humans.” In addition to Sipkins, study authors include lead author Trevor T. Price; Monika L. Burness; Ayelet Sivan; Matthew J. Warner; Renee Cheng; Clara H. Lee; Lindsey Olivere; Karrie Comatas; John Magnani; H. Kim Lyerly; Qing Cheng; and Chad M. McCall.The research was supported by the Young Investigator Award program of the American Society of Clinical Oncology, a Developmental Research Project Award from the University of Chicago Breast Cancer Specialized Program of Research Excellence AQ16, and the Duke Cancer Institute. The authors cite one disclosure: John Magnani is vice president and chief scientific officer of GlycoMimetics Inc. GlycoMimetics has a patent for GMI-1271, which was used in the study to inhibit E-selectin in breast cancer cells. ###
Newswise — A small survey of residents of a Florida Keys neighborhood where officials hope to release genetically modified mosquitos to potentially reduce the threat of mosquito-borne illnesses such as Zika finds a lack of support for the control method, according to new research from former and current students at the Johns Hopkins Bloomberg School of Public Health. The findings, published last month in PLOS Currents Outbreaks, suggest that people’s attitudes toward this new mosquito control method may be tied to pre-existing beliefs about risks of contracting diseases including dengue, chikungunya and Zika from the insects. The researchers say that people who do not feel that they are at risk from mosquito-borne diseases or who don’t believe that mosquitoes are a nuisance express greater discomfort with the idea of introducing male Aedes aegypti mosquitoes which are bred to mate with wild females and produce offspring with a defective gene that kills them, thereby reducing the population of disease-carrying mosquitoes. The novel mosquito control method has been tried in Brazil and Panama with some success, and the U.S. Food and Drug Administration is considering a trial in Key Haven, a community in the Florida Keys. Aedes aegypti carry all three diseases, though no local mosquito-borne cases of Zika virus have been reported in the United States. Zika has been linked to brain-related birth defects in babies born to pregnant mothers who contract the virus. The scientists, current students and recent graduates of the Bloomberg School, say the research could help public health and community leaders address head-on the objections of residents where such control measures are being contemplated, as the fight against mosquito-borne illnesses heats up. The survey was conducted in the second half of 2015, after locally transmitted dengue and chikungunya cases had been discovered in Florida, but before the Zika epidemic in South and Central America became big news. There is concern that Zika could spread north into the continental U.S. The band from southern Florida, including the Keys, to southern Texas, as well as Hawaii, are believed to be part of the region of the U.S. most at risk. A British company, Oxitec, has been trying for years to get approval to test their genetically modified mosquitoes in the Keys. Some local residents have tried to kill the field trial, concerned about unanticipated consequences of introducing these lab-grown insects into the wild. “With the start of mosquito season here and all of the media coverage of Zika, public health officials are going to be faced with important decisions about mosquitoes and how to best protect citizens,” says Meghan McGinty, MPH, MBA, a recent PhD recipient from the Bloomberg School and one of the researchers. “People will have objections and it is critical for them to be heard. Our research provides a starting point to understand how the community feels and to begin a dialogue about how to address mosquito-borne diseases.” For the study, the researchers mailed a survey in July 2015 to all 456 households in the Key Haven community outside Key West; they received 89 responses. Residents were evenly split over whether they consider mosquitoes a nuisance, but two-thirds agreed there was a need to reduce the mosquito population. Women were more opposed to the genetically modified mosquitoes than men. The most popular mosquito control method was draining standing water to reduce breeding, followed by treating standing water with larvicides designed to kill new mosquitoes before they hatch and spraying insecticides. The least popular was using genetically modified mosquitoes to reduce the population. Fifty-eight percent of respondents said they either “oppose” or “strongly oppose” the use of genetically modified mosquitoes to combat the risk of disease. The most common objection was a concern over disturbing the local ecosystem by eliminating mosquitoes from the food chain. Respondents were also concerned that using genetically modified mosquitoes could lead to an increase in the use of other genetically modified products. Since the survey was conducted before the extent of the Zika epidemic was widely known, respondents were only asked about their concerns about dengue and chikungunya (the area was hit by a dengue outbreak several years ago). Sixty-three percent said they were “a little worried” or “very worried” about becoming sick from one of those mosquito-borne illnesses, and most said they or someone they knew would contract one of the diseases. Researcher Crystal Boddie, MPH, a DrPH candidate in the Bloomberg School’s Department of Health Policy and Management, who