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Newswise — Patients who take medication for depression report more side effects if they also suffer from panic disorder, according to a new study led by researchers from the University of Illinois at Chicago published in the Journal of Clinical Psychiatry. The researchers looked at data from 808 patients with chronic depression who were given antidepressants as part of the Research Evaluating the Value of Augmenting Medication with Psychotherapy (REVAMP) trial. Of those patients, 85 also had diagnoses of panic disorder. Among all participants, 88 percent reported at least one side effect during the 12 week trial, which ran from 2002 through 2006. Every two weeks, antidepressant side effects were assessed, and categorized as gastrointestinal, cardiovascular, dermatological, neurological, genitourinary, sleep, or sexual functioning. The researchers found that patients with depression and panic disorder were more likely than those with only depression to self-report gastrointestinal (47 percent vs. 32 percent), cardiovascular (26 percent vs. 14 percent), neurological (59 percent vs. 33 percent), and genital/urinary side effects (24 percent vs. 8 percent). Co-occurring panic disorder was not associated with eye or ear issues or dermatological, sleep or sexual functioning side effects compared to participants without panic disorder. “People with panic disorder are especially sensitive to changes in their bodies,” said Stewart Shankman, professor of psychology and psychiatry at UIC and corresponding author on the paper. “It’s called ‘interoceptive awareness.’“Because these patients experience panic attacks — which are sudden, out-of-nowhere symptoms that include heart racing, shortness of breath, and feeling like you’re going to die — they are acutely attuned to changes in their bodies that may signal another panic attack coming on. So it does make sense that these tuned-in patients report more physiological side effects with antidepressant treatment.” Response to antidepressants varies greatly, and side effects are common. Many patients who experience side effects switch medication or change dosage. Some discontinue therapy altogether. Participants with co-occurring panic disorder were also more likely to report a worsening of their depressive symptoms over the 12 weeks if they reported multiple side effects. “In patients with panic disorder, the more side effects they reported, the more depressed they got,” said Shankman. “Whether the side effects are real or not doesn’t matter, but what was real was that their depression worsened as a function of their side effects.” Shankman cautions that physicians and therapists should be aware that their patients with panic disorder may report more side effects, and they should “do a thorough assessment of these side effects to try to tease out what might be the result of hypersensitivity, or what might be a side effect worth switching doses or medications for.” Co-authors on the paper are Stephanie Gorka, and Andrea Katz of UIC; Daniel Klein of Stony Brook University; Dr. John Markowitz of Columbia University College of Physicians and Surgeons; Bruce Arnow, Rachel Manber and Alan Schatzberg of the Stanford University School of Medicine; Barbara Rothbaum of Emory University School of Medicine; Dr. Michael Thase of the University of Pennsylvania School of Medicine; Dr. Martin Keller of Brown University School of Medicine; Dr. Madhukar Trivedi of University of Texas Southwestern Medical Center; and Dr. James Kocsis of Weill-Cornell Medical College. This research was supported by grants U01 MH62475, U01 MH61587, U01 MH62546, U01 MH61562, U01 MH63481, U01 MH62465, U01 MH61590, U01 MH61504 and U01 MH62491 from the National Institute of Mental Health.    
