Body

What The Study Did: Researchers evaluated the association between having any prior psychiatric diagnosis and COVID-19- related mortality of hospitalized patients with COVID-19.

Authors: Luming Li, M.D., of the Yale University School of Medicine in New Haven, Connecticut, is the corresponding author.

To access the embargoed study: Visit our For The Media website at this link https://media.jamanetwork.com/

(doi:10.1001/jamanetworkopen.2020.23282)

Editor's Note: The article includes conflict of interest disclosures. Please see the article for additional information, including other authors, author contributions and affiliations, conflict of interest and financial disclosures, and funding and support.

What The Study Did: In this randomized clinical trial, daily hydroxychloroquine didn't prevent SARS-CoV-2 infection among hospital-based health care workers, although the trial was terminated early.

Authors: Ravi K. Amaravadi, M.D., of the University of Pennsylvania in Philadelphia, is the corresponding author.

To access the embargoed study: Visit our For The Media website at this link https://media.jamanetwork.com/

(doi:10.1001/jamainternmed.2020.6319)

Editor's Note: The article includes conflict of interest and funding/support disclosures. Please see the article for additional information, including other authors, author contributions and affiliations, conflict of interest and financial disclosures, and funding and support.

Recreational use of the illicit drug methamphetamine has long been associated with increases in overall impatient and risky behavior. Now, a new study by Johns Hopkins Medicine researchers affirms that meth use increases not only sexual desire but also, specifically and measurably, the risk of casual sex without a condom for those who have an increase in sexual desire.

The findings of the study, described in the Sept. 28 issue of Experimental and Clinical Psychopharmacology, illuminate the complicated relationship between sexual arousal and decision making. The study demonstrated that the more intense the sexual arousal, the more likely study participants were to rapidly shift their stated preference for using a condom to more risky snap decisions to have unprotected sex.

"I discourage anyone from using illicit meth, but if someone is going to use it, they need to be aware that one of the many dangers is that they are more likely to make unsafe decisions when it comes to sex," says Matthew W. Johnson, Ph.D., professor of psychiatry and behavioral sciences at the Johns Hopkins University School of Medicine. "Just knowing that, specifically for new users, may help them plan ahead and have a condom at hand just to be prepared."

According to the U.S. Centers for Disease Control and Prevention (CDC), rates of HIV and other sexually transmitted infections (STIs) are extremely high among methamphetamine users. This largely mirrors what is known about the impact of stimulants, including cocaine, on sexual risk behavior.

"This isn't just about the needle sharing factor for the spread of HIV or other infections," says Johnson. "It's more about how people engage in risky behaviors in association with these drugs and sex, which is largely connected with the concept of delay discounting, or the degree to which people take the future into account in their decision making."

For the study, the researchers recruited otherwise healthy recreational meth users from Baltimore and surrounding areas. Participants included 13 men and six women, averaging 27 years of age.

In a clinical and controlled setting, participants were randomly assigned to take capsules containing 0 milligrams (placebo), 20 milligrams or 40 milligrams of methamphetamine in three separate sessions.

After each dose, participants were presented with hypothetical settings in which they had to select all the people with whom they would consider having sex from among 60 photographs of clothed men (30) and women (30). The photographs represented a diverse sample in terms of race/ethnicity, age, weight, body shape, clothing style and attractiveness. From the selected photographs, participants then chose the person they would most want to have sex with, as well as the person they would least want to have sex with. Participants also selected the person they judged as least likely to have an STI and the person most likely to have an STI.

The results showed that, in the 40 milligram sessions, participants selected on average 9.5 partners with whom they would consider having sex, nine partners in the 20 milligram sessions and 7.4 partners in the placebo session.

Participants were also asked to imagine they weren't in a committed relationship, the photographed person wanted to have sex now and there was no risk of pregnancy if a condom wasn't used.

They were then shown the photographs of their selected partners and asked to rate their likelihood of using a condom in a hypothetical casual sex situation in which a condom was immediately available. The rating scale went from 0 (I will definitely have sex with this person now without a condom) to 100 (I will definitely have sex with this person with a condom). Next, the participants were asked to rate their likelihood of using a condom in the same scenario except that a condom wasn't immediately available. In this scenario, the 100% value in the range represented "I will definitely wait to have sex with this person until a condom is available." Participants ranked seven time delays: one hour, three hours, six hours, one day, one week, one month and three months.

Participants didn't report significantly different likelihoods of using an immediately available condom during the 20 milligram or 40 milligram sessions relative to placebo sessions. However, the researchers found that having to wait for a condom had a large effect on the likelihood of condom use with the most desirable sexual partners -- from 87% when immediately available to 62% when delayed by one day.