is also employed at the University of Pittsburgh Medical Center’s Center for Health Security in Baltimore, says that those who were most concerned about the risk of contracting one of the mosquito-borne illnesses were more likely to support the release of the new mosquitoes. The researchers recognize that their sample size is small and that with the rising threat of Zika, opinions may have changed about the use of these genetically modified mosquitoes. Still, Boddie says, “the survey provides a baseline of information about residents’ attitudes and concerns and can help health officials better educate the public about the risks and benefits of these genetically modified mosquitoes. Then we need to have an honest conversation about where this control method does – or does not – fit in.” “Genetically Modified (GM) Mosquito Use to Reduce Mosquito-Transmitted Disease in the US: A Community Opinion Survey” was written by Amesh Adalja, Tara Kirk Sell, Meghan McGinty and Crystal Boddie.
Newswise — According to a recent survey by FAIR Health, a nonprofit organization that gathers information on health data, more than 50 percent of millennials use means such as retail clinics, urgent care centers or emergency rooms for nonemergency medical care. University of Alabama at Birmingham School of Medicine Associate Dean of Rural and Primary Care William Curry, M.D., says convenience is the main factor. “Those care providers are convenient, and often they provide exactly the care someone needs,” Curry said. “It’s important to realize they cannot take the place of a primary care provider for the screening, prevention and long-term follow-up that we all need, customized to each of us.” Curry says that generally healthy and busy younger people of every generation typically assume everything was fine as long as they felt good, but screening and preventive services have proved to be worthwhile at every age. He says millennials may have additional barriers to hearing and believing primary care is important. “For one thing, medicine has oversold and misdirected some efforts, making skepticism understandable,” Curry said. “We have ‘medicalized’ so much that the volume of recommendations and warnings can lead to information overload and alarm fatigue.” Millennials typically turn to Google and WebMD before visiting actual doctors, whom they are less likely to visit repeatedly or regularly. “Millennials have grown up with the internet and great digital tools that bring libraries and opinions to their fingertips,” he said. “I see them sometimes assuming all that information is equally reliable when it is not.” Curry says millennials sometimes believe they can find simpler, less demanding alternatives through the internet and a dietary regimen or natural remedy. “These may be helpful or not, but they unfortunately can’t take the place of medical screening and prevention that has been proved effective,” he said. “The short solution is to have a healthy skepticism but to accept good evidence of value.” Curry also believes a lack of primary care physicians is another reason millennials are less likely to seek one out. “The shortages of primary care physicians are bad enough just from the lack of supply and the growth of the population,” Curry said. “With more people having insurance, demand for primary care services increases.” He says Alabama has been more accommodating to shortages of primary care physicians for a much longer time compared to states like Massachusetts. Why does it matter? Curry says there are many advantages for millennials to find a primary care physician. He says seeing someone who knows you and has a baseline record is quicker — and there is less chance that something will be overlooked. Curry says relationships matter, and patients are more likely to get the correct diagnoses and treatments if they have a primary care provider. For those with a personal history of a chronic health problem or of a family history of problems that often are inherited, such as diabetes, high blood pressure, heart disease, stroke, high cholesterol, chronic lung disease, or others, it is especially important to have a primary care physician, regardless of age. Everyone should be screened for certain disorders, many of which can be present without symptoms for years. Women should get cervical cancer screenings and vaccinations. If all is well, repeat checks can be as infrequent as every three to five years for people under the age of 30. These approaches can prevent avoidable complications such as heart attack, stroke, kidney failure or vision loss. “Unfortunately, if people wait for symptoms, a lot of damage will have occurred,” Curry said. What do I look for? Curry says it is important to research when it comes to looking for a primary care physician. “Find someone who is available and with whom you feel comfortable,” he said. “Check their profile for where they trained and whether they are board-certified. Do they have an internet patient portal to make communication easy for test results or questions? Are office hours a fit for your schedule? What kind of coverage is available from a partner or associate if your physician is out? Do they have nurse practitioners or physician assistants in the practice to improve access?” He says, if possible, talk to someone with experience as a patient there, or check online comments or ratings; but keep in mind these ratings may not be entirely reliable.