Newswise — Overweight and obese children are at the highest risk for the most common complications from surgery, an infection at the site of the surgical procedure. This according to a new study, recently published in the medical journal, Surgical Infections.While obesity is a well-known risk factor for surgical site infections (SSI) among adult patients, this is the first research showing it is equally significant in pediatric populations. And since the incidence of childhood obesity in the US has nearly tripled since the 1970s, this indicates more and more children will possibly be at risk for these infections. “Research on this topic among children and adolescents is scarce,” said Catherine Hunter, MD, Pediatric Surgeon at Ann & Robert H. Lurie Children’s Hospital of Chicago and an Assistant Professor of Surgery and Pediatrics, Northwestern University Feinberg School of Medicine. (https://www.luriechildrens.org/en-us/care-services/find-a-doctor/Pages/Hunter_Catherine_3205.aspx) “The information from this first-of-its-kind study can now be used in assessing and counseling preoperative pediatric surgical patients and their families.” The study, titled “Overweight and Obese Pediatric Patients Have an Increased Risk of Developing a Surgical Site Infection,” included a search of the American College of Surgeons (ACS) National Surgical Quality Improvement Program-Pediatric (NSQIP-P) database, as well as a follow-up single center retrospective review. The latter review allowed for a more detailed analysis using specific outcomes variables that could not be analyzed using the NSQIP-P database, including looking at those overweight and obese pediatric patients who developed SSI despite having few other identifiable risk factors for infection. Cases from a total of 1,380 patients aged 2-18 (mean patient age 10.4 years) from the NSQIP-P database who had undergone major surgical procedures in 2012 and 2013 and who developed post-operative wound infections up to 30 days after surgery were reviewed. Patients were classified as underweight, normal/healthy weight, overweight, or obese, according to standard CDC pediatric growth charts, with a 95% confidence interval. Forty-percent of these patients who had SSIs were overweight or obese and without differences in gender. In the single site retrospective review, data from another 115 patients were considered. Of this population the average age was slightly younger at 9 years and 30% were overweight or obese. “When considering children, adolescents and adults, there are several theories as to why overweight or obese patients are at higher risk for infection,” said Dr. Hunter. “These include impaired wound healing due to the lower oxygen tension found in the excess fat tissue surrounding the wound as well as impaired lymphocyte responsiveness. However more studies need to look at this further.” Lurie Children’s is the only children’s hospital in Illinois and one of only a very few in the country, recognized by the American College of Surgeons as a Level I pediatric surgery center, the highest quality designation possible. It is ranked as one of the nation’s top children’s hospitals in the U.S. News & World Report, and is the pediatric training ground for Northwestern University Feinberg School of Medicine. Last year, the hospital served more than 174,000 children from 50 states and 48 countries.####### SEE ORIGINAL STUDY    
Newswise — EAST LANSING, Mich. – Michigan State University researchers have discovered that a chemical compound, and potential new drug, reduces the spread of melanoma cells by up to 90 percent. The man-made, small-molecule drug compound goes after a gene’s ability to produce RNA molecules and certain proteins in melanoma tumors. This gene activity, or transcription process, causes the disease to spread but the compound can shut it down. Up until now, few other compounds of this kind have been able to accomplish this. “It’s been a challenge developing small-molecule drugs that can block this gene activity that works as a signaling mechanism known to be important in melanoma progression,” said Richard Neubig, a pharmacology professor and co-author of the study. “Our chemical compound is actually the same one that we’ve been working on to potentially treat the disease scleroderma, which now we’ve found works effectively on this type of cancer.” Scleroderma is a rare and often fatal autoimmune disease that causes the hardening of skin tissue, as well as organs such as the lungs, heart and kidneys. The same mechanisms that produce fibrosis, or skin thickening, in scleroderma also contribute to the spread of cancer. Small-molecule drugs make up over 90 