Newswise — ANN ARBOR, Michigan — A prototype wearable device, tested in animal models, can continuously collect live cancer cells directly from a patient’s blood. Developed by a team of engineers and doctors at the University of Michigan, it could help doctors diagnose and treat cancer more effectively. “Nobody wants to have a biopsy. If we could get enough cancer cells from the blood, we could use them to learn about the tumor biology and direct care for the patients. That’s the excitement of why we’re doing this,” says Daniel F. Hayes, M.D., the Stuart B. Padnos Professor of Breast Cancer Research at the University of Michigan Rogel Cancer Center and senior author on the paper in Nature Communications. Tumors can release more than 1,000 cancer cells into the bloodstream in a single minute. Current methods of capturing cancer cells from blood rely on samples from the patient—usually no more than a tablespoon taken in a single draw. Some blood draws come back with no cancer cells, even in patients with advanced cancer, and a typical sample contains no more than 10 cancer cells. Over a couple of hours in the hospital, the new device could continuously capture cancer cells directly from the vein, screening much larger volumes of a patient’s blood. In animal tests, the cell-grabbing chip in the wearable device trapped 3.5 times as many cancer cells per milliliter of blood as it did running samples collected by blood draw. “It’s the difference between having a security camera that takes a snapshot of a door every five minutes or takes a video. If an intruder enters between the snapshots, you wouldn’t know about it,” says Sunitha Nagrath, Ph.D., associate professor of chemical engineering at U-M, who led the development of the device. Research shows that most cancer cells can’t survive in the bloodstream, but those that do are more likely to start a new tumor. Typically, it is these satellite tumors, called metastases, that are deadly, rather than the original tumor. This means, cancer cells captured from blood could provide better information for planning treatments than those from a conventional biopsy. The team tested the device in dogs at the Colorado State University’s Flint Animal Cancer Center in collaboration with Douglas Thamm, VMD, a professor of veterinary oncology and director of clinical research there. They injected healthy adult animals with human cancer cells, which are eliminated by the dogs’ immune systems over the course of a few hours with no lasting effects. For the first two hours post-injection, the dogs were given a mild sedative and connected to the device, which screened between 1-2 percent of their blood. At the same time, the dogs had blood drawn every 20 minutes, and the cancer cells in these samples were collected by a chip of the same design. The device shrinks a machine that is typically the size of an oven down to something that could be worn on the wrist and connected to a vein in the arm. For help with the design, the engineering team turned to Laura Cooling, M.D., a professor of clinical pathology at U-M and associate director of the blood bank, where she manages the full-size systems. “The most challenging parts were integrating all of the components into a single device and then ensuring that the blood would not clot, that the cells would not clog up the chip, and that the entire device is completely sterile,” says Tae Hyun Kim, Ph.D., who earned his doctorate in electrical engineering in the Nagrath Lab and is now a postdoctoral scholar at the California Institute of Technology. They developed protocols for mixing the blood with heparin, a drug that prevents clotting, and sterilization methods that killed bacteria without harming the cell-targeting immune markers, or antibodies, on the chip. Kim also packaged some of the smallest medical-grade pumps in a 3D-printed box with the electronics and the cancer-cell-capturing chip. The chip itself is a new twist on one of the highest-capture-rate devices from Nagrath’s lab. It uses the nanomaterial graphene oxide to create dense forests of antibody-tipped molecular chains, enabling it to trap more than 80 percent of the cancer cells in whole blood that flows across it. The chip can also be used to grow the captured cancer cells, producing larger samples for further analysis. In the next steps for the device, the team hopes to increase the blood processing rate. Then, led by Thamm, they will use the optimized system to capture cancer cells from pet dogs that come to the cancer center as patients. Chips targeting proteins on the surfaces of canine breast cancer cells are under development in the Nagrath lab now. Hayes estimates the device could begin human trials in three to five years. It would be used to help to optimize treatments for human cancers by enabling doctors to see if the cancer cells are making the molecules that serve as targets for many newer cancer drugs. “This is the epitome of precision medicine, which is so exciting in the field of oncology right now,” says Hayes. Note: Patients with questions about cancer treatment options can call the U-M Cancer AnswerLine at 800-865-1125. Funding: Susan G. Komen Foundation, the Fashion Footwear Charitable Foundation of New York/QVC Present Shoes on Sale, National Institutes of Health Citation: Nature Communications, “A temporary indwelling intravascular aphaeretic system for in vivo enrichment of circulating tumor cells,” doi: 10.1038/s41467-019-09439-9, published April 1, 2019
Newswise — ORLANDO, Fla., April 1, 2019 — Major depression, obesity and chronic pain are all linked to the effects of one protein, called “FK506-binding protein 51,” or FKBP51. Until now, efforts to inhibit this target have been hampered by the difficulty of finding something specific enough to do the job and not affect similar proteins. Now a research group has developed a highly selective compound that can effectively block FKBP51 in mice, relieving chronic pain and having positive effects on diet-induced obesity and mood. The new compound also could have applications in alcoholism and brain cancer. The researchers will present their results today at the American Chemical Society (ACS) Spring 2019 National Meeting & Exposition. ACS, the world’s largest scientific society, is holding the meeting here through Thursday. It features nearly 13,000 presentations on a wide range of science topics. “The FKBP51 protein plays an important role in depression, obesity, diabetes and chronic pain states,” says Felix Hausch, Ph.D., the project’s principal investigator. “We developed the first highly potent, highly selective FKBP51 inhibitor, called SAFit2, which is now being tested in mice. Inhibition of FKBP51 could thus be a new therapeutic option to treat all of these conditions.” Hausch, who is at the Technical University of Darmstadt, started the project when studies were published linking the protein to depression. “I was intrigued by the peculiar regulatory role it seemed to play in cells,” he says. “And there was a known natural product that could serve as a starting point. Collectively, this looked like an interesting protein to work on.” FKBP51 is expressed in multiple places throughout the body, such as the brain, skeletal muscle tissue and fat. It also has multiple effects. For example, the protein can restrict the uptake of glucose and the browning of fat, so that the body stores fat instead of burning it. It also affects stress responses. So, Hausch and his colleagues figured that blocking this protein could be the key to developing drugs to treat a variety of conditions. But FKBP51 looks a lot like its closest protein cousin, FKBP52. “These two proteins are very similar in structure, but they are doing opposing things in cells,” Hausch says. “We have this yin-yang situation. Selectivity between these two proteins is thought to be crucial, but this is hard to achieve since the