NOVEL PROTEIN INHIBITORS ENGINEERED AS ALTERNATIVE APPROACH TO POTENTIALLY TREAT CANCER AND OTHER DISEASES
Newswise — Researchers from the Charles E. Schmidt College of Medicine at Florida Atlantic University have engineered endogenous protein inhibitors of protein-degrading enzymes as an alternative approach to synthetic inhibitors for potentially treating cancer and other diseases. Results of their study, titled “Thermodynamics of Selectivity in N-TIMP/MMP Interactions,” were recently published in the Journal of Biological Chemistry.They have been investigating a group of four proteins called tissue inhibitors of metalloproteinases (TIMPs) that inhibit and control the activities of a group of 23 enzymes called matrix metalloproteinases (MMPs). Pharmaceutical companies have previously investigated the possible use of synthetic MMP inhibitors for treating cancer and other diseases, but they failed in clinical trials due to side effects, most likely because they were insufficiently specific and inhibited MMPs needed for normal physiological processes. “There are 23 MMPs in humans that degrade or hydrolyze all of the protein components of extracellular matrices such as cartilage, bone, and basement membranes,” said Keith Brew, Ph.D., a professor of biomedical science in FAU’s College of Medicine. “If the regulation of their activities fails, MMPs can damage cells and extracellular structures, and their unregulated activities that are linked to serious diseases including osteoarthritis, heart disease, and cancer metastasis.” The TIMPs developed by Brew were designed to make them specific inhibitors of selected MMP targets to potentially treat osteoarthritis and cancer. “In our study, we have been able to determine the thermodynamic profiles for the interactions of normal and mutant TIMPs with three MMPs, so that we can develop an understanding of the relationship between structural changes produced by the mutations and the changes in their abilities to inhibit different MMPs,” said Brew. To accomplish this, the researchers used a technique called “isothermal titration calorimetry” (ITC), which measures the minute amounts of heat that are given out or absorbed when two molecules interact together (the enthalpy of binding). When they measured how this varies as they increased the quantities of one protein under different conditions of temperature and solvent, they were able to determine the enthalpy change (heat absorbed or released), entropy change (a measure of dynamics in the proteins and their surroundings) and heat capacity change, enabling them to separately estimate the changes in protein and solvent dynamics. Unlike most other protein-to-protein interactions, they found that TIMP/MMP interactions are driven by entropy increases, and not by enthalpy (which derives from specific interactions between chemical groups in the interacting molecules). They found that proportions of entropy coming from internal dynamics in the protein and from the solvent varies for different interactions, and is affected by TIMP mutations, but that the MMP component has a major role in determining the proportions. “When we think of two proteins binding together, we have to consider that they are dynamic molecules, each consisting of a population of interconverting three-dimensional structures,” said Brew. “Complex formation involves the selection of subpopulations that are compatible with each other in structures and dynamics, a process called ‘conformer selection.’ And, it appears that the MMP component has a major role in this process making the rational design of selective mutants difficult.” Co-authors of the study also include FAU’s College of Medicine and Charles E. Schmidt College of Science Ph.D. students Haiyin Zou and Ying Wu. This research is supported by the National Institutes of Health (NIH), grant AR40994.- FAU - About Florida Atlantic University:Florida Atlantic University, established in 1961, officially opened its doors in 1964 as the fifth public university in Florida. Today, the University, with an annual economic impact of $6.3 billion, serves more than 30,000 undergraduate and graduate students at sites throughout its six-county service region in southeast Florida. FAU’s world-class teaching and research faculty serves students through 10 colleges: the Dorothy F. Schmidt College of Arts and Letters, the College of Business, the College for Design and Social Inquiry, the College of Education, the College of Engineering and Computer Science, the Graduate College, the Harriet L. Wilkes Honors College, the Charles E. Schmidt College of Medicine, the Christine E. Lynn College of Nursing and the Charles E. Schmidt College of Science. FAU is ranked as a High Research Activity institution by the Carnegie Foundation for the Advancement of Teaching. The University is placing special focus on the rapid development of critical areas that form the basis of its strategic plan: Healthy aging, biotech, coastal and marine issues, neuroscience, regenerative medicine, informatics, lifespan and the environment. These areas provide opportunities for faculty and students to build upon FAU’s existing strengths in research and scholarship. For more information, visit www.fau.edu.
