Newswise — New Brunswick, N.J February 22, 2021 – The most frequently mutated gene in human cancers is called p53. Patients with Li-Fraumeni syndrome, which is a rare disorder that increases the risk of developing several types of cancer, often have an increased risk to develop cancers at early ages if they inherit p53 mutations. Recent studies suggest that some individuals with inherited p53 mutations do not have the early onset or high frequency of cancers, suggesting that other genetic, environmental, immunological, epigenetic, or random factors play a part in the development of cancers. A recent study from Rutgers Cancer Institute of New Jersey tested this possibility by analyzing tumor formation and p53 mutations in mice from different genetic backgrounds. Observations from this work may further elucidate the diversity of cancers in different Li-Fraumeni patients. Senior and corresponding author of the work Wenwei Hu, PhD, researcher at Rutgers Cancer Institute and professor of radiation oncology at Rutgers Robert Wood Johnson Medical School, along with lead and corresponding author Chang S. Chan, PhD, researcher at Rutgers Cancer Institute and associate professor of medicine at Rutgers Robert Wood Johnson Medical School, share more about the findings published in Life Science Alliance (http://doi.org/10.26508/lsa.202000952). Why is this topic important to explore? Mutations in the p53 gene are the single most common spontaneous genetic alterations observed in human cancers. Approximately one in 20,000 individuals inherit heterozygous p53 mutations, resulting in early onset and high frequency of cancers in each patient over a lifetime. Individuals with an inherited p53 mutation have a much higher risk compared to the general population of developing adrenal cortical carcinoma, choroid plexus carcinoma, medullary blastoma, rhabdomyosarcoma and osteogenic sarcoma. There is also a high relative risk of developing breast cancer, lipomas and liposarcomas, and leiomyosarcomas. However, even within family members who share the same p53 mutation, there is great variability in what cancer types they get and when they get it, thus, it is important to explore the influence of genetics and non-genetic factors on tumor formation and tumor type. These may include environment, immunological or random factors. Describe the work and tell us what the team discovered. We created seven sets of mice with different genetic backgrounds, all having the same p53 mutation. These mice are prone to developing a variety of tumor types because of the p53 mutation they harbor. The tumor types these mice develop are very similar to human Li-Fraumeni patients. The mice from each genetic background are almost genetically identical and the environments are controlled to be the same. This allows us to compare the variability of the tumors within genetically identical mice to mice with different genetic backgrounds, and thus tease apart the contribution of genetics and randomness to tumor formation. We discovered that certain genetic backgrounds greatly increase the chance of developing specific tumor types and the number of tumors in a single mouse. The age at which a tumor occurs is correlated with the tissue type of that tumor, although identical tumor tissue types can occur at very different ages. Sex of the mice also impact the risk for cancer in certain genetic backgrounds. These observations present evidence for both genetic and random effects upon tumor formation in diverse groups of mice. This helps to explain the great diversity of cancers in different Li-Fraumeni patients over their lifetimes. What are the implications of these findings? Although the results are consistent with a series of genetic modifiers that influence the age of onset of a tumor and the tumor tissue type, the results also support random factors playing a role in the development of tumors. The most obvious random event is a spontaneous mutation in one of the many different tissue specific stem cells of the body that increase cancer risk. Other random factors may include different microbiomes from mouse to mouse, random errors in development and the adaptive immune system which is different between identical strains of mice or identical twins. The approach in this work can lead to the identification of the gene or genes that predispose individuals to early onset tumors, the selection of the tissue type of a tumor, and enhancement of tumor risk. Genome sequencing of these tumors will help identify the genes whose mutations act with p53 mutations to influence benign and malignant tumors. Along with Drs. Hu and Chan, other authors include Yvonne Sun, PMV Pharma; Hua Ke, Yuhan Zhao, Merzu Belete, Cen Zhang and Zhaohui Feng, Rutgers Cancer Institute; and Arnold J. Levine, Simons Center for Systems Biology, Institute for Advanced Study in Princeton. This research was supported by grants from the National Institutes of Health, National Cancer Institute (P01CA087497-18, R01CA203965) and Department of Defense (W81XWH-18-10238). Other acknowledgements, author disclosures and other information can be found here.