two proteins are so similar. We discovered that FKBP51 can change its shape in a way that FKBP52 can’t, and this allowed the development of highly selective inhibitors.” The researchers have now used nuclear magnetic resonance techniques to detect a previously hidden binding site in FKBP51. The approach could help other researchers identify similar “cryptic” binding sites in challenging drug targets in the future, Hausch says. His team is now testing SAFit2, the lead FKBP51 inhibitor they developed from these studies, in animals. “It indeed helps mice cope better in stressful situations,” Hausch says. In mice, SAFit2 reduced stress hormone levels, promoted more active stress coping, was synergistic with antidepressants, protected against weight gain, helped normalize glucose levels and reduced pain in three animal models. According to Hausch, much more needs to be done to get FKBP1 inhibitors to the point where they could be used as a drug molecule in human testing. In the meantime, the team is also exploring FKBP51 inhibitors in other applications. So far, the group has conducted a number of mouse studies on the involvement of FKBP51 in alcoholism, but results are still preliminary. In addition, Hausch points out that certain types of glioblastoma tumors overexpress FKBP51. He hopes that this result indicates FKBP51 inhibitors could be used in cancer treatment, when patients’ tumors mutate beyond current drugs’ capacity to treat them. “We may be able to resensitize them to different types of chemotherapy using these specific inhibitors,” he says. The researchers acknowledge support and funding from European Research Area Industrial Biotechnology, the Federal Ministry of Education and Research and the Pioneer Fund of the Technical University of Darmstadt. The American Chemical Society, the world’s largest scientific society, is a not-for-profit organization chartered by the U.S. Congress. ACS is a global leader in providing access to chemistry-related information and research through its multiple databases, peer-reviewed journals and scientific conferences. ACS does not conduct research, but publishes and publicizes peer-reviewed scientific studies. Its main offices are in Washington, D.C., and Columbus, Ohio. This research will be presented at a meeting of the American Chemical Society.
They are seizures, but they aren’t epilepsy. They’re called by many names: psychogenic non-epileptic seizures, non-epileptic attack disorder, dissociative seizures, stress-induced seizures, pseudoseizures. They’re not epilepsy, but they do cause upheaval in education, employment, relationships and independence. They’re ranked in the top three neuropsychiatric problems worldwide. Nina Pye was a college student in the United Kingdom when she began collapsing. After months of tests and frustration, she learned she had psychogenic non-epileptic seizures. That wasn't the end of the story; it was only the beginning. Here's Nina. Nina Pye: They started sometime in January 2015; I was at college doing performing arts. I can remember the first one. I was in a dance class and all of a sudden my heart started racing for no reason. You know how you get when you’re anticipating something and you’re kind of a bit nervous about it — you get a heart-racing feeling and it doesn’t feel good? I got that, and it was weird because there was nothing making me anxious; I love dance. There was no reason for me to feel like this. It felt like all the energy drained from my body. I felt like I was going to faint, but I didn’t feel faint, and I fell to the floor. I stayed there unable to move for a few seconds, and then I got back up again. It was so weird because I didn’t actually faint, and I’ve never fainted or had anything like that so I was like what happened? Did I lose my balance? It felt like I should have had control over it. I just got back up again, no big deal was made and I carried on. Something like a week or two later I fell down again, and this time I stayed down. I remember lying there unable to get up. I could hear everything going on around me but it felt very distant. I felt like I was slightly outside of my body — it was a really weird feeling. And I’m thinking “What’s going on?” I don’t feel like anything is seriously wrong with me, it’s just that my body wants to get on the floor for a while. It’s like spontaneous lying down, except I fall. This happened a few times and each time it got longer and longer and eventually it got long enough that my college called an ambulance. My dad had died in 2013 and it was all quite fresh and new for me. I was schooled at home until college, and I didn’t have a good relationship with my father. He was abusive. Despite that, I was close to my parents, so when he died it was surreal and I didn’t find a way of dealing with it. And my mum was ill as well, she had terminal cancer, so there was a lot of stress in my life at that point. When these attacks happened, I assumed they were some kind of stress reaction. I didn’t necessarily deal with things emotionally, so it would come out in a lot of physical issues, like stomach cramps, eating issues, anxiety, depression. So when this started happening I jumped to the conclusion that it was stress and probably nothing. When I went to the hospital, they started running tests. At first they thought it was my heart; they did the 24-hour monitor and all of that. They didn’t jump to seizures or epilepsy because it was just a faint, a collapse, there was no seizure-like activity. After the first couple of hospital visits, my experience with hospitals completely changed. The more often it happened, they just… paramedics assumed I was faking and was doing this as a cry for attention. I didn’t know what to feel. I wondered, “Is there something wrong? Am I putting this on and not knowing it?” They found nothing physically wrong. I was a bit malnourished but that was it. It went on for a couple of months before I told anyone else; I didn’t even tell my mum until they started getting more frequent and other people started seeing it happen. I was passed around from cardiologist to neurologist, went for all of these tests. It was a strange time because I’d never had anything like this. I’d had back surgery for scoliosis but this felt different and weird and concerning. They were talking about did I have a brain tumor, heart issues, all that. I started to shake when I went down and have spasms, and so they thought maybe I had epilepsy. This carried on for a few more months and I kept ending up in the emergency room, and some medical staff treated it seriously and others said oh she’s faking, it’s just an attention thing. I had paramedic after paramedic saying “This is what some people do — they find a thrill in having ambulances called for them.” I had paramedics ask me, “Don’t you realize we have actual lives to save?” Yeah, I do know that, I’ve lost a parent, I know what ambulances do. Do you think I want ambulances called for me? I know it’s not life threatening but I can’t help it. I can’t tell people that I don’t need an ambulance because I don’t know when these are going to happen. I went to stay with my family three or four months after these started. I had a seizure while I was there and ended up going to a hospital in London. Because my family saw it, they pushed to get a diagnosis and were doing research to try to figure out what it was. We discovered cataplexy and narcolepsy, and the symptoms fit. So I went to a private neurologist who referred me to a sleep center. Everything came back inconclusive; they said I had mild sleep apnea and that was it. But, I had a seizure there and they had a visiting neurologist and he saw it, and he said “Yeah, you have dissociative seizures. It happens to a lot of people who’ve had something psychologically traumatic in their life, or PTSD.” I suffer from PTSD. So when I found this out, I felt