Newswise — Researchers from University College London have discovered that the widely used antiinflammatory drug HUMIRA doesn’t just work by inhibiting its target protein, TNF, but by enhancing a particular function of TNF in rheumatoid arthritis patients. The study, “Anti-TNF drives regulatory T cell expansion by paradoxically promoting membrane TNF–TNF-RII binding in rheumatoid arthritis,” which will be published online June 6 in The Journal of Experimental Medicine, may help explain the divergent efficacies of different TNF-targeting drugs. TNF is an important inflammatory molecule produced by the immune system, and TNF inhibitors are commonly used to treat inflammatory diseases such as rheumatoid arthritis and Crohn’s disease. One such inhibitor is the monoclonal anti-TNF antibody adalimumab, commonly marketed under the brand name HUMIRA. Michael Ehrenstein and colleagues at University College London previously found that treating rheumatoid arthritis patients with adalimumab increased the number of regulatory T cells capable of suppressing inflammation. Researchers presumed that this was because, in the absence of adalimumab, TNF blocks the development of these regulatory T cells. Mysteriously, however, another TNF inhibitor, etanercept, doesn’t induce the formation of these inflammation-suppressing T cells in rheumatoid arthritis patients. Ehrenstein and his colleague, Dao Xuan Nguyen, now report that, unlike etanercept, adalimumab actually enhances the ability of TNF to induce the formation of antiinflammatory T cells. In particular, Nguyen and Ehrenstein discovered that adalimumab increases the expression of TNF on the surface of patient monocytes and promotes the association of these TNF molecules with receptor proteins on the surface of regulatory T cells. This activates a signaling pathway that endows the T cells with the capacity to suppress inflammation. Adalimumab may therefore block the proinflammatory functions of soluble TNF secreted by immune cells, while augmenting the activity of membrane-bound TNF that ultimately helps to resolve inflammation. “These results highlight how a treatment that targets a pivotal inflammatory cytokine not only preserves but actually boosts the pro-resolution forces driven by that pathway, thereby introducing a novel therapeutic paradigm,” Ehrenstein says. Nguyen, D.X., and M.R. Ehrenstein. 2016. J Exp. Med. http://dx.doi.org/10.1084/jem.20151255 # # #
Newswise — MADISON, Wis. — A new mouse model, developed by researchers at the University of Wisconsin–Madison, is the first to show that when more of a specific biological molecule moves between different parts of nerve cells in the mouse brain, it can lead to behaviors that resembles some aspects of autism spectrum disorder (ASD) in humans. This biological molecule, called acetyl-CoA, is a major part of the process cells use to make energy from food. It’s also used within cells to tag different proteins, which influences where and how they function. Local concentrations of acetyl-CoA and its movement, or flux, between different areas within cells is tightly regulated. “We show, for the very first time, that changes in acetyl-CoA flux, and not just changes in its levels, in individual neurons can affect neuronal activity,” says Luigi Puglielli, a professor in the Department of Medicine of the UW-Madison School of Medicine and Public Health and the UW’s Waisman Center. In the study, published this week in The Journal of Experimental Medicine, the researchers engineered mice to make the human version of a protein that ferries acetyl-CoA into a specific compartment within cells. Mouse models of ASD can help scientists understand the molecular basis of the disorder. Previous studies revealed that mutations in this ferrying protein, which is called AT-1, are associated with spastic paraplegia, severe developmental delays and autism spectrum disorder in humans. But how mutations in AT-1 are linked to these developmental disorders was unknown. The current study showed that changes in the amount of