Newswise — An international study has shown, for the first time, that the capacity of the human brain to recover and rewire itself peaks around two weeks after a stroke and diminishes over time. The finding, published today in the Neurorehabilitation and Neural Repair journal, is the result of a study in London and Adelaide that followed the recovery of 60 stroke patients up to one year after their stroke. Lead author Dr Brenton Hordacre, from the University of South Australia, says the multi-site study showed conclusive evidence that the brain only has a small window of opportunity to more easily repair itself after stroke. “Earlier animal studies suggested this was the case, but this is the first time we have conclusively demonstrated this phenomenon exists in humans,” Dr Hordacre says. The researchers scanned the brains of stroke survivors as they recovered over 12 months. They found that in the initial days following an ischemic stroke (caused by a blocked artery to the brain), the brain has a greater capacity to modify its neural connections and its plasticity is increased. “It is during this early period after stroke that any physiotherapy is going to be most effective because the brain is more responsive to treatment. “Earlier experiments with rats showed that within five days of an ischemic stroke they were able to repair damaged limbs and neural connections more easily than if therapy was delayed until 30 days post stroke.” The researchers used continuous transcranial magnetic stimulation (cTBS) to repetitively activate different hemispheres of the motor cortex to measure brain plasticity. The Adelaide laboratory tested the stroke damaged motor cortex, which is the main area that controls movement. The London laboratory tested the non-stroke damaged hemisphere which is also important to help recovery. “Our assessments showed that plasticity was strongest around two weeks after stroke in the non-damaged motor cortex. Contrary to what we expected, there was no change in the damaged hemisphere in response to cTBS.” Dr Hordacre says the findings confirm the importance of initiating therapy as soon as possible after a stroke. Current evidence indicates that less than eight minutes of daily therapy is dedicated to upper limb recovery within the first four weeks of a stroke. “Delivering more treatment within this brief window is needed to help people recover after stroke. “The next step is to identify techniques which prolong or even re-open a period of increased brain plasticity, so we can maximise recovery,” Dr Hordacre says. The paper, “Evidence for a Window of Enhanced Plasticity in the Human Motor Cortex following Ischemic Stroke” is available at: https://journals.sagepub.com/doi/full/10.1177/1545968321992330 Researchers from the following institutions were involved in the study: University of South Australia; University College London (UCL); University of Adelaide; Hospital Universitario Ramón y Cajal and Hospital Ruber Internacional in Madrid; Queen Mary University, London; the Royal London Hospital; National Hospital for Neurology and Neurosurgery, London; Murdoch University, WA; Royal Adelaide Hospital; and the Physio Clinic, Adelaide Photo Credit: University of South Australia Less than eight minutes of daily therapy is dedicated to upper limb recovery within the first four weeks of a stroke.
Newswise — DALLAS – Feb. 11, 2021 – A study led by UT Southwestern has identified a mechanism that controls the activity of proteins known as chaperones, which guide proteins to fold into the right shapes. The findings, published online today in Nature Communications, could shed light on hundreds of degenerative and neurodegenerative diseases caused by protein misfolding, such as Alzheimer’s, Parkinson’s, and Huntington’s, potentially leading to new treatments for these devastating conditions. Every protein in the body is originally produced in a linear chain, with amino acid building blocks strung together one after another. But to fulfill their roles in cells, explains study leader Lukasz Joachimiak, Ph.D., assistant professor in the Center for Alzheimer’s and Neurodegenerative Diseases at UT Southwestern, these chains need to fold into precise shapes. Chaperones help proteins accomplish this by protecting their vulnerable portions while they shift into position and steering them to adopt the proper shape. Every cell has a variety of chaperones that recognize and act on individual protein types. However, every chaperone isn’t active all the time, Joachimiak says. Unknown regulatory mechanisms appear to control when certain chaperones step in to guide their respective proteins to fold and when they stand aside. Joachimiak, also a member of the Peter O’Donnell Jr. Brain Institute, and his colleagues studied a family of chaperone proteins known as Hsp40s that work in combination with other chaperones known as Hsp70s. Members of these co-chaperones are involved in the proper folding of many proteins, including tau, which play a key role in causing Alzheimer’s disease when it’s misfolded. Hsp40 chaperones bind to Hsp70s through a specific portion on the Hsp40s called the J domain. But how the Hsp40s turn off this binding when it is not needed has been unclear. To help answer this question, Joachimiak and his colleagues used a specific Hsp40 called DnaJB8 as a model. When the researchers genetically modified these proteins to glow green inside cells, they found that they didn’t just exist as individual, free-floating