relieved but ashamed as well. I thought, “Oh, it really is all in my head then.” I judged myself. It didn’t help that they are called psychogenic seizures. I felt very misunderstood. I ended up homeless for a time, not because of the seizures but because of the breakdown in the relationship with my mum. I was kicked out of college because they couldn’t deal with the seizures, which I didn’t think was possible, that you could be kicked out for something you had no control over. It was a pretty dark time in my life. A few other things happened, and it was one thing after the other. Around mid-2015 it got so bad that I made attempts to end my life three times in one month. Then my family started to take me seriously and realized I was really unwell, both mentally and physically. They took me back to London to live with them. It was a relief because I didn’t have to live in a homeless unit, which was horrible. I had no money, couldn’t work, couldn’t go to college and I thought this was my life sentence, this strange condition that had just happened and had no cure. I couldn’t get on with any antidepressants, they caused me so many side effects that I couldn’t take them. There was no support, there was no counseling. Everything that I was referred to never happened. I got 6 weeks of cognitive behavioral therapy (CBT) and that was the only proactive treatment I had for my seizures. At my worst point I had 20 seizures a day. I was banging my head on doorframes or floors, I was collapsing in the middle of roads, grazing my legs and my elbows. How I escaped without broken bones I don’t know. Everywhere I went, there was such a lack of understanding. Later in 2015, the seizures began to ease up. I’d had my CBT by then and was beginning to deal with issues that had arisen from my father dying, and my PTSD was beginning to get a little better. I was able to have unbroken nights of sleep without awful dreams, and have a normal day, and go out and get some independence. It started to feel like “Okay, this is something I can work through and get over.” I qualified as a level 1 cricket coach; my uncle was involved in cricket coaching and I was looking for something to do, just anything, and I love sports and working with kids. That was amazing and because I was really into dance, I managed to teach the kids to dance. I had roomfuls of these 8, 9, 10-year-old boys who wanted to just play cricket and football — I had them dancing. I started making progress, and once I started it accelerated really fast. Looking back, now that the seizures have come and gone and come back again, I don’t think it was necessarily good that they went away so quickly, because I don’t think I found a way of dealing with them — I just found a way to suppress them. So while I made a huge amount of progress and I was able to dance again and have some independence, there was a lot I hadn’t dealt with. I joined a dance troupe that my cousin was running. It’s not really something that most people would consider doing for seizures but I did that for about four years. I just recently left. I think the dancing helped me deal with some of the stuff I’ve been through – it worked as therapy for me. And the traveling we got to do and all of it, it pushed me out of my comfort zone and gave me mental strength. I made close friendships with the other people in the band and became very close with my cousin, and things were going quite well. And then in May 2016 my mother passed away from her fight with cancer. 2017 I think was probably my best year, despite everything; I was moving house and traveling and dancing. There was a lot of stress as well, though, and I wasn’t really dealing with the fact that my mother had died. I was just engrossed in the practical matters and not dealing with the emotional side of things. So by the end of 2017, the seizures were creeping back into my life again. In 2018 there was a lot of stress, things going wrong, breakdowns in relationships. But it kind of prompted me to go okay, this time I really want to do it right – I want to find the root of what makes me have a seizure and deal with it so that they don’t come back at all. It didn’t really happen like that. Other things got in the way. In September 2018 I returned to education. As well as dance, my other passion is medicine; I’ve always been interested in medicine and wanted a career in it. I enrolled in an access to university course, which is quite intense – it fits two A-level years into one year. At the enrollment day I told the school that look, I have seizures and they’re reasonably under control, but they will happen from time to time. They said okay, that’s fine, and set up a treatment plan with me. It’s not just the seizures, it’s the anxiety and brain fog and the general feeling of exhaustion when you’re fighting against your own body. Unfortunately my grandfather passed away at the beginning of this year; he was like a second father to me, although recently we weren’t as close. I kind of pushed him away because I couldn’t deal with any more family issues. But it has still been a great loss for me, and the repeated pattern of not really dealing with it and pretending everything is fine has not really worked for me. Now, seizures happen about once a week. Sometimes I can go a few weeks without having one. I’m hoping to build up to the point where I can go many months without one, but I think that will take some time. I want to not repress anything and deal with everything properly. The past few months I’ve reached out to other people online who are going through similar things. I thought I was alone and this was such a rare condition and little understood, but I found groups of people going through the exact same thing. They had the same experiences with the medical profession and the lack of understanding. Some people who were trying to have jobs and support themselves, some trying to get through university and support themselves. They experienced the issues in relationships, and just how hard it is generally to cope with. However hard it is for anyone else to cope with, it’s harder for us; we can’t get away from it. I wish there was more knowledge and understanding about the difference between epileptic and non-epileptic seizures. I wish medical professionals especially knew the difference and the right ways to treat people. They kind of have two extremes: Treat it like epilepsy, which can be dangerous if you’re given medication for epileptic seizures, or the other extreme of there’s actually nothing wrong with you, which is unfair. It’s in interesting journey I’ve been on and the seizures are just a small part of it, but I feel very strongly about raising awareness about them and finding ways to get people to be more supportive and more help to be available and more understanding, more knowledge for people who suffer with these seizures and their families, friends and carers. Doctors and paramedics should know about this and should have training. I feel like it’s so inadequate, considering how many people suffer with these seizures and how many are initially diagnosed with epilepsy and then find out they’re non-epileptic seizures. In truth, it helps to have doctors who are “people people” – they like people, they get on with people. You have to face people all the time, and you have to face people on their worst day. They’re having the worst day of their live when you see them, especially in hospitals and emergency departments. It doesn’t take too much to just show a little bit of understanding. I know there are people who abuse the system. I know there are fakers, I know there are drug abusers, but at the end of the day, they’re ill too. It’s a different kind of ill. Everyone is ill, but if someone is going to all the trouble of faking something or going to all this trouble to get drugs, there’s something there that needs to be treated too.