AT-1 in nerve cells can profoundly influence how much acetyl-CoA is found in different areas within those cells. When AT-1 levels are high, as is the case in the brains of the mice with the human AT-1 protein, increased movement of acetyl-CoA into specific areas within cells sets off a chain reaction of consequences that the researchers think ultimately leads to the mice showing autism-like behaviors. “We could call AT-1 a ‘master regulator’ of intracellular acetyl-CoA flux, which, in turn, can be said to be a master regulator of essential neuronal functions,” says Puglielli. In the brains of mice with human AT-1, atypical localization of acetyl-CoA in the nerve cells causes a slew of more than 400 genes to become dysregulated and pump out higher levels of proteins. Several of these proteins play important roles in regulating both the growth of neurons and how nerve impulses travel through them. The global changes in protein levels caused by manipulating these master regulators leads to significant changes in what nerve cells look like and how they function in these mice. For instance, the ends of the nerve cells become more branched and spiny and their ability to mediate typical learning and memory formation is compromised. Puglielli and his colleagues think these changes in how the nerve cells look and function ultimately caused the AT-1 mice to behave atypically, in ways that resemble aspects of ASD in humans. “We need to be able to modify genetic, molecular and biochemical aspects of the disorder,” says Puglielli. “These sort of manipulations and studies cannot be performed in humans, hence the need to develop and study mouse models.” While mouse models can provide vital information about human disorders, such as ASD, the researchers urge caution while interpreting findings. “ASD is difficult to define in humans and there are different behaviors that we globally include under the umbrella of autism,” says Puglielli. “If it is difficult to define autism — a human disorder — in humans, you can imagine how much more difficult it is to define in mice.” Puglielli and his colleagues are now looking at other proteins that regulate acetyl-CoA movement within cells. “Mutations in these proteins are also associated with different disorders, including ASD and intellectual disability,” he says. “A comprehensive analysis of the functions of these proteins will help us dissect more aspects of how acetyl-CoA flux is relevant to ASD.” —Adityarup “Rup” Chakravorty
Newswise — Drug-cue associations can have a powerful influence over individuals with drug and alcohol use disorders, often leading to relapse in those attempting to stay abstinent. Few studies have investigated how drugs affect learning or memory for drug-associated stimuli in humans. This study examined the direct effects of alcohol on memory for images of alcohol-related beverages, such as beer bottles or liquor glasses, or neutral beverages, such as water bottles or soda cans, in social drinkers. Researchers assigned subjects to one of three conditions: one group (n=20) received an intoxicating dose of alcohol (0.8 g/kg) before viewing visual images, called the Encoding condition; a second group (n=20) received the same amount of alcohol immediately after viewing them, called the Consolidation condition. A third group (n=19) received a placebo both before and after viewing the images, called the Control condition. Memory retrieval was tested exactly 48 hours later, in a drug-free state. Results indicate that alcohol impairs memory in the Encoding condition and enhances memory in the Consolidation condition. However, individual differences in sensitivity to alcohol’s positive rewarding effects are associated with a greater tendency to remember alcohol-related environmental stimuli encountered while intoxicated. In other words, these individuals may form stronger memory associations with alcohol-related stimuli, which may then strengthen their drinking behavior and/or place them at a greater risk of relapse if they decide to stop drinking.