Overall, methamphetamine had a large effect on sexual desire. A 20 milligram dose caused a 2.4 times increase in ratings of sexual desire compared to placebo. This increase was 3.5 times higher for the 40 milligram dose.

Study findings also showed that the greater the increase in sexual desire, the less likely it was for the person to want to wait for a condom. For example, when determining the most desirable partner for the 10% of study participants who showed the greatest increase in sexual desire as a result of getting the higher drug dose, condom use dropped from 80% when on placebo to 55% when on the 40 milligram dose when they had to wait for a day.

Johnson says previous research showed that "decision making with hypothetical scenarios in the lab is aligned to real world behavior involving both risk and delay discounting. So, by using hypothetical situations, we can have some confidence when we say that for some participants, the decision to use a condom was influenced by delay, and that increases in desire were associated with the likelihood of choosing not to use a condom."

WHAT:
A Phase 1 trial of an investigational mRNA vaccine to prevent SARS-CoV-2 infection has shown that the vaccine is well-tolerated and generates a strong immune response in older adults. A report published today in the New England Journal of Medicine describes the findings from the study, which was supported by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health. SARS-CoV-2 is the virus that causes COVID-19 disease.

The experimental vaccine, mRNA-1273, was co-developed by researchers at NIAID and Moderna, Inc. of Cambridge, Massachusetts. The Phase 1 trial began on March 16, 2020, and was expanded to enroll older adults about one month later. Older adults are more vulnerable to complications of COVID-19 and are an important population for vaccination. Understanding how the vaccine affects older adults is a critical part of measuring its safety and efficacy.

The trial was conducted at Kaiser Permanente Washington Health Research Institute (KPWHRI) in Seattle, Emory University in Atlanta, and NIAID's Vaccine Research Center (VRC) clinic at the NIH Clinical Center in Bethesda, Maryland. Julie Ledgerwood, D.O., deputy director and chief medical officer at the VRC, oversaw the study at the NIH site. The Coalition for Epidemic Preparedness Innovations (CEPI) supported the manufacturing of the vaccine candidate for this trial. This trial is supported by the Infectious Diseases Clinical Research Consortium (IDCRC) through NIAID.

In its expansion to include older adults, the trial enrolled 40 healthy volunteers: 20 adults ages 56 to 70 years, and 20 adults ages 71 years and older. Ten volunteers in each age group received a lower dose of the vaccine (25 μg), and 10 volunteers in each age group received a higher dose (100 μg). After approximately one month, volunteers then received a second dose of the same vaccine at the same dosage. Throughout the study, volunteers attended clinic visits to track their responses to the vaccine and assess safety.

Overall, the researchers found that the investigational vaccine was well-tolerated in this older age group. Although some volunteers experienced some transient adverse effects, including fever and fatigue after vaccination, the researchers found that they also exhibited a good immune response to the vaccine: the blood of vaccinated volunteers contained robust binding and neutralizing antibodies against SARS-CoV-2. Importantly, the immune response to the vaccine seen in older volunteers was comparable to that seen in younger age groups.

The study will continue to follow the older volunteers for approximately a year after second vaccination to monitor the long-term effects of the vaccine. According to the researchers, these Phase 1 trial results further support testing of the investigational vaccine in older adults in an ongoing large Phase 3 trial.

SCOTTSDALE, Ariz. -- Sept. 29, 2020 -- Led by the Translational Genomics Research Institute (TGen), an affiliate of City of Hope, and by HonorHealth Research and Innovation Institute, an international team of researchers have described in detail the individual cells that comprise the pancreatic cancer microenvironment, a critical step in devising new treatment options for patients with this aggressive and difficult-to-treat disease.

The study results were published today in the scientific journal Genome Medicine, a publication of Springer Nature.

Researchers used a relatively new technique known as single-cell sequencing to genetically identify cell types, and subtypes, that occur in pancreatic tumors, and identify the various cells in the tumor's stroma, a substance surrounding the tumor that can hide the cancer from the body's immune system.

While single-cell transcriptomics has been used previously to study the cellular composition of primary tumor tissues of pancreatic ductal adenocarcinoma (PDAC), this study also used the technology to profile individual cells from dissociated primary tumors and biopsies of metastatic tissues, those cancerous lesions that have spread throughout the body from the primary tumor.

This study was carried out in collaboration with investigators from Samsung Medical Center and City of Hope, a world-renowned independent research and treatment center for cancer, diabetes and other life-threatening diseases. Primary tumors and core needle biopsies of metastatic lesions from PDAC patients were sequenced using the Chromium single cell RNA-Seq platform.