Newswise — White blood cells known as B cells have been shown to be effective for predicting which cancer patients will respond to immune checkpoint blockade (ICB) therapy, according to a study at The University of Texas MD Anderson Cancer Center. Study results will be presented April 2 at the AACR Annual Meeting 2019in Atlanta. The study, led by Jennifer Wargo, M.D., professor in the Surgical Oncology and Genomic Medicine, found that some B cells with unique characteristics predicted response and may be contributing mechanistically to the immune system’s response. The B cells had activated effector phenotypes and were located within lymphoid formations found at the tumor site, known as tertiary lymphoid structures (TLS). The researchers looked at samples from metastatic melanoma and kidney cancer patients who had received ICB as their initial treatment. The B cells may be impacting the immune system’s response through secretion of antibodies and/or by processing and delivering antigens to white blood cell subtypes called T lymphocytes. “This is an exciting and emerging area of study that appears to hold promise for more accurately understanding which patients are most likely to be treated effectively with ICB therapy, and it also could help us identify new therapeutic targets.” said Wargo. “We are able to demonstrate through single-cell RNA sequencing that switched memory B cells and plasma cells were significantly associated with ICB response in a cohort of metastatic melanoma.” While cytotoxic T-cell markers, PD-L1, and mutational burden have been previously identified as biomarkers of response to ICB, there is a growing appreciation of B cells as biomarkers mediators of response, although B cells have also been linked to negative cancer outcomes. “Whole transcriptomic analysis of the cohort of melanoma patients receiving ICB initially revealed that most differentially expressed genes by response were related to B cells,” said Wargo. “In further investigation of specific characteristics of B cells located within the tumor, we identified naive, class-switched and unswitched memory B cells, and plasma cell-like populations.” Class-switch references a B cell’s ability to change production of an antibody from one class to another. The team found higher frequencies of class-switched memory B and plasma-like cells in patients who responded to ICB. Patients who did not respond to ICB had higher levels of naïve B cells which have not yet been activated for a designated purpose. “We don’t have a complete understanding of how these B cells contribute to therapeutic response, but we and others are working on this, and we hope this research will stimulate additional study in this area,” said Wargo. “There is still much to learn and the strongest gains are made through collaboration. It is something we owe to our patients.” MD Anderson study team participants included Sangeetha Reddy, M.D.; Beth Helmink, M.D., Ph.D.; Vancheswaran Gopalakrishnan, M.D.; Elizabeth Burton; and Jeffrey Gershenwald, M.D.; all of Surgical Oncology; Jianjun Gao, M.D., Ph.D.; and Padmanee Sharma, M.D., Ph.D., of Genitourinary Medical Oncology; Shoaojun Zhang, Ph.D.; Guangchun Han, Ph.D.; and Linghua Wang, Ph.D.; of Genomic Medicine; Jorge Blando, D.V.M.; Wenbin Liu; Hao Zhao, D.Phil.; and James Allison, Ph.D.; of Immunology; Hussein Tawbi, M.D., Ph.D.; Rodaba Amaria, M.D.; and Michael Davies, M.D., Ph.D., of Melanoma Medical Oncology; Michael Tetzlaff, M.D., Ph.D., of Pathology; and Rafet Basar, M.D.; and Katy Rezvani, M.D., Ph.D., of Stem Cell Transplantation and Cellular Therapy. The Broad Institute of the Massachusetts Institute of Technology also participated in the study. The study was funded by the Parker Institute for Cancer Immunotherapy, and was also supported with funding from the Melanoma Moon Shot™, part of MD Anderson’s Moon Shots Program™, a collaborative effort to accelerate the development of scientific discoveries into clinical advances that save patients’ lives. A complete list of disclosures can be found in the AACR abstract.