Newswise — Physicians have long used magnetic resonance imaging (MRI) to detect cancer but results of a University of California San Diego School of Medicine study describe the potential use of restriction spectrum imaging (RSI) as an imaging biomarker that enhances the ability of MRI to differentiate aggressive prostate cancer from low-grade or benign tumors and guide treatment and biopsy. “Noninvasive imaging is used to detect disease, but RSI-MRI takes it a step further,” said David S. Karow, MD, PhD, assistant professor of radiology at UC San Diego School of Medicine and the study’s senior author. “We can predict the grade of a tumor sometimes without a biopsy of the prostate tissue. This is taking all that’s good about multi-parametric MRI and making it better.” The addition of RSI to a pelvic MRI added between 2.5 to 5 minutes to scanning time making it a fast and highly accurate tool with decreased risk compared to contrast MRI which involves injecting patients with dye, said Karow. In the study, published online June 1 in Clinical Cancer Research, the authors said RSI-MRI corrects for magnetic field distortions found in other imaging techniques and focuses upon water diffusion within tumor cells that exhibit a high nuclear volume fraction. By doing this, the ability of imaging to accurately plot a tumor’s location is increased and allows for differentiation between tumor grades. The higher the grade, the more aggressive the cancer. Patients can have more than one tumor with different grades, however. Karow said RSI-MRI can be used to guide treatment or biopsy to target the region of highest-grade cancer. An early diagnosis of prostate cancer typically improves a patient’s prognosis. According to the National Cancer Institute, prostate cancer is the second leading cause of cancer death in men in the United States, with more than 26,000 estimated deaths this year and 180,890 new diagnoses predicted. The average age at the time of diagnosis is 66. At UC San Diego Health, more than 1,000 patients have been imaged with RSI-MRI since 2014 and a subset have subsequently undergone MR-fused ultrasound guided prostate biopsy, said J. Kellogg Parsons, MD, MHS, UC San Diego School of Medicine associate professor of surgery and study co-author. “Previously, we relied completely on systematic — but random — biopsies of the prostate to diagnose cancer, which has been the standard practice in our field for years. Now, we use RSI-MRI to precisely target specific areas of concern and enhance the accuracy of our diagnosis,” said Parsons, surgical oncologist at Moores Cancer Center at UC San Diego Health. “Greater accuracy means improved care tailored to each individual patient. With RSI-MRI, we are better able to identify which cancers are more aggressive and require immediate treatment, and which ones are slow growing and can be safely observed as part of a program called active surveillance.” Although this study focused on 10 patients, more than 2,700 discrete data points were evaluated. Next steps include introducing the technology to other hospitals and to study whether it can be used in isolation from other screening tools. In prior papers published in the journalsAbdominal Radiology and Prostate Cancer Prostatic Diseases, the same authors reported that RSI-MRI increases detection capability and can perform better than traditional multi-parametric MRI when used in isolation. These data suggest that RSI-MRI could eventually serve as a stand-alone, non-contrast screening tool that would take 15 minutes compared to a normal contrast-enhanced exam lasting 40 to 60 minutes. “What our evidence shows so far is the imaging benefit is coming from RSI-MRI,” said Karow. “I think this technique could become standard of care and mainstream for the vast majority of men who are at risk for prostate cancer. Full contrast MRI is expensive and risky for most men. This is the kind of exam that could be done on a routine clinical basis.” Anders Dale, PhD, professor of radiology and neurosciences and co-director of the Multimodal Imaging Laboratory at UC San Diego, and Nate White, PhD, assistant professor of radiology, initially co-invented RSI-MRI to characterize aggressive brain tumors. “RSI-MRI could be a transformational imaging technology for oncologists in the same way CT scans altered the way effects of treatment are quantitated from plain X-rays,” said Jonathan W. Simons, MD, Prostate Cancer Foundation president and Chief Executive Officer. “Based on the investigations at UC San Diego, this is a particular promise that needs more validation. Now testable is the hypothesis that RSI-MRI could identify oligometastatic prostate cancer that became curable through its identification by RSI-MRI.” Additional study co-authors include: Ghiam Yamin, Natalie M. Schenker-Ahmed, Ahmed Shabaik, Dennis Adams, Hauke Bartsch, Joshua Kuperman, Nate White, Rebecca A. Rakow-Penner, Kevin McCammack, Christopher J. Kane, and Anders M. Dale, all at UC San Diego. This research was funded, in part, by Department of Defense Prostate Cancer Research Program (W81XWH-13-1-0391), American Cancer Society Institutional Research grant (70-002), UCSD Clinician Scientist Program (5T32EB005970-07), UCSD School of Medicine Microscopy Core and NINDS P30 core grant (NS047101), General Electric Investigator Initiated Research Award (BOK92325), and the National Science Foundation (1430082). ###