units – the DnaJB8 chaperones tended to form aggregates, suggesting they had some way to stick to each other. They retained this ability to agglomerate when they were isolated in petri dishes. Using computer modeling and guided by biochemical experiments, the researchers discovered that two separate parts of this chaperone were drawn to each other through a type of chemistry called electrostatic interactions: Part of the J domain was drawn to a different part of this protein called the C-terminal domain through charged interactions. Modeling also showed that the J domain and the C-terminal domain stuck together on single molecules as well. Joachimiak and his team validated these findings on real DnaJB8 proteins using a technique called solid-state nuclear magnetic resonance. They also showed that the J and C-terminal domains stuck to each other when they were isolated from the full DnaJB8 molecule. The researchers suspected that the interaction between these two domains could prevent DnaJB8 from binding to its co-chaperone, an Hsp70, preventing them from jointly doing their job of guiding protein folding. Sure enough, experiments showed that the C-terminal domain of DnaJB8 competed with an Hsp70 called HspA1A when it was added to DnaJB8 in a test tube, blocking HspA1A from binding to the J domain when the C-terminal domain was bound instead. Joachimiak notes that something may go awry in this or other regulatory mechanisms that control the activity of chaperones in protein misfolding diseases. Finding ways to control this activity through pharmaceuticals or other means could provide a new way to treat these conditions to attack the problem at its source. “We may be able to leverage this mechanism to directly target these chaperones, activating them at will,” says Joachimiak, who is also an assistant professor of biochemistry and an Effie Marie Cain Scholar in Medical Research. “Our results could have an impact on hundreds of diseases where proteins become bad players by misfolding.” Other UT Southwestern researchers who contributed to this study include Bryan D. Ryder, Sofia Bali, and Jaime Vaquer-Alicea. This work was supported by a grant from The Welch Foundation (I-1928-20170325). About UT Southwestern Medical Center UT Southwestern, one of the premier academic medical centers in the nation, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty has received six Nobel Prizes, and includes 23 members of the National Academy of Sciences, 17 members of the National Academy of Medicine, and 13 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 2,500 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in about 80 specialties to more than 105,000 hospitalized patients, nearly 370,000 emergency room cases, and oversee approximately 3 million outpatient visits a year.
Newswise — COLUMBUS, Ohio – A new national survey of more than 2,000 Americans by The Ohio State University Wexner Medical Center finds most plan to continue many of the pandemic precautions in the name of public health, even when the pandemic is over. As more people get vaccinated against COVID-19, there’s growing optimism for a happier and healthier future. But experts warn that life will not return to normal right away, and people should expect many health precautions and restrictions implemented during the pandemic to stick around for the foreseeable future. “While the progress we’re making toward recovery is exciting, it’s critical that we don’t ease up on the precautions that we know have worked thus far,” said Dr. Iahn Gonsenhauser, chief quality and patient safety officer at The Ohio State Wexner Medical Center. “Masks and physical distancing are still our best weapons for limiting spread and, now that we have a vaccine, will make those precautions even more effective and will drive new cases way down if we stay the course.” The survey found that nearly three-quarters (72%) of Americans plan to continue to wear masks in public, four out of five (80%) will still avoid crowds and 90% plan to keep up frequent handwashing and sanitizer use after COVID-19. Gonsenhauser says it’s encouraging that people are willing to continue these practices and that this year’s flu season is proof of their effectiveness. “Flu cases and hospitalizations are way down compared to recent years. A lot of that is likely because precautions like masking, physical distancing and hand hygiene are working to prevent the flu,” Gonsenhauser said. “I think a lot of people realize what we’ve learned from COVID-19 can be applied more generally to keep our population healthy.” After nearly a year of living in a world drastically changed by the pandemic, continuing these practices may ease the anxiety of returning to public spaces. Wearing a mask, for example, can provide a sense of control and comfort to those with lingering pandemic fears. Experts also predict that there are some aspects of society that will never return to pre-pandemic standards, and that’s not all bad. Work from home options will likely stick around in many industries and the convenience of seeing your doctor virtually through a telehealth visit is likely to remain and even expand in the future. Photo: The Ohio State University Wexner Medical Center Mike Nicholson livestreams his hip-hop fitness classes and has had limited in-person attendance for months. He’s looking forward to welcoming more people back to class. But to get there, everyone will have to keep following COVID-19 safety protocols.