Newswise — People under age 50 with hearing loss misuse prescription opioids at twice the rate of their hearing peers, and are also more likely to misuse alcohol and other drugs, a new national study finds. This means that health care providers may need to take special care when treating pain and mental health conditions in deaf and hard-of-hearing young adults, the researchers say. Writing in the April issue of the American Journal of Preventive Medicine, a team from the University of Michigan and VA Ann Arbor Healthcare System describe their findings from data on 86,186 adults who took part in the National Survey on Drug Use and Health. In all, adults under 50 with hearing loss were more likely than others in their age group to have a substance use disorder of any kind, while those over 50 with hearing loss did not differ from their peers in rates of substance issues. Even after the researchers adjusted for differences in social, economic and mental health between the hearing and hard-of-hearing populations, the differences remained. Adults under age 35 with a hearing loss were two and a half times more likely to have a prescription opioid use disorder. Those between age 35 and 49 who had hearing loss were nearly twice as likely as their hearing peers to have disorders related to both prescription opioids and alcohol. Michael McKee, M.D., M.P.H., led the research effort after noticing that that a disproportionate share of his younger patients with hearing loss were struggling with substance use disorders. McKee runs the Deaf Health Clinic that provides primary care and mental health care to d/Deaf and hard-of-hearing patients of Michigan Medicine, U-M’s academic medical center. “Hearing loss is connected with a variety of health problems, including mental and physical health, that may place these individuals at risk for pain disorders,” says McKee. “Also, the marginalizing effects of hearing loss, such as social isolation, may be creating higher rates of substance use disorders too.” For those whose health care providers know of their hearing loss, McKee suspects that the higher rate of prescription opioid use disorder may stem from a higher rate of being placed on controlled substances to quickly address pain issues, perhaps because of communication barriers. “It may be easier to write a prescription rather than engage in complex patient-provider communication between a hearing provider and non-hearing patient,” he says. But the research suggests that part of the issue may be lack of awareness by health care providers of their younger patients’ degree of hearing loss. In all, five percent of adults of all ages taking part in the survey said they had serious hearing loss or were deaf. The proportion ranged from 1.5 percent of those under age 35, to 2.2 percent of those between 35 and 49, to 9.4 percent of those over 50. McKee, a U-M Department of Family Medicine physician who uses a cochlear implant to offset his own hearing loss, says health care providers may be more attuned to potential communication and prescription concerns with older patients. This would mean they would be more likely to avoid many of the prescription use disorders seen in the other two age categories. “We need to first inquire and ensure effective and accessible communication with our patients. We need to be willing to engage in a dialogue to explore the root of their pain/mental health issues rather than just dispensing a prescription that may lead to dependency or addiction,” he says. This means providers should use “universal communication precautions” – approaching each patient without assumptions about their communication abilities, assessing for hearing loss and other communication-related issues, and determining how to accommodate each patient. McKee also notes that lack of access to addiction-related care for deaf and hard-of-hearing patients may play a role. McKee and several co-authors are faculty in the U-M Medical School and members of the U-M Institute for Healthcare Policy and Innovation. They include disability researcher Michelle Meade, Ph.D. of the Department of Physical Medicine and Rehabilitation, chair of Family Medicine Philip Zazove, M.D. and Mark Ilgen, Ph.D., director of the U-M Addiction Treatment Service. The research team also included Haylie Stewart and Mary Jannausch from the U-M Department of Psychiatry and VA Center for Clinical Management and Research, of which Ilgen is also a member.
CDC data confirm: Progress in HIV prevention has stalled Need for immediate action —‘Ending the Epidemic: A Plan for America’ The dramatic decline in annual HIV infections has stopped and new infections have stabilized in recent years, according to a CDC report published today. The report provides the most recent data on HIV trends in America from 2010 to 2016. It shows that after about five years of substantial declines, the number of HIV infections began to level off in 2013 at about 39,000 infections per year. “Now is the time for our Nation to take bold action. We strongly support President Trump’s plan to end the HIV epidemic in America,” said CDC Director Robert R. Redfield, M.D. “We must move beyond the status quo to end the HIV epidemic in America.” The ‘Ending the HIV Epidemic’ Initiative During his State of the Union address to the nation on Feb. 5, President Trump called for support of a national planExternal to end the HIV epidemic in America that is built upon four key strategies, including: Diagnosing HIV as early as possible after infection. Treating HIV rapidly and effectively to achieve sustained viral suppression. Protecting people at risk for HIV using proven prevention approaches like pre-exposure prophylaxis (PrEP), a daily pill to prevent HIV. Responding rapidly to growing HIV clusters to stop new infections. The proposed initiative is designed to rapidly increase use of these strategies in the 48 counties with the highest HIV burden, as well as in Washington, D.C.; San Juan, Puerto Rico; and seven states with a disproportionate rural HIV burden. The goal is to reduce new HIV infections by 90 percent over 10 years. (For more details: HIV.govExternal.) “We have an historic opportunity to improve the precision of prevention,” said Jonathan Mermin, M.D., M.P.H., director, CDC’s National Center for HIV/AIDS, Viral Hepatitis, STD and TB Prevention. “This infusion of resources will finally relegate America’s HIV epidemic to the pages of history. New HIV Infections in America In addition to the overall trend, the new report examines HIV infections among multiple subgroups. Data indicate that annual HIV infections declined in some populations, but increased in others. CDC estimates that from 2010 to 2016, annual HIV infections: Remained stable among gay and bisexual men, who continue to account for the largest portion (about 70 percent) of new infections. However, trends varied by race/ethnicity and age: By race/ethnicity, infections remained stable among black gay and bisexual men; increased 30 percent among Latino gay and bisexual men; and decreased 16 percent among white gay and bisexual men. By race/ethnicity and age, infections decreased more than 30 percent among black gay and bisexual males ages 13 to 24; remained stable among Latino gay and bisexual males ages 13 to 24; and increased about 65 percent among both black and Latino gay and bisexual males ages 25 to 34. Decreased about 17 percent among heterosexual men and women combined, including a 15 percent decrease among heterosexual African American women. Decreased 30 percent among people who inject drugs, but appear to have stabilized in more recent years. CDC estimates that the decline in HIV infections has plateaued because effective HIV prevention and treatment are not adequately reaching those who could most benefit from them. These gaps remain particularly troublesome in rural areas and in the South and among disproportionately affected populations like African-Americans and Latinos. “After a decades-long struggle, the path to eliminate America’s HIV epidemic is clear,” says Eugene McCray, M.D., director of CDC’s Division of HIV/AIDS Prevention. “Expanding efforts across the country will close gaps, overcome threats, and turn around troublesome trends.” HIV Prevention that Works Some intensified local efforts to prevent HIV have already proven effective. For example, urban areas like New York and Washington, D.C., have developed and enacted plans to eliminate their local HIV epidemics — and they are seeing the results of those commitments. New HIV infections decreased about 23 percent in New York and about 40 percent in Washington, D.C., from 2010 to 2016. CDC provides funds to state health departments and some large local health departments and community-based organizations to deliver interventions proven to reduce HIV infections. Click here for more information about CDC’s approach to HIV prevention. The new initiative would supplement and accelerate these efforts over the next 10 years.