"Single-cell transcriptome analysis can offer important clinical insights on individual cell subpopulations and provide clues for developing novel therapeutic strategies for both targeted therapies and immunotherapies," said Haiyong Han, Ph.D., a professor in TGen's Molecular Medicine Division and head of the institute's Pancreatic Cancer Research Laboratory.

"Understanding the diversity and complexity of the PDAC tumor and stromal compartments in individual tumors may help identify unique intervention points and potentially inform treatment and maintenance strategies for patients with advanced disease," said Dr. Han, the study's senior author.

Distinct cell types and subtypes were identified in the analysis, including tumor cells, endothelial cells, cancer associated fibroblasts, and immune cells, and the expression levels of various genes in the individual cell populations correlated with patient clinical outcomes.

"Working with our partners and colleagues by utilizing the technology of singe cell sequencing, we can continue to learn more about the biology of pancreas cancer. These insights may potentially help us determine more treatment options for our patients," said Erkut Borazanci, M.D., M.S., a medical oncologist and physician-investigator at HonorHealth Research and Innovation Institute, a clinical associate professor at TGen, and one of the paper's authors.

Pancreatic cancer is an aggressive disease that carries a high mortality rate. It is the third-leading cause of cancer death in the U.S., following lung and colorectal cancers. In 2020, the five-year survival rate for pancreatic cancer is only about 10%, though that represents progress from the dismal 6% rate in 2014.

Next, researchers plan to use more advanced single-cell spatial transcriptomics analysis to further investigate the cellular relationships related to survival rates using real-time methods. Broader use of this technology could potentially guide the search for new agents to treat pancreatic cancer.

CHICAGO and SEATTLE - September 30, 2020 - Modifiable health risks, such as obesity, high blood pressure, and smoking, were linked to over $730 billion in health care spending in the US in 2016, according to a study published in The Lancet Public Health. Researchers from the Institute for Health Metrics and Evaluation (IHME), an independent global health research center at the University of Washington School of Medicine, and Vitality Group, found that the costs were largely due to five risk factors: overweight and obesity, high blood pressure, high blood sugar, poor diet, and smoking. Spending associated with risk factors in 2016 constituted 27% of the $2.7 trillion spent on health care that was included in the study.

"Given that US healthcare expenses are almost double that of other developed nations, we set out to understand how much of these costs could be attributed to modifiable risk factors," said Francois Millard, chief actuarial officer, Vitality and a study author. "While the relationship between lifestyle risks and medical conditions is understood, this is the first study to offer a comprehensive analysis of health spending related to these risks. This helps inform how our society is investing its resources, and why health should be at the center of all policy discussion, not just those related to sickness. We are seeing with COVID-19 that prevention is paramount to our own health and the health of our economies. It's time to apply the same urgency to these other preventable diseases."

Prior to this study, information had not been available on the combined effects of all major risks and the association with health care spending. These new findings fill an important gap in understanding the potential impact of private and public health promotion and prevention initiatives, including programs such as Vitality.

"This study builds on previous work to understand which health conditions contribute the most to increases in health care spending in the US," said Joseph Dieleman, PhD, senior author on the study, health economist, and associate professor at IHME. "Looking at risks allows us to better understand where these costs start, since unmanaged risk factors often lead to more serious health conditions later in life. While we can't draw conclusions about possible reductions in spending from this research, the findings illustrate the huge costs tied to poor diets, high blood pressure, smoking, and obesity. Moving forward, it's crucial to focus on preventing and managing these key risks before they turn into costly diseases, so that more people have the chance to live a long and healthy life."

Additional study findings:

Controllable and treatable risk were strongly related to costly US medical conditions - including cardiovascular disease, cancers, diabetes, and chronic respiratory diseases.

Costs were driven largely by five modifiable risk factors - overweight and obesity (high body mass index), $238.5 billion; high blood pressure, $179.9 billion; high fasting plasma glucose, $171.9 billion; dietary risks, $143.6 billion; and tobacco smoke, $130.0 billion.

Health care spending increases significantly with age, with the greatest proportion of risk-attributable spending associated with those aged 65 years and older (44.8%).

Building on a companion analysis by IHME of US health care spending published earlier this year in JAMA, the study extends findings from that research by estimating the proportion of spending attributable to 84 modifiable risk factors by health condition, age group, and sex. These findings have significant implications for public health care spending and private health insurance in both the US and other high-income countries. While it is not feasible to realize the full potential savings estimate from this research, significant improvements in health, reductions in medical conditions, and control of associated health care costs may be possible over time.