Newswise — Statistics show that some 15 million Americans don’t work the typical nine-to-five. These employees (or shift workers), who punch in for graveyard or rotating shifts, are more prone to numerous health hazards, from heart attacks to obesity, and now, new research, published in Endocrinology, shows shift work may also have serious implications for the brain. “The body is synchronized to night and day by circadian rhythms—24-hour cycles controlled by internal biological clocks that tell our bodies when to sleep, when to eat and when to perform numerous physiological processes,” said David Earnest, Ph.D., professor in the Department of Neuroscience and Experimental Therapeutics at the Texas A&M Health Science Center College of Medicine. “A person on a shift work schedule, especially on rotating shifts, challenges, or confuses, their internal body clocks by having irregular sleep-wake patterns or meal times.” According to Earnest, it’s not the longer hours—or the weird hours—necessarily that is the problem. Instead, it is the change in the timing of waking, sleeping and eating every few days that “unwinds” our body clocks and makes it difficult for them to maintain their natural, 24-hour cycle. When body clocks are disrupted, as they are when people go to bed and get up at radically different times every few days, there can be a major impact on health. Earnest and his colleagues have found that shift work can lead to more severe ischemic strokes, the leading cause of disability in the United States, which occur when blood flow is cut off to part of the brain. Using an animal model, Earnest and his team, including colleague Farida Sohrabji, Ph.D., also a professor in the Department of Neuroscience and Experimental Therapeutics and director of the Women’s Health in Neuroscience Program, found that subjects on shift work schedules had more severe stroke outcomes, in terms of both brain damage and loss of sensation and limb movement than controls on regular 24-hour cycles of day and night. Of interest, their study—supported by the American Heart Association—found that males and females show major differences in the degree to which the stroke was exacerbated by circadian rhythm disruption; in males, the gravity of stroke outcomes in response to shift work schedules was much worse than in females. “These sex differences might be related to reproductive hormones. Young women are less likely to suffer strokes, as compared with men of a similar age, and when they do, the stroke outcomes are likely to be less severe. In females, estrogen is thought to be responsible for this greater degree of neuroprotection,” Sohrabji said. “Essentially, estrogen helps shield the brain in response to stroke.” However, older women approaching menopause show increasing incidence of ischemic stroke and poor prognosis for recovery, compared with men at the same age. Some of Earnest’s previous work has shown that a high-fat diet can also alter the timing of internal body clocks, as well as dramatically increase inflammatory responses that can be a problem in cardio- and cerebrovascular disease (conditions caused by problems that affect the blood supply to the brain—which includes stroke). “Next we would like to explore whether inflammation is a key link between circadian rhythm disruption and increased stroke severity,” Earnest said. “With this information, we may be able to identify therapeutic interventions that limit damage after a stroke in patients with a history of shift work.” “This research has clear implications for shift workers with odd schedules, but probably extends to many of us who keep schedules that differ greatly from day-to-day, especially from weekdays to weekends,” Earnest added. “These irregular schedules can produce what is known as ‘social jet lag,’ which similarly unwinds our body clocks so they no longer keep accurate time, and thus can lead to the same effects on human health as shift work.” An immediate impact of these studies on human health is that individuals in shift work-type professions should be monitored more closely and more frequently for cardio- and cerebrovascular disease and risk factors such as hypertension and obesity. In the meantime, Earnest suggests that those with irregular sleeping patterns should at least try to maintain regular mealtimes, in addition to avoiding the usual cardiovascular risk factors like a high-fat diet, inactivity and tobacco use.