Newswise — By sequencing the entire genomes of tumor cells from six people with a rare cancer of the nose and sinus cavity, Johns Hopkins researchers report they unexpectedly found the same genetic change¾one in a gene involved in muscle formation¾in five of the tumors. “In terms of research linking genetic alterations to cancers, this is a true mountain and not a molehill,” says Gary Gallia, M.D., Ph.D., associate professor of neurosurgery at the Johns Hopkins University School of Medicine. “It’s fairly rare that a single gene is tied so tightly to the same cancers in unrelated people.” In a report on their findings, published Dec. 21, 2018, in Nature Communications, the researchers say the deletions they identified in a gene that codes for dystrophin, a rod-shaped protein that helps anchor muscle fibers in place, were found in olfactory neuroblastoma cells. Olfactory neuroblastomas make up just 6 percent of all sinus and nasal cancers, with a prevalence rate of one person out of every 2.5 million. Nationwide, that translates to about 100 to 200 diagnosed cases each year. Johns Hopkins Medicine’s neurosurgery skull base center is among the most experienced in treating patients with olfactory neuroblastoma. The center also has a robust supply of tissue samples from these tumors. The researchers say their findings contribute not only to a better understanding of the cause of these cancers, but also to the potential for creating animal and cell models for further study and development of treatments that target the tumor’s genetic roots. “Now that we believe we know the genetic cause of olfactory neuroblastoma, we can devise ways to disrupt the cancer, learn how it forms and explore new ways to treat it,” says Chetan Bettegowda, M.D., Ph.D.,associate professor of neurosurgery at the Johns Hopkins University School of Medicine and director of the Johns Hopkins meningioma center. “This was really an unexpected but fruitful finding.” Bettegowda says their finding was unexpected because perceptions of nasal and sinus tissue don’t immediately bring to mind a dominant role for muscle tissues. But, among geneticists, he says, it’s well known that many developmental genes that help form the tissues of the human body are multipurpose. For their study, the researchers first sequenced the tumor and matched normal DNA of nine men and two women with olfactory neuroblastoma taken from patients treated at Johns Hopkins over seven years. The patients ranged in age from 33 to 69. The researchers sequenced the parts of the genomes that make up the genes and not the spaces between the genes. Although they found two tumor samples had mutations in a large gene that makes the protein Titan, the researchers were unsure if these mutations may have contributed to formation of the cancer, as they didn’t see much else in common among the samples. Next, they chose six of these samples at random and did whole genome sequencing that looks at the DNA that makes up the genes and the DNA between the genes. This time they found that five of the six samples had deletions on the X chromosome, and in every case, the deleted portion of DNA spanned the gene DMD, which codes for the protein dystrophin, one of the genes implicated in muscular dystrophy. They then reexamined the original tumor samples, as well as a few others, with other techniques to look for deletions in dystrophin. In total, they found 12 out of 14 tumors had deletions in the DMD gene. In one tumor that didn’t have a DMD deletion, they found a deletion in another muscular dystrophy gene: LAMA2. Dystrophin is one of the longest genes in the human genome, and has 79 pieces of DNA interspersed with bits that don’t code for the gene. Because of the gene’s large size, if part of a chromosome in which it resides is deleted or rearranged, it’s statistically more likely to interrupt a large gene like dystrophin. The researchers aren’t sure if the dystrophin protein is made in the olfactory neuroblastoma or if a shortened mutated form messes up the inner workings of the cells that form the tumor. These are experiments for future studies, they say. The researchers still also don’t know what kind of cells the cancer originates from, although they are thought to arise from the neuroepithelium—the lining—of the sinuses at the point where the smell nerves poke through. As for whether their findings point to potential new therapies for this cancer, Bettegowda says, “Some low-hanging fruit could be to test certain therapies in the lab that have been tried in people with muscular dystrophy. Although those therapies have failed in treating muscles dystrophies, these conditions affect every cell in the body. But this cancer is found in one specific location, so the treatments might have a better chance of finding a target.” Typical signs of olfactory neuroblastoma are congestion, sinusitis, loss of sense of smell and nosebleeds. Other authors include Ming Zhang, Christine Hann, Alison Klein, Qing Wang, Bert Vogelstein, Kenneth Kinzler and Nickolas Papadopoulos of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins; Yi Ning, Michael Haffner, Denise Batista, Ralph Hruban, Masaru Ishii, Douglas Reh, Lisa Rooper, Rafael Tamargo, Tara Williamson, Tianna Zhao and Alan Meeker of Johns Hopkins; Zev Binder of the University of Pennsylvania; Justin Bishop of the University of Texas Southwestern Medical Center; Vafi Salmasi of Stanford University; Ying Zou of the University of Maryland and Nishant Agrawal of University of Chicago. The research was supported by the Virginia and D.K. Ludwig Fund for Cancer Research, the Sol Goldman Sequencing Facility at Johns Hopkins, the Johns Hopkins Clinician Scientist Career Development Award, the Burroughs Wellcome Fund Career Awards for Medical Scientists, the Doris Duke Charitable Foundation (2014107), the Department of Neurosurgery at Johns Hopkins and the National Cancer Institute (P50- CA062924). COI: Papadopoulos, Kinzler and Vogelstein are founders of Personal Genome Diagnostics and PapGene. Kinzler and Vogelstein are members of the scientific advisory board of Sysmex Inostics. Vogelstein is a member of the scientific advisory boards of Morphotek and Exelixis. These companies and others have licensed technologies from Johns Hopkins, and Papadopoulos, Kinzler and Vogelstein receive equity or royalties from these licenses.