percent of the drugs on the market today and Neubig’s co-author Kate Appleton, a postdoctoral student, said the findings are an early discovery that could be highly effective in battling the deadly skin cancer. It’s estimated about 10,000 people die each year from the disease. Their findings are published in the January issue of Molecular Cancer Therapeutics. “Melanoma is the most dangerous form of skin cancer with around 76,000 new cases a year in the United States,” Appleton said. “One reason the disease is so fatal is that it can spread throughout the body very quickly and attack distant organs such as the brain and lungs.” Through their research, Neubig and Appleton, along with their collaborators, found that the compounds were able to stop proteins, known as Myocardin-related transcription factors, or MRTFs, from initiating the gene transcription process in melanoma cells. These triggering proteins are initially turned on by another protein called RhoC, or Ras homology C, which is found in a signaling pathway that can cause the disease to aggressively spread in the body. The compound reduced the migration of melanoma cells by 85 to 90 percent. The team also discovered that the potential drug greatly reduced tumors specifically in the lungs of mice that had been injected with human melanoma cells. “We used intact melanoma cells to screen for our chemical inhibitors,” Neubig said. “This allowed us to find compounds that could block anywhere along this RhoC pathway.” Being able to block along this entire path allowed the researchers to find the MRTF signaling protein as a new target. Appleton said figuring out which patients have this pathway turned on is an important next step in the development of their compound because it would help them determine which patients would benefit the most. “The effect of our compounds on turning off this melanoma cell growth and progression is much stronger when the pathway is activated,” she said. “We could look for the activation of the MRTF proteins as a biomarker to determine risk, especially for those in early-stage melanoma.” According to Neubig, if the disease is caught early, chance of death is only 2 percent. If caught late, that figure rises to 84 percent. “The majority of people die from melanoma because of the disease spreading,” he said. “Our compounds can block cancer migration and potentially increase patient survival.” The National Institutes of Health and MSU's annual Gran Fondo cycling event, which raises money for skin cancer research, funded the study. Additional researchers from MSU and the University of Michigan contributed to the project. ###
Newswise — Chicagoland families affected by autism can participate in the nation’s largest study to uncover genetic links to the condition by attending an on-site registration and data collection event in the western suburbs, Saturday, January 14. Families with a loved one on the autism spectrum are asked to share demographic, medical and behavioral information at: Right Fit Sports-Fitness-Wellness, 7101 S Adams, Willowbrook, 10 a.m. to 1 p.m.; or Turning Pointe, 1500 West Ogden Avenue, Naperville, 2 p.m. to 5 p.m. Participants with autism will receive a $50 gift card in the mail upon completion of their study. The research project, called SPARK (Simons Foundation Powering Autism Research for Knowledge), is hoping to collect family information and DNA samples from 50,000 people with autism and their family members. In Chicago, SPARK has partnered exclusively with Rush University Medical Center (RUMC).Families will be asked to fill out a short on-line family history form and complete a DNA test consisting of a simple spit sample or cheek swab. Participants are encouraged to register for the event in advance, however walk-ins are welcome. Those who register in advance will receive one free personal fitness session from Right Fit Sports Fitness Wellness. Right Fit specializes in movement and fitness programs for youth and adults on the autism spectrum. To register or for more information, contact the Autism Assessment, Research, Treatment and Services Center (AARTS) at Rush, (312) 563-2765, or email: Kathryn_A_Heerwagen@rush.edu. Autism is known to have a strong genetic component. To date, approximately 50 genes have been identified that almost certainly play a role in autism, and scientists estimate that an additional 300 or more are involved. For those who want to participate, but can’t attend the on-site testingor for more information, visit:www.SPARKforAutism.org/rush. The AARTS Center provides unparalleled expertise in diagnosis, treatment and research for individuals with autism spectrum disorder.    