Newswise — You might remember you ate cereal for breakfast but forget the color of the bowl. Or recall watching your partner put the milk away but can't remember on which shelf. A new Northwestern Medicine study improved memory of complex, realistic events similar to these by applying transcranial magnetic stimulation (TMS) to the brain network responsible for memory. The authors then had participants watch videos of realistic activities to measure how memory works during everyday tasks. The findings prove it is possible to measure and manipulate realistic types of memory. "On a day-to-day basis we must remember complex events that involve many elements, such as different locations, people and objects," said lead author Melissa Hebscher, a postdoctoral fellow at Northwestern University Feinberg School of Medicine. "We were able to show that memory for complex, realistic events can be improved in a safe and non-invasive way using brain stimulation." The study was conducted on healthy young adults in a controlled laboratory setting. These methods, however, also could eventually be used to improve memory in individuals with memory disorders due to brain damage or neurological disorders, Hebscher said. The study will be published Feb. 4 in the journal Current Biology. A new approach to studying memory: Incorporating video The study authors used TMS with the goal of altering brain activity and memory for realistic events. Immediately following stimulation, subjects performed a memory task while having their brains scanned using functional magnetic resonance imaging (fMRI). Instead of showing study participants pictures or lists of words - typical practices in laboratory tests that analyze memory - participants in this study watched videos of everyday activities such as such as someone folding laundry or taking out the garbage. "Our study used video clips that more closely replicate how memory works on a day-to-day basis," Hebscher said. Following stimulation, study participants more accurately answered questions about the content of the video clips, such as identifying the shirt color an actor was wearing or the presence of a tree in the background. Additionally, the study found that brain stimulation led to higher quality reinstatement of memories in the brain. Reinstatement is when the brain replays or relives an original event, Hebscher said. Following stimulation, a person's brain activity while watching a video more closely resembled their brain activity when remembering that same video. "This is why remembering can sometimes feel like 'mental time travel,'" Hebscher said. "Our findings show that stimulation enhances this 'mental time travel' in the brain and improves memory accuracy. These findings have implications for the development of safe and effective ways to improve real-world memory." How the study worked The study authors used a brain imaging technique called multi-voxel pattern analysis to compare patterns of brain activity when subjects were watching a video to brain activity when subjects were remembering that same video. The scientists measured the effect of stimulation by comparing memory and brain activity following stimulation of the memory network to the same measures following stimulation of a control brain region that does not belong to the memory network. During the memory test, subjects watched a large set of video clips and later remembered them and answered true/false questions about the content of the videos. The researchers found that memory network stimulation improved the number of questions that subjects answered correctly. It also increased reinstatement of videos in brain regions associated with visual processing. "Follow-up studies will work to gather more reliable measures of the brain network responsible for memory in healthy subjects as well as in patients with memory disorders," Hebscher said. "Having a more reliable measurement of this network will help us more easily identify reinstatement in the brain and may help improve the effectiveness of stimulation for enhancing memory."
Newswise — Nurses play a crucial role in helping to reduce the stress experienced by family members of critically ill patients, according to an article in Critical Care Nurse (CCN). Having a family member, regardless of their age, admitted to an intensive care unit (ICU) is a stressful event, and research has documented that such stress may contribute to depression, anxiety and posttraumatic stress disorder (PTSD). The Society of Critical Care Medicine (SCCM) recently updated guidelines for family-centered care in ICU settings, which state that part of a nurse’s role is to assess stress among family members of a critically ill patient and to intervene to help reduce this stress. “Nursing Interventions to Reduce Stress in Families of Critical Care Patients: An Integrative Review” responds to the SCCM guidelines by aiming to establish the state of knowledge regarding the stress experienced by families with a loved one in the ICU and to identify specific nursing interventions that may help. Authors Valèrie Lebel, PhD, RN, and Sylvie Charette, PhD, RN, are professors in the department of nursing, at the Universitè du Quèbec en Outaouais (University of Quebec Outaouais), in Canada. “The COVID-19 pandemic has reinforced that ICU nurses are the main point of interaction between the healthcare team and the family and that they are crucial to supporting the family through the ICU experience,” Lebel said. “A family-centered approach makes it possible to implement tailored interventions that are flexible and accommodate individual coping strategies.” Their