Newswise — Radiologists quickly learn to read 3D mammography more accurately than they read standard 2D mammograms, a first-of-its-kind study by a UC Davis researcher has found. Published today in Radiology, the study led by Diana Miglioretti found that radiologists who interpret traditional mammograms, which are two-dimensional, required little start up time for transitioning to reading digital breast tomosynthesis (DBT), or 3D mammography, with improved screening accuracy. Researchers found radiologists recalled patients for additional testing at a lower rate on DBT than they did on 2D mammography, without sacrificing cancer detection. A patient may be recalled if there is a suspicious finding on the screening examination that requires follow-up imaging and possibly biopsy to determine if it is cancer. Three-dimensional views taken as part of a DBT screening help the radiologist confirm that some findings on 2D images are not cancer and so fewer patients have to be recalled. These improvements were seen regardless of the patient’s breast density. “We found that patients with or without dense breasts benefit from lower recall rates with 3D mammography and there is no trade off with cancer detection,” said Miglioretti, dean’s professor of biostatistics in the UC Davis Department of Public Health Sciences. “In fact, we were surprised to find that improvements in recall rates were larger in women without dense breasts.” Broad range and large number of radiologists sampled The study included data from 104 radiologists from 53 facilities in five U.S. states, collected by the Breast Cancer Surveillance Consortium (BCSC) to evaluate whether radiologists experience a learning curve for 3D mammography interpretive performance. The study is the largest of its kind and represented a broad range of radiology centers and providers. It is novel because it tracked radiologists’ performance over time as they transitioned from digital mammography to DBT. DBT takes multiple X-ray images of each breast from many angles which are then computer assembled into a three-dimensional image of the breast that the radiologist can scroll through. The U.S. Food and Drug Administration requires only eight hours of additional training for qualified radiologists to be able to interpret DBT studies. Researchers wondered if there was a learning curve associated with the interpretive performance of this new technology and if any improvements are sustained by radiologists over time. “We found both breast imaging subspecialists and general radiologists improved their screening performance when they switched from 2D to 3D mammography,” said Miglioretti. “These improvements were sustained for at least two years after adoption of the new technology.” Most women in the U.S. do not have their mammograms interpreted by a breast imaging subspecialist, nor do they have access to academic medical centers. The study evaluated radiologists with a mix of experience at both academic and nonacademic facilities. Both breast imaging subspecialists and general radiologists improved their interpretive performance quickly after adopting DBT, with lower recall rates and similar cancer detection rates as for digital mammography. “Women who want to reduce their chances of being recalled for additional testing may want to ask for digital breast tomosynthesis at their next screening exam,” said Miglioretti. Other collaborating researchers included Linn Abraham and Diana S.M. Buist, Kaiser Permanente Washington Health Research Institute; Christoph I. Lee, University of Washington; Sally Herschorn and Brian L. Sprague, University of Vermont; Louise M. Henderson, UNC Chapel Hill; Anna N.A. Tosteson, Dartmouth University; Karla Kerlikowske, UCSF. This research was supported by a Patient-Centered Outcomes Research Institute Program Award (PCS-1504-30370). Data collection was additionally supported by the Agency for Healthcare Research and Quality (R01 HS018366-01A1); National Cancer Institute (P01CA154292, U54CA163303); and the University of Vermont Cancer Center (Lake Champlain Cancer Research Organization grant 032800). Dr .Lee was supported by the American Cancer Society (126947-MRSG-1416001CPHPS).
Newswise — A surgeon sometimes moves from one surgery to the next before the first one is completed, leaving junior surgeons, residents and physician assistants to complete the noncritical portions of the procedure. The practice happens tens of thousands of times per year, but one might wonder: Are such overlapping operations safe? For the most part they are, but with two important exceptions, according to research by investigators at Harvard Medical School and Stanford University published Feb. 26 in JAMA and thought to be one of the most comprehensive analyses on the subject to date. The results, based on a comparison of outcomes from more than 60,000 surgical procedures, reveal that overall, overlapping surgeries do not increase the risk for post-surgical complications and patient death in the immediate aftermath of the procedure. However, there were two important exceptions. Patients deemed high risk—those with a relatively high predicted probability of complications from surgery, due to age and preexisting medical conditions—as well as patients undergoing coronary artery bypass experienced higher mortality and complication rates during overlapping surgeries. Additionally, overlapping procedures ran about a half hour longer on average than nonoverlapping procedures, the study found. “For most surgeries, and most patients, our findings should be reassuring,” said Anupam Jena, the Ruth L. Newhouse associate professor of health care policy in the Blavatnik Institute at Harvard Medical School and an internal medicine physician at Massachusetts General Hospital. “But for certain types of procedures and certain patients, the evidence suggests that we need to be thoughtful about whether a particular individual is a good candidate for overlapping surgery.” Jena was senior author of the study. As with any treatment, careful patient selection and an individualized approach based on the patient’s risk profile and preexisting conditions are critical, the researchers added. “As with anything else in medicine, one size does not fit all,” Jena said. Additionally, the investigators caution, the study was designed to capture only mortality and complication rates during the brief hospitalization period following surgery. It was not equipped to measure the long-term mortality and complications among patients once they were discharged. The mortality rate was 1.6 percent for patients undergoing nonoverlapping surgeries, compared with 1.9 percent among patients undergoing overlapping procedures. Postoperative complications occurred in 11.8 percent of patients undergoing nonoverlapping procedures, compared with 12.8 percent among those undergoing overlapping surgeries. Overlapping surgeries ran notably longer—204 minutes, compared with 173 minutes for nonoverlapping procedures. For high-risk patients, the mortality rate was 5.8 percent for patients undergoing overlapping surgeries, compared with 4.7 percent among patients undergoing nonoverlapping procedures. The complication rate was 29.2 percent for patients undergoing overlapping surgeries, compared with 27 percent among patients undergoing nonoverlapping procedures. For patients undergoing coronary artery bypass graft surgery, the mortality rate was 4 percent in surgeries with overlap versus 2.2 percent in surgeries without