The research offers policymakers, actuaries, consultants, and health plan administrators data that support the need to focus public and private health programs on initiatives with the greatest potential to improve health and reduce health care costs. Favorable outcomes have been achieved, for example, through smoking cessation programs that have reduced lung cancer and its treatment costs, and weight-reduction programs that have far-reaching impact on several of the cited conditions.

Amsterdam, NL, September 30, 2020 - Isokinetic dynamometry is a major tool in the measurement of muscle strength in the fields of sports medicine, orthopedic and neurological rehabilitation and exercise physiology. Its use in older individuals now extends far beyond orthopedics to such conditions as chronic obstructive pulmonary disease (COPD) and stroke. In a collection of articles published in Isokinetics and Exercise Science, experts address its validity, reliability and responsiveness in older adults.

Isokinetic dynamometers are mechanical devices that are used to test muscle strength. They resist applied forces and control the speed of movement at a predetermined rate and can be used to test limb and/or trunk muscle strength. Although many older adults are weak due to age or an array of pathologies, the extent of their weakness might escape notice apart from testing with an isokinetic or other type of dynamometer.

This collection of articles is guest-edited by Richard W. Bohannon, DPT, EdD, of Physical Therapy Consultants, North Carolina, USA. Dr. Bohannon is a noted authority in the field who is recognized internationally for his expertise in muscle performance following stroke, hand-held dynamometry and mobility. He is a licensed physical therapist with 40 years of clinical experience in diverse practice settings including acute care, rehabilitation, outpatient, and home care, and is Editor-in-Chief of the Archives of Gerontology and Geriatrics.

In this issue, experts review the literature and summarize current knowledge about the use of isokinetic testing of muscle weakness in orthopedic shoulder problems, sarcopenia or frailty, knee osteoarthritis, COPD and stroke. In the past, isokinetic dynamometers have been used primarily with patients with orthopedic problems, particularly of the knee and shoulder. "The research on stroke and COPD, however, shows that the utility of isokinetic dynamometry now extends far beyond orthopedics and can be used to measure trunk muscle strength as well," explained Dr. Bohannon.

In the United States, COPD is most prevalent among older adults. As would be expected, these patients have lung-related impairments (e.g., difficulty breathing) as well as activity limitations (e.g., walking long distances) resulting from their obstructive pathology. Although not as widely recognized, patients with COPD have also been shown to demonstrate impairments in skeletal muscle strength as well. Isokinetic dynamometry is probably the most widely researched strength testing procedure applied to patients with the disease. A review of 27 studies provides considerable evidence for the validity of isokinetic testing of muscle strength among older adults with COPD, but there is only limited evidence for its reliability, and no statistical evidence for its responsiveness.

"If isokinetic testing is to be recommended in COPD, further evidence for its reliability and responsiveness is required," noted Dr. Bohannon. "The reliability coefficients reported for isokinetic measurements in COPD are high, but they were limited to test-retest reliability and derived from studies of less than 15 participants. These limitations, along with the absence of any anchor-based estimates of responsiveness, compromise the ability to establish meaningful goals. They also compromise the capacity to interpret changes in patient performance over time."

The World Stroke Organization has estimated the worldwide incidence of stroke is 15 million per year and that stroke is the second leading cause of death for adults older than 60 years. A review of 76 studies reveals that research largely supports the validity and reliability of isokinetic strength testing of older patients with stroke, but few data are available that provide specific information on the responsiveness for such measures. "Isokinetic dynamometry is a valid and reliable measure of muscle strength after stroke," noted Dr. Bohannon. "However, the research is mostly limited to the "young" old and is not particularly practical."

"Dynamometers are essential for obtaining precise measures of muscle strength and are applicable across many diagnostic groups," commented Dr. Bohannon. "The biggest problem associated with isokinetic dynamometers is their cost and lack of portability. Older individuals tested with dynamometers are most likely to be ambulatory and community-dwelling as the devices lack portability. Unfortunately, these problems are not likely to be solved."

What are the risks to an unborn child if a woman contracts COVID-19 while pregnant, and how can doctors identify which pregnancies are at greater risk of adverse outcomes if a pregnant mother tests positive?

A new study of 388 pregnancies in 22 different countries - the largest study of pregnant mothers with COVID-19 published to date - provides some answers to these questions. The results are published in an article, "Risk factors associated with adverse fetal outcomes in pregnancies affected by Coronavirus," published in De Gruyter's Journal of Perinatal Medicine.

In a previous study of this group of women, the researchers found that maternal mortality levels were relatively low but some women experienced serious illness, with approximately 