literature search of three databases (MEDLINE, CINAHL, and Cochrane) identified 934 research articles with select keywords related to the topic in the abstract or summary. The search covered the period from 2007, when the first SCCM family-centered care guidelines were issued, through 2019. From these, they removed duplicates and applied inclusion criteria, resulting in a total of 38 articles for the integrative review. Of these, 18 studies dealt with the neonatal ICU setting, nine were in pediatric ICUs, and 11 were in adult ICUs, most of which were medical and surgical ICUs. The article summarizes the design and findings of all 38 research studies, with principal stressors for families and related nursing interventions. The analysis found that, in all three care settings, the sources of stress fell into four main categories: Changes in the relationship between the patient and family Altered appearance and behavior of the patient Highly specialized care setting with unfamiliar medical equipment and healthcare staff Communication and counseling with the healthcare staff For each stressor, the researchers identified specific nursing interventions, such as using a family-centered approach to care and implementing appropriate stress-reducing interventions. Overall, their findings recommend that nursing interventions focus on valuing the role of family members in patient care, improving communication and providing accurate information. Reducing family members’ stress during a loved one’s ICU stay may also help with efforts to reduce family post-ICU syndrome, with its mental health issues and decreased quality of life. In addition, more research is needed to develop tools to evaluate family members’ level of stress and principal stressors, as well as the most effective interventions to improve the family’s experience of intensive care. As the American Association of Critical-Care Nurses’ (AACN’s) bimonthly clinical practice journal for acute and critical care nurses, CCN is a trusted source of information related to the bedside care of critically and acutely ill patients. Access the article abstract and full-text PDF by visiting the CCN website at http://ccn.aacnjournals.org.
Newswise — In a career spanning more than two decades, orthopedic surgeon Geoffrey Westrich has seen numerous advances in joint replacement surgery that benefit patients. He believes robotic-assisted knee replacement, which allows for an ultraprecise procedure, is one of the most exciting. Dr. Westrich, who specializes in knee and hip replacement at Hospital for Special Surgery in New York City, reached a milestone last year when he performed his 500th robotic-assisted knee replacement. He uses the MAKO robotic system, which is FDA-approved for both total and partial knee replacements. "Joint replacement is highly successful in relieving arthritis pain and improving quality of life, and the robotic system allows us to really customize the procedure for each patient," says Dr. Westrich. “The MAKO system allows for optimal alignment and positioning of the knee implant, as well as optimal ligament balancing, all critically important for the best outcome and long-term success of the surgery. Such precision could potentially lead to a longer-lasting knee replacement.” Dr. Westrich says over the past few years, he has seen more patients in their 40s and 50s with arthritis who are candidates for a knee replacement. The main concern for patients in this age group is that the implant may wear out over time. Although a knee replacement could last 20 years, or even longer, it doesn’t last indefinitely. For younger individuals in particular, robotic-assisted surgery has made joint replacement an attractive option, as it could prolong the life of the implant, according to Dr. Westrich. Over the past couple of years, studies have focused on the pinpoint accuracy of the robotic-assisted knee replacement system. A study by Dr. Westrich and colleagues published in the Journal of Knee Surgery this year found that the technology was advantageous in the training of orthopedic surgeons, as it allowed for increased accuracy and precision. A separate study in the Bone & Joint Journal in 2018 by researchers in the United Kingdom found robotic-assisted total knee replacement was associated with decreased pain after surgery, improved early functional recovery and a shorter hospital stay. Before surgery, a CT scan is taken of the patient’s knee. The scan is then uploaded into the Mako system software, where a 3D model of the joint is created. The 3D model is used to plan and assist the surgeon in performing the joint replacement. In the operating room, the orthopedic surgeon controls a robotic arm that uses computer‐guided mapping software, similar to GPS, integrated into the surgical instruments to position the implant in the knee joint. The digital tracking system constantly monitors and updates the patient’s anatomy and enables the surgeon to make real‐time adjustments to optimize implant placement, alignment, ligament balance and joint motion. This provides each patient with a personalized surgery tailored to his or her individual anatomy. “With more accurate alignment and positioning, the implant should experience less wear and friction, and it could ultimately last longer,” says Dr. Westrich, who notes that studies will be needed to confirm this over the long term. He says the precision of the robotic‐assisted procedure also offers more protection to the surrounding soft tissues and enables more healthy bone to be preserved, an advantage in the event another knee replacement is needed down the road.