overlap. Complication rates were also higher in coronary artery bypass graft surgeries that involved overlap. The study analyzed outcomes among 66,430 patients, ages 18 to 90, undergoing eight common procedures at eight medical centers across the United States between 2010 and 2018. The procedures included knee and hip repairs, spinal surgeries, brain surgeries and coronary artery bypass grafting, a type of cardiac surgery to restore blood flow to the heart. Previous studies of overlapping surgeries tended to have more limited scope of analysis, the researchers said. For example, some focused on a single type of surgery or on results at a single hospital. In the current study, the authors used a national anesthesia registry to look at the start and end times of surgeries by individual surgeons so they could distinguish consecutive and overlapping surgeries. This enabled the researchers to tease out differences in outcomes for individual surgeons when they were performing one surgery at a time versus performing overlapping surgeries. By contrast, previous studies have compared overall outcomes, which may mask differences across individual operators. It is important to remember that overlapping surgeries have clear advantages, the researchers said, including maximizing the use of top surgeons and busy operating rooms, increasing patient access to necessary care and providing crucial training experience for junior surgeons. However, the researchers cautioned, such benefits must be weighed carefully against any potential risk to patients. Although overlapping surgeries are deemed generally safe, critics have suggested definitive evidence is lacking. The possibility of overlapping surgeries and any potential risks associated with a given patient or procedure should be disclosed to patients, who should feel empowered to ask whether their surgeon will be operating on other patients simultaneously and whether they are a good candidate for overlapping surgery. “Patient trust and patient empowerment should be paramount,” Jena said. “While the overall findings of the study suggest that overlapping surgeries appear to be safe, we found evidence that this may not be true for all patients and all procedures,” said the study’s lead author, Eric Sun, assistant professor in the Department of Anesthesiology, Perioperative and Pain Medicine at Stanford University. “Improving efficiencies and providing training opportunities should never come at the cost of patient safety, and we need good evidence to guide us as we make decisions about surgery, both as a matter of policy and as a matter of individual patient care.” Researchers from the University of Michigan and the University of Pennsylvania also contributed to this paper.This research was supported with funds from the Office of the Director, National Institutes of Health (NIH Early Independence Award, Grant 1DP5OD017897) and to the National Institute on Drug Abuse (K08DA042314). Relevant disclosures:Jena reports receiving consulting fees unrelated to this work from Pfizer, Hill-Rom Services, Bristol-Myers Squibb, Novartis, Amgen, Eli Lilly & Company, Vertex Pharmaceuticals, AstraZeneca, Celgene, Tesaro, Sanofi-Aventis, Biogen, Precision Health Economics, and Analysis Group. Sun acknowledges consulting fees unrelated to this work from Egalet, Inc., and the Mission LISA Foundation.
UCI-led study reveals how blood cells help wounds heal scar-free Insights into the diversity of wound fibroblasts Irvine, Calif., Feb. 08, 2019 — New insights on circumventing a key obstacle on the road to anti-scarring treatment have been published by Maksim Plikus, an associate professor in developmental and cell biology at the UCI School of Biological Sciences and colleagues in Nature Communications. The research team discovered that the natural scar-free skin repair process relies partially on assistance from circulating blood cells. The results point the way toward possible treatments for scar-free wound healing that target the body’s own blood cells. Skin injuries activate rapid wound repair, which often culminates with the formation of scars. Unlike normal skin, scars are devoid of hair follicles and fat cells, and creating new hair and fat is necessary for regenerating an equivalent of normal skin. In a 2017 paper published in Science, Plikus and colleagues identified that adult mice can naturally regenerate nearly normal-looking skin when new hair follicles and fat cells form in healing wounds. New fat cells regenerate from myofibroblasts, a type of wound fibroblast that was previously not thought to be capable of converting into other cell types. This discovery brought renewed attention to wound fibroblasts as attractive targets for anti-scarring therapies. In the current study, co-led by George Cotsarelis from University of Pennsylvania, the research team sought to further characterize wound fibroblasts and determine if they’re all the same and equally capable of regenerating new fat cells. Using a panel of single-cell tools as a type of “computational microscope” that examines thousands of individual cells at once, the research team observed an unexpectedly high degree of fibroblast diversity. “We saw that wound fibroblasts are surprisingly very diverse and that there are as many as twelve different cell sub-types. We understand their molecular signatures and are beginning to learn about their unique biology. For example, we already know that distinct fibroblast sub-types ‘prefer’ only certain parts of the wound. This suggests that they play specific roles in different locations within the wound, and possibly at different times during the repair process,” said Christian Guerrero-Juarez, a postdoctoral fellow at UCI and first author on the project. After a closer look at wound fibroblasts, the team noted that a sizable group of cells had the molecular telltale signs of having originated from blood. “Molecular profiling of wound fibroblasts strongly suggests that as many as 13% of them at some point in their past were blood cells that converted into collagen-producing fibroblasts, but kept residual blood-specific genes still turned on,” said Plikus. Indeed, blood cell-derived fibroblasts have been reported by others in the past, including located in wound scars. “What is truly novel about our observation is that these fibroblast-making blood cells, which are called myeloid cells, can reprogram into new fat cells,” Plikus said. “In essence, we observed that for wounds to achieve scar-less regeneration, the body must mobilize multiple cellular resources, which includes remotely circulating blood progenitors.” Because myeloid cells can be fairly easy to harvest and enrich using existing techniques, the new findings open the exciting possibility that the skin’s healing ability can be enhanced via delivery of regeneration-competent blood-derived progenitors to the site of the wound. As an immediate next step, an information-rich catalog of diverse wound fibroblasts will help form a platform for the team to begin identifying new sub-types of cells that enhance scarring, or promote repair toward scar-less skin regeneration. Additional contributors to this study were Priya Dedhia, Suoqin Jin, Rolando Ruiz-Vega, Dennis Ma, Yuchen Liu, Kosuke Yamaga, Olga Shestova, Denise Gay, Zaixin Yang, Kai Kessenbrock, Qing Nie and Warren Pear. The research received support from the National Institutes of Health, the National Science Foundation, the Simons Foundation and the Pew Charitable Trusts.