Newswise — How does stress – which, among other things, causes our bodies to divert resources from non-essential functions – affect the basic exchange of materials that underlies our everyday life? Weizmann Institute of Science researchers investigated this question by looking at a receptor in the brains of mice, and they came up with a surprising answer. The findings, which recently appeared in Cell Metabolism, may in the future aid in developing better drugs for stress-related problems and eating disorders. Dr. Yael Kuperman began this study as part of her doctoral research in the lab of Prof. Alon Chen of the Department of Neurobiology. Dr. Kuperman, presently a staff scientist in the Veterinary Resources Department, Prof. Chen, and research student Meira Weiss focused on an area of the brain called the hypothalamus, which has a number of functions, among them helping the body adjust to stressful situations, controlling hunger and satiety, and regulating blood glucose and energy production. When stress hits, cells in the hypothalamus step up production of a receptor called CRFR1. It was known that this receptor contributes to the rapid activation of a stress-response sympathetic nerve network – increasing heart rate, for example. But since this area of the brain also regulates the body’s exchange of materials, the team thought that the CRFR1 receptor might play a role in this, as well. Prof. Chen and his group characterized the cells in a certain area of the hypothalamus, finding that the receptor is expressed in around half of the cells that arouse appetite and suppress energy consumption. These cells comprise one of two main populations in the hypothalamus – the second promotes satiety and the burning of energy. “This was a bit of a surprise,” says Dr. Kuperman, “as we would instinctively expect the receptor to be expressed on the cells that suppress hunger.” To continue investigating, the researchers removed the CRFR1 receptor in mice from just the cells that arouse appetite in the hypothalamus, and then observed how this affected the animals’ bodily functions. At first, the team did not see any significant changes, confirming that this receptor is saved for stressful situations. But when they exposed the mice to stress – cold or hunger – they got another surprise. When exposed to cold, the sympathetic nervous system activates a unique type of fat called brown fat, which produces heat to maintain the body’s internal temperature. When the receptor was removed, the body temperature dropped dramatically – but only in the female mice. Their temperatures failed to stabilize even afterward the stressor was removed, while male mice showed hardly any change. Fasting produced a similarly drastic response in the female mice. Normally, when food is scarce, the brain sends a message to the liver to produce glucose, conserving a minimum level in the blood. But when food was withheld from female mice missing the CRFR1 receptor, the amount of glucose their livers produced dropped significantly. In hungry male CRFR1-deficient mice, the result was similar to the effects of exposure to cold: the exchange of materials in their bodies was barely affected. “We discovered that the receptor has an inhibitory effect on the cells, and this is what activates the sympathetic nervous system,” says Dr. Kuperman. Among other things – revealing exactly how this receptor works and how it contributes to the stress response – the findings show that male and female bodies may exhibit significant differences in the ways that materials are exchanged under stress. Indeed, the fact that the receptor suppresses hunger in females may help explain why women are much more prone to eating disorders than men. Because drugs can enter the hypothalamus with relative ease, the findings could be relevant to the development of treatments for regulating hunger or stress responses, including anxiety disorders or depression. Indeed, several pharmaceutical companies have already begun developing psychiatric drugs to block the CRFR1 receptor. The scientists caution, however, that because the cells are involved in the exchange of materials, blocking the receptor could turn out to have such side effects as weight gain. Prof. Alon Chen’s research is supported by the Henry Chanoch Krenter Institute for Biomedical Imaging and Genomics; the Perlman Family Foundation, Founded by Louis L. and Anita M. Perlman; the Adelis Foundation; the Irving I Moskowitz Foundation; the European Research Council; the estate of Tony Bieber; and the Ruhman Family Laboratory for Research in the Neurobiology of Stress.The Weizmann Institute of Science in Rehovot, Israel, is one of the world’s top-ranking multidisciplinary research institutions. The Institute’s 3,800-strong scientific community engages in research addressing crucial problems in medicine and health, energy, technology, agriculture, and the environment. Outstanding young scientists from around the world pursue advanced degrees at the Weizmann Institute’s Feinberg Graduate School. The discoveries and theories of Weizmann Institute scientists have had a major impact on the wider scientific community, as well as on the quality of life of millions of people worldwide.