Newswise — The overuse of antibiotics occurs due to the mistaken widespread belief that they are beneficial for a broad array of conditions and because many physicians are willing to prescribe antibiotics if patients ask for the medication, according to a Rutgers study. The study, published in the journal BioEssays, reviewed more than 200 peer-reviewed studies to examine the causes behind antibiotic overuse, which can lead harmful bacteria to become drug-resistant and cause harmful effects on the microbiome, the collection of beneficial germs that live in and on our bodies. Martin Blaser, director of the Center for Advanced Biotechnology and Medicine at Rutgers and lead author, said the global use of antibiotics between 2000 and 2015 increased 39 percent, with a 77 percent increase in low- and middle-income countries. He discusses the study’s findings. What health concerns result from the disruption of the microbiome by antibiotics?In children, improper antibiotic use can alter the microbiome while their immunological, metabolic and neural systems are developing. Epidemiological studies associate antibiotic exposure with an increased risk of disease of allergic, metabolic and cognitive disorders that have grown more common in children during the antibiotic era. In adults, there is increasing evidence that antibiotics may enhance risk for metabolic and neoplastic diseases, including diabetes, kidney stones and growths in the colon and rectum that can lead to cancer. What are the trends you found in antibiotic use?Studies in the United States, United Kingdom and China found numerous online pharmacies selling antibiotics without a prescription. This problem also is large in Iowa- to middle-income countries, where 60 percent of antibiotics are sold without prescriptions, often by untrained medical practitioners. Perhaps of special concern during the COVID-19 pandemic is the finding that telemedicine services are another potential source of questionable antibiotic sales in the United States. A recent analysis found that patients with acute respiratory infections were more often prescribed broad-spectrum antibiotics if they had a tele-health doctor visit, compared to an in-person visit. Worldwide, antibiotic use is highest in young children, especially in low-income areas. This is often in response to the fact that young children are prone to have four to six upper respiratory tract infections each year. Although most of these infections are treated by antibiotics, 80 percent are not caused by bacteria and would therefore derive no benefit from antibiotics. Are some practitioners more likely to prescribe antibiotics?Our findings are consistent with the hypothesis that older physicians are more likely than their younger colleagues to prescribe antibiotics. For example, one study found that physicians over 30 were several times more likely to prescribe antibiotics for common respiratory conditions that do not necessarily require them. Another study found that physicians with over 25 years in practice were disproportionately likely to issue prescriptions of more than eight days. What misinformation did you find among the public?Many people believe that antibiotics are effective against bacterial and viral illnesses, lumping all types of pathogens together and adopting a “germs are germs” attitude. Others believe that taking antibiotics can’t hurt. Across Europe, for example, 57 percent of people surveyed were unaware that antibiotics were ineffective against viruses, and 44 percent did not know that antibiotics have no effect against colds or influenza. What other reasons did you find for inappropriate prescription of antibiotics?Antibiotics are commonly used across the world to self-treat health problems for which they were never intended, such as in Nigeria, where women are increasingly using antibiotics to reduce menstrual cramps. In low- to middle-income countries, antibiotics are often seen as strong, magical medicines, capable of both curing and preventing a range of illness. In many countries people also take them to return to work or school when ill. One of the studies found that 63 percent of Chinese university students kept a personal antibiotic stock at home. Parents may appeal for an antibiotic for their children so that they can go to work or for the children to return to school or daycare. A U.S. study found that 43 percent of parents of a child with cold symptoms believed that antibiotics were necessary. In addition, some doctors are inclined to prescribe an antibiotic to maintain a good relationship with patients who expect to receive medication. Patients may not demand antibiotics outright, but rather infer their need for them by how they describe the severity of their illness or note that they worked in the past for a similar issue. People have become less willing to wait and let an illness run its course. The perception that there is a pill for ills of all kinds leads the public to demand immediate relief for symptoms from practitioners and to self-medicate. Every time an antibiotic is given, money changes hands. This is especially a problem in low- and middle-income countries, where pharmacists are happy to dispense without a prescription to their customers. The rural health practitioners in China are paid every time they dispense an antibiotic as well. Such monetary incentives favor the wide use of antibiotics. How can antibiotic overuse be addressed?Clinicians need to be better educated about the long-term effects on the microbiome and learn about better ways to speak with their patients about antibiotic risks and benefits. They also need to improve their communication about the consequences of antibiotic treatments and identify antibiotic alternatives. Blaser conducted the study with three eminent anthropologists (Melissa Melby, University of Delaware; Margaret Lock, McGill University; and Mark Nichter, University of Arizona). All are members of the Canadian Institute for Advanced Research (CIFAR).
One form of immunotherapy weakens cancer and renders it vulnerable to another form, creating one-two punch Newswise — HAMILTON, ON, Jan. 21, 2020 — McMaster University researchers have established in lab settings that a novel combination of two forms of immunotherapy can be highly effective for treating lung cancer, which causes more deaths than any other form of cancer. The new treatment, yet to be tested on patients, uses one form of therapy to kill a significant number of lung tumor cells, while triggering changes to the tumor that enable the second therapy to finish the job. The first therapy employs suppressed “natural killer” immune cells by extracting them from patients’ tumours or blood and supercharging them for three weeks. The researchers condition the cells by expanding and activating them using tumour-like feeder cells to improve their effectiveness before sending them back into battle against notoriously challenging lung tumors. The supercharged cells are very effective on their own, but in combination with another form of treatment called checkpoint blockade therapy, create a potentially revolutionary treatment. “We’ve found that re-arming lung cancer patients’ natural killer immune cells acts as a triple threat against lung cancer,” explains Sophie Poznanski, the McMaster PhD student and CIHR Vanier Scholar who is lead author of a paper published today in the Journal for ImmunoTherapy of Cancer. “First, these highly activated cells are able to kill tumour cells efficiently. Second, in doing so, they also reactivate tumour killing by exhausted immune cells within the patients’ tumours. And third, they release factors that sensitize patients’ tumours to another immunotherapy called immune checkpoint blockade therapy. “As a result, we’ve found that the combination of these two therapies induces robust tumour destruction against patient tumours that are initially non-responsive to therapy.” Previous breakthroughs in checkpoint blockade therapy had earned Japanese researcher Tasuku Honjo and American immunologist James Allison the 2018 Nobel Prize for Medicine or Physiology. Checkpoint blockade therapy works by unlocking cancer’s defence against the body’s natural immune response. The therapy can be highly effective in resolving even advanced cases of lung cancer – but it only works in about 10 per cent of patients who receive it. The research team, featuring 10 authors in total, has shown that the supercharged immune cells, when deployed, release an agent that breaks down tumors’ resistance to checkpoint blockade therapy, allowing it to work on the vast majority of lung-cancer patients whose tumors would otherwise resist the treatment. Once activated, the natural killer cells are able to secrete inflammatory factors that help enhance the target of the blockchain that the other immunotherapy treats. “We needed to find a one-two punch to dismantle the hostile lung tumor environment,” says Ali Ashkar, a professor of Medicine and a Canada Research Chair who is Poznanski’s research supervisor and the corresponding author on the paper. “Not only is this providing a new treatment for hard-to-treat lung cancer tumors with the natural killer cells, but that treatment also converts the patients who are not responsive to PD1-blockade therapy into highly responsive candidates for this effective treatment”. Such progress is possible because of the close collaboration among clinical practitioners and lab-based researchers at McMaster and its partner institutions, Ashkar says. He said the team’s clinical practitioners, who work with cancer patients every day, provided critical wisdom and collected vital samples from patients at St. Joseph’s Healthcare Hamilton. Ashkar says those clinicians’ insights and the samples were integral to the research. Co-author Yaron Shargall, a professor in and Chief of the Division of Thoracic Surgery at McMaster’s Michael G. DeGroote School of Medicine and a thoracic surgeon at St. Joseph’s Healthcare Hamilton, says the promising outcome is the result of close links between basic science and clinical medicine. “It was successful mostly due to the facts that the two groups have spent long hours together, discussing potential ways of combining forces and defining a linkage between a highly specific basic science technology and a very practical clinical, day-to-day dilemmas,” he said. “This led to a flawless collaboration which resulted in a very elegant, potentially practice-changing, study.” The researchers are now working to organize a human clinical trial of the combined therapies, a process that could be under way within months, since both immunotherapies have already been approved for individual use. Photo info: Georgia Kirkos, McMaster University McMaster University researchers Ali Ashkar and Sophie Poznanski.
Newswise — One of the most vexing aspects of the COVID-19 pandemic is doctors’ inability to predict which newly hospitalized patients will go on to develop severe disease, including complications that require the insertion of a breathing tube, kidney dialysis or other intensive care. Knowledge of a patient’s age and underlying medical conditions can help predict such outcomes, but there are still surprises when younger, seemingly healthier patients suffer severe complications that can lead to death. Now, scientists at Washington University School of Medicine in St. Louis have shown that a relatively simple and rapid blood test can predict — within a day of a hospital admission — which patients with COVID-19 are at highest risk of severe complications or death. The study, published Jan. 14 in JCI Insight, involved nearly 100 patients newly admitted to the hospital with COVID-19. The blood test measures levels of mitochondrial DNA, a unique type of DNA molecule that normally resides inside the energy factories of cells. Mitochondrial DNA spilling out of cells and into the bloodstream is a sign that a particular type of violent cell death is taking place in the body. “Doctors need better tools to evaluate the status of COVID-19 patients as early as possible because many of the treatments — such as monoclonal antibodies — are in short supply, and we know that some patients will get better without intensive treatments,” said co-senior author Andrew E. Gelman, PhD, the Jacqueline G. and William E. Maritz Endowed Chair in Immunology and Oncology in the Department of Surgery. “There’s so much we still don’t understand about this disease,” he added. “In particular, we need to understand why some patients, irrespective of their ages or underlying health in some cases, go into this hyperinflammatory death spiral. Our study suggests that tissue damage may be one cause of this spiral, since the mitochondrial DNA that is released is itself an inflammatory molecule.” The researchers said the test could serve as a way to predict disease severity as well as a tool to better design clinical trials, identifying patients who might, for example, benefit from specific investigational treatments. They also said they would like to evaluate whether the test could serve as a way to monitor the effectiveness of new therapies. Presumably, effective treatments would lower mitochondrial DNA levels. “We will need larger trials to verify what we found in this study, but if we could determine in the first 24 hours of admission whether a patient is likely to need dialysis or intubation or medication to keep their blood pressure from dropping too low, that would change how we triage the patient, and it might change how we manage them much earlier in the disease course,” said co-senior author Hrishikesh S. Kulkarni, MD, an assistant professor of medicine. The researchers, including co-first authors Davide Scozzi, MD, PhD, a staff scientist, and Marlene Cano, PhD, a postdoctoral research scholar, evaluated 97 patients with COVID-19 at Barnes-Jewish Hospital, measuring their mitochondrial DNA levels on the first day of their hospital stays. They found that mitochondrial DNA levels were much higher in patients who eventually were admitted to the ICU, intubated or died. The researchers found this association held independently of a patient’s age, sex and underlying health conditions. On average, mitochondrial DNA levels were about tenfold higher in patients with COVID-19 who developed severe lung dysfunction or eventually died. Those with elevated levels were almost six times more likely to be intubated, three times more likely to be admitted to the ICU and almost twice as likely to die compared with those with lower levels. Further, the test predicted outcomes as well as or better than existing markers of inflammation currently measured in patients hospitalized with COVID-19. Most other markers of inflammation measured in patients with COVID-19, including those still under investigation, are general markers of systemic inflammation, rather than inflammation specific to cell death, according to the researchers. “Viruses can cause a type of tissue damage called necrosis that is a violent, inflammatory response to the infection,” Gelman said. “The cell breaks open, releasing the contents, including mitochondrial DNA, which itself drives inflammation. In COVID-19 patients, there has been anecdotal evidence of this type of cell and tissue damage in the lung, heart and kidney. We think it’s possible that measures of mitochondrial DNA in the blood may be an early sign of this type of cell death in vital organs.” The researchers also emphasized that the test is quick and straightforward to perform in most hospital settings because it uses the same machinery that processes the standard PCR test for COVID-19. The method they developed allows mitochondrial DNA levels to be quantified directly in the blood. Without requiring intermediate steps to extract the DNA from the blood, the technique returned results in less than an hour. Before they can apply for approval from the Food and Drug Administration (FDA), the scientists will need to verify that the test is accurate in a larger multi-center trial. They have plans to expand the research to more sites. The study utilized samples obtained from the School of Medicine’s COVID-19 biorepository, which was developed by co-authors Jane O’Halloran, MD, PhD, an assistant professor of medicine; Charles Goss, PhD, an instructor in biostatistics; and Phillip Mudd, MD, PhD, an assistant professor of emergency medicine. Photo Info: WANDY BEATTY A new study from Washington University School of Medicine in St. Louis suggests that measuring mitochondrial DNA in the blood of patients with COVID-19 can help predict which patients are at highest risk of severe disease, requiring more intensive care. Mitochondrial DNA levels are a measure of tissue damage. Pictured are damaged mitochondria (dark grey areas) released from human lungs. The small dark dots surrounding the mitochondria are magnetic beads that carry antibodies used to isolate and study unhealthy mitochondria that have been released from dying tissues.