Newswise — A study led by researchers at Children’s Hospital Los Angeles demonstrates what lead investigator Bradley Peterson, MD, calls “a critical mass of evidence” of a common underlying lifelong vulnerability in both children and adults who stutter. They discovered that regional cerebral blood flow is reduced in the Broca’s area – the region in the frontal lobe of the brain linked to speech production – in persons who stutter. More severe stuttering is associated with even greater reductions in blood flow to this region. In addition, a greater abnormality of cerebral blood flow in the posterior language loop, associated with processing words that we hear, correlates with more severe stuttering. This finding suggests that a common pathophysiology throughout the neural “language” loop that connects the frontal and posterior temporal lobe likely contributes to stuttering severity. Peterson, who is director of the Institute for the Developing Mind at CHLA and a professor of the Keck School of Medicine at the University of Southern California, says that such a study of resting blood flow, or perfusion, has never before been conducted in persons who stutter. His team also recently published a study using proton magnetic resonance spectroscopy to look at brain regions in both adults and children who stutter. Those findings demonstrated links between stuttering and changes in the brain circuits that control speech production, as well as those supporting attention and emotion. The present blood flow study adds significantly to the findings from that prior study and furthermore suggests that disturbances in the speech processing areas of the brain are likely of central importance as a cause of stuttering. According to Peterson, the new study – published on December 30 in the journal Human Brain Mapping – provides scientists with a completely different window into the brain. The researchers were able to zero in on the Broca’s area as well as related brain circuitry specifically linked to speech, using regional cerebral blood flow as a measure of brain activity, since blood flow is typically coupled with neural activity. “When other portions of the brain circuit related to speech were also affected according to our blood flow measurements, we saw more severe stuttering in both children and adults,” said first author Jay Desai, MD, a clinical neurologist at CHLA. “Blood flow was inversely correlated to the degree of stuttering – the more severe the stuttering, the less blood flow to this part of the brain,” said Desai, adding that the study results were “quite striking.” Additional contributors to the study include Ravi Bansal, Children’s Hospital Los Angeles and the Keck School of Medicine of USC; Yuankai Huo and Zhishun Wang, Columbia University; Steven C. R. Williams, David Lythgoe and Fernando O. Zelaya, King’s College, London, UK. This work was supported in part by Children’s Hospital Los Angeles, the National Institute of Mental Health grant K0274677, the Milhiser family fund and the Murphy endowment at Columbia University. About Children’s Hospital Los AngelesChildren's Hospital Los Angeles has been named the best children’s hospital in California and among the top 10 in the nation for clinical excellence with its selection to the prestigious U.S. News & World Report Honor Roll. Children’s Hospital is home to The Saban Research Institute, one of the largest and most productive pediatric research facilities in the United States. Children’s Hospital is also one of America's premier teaching hospitals through its affiliation since 1932 with the Keck School of Medicine of the University of Southern California. For more information, visit CHLA.org. Follow us on Twitter, Facebook, YouTube and LinkedIn, or visit our blog at http://researchlablog.org/.
Newswise — (NEW YORK —) Funding and publication of gun violence research are disproportionately low compared to other leading causes of death in the United States, according to new research from the Icahn School of Medicine at Mount Sinai published online today in the Journal of the American Medical Association (JAMA). The study also determined that over a ten-year period, in relation to mortality rates, gun violence was the least-researched cause of death and the second-least funded cause of death, after falls. Researchers analyzed mortality statistics from the Centers for Disease Control and Prevention (CDC) from 2004 to 2014 to determine the top 30 causes of death in the U.S. Findings indicated that gun violence killed about as many people as sepsis; however, funding for gun violence research was about 0.7% of that for sepsis, and publication volume was about 4%. “We’re spending and publishing far less than what we ought to be based on the number of people who are dying,” said David E. Stark, MD, MS, Assistant Professor, Department of Health System Design and Global Health, Icahn School of Medicine at Mount Sinai, and lead author of the study. “Research is the first stop on the road to public health improvement, and we’re not seeing that with gun violence the way we did with automobile deaths.” More than 30,000 people die each year from gun violence in the U.S., a higher rate of death than any industrialized country in the world. Historically, research on gun violence has been limited in the U.S., mainly due to language inserted in a 1996 congressional appropriations bill that states, “none of the funds made available for injury prevention and control at the Centers for Disease Control and Prevention may be used to advocate or promote gun control.” Although the legislation does not ban gun-related research outright, funding remains anemic for the research community. “Dr. Stark’s research is important because the data is compelling; gun violence had less funding and fewer publications than comparable injury-related causes of death including motor vehicle accidents and poisonings,” said Prabhjot Singh, MD, PhD, Chair, Department of Health System Design and Global Health, Icahn School of Medicine. “We know that gun violence disproportionately affects vulnerable communities, including young people, and inflicts many more nonfatal injuries than deaths. As a result, we suspect the magnitude of this disparity in research funding, when considering years of potential life lost or lived with disability, is even greater,” said Dr. Singh. Additional study collaborators include Nigam H. Shah, M.B.B.S., PhD, of the Stanford University School of medicine, Stanford, California. The research was supported by the National Library of Medicine of the National Institutes of Health (NIH) under Award Number T15LM007033. About the Mount Sinai Health SystemThe Mount Sinai Health System is an integrated health system committed to providing distinguished care, conducting transformative research, and advancing biomedical education. Structured around seven hospital campuses and a single medical school, the Health System has an extensive ambulatory network and a range of inpatient and outpatient services—from community-based facilities to tertiary and quaternary care. The System includes approximately 7,100 primary and specialty care physicians; 12 joint-venture ambulatory surgery centers; more than 140 ambulatory practices throughout the five boroughs of New York City, Westchester, Long Island, and Florida; and 31 affiliated community health centers. Physicians are affiliated with the renowned Icahn School of Medicine at Mount Sinai, which is ranked among the highest in the nation in National Institutes of Health funding per investigator. The Mount Sinai Hospital is on the “Honor Roll” of best hospitals in America, ranked No. 15 nationally in the 2016-2017 “Best Hospitals” issue of U.S. News & World Report. The Mount Sinai Hospital is also ranked as one of the nation’s top 20 hospitals in Geriatrics, Gastroenterology/GI Surgery, Cardiology/Heart Surgery, Diabetes/Endocrinology, Nephrology, Neurology/Neurosurgery, and Ear, Nose & Throat, and is in the top 50 in four other specialties. New York Eye and Ear Infirmary of Mount Sinai is ranked No. 10 nationally for Ophthalmology, while Mount Sinai Beth Israel, Mount Sinai St. Luke's, and Mount Sinai West are ranked regionally. Mount Sinai’s Kravis Children’s Hospital is ranked in seven out of ten pediatric specialties by U.S. News & World Report in "Best Children's Hospitals." For more information, visit http://www.mountsinai.org/, or find Mount Sinai on Facebook, Twitter and YouTube. # # #
Newswise — Researchers from North Carolina State University, the University of North Carolina at Chapel Hill and First Affiliated Hospital of Zhengzhou University have developed a synthetic version of a cardiac stem cell. These synthetic stem cells offer therapeutic benefits comparable to those from natural stem cells and could reduce some of the risks associated with stem cell therapies. Additionally, these cells have better preservation stability and the technology is generalizable to other types of stem cells. Stem cell therapies work by promoting endogenous repair; that is, they aid damaged tissue in repairing itself by secreting “paracrine factors,” including proteins and genetic materials. While stem cell therapies can be effective, they are also associated with some risks of both tumor growth and immune rejection. Also, the cells themselves are very fragile, requiring careful storage and a multi-step process of typing and characterization before they can be used. Ke Cheng, associate professor of molecular biomedical sciences at NC State University, associate professor in the joint biomedical engineering program at NC State and UNC and adjunct associate professor at the UNC Eshelman School of Pharmacy, led a team in developing the synthetic version of a cardiac stem cell that could be used in off-the-shelf applications. Cheng and his colleagues fabricated a cell-mimicking microparticle (CMMP) from poly (lactic-co-glycolic acid) or PLGA, a biodegradable and biocompatible polymer. The researchers then harvested growth factor proteins from cultured human cardiac stem cells and added them to the PLGA. Finally, they coated the particle with cardiac stem cell membrane. “We took the cargo and the shell of the stem cell and packaged it into a biodegradable particle,” Cheng says. When tested in vitro, both the CMMP and cardiac stem cell promoted the growth of cardiac muscle cells. They also tested the CMMP in a mouse model with myocardial infarction, and found that its ability to bind to cardiac tissue and promote growth after a heart attack was comparable to that of cardiac stem cells. Due to its structure, CMMP cannot replicate – reducing the risk of tumor formation. “The synthetic cells operate much the same way a deactivated vaccine works,” Cheng says. “Their membranes allow them to bypass the immune response, bind to cardiac tissue, release the growth factors and generate repair, but they cannot amplify by themselves. So you get the benefits of stem cell therapy without risks.” The synthetic stem cells are much more durable than human stem cells, and can tolerate harsh freezing and thawing. They also don’t have to be derived from the patient’s own cells. And the manufacturing process can be used with any type of stem cell. “We are hoping that this may be a first step toward a truly off-the-shelf stem cell product that would enable people to receive beneficial stem cell therapies when they’re needed, without costly delays,” Cheng says. The research appears in the journal Nature Communications. Cheng is corresponding author. The work was funded in part by the National Institutes of Health, NC State Chancellor’s Innovation Fund and University of North Carolina General Assembly Research Opportunities Initiative grant. The co-first authors of this paper are. Junnan Tang, Deliang Shen, and Thomas Caranasos. Cheng’s collaborators are Quancheng Kan and Jinying Zhang at The First Affiliated Hospital of Zhengzhou University, Henan, China. -peake- Note to editors: An abstract of the paper follows. “Therapeutic microparticles functionalized with biomimetic cardiac stem cell membranes and secretome” DOI: 10.1038/NCOMMS13724 Authors: Junnan Tang, Deliang Shen, Thomas George Caranasos, Zegen Wang, Tyler A. Allen, Adam Vandergriff, Michael Taylor Hensley, Phuong-Uyen Dinh, Jhon Cores, Taosheng Li, Jinying Zhang, Quancheng Kan, Ke Cheng Published: Dec. 26, 2016 in Nature Communications Abstract: Stem cell therapy represents a promising strategy in regenerative medicine. However, cells need to be carefully preserved and processed before usage. In addition, cell transplantation carries immunogenicity and/or tumorigenicity risks. Mounting lines of evidences indicate that stem cells exert their beneficial effects mainly through secretion (of regenerative factors) and membrane-based cell-cell interaction with the injured cells. Herein, we fabricated a synthetic cell-mimicking microparticle (CMMP) that recapitulates stem cell functions in tissue repair. CMMPs carries similar secreted proteins and membranes as genuine cardiac stem cells do. In a mouse model of myocardial infarction, injection of CMMPs leads to preservation of viable myocardium and augmentation of cardiac functions similar to cardiac stem cell therapy. CMMPs (derived from human cells) do not stimulate T cells infiltration in immuno-competent mice. In conclusion, CMMPs act as “synthetic stem cells” which mimic the paracrine and biointerfacing activities of natural stem cells in therapeutic cardiac regeneration.
Newswise — BIRMINGHAM, Ala. – Many people start the new year with a list of lofty goals for self-improvement, but statistics say most of the 45 percent of Americans who typically make resolutions don’t keep them all year long. In fact, according to the Statistic Brain Research Institute, only 8 percent of Americans who make resolutions are successful in achieving them, and other studies suggest that 80 percent of people will abandon those resolutions by February. The No. 1 resolution on most lists? Losing weight. But even though statistics say resolutions do not typically yield results, they can still be worthwhile . According to UAB Director of Employee Wellness Anna Threadcraft, RDN, there are four ways in which people can manage expectations of being healthy and keep their New Year’s resolutions: •Start Small: When it comes to making health goals, start small. Begin incorporating small, sustainable changes into your lifestyle that you can stick with, not just the ones that sound good but you know you’ll never maintain. •Plan Ahead: Whether you’re married or single, your first date in 2017 needs to be with your grocery story. It’s much easier to make wise choices if you have healthy options readily available. •Be Accountable: A lot of people fall off the wellness wagon within a few short weeks after setting goals, so set yourself up for success. Place a reminder or check-in on your phone, or send a prescheduled email to yourself. Include reminders of why you’re working on the goals, and ask yourself the questions you know you want to confidently answer when the reminder comes through. •Rest: We underestimate the simple power of being rested. Before you start making any huge health changes that require great effort, consider your sleeping patterns. There may be room for some simple improvement that goes a long way. Changes might include making a point to get more sleep in general, or working on improving the quality of what you already get. When you are well-rested, you make better decisions, plan better and typically embrace life with a better attitude all the way around. But many people do not focus just on physical health. UAB clinical psychologist Josh Klapow, Ph.D., says people should focus on mental wellness as well. “Our thoughts and feelings have a direct impact on our overall well-being,” he said. Klapow says taking hold of stress can have a lasting impact on mental wellness. “Daily stresses have a funny way of building up to a point where people can feel overwhelmed,” he said. “Stressful situations can’t always be stopped, but there are ways to manage the feelings of stress.” Klapow suggests writing down those stressful situations and putting checkmarks next to the ones that can be changed. “Monitoring stress levels is a good habit to make, and taking short mental breaks can be helpful in breaking up the high-tension moments,” Klapow said. “Carving out a little time for something as simple as a daily walk can also reduce feelings of stress.” Threadcraft and Klapow agree that having a plan to move forward, setting specific goals and keeping track of progress are great action items to keep in mind when heading toward the new year.
Newswise — (Cambridge, Mass.) — The use of proteasome inhibitors to treat cancer has been greatly limited by the ability of cancer cells to develop resistance to these drugs. But Whitehead Institute researchers have found a mechanism underlying this resistance—a mechanism that naturally occurs in many diverse cancer types and that may expose vulnerabilities to drugs that spur the natural cell-death process. This finding—which also identifies a biomarker that can be used to gain a deeper understanding of the proteasome inhibitor-resistant state— is reported in the Proceedings of the National Academy of Sciences (PNAS) in an article entitled, Suppression of 19S proteasome subunits marks emergence of an altered cell state in diverse cancers. Proteasomes are large protein complexes that mediate protein degradation and play a crucial role in maintaining protein equilibrium within the cell. When cells become cancerous, tremendous stresses are placed on the cellular machinery responsible for maintaining protein equilibrium—and that machinery is the target of anti-cancer drugs called proteasome inhibitors. Although proteasome inhibitors are very efficient in selective killing of cancer tumor cells grown in a dish (in-vitro), their success in the clinic has largely been undermined by the development of resistance—mechanisms of which are poorly understood. “However, recently, we discovered a counterintuitive mechanism by which cells can acquire resistance to proteasome inhibitors in vitro,” explains Peter Tsvetkov, lead author of the PNAS article and a post-doctoral researcher at Whitehead Institute. “Now, in this report, we show that this mechanism is at work in many human cancers. Moreover, we have determined that the mechanism is symptomatic of a broadly altered state in the cell, with a unique gene signature and newly exposed vulnerabilities that can be targeted with existing drugs.” Notably, the mechanism was clearly associated with poor outcome in patients with the blood cancer myeloma, where proteasome inhibitors are a mainstay of treatment. Analyzing data from thousands of cancer lines and tumors, the researchers found that those demonstrating resistance to proteasome inhibitor drugs were marked by suppressed expression of one or more of the cells’ proteasome cap subunits (which are a subsets of the larger proteasome). Suppressing the expression of even one of the many subunits making up the cap will impair the assembly of the whole cap, resulting in a proteasome-inhibitor resistant state. “This fact reinforces just how complex the mechanisms of resistance to chemotherapy can be,” says Luke Whitesell, a senior author of the PNAS paper and senior scientist at Whitehead Institute Nevertheless, this new report reveals a strategy to address such resistance which may have broad utility. The researchers found that, beyond conferring resistance to proteasome inhibitors, the suppressed expression of proteasome subunits reflects a broad remodeling of the cell’s gene signature. Furthermore, this can also serve as a biomarker to stratify patients for treatment. “That signature marks a heritably altered and therapeutically relevant state in diverse cancers—a state that may expose vulnerability to specific drugs that are already in use in the clinic,” Tsvetkov observes. “Cancers can achieve this resistance by multiple mechanisms, genetic or epigenetic. But these findings point us to new strategies and novel compounds that can be developed as treatments that will be more effective for an array of cancer types because they are less susceptible to the emergence of resistance.” This work was supported by EMBO fellowship ALTF 739-2011 and the Charles A. King trust postdoctoral fellowship program. Written by Merrill S. Meadow * * * Luke Whitesell is Senior Science at Whitehead Institute. Peter Tsvetkov is a post-doctoral researcher at Whitehead Institute. * * * Full Citation: Suppression of 19S proteasome subunits marks emergence of an altered cell state in diverse cancers Proceedings of the National Academy of Sciences, online publication: Dec. 26, 2016 Peter Tsvetkov*,1, Ethan Sokol1,2, Dexter Jin1,2, Zarina Brune1, Prathapan Thiru1, Mahmoud Ghandi3, Levi A. Garraway3,4,5, Piyush Gupta1,2,6,7, Sandro Santagata8, Luke Whitesell1, Susan Lindquist **,1,2,9, 1 Whitehead Institute for Biomedical Research, Cambridge, MA, 02142 2 Department of Biology, Massachusetts Institute of Technology, Cambridge, MA3 Broad Institute, 415 Main St. Cambridge, MA 021424 Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA5 Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 6 Koch Institute for Integrative Cancer Research, Cambridge, MA7 Harvard Stem Cell Institute, Cambridge, MA 021388 Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA9 HHMI, Department of Biology, MIT, Cambridge MA 02139* Corresponding author**Deceased Whitehead Institute is a world-renowned non-profit research institution dedicated to improving human health through basic biomedical research. Wholly independent in its governance, finances, and research programs, Whitehead shares a close affiliation with Massachusetts Institute of Technology through its faculty, who hold joint MIT appointments.
Newswise — Human papillomavirus-positive oropharynx cancers (cancers of the tonsils and back of the throat) are on rise. After radiation treatment, patients often experience severe, lifelong swallowing, eating, and nutritional issues. However, new clinical trial research shows reducing radiation for some patients with HPV-associated oropharyngeal squamous cell carcinomas can maintain high cure rates while sparing some of these late toxicities. “We found there are some patients have very high cure rates with reduced doses of radiation,” said Barbara Burtness, MD, Professor of Medicine (Medical Oncology), Yale Cancer Center, Disease Research Team Leader for the Head and Neck Cancers Program at Smilow Cancer Hospital, and the chair of the ECOG-ACRIN head and neck committee. “Radiation dose reduction resulted in significantly improved swallowing and nutritional status,” she said. The study, published in the December 26 issue of the Journal of Clinical Oncology, showed that patients treated with reduced radiation had less difficulty swallowing solids (40 percent versus 89 percent of patients treated with standard doses of radiation) or impaired nutrition (10 percent versus 44 percent of patients treated with regular doses of radiation). “Today, many younger patients are presenting with HPV-associated squamous cell carcinoma of the oropharynx,” said Dr. Burtness. “And while traditional chemoradiation has demonstrated good tumor control and survival rates for patients, too often they encounter unpleasant outcomes that can include difficulty swallowing solid foods, impaired nutrition, aspiration and feeding tube dependence,” said Dr. Burtness. “Younger patients may have to deal with these side effects for decades after cancer treatment. We want to help improve our patients’ quality of life.” The study included 80 patients from 16 ECOG-ACRIN Cancer Research Group sites who had stage three or four HPV-positive squamous cell carcinoma of the oropharynx, and were candidates for surgery. Eligible patients received three courses of induction chemotherapy with the drugs cisplatin, paclitaxel, and cetuximab. Patients with good clinical response then received reduced radiation. Study results also showed that patients who had a history of smoking less than 10 packs of cigarettes a year had a very high disease control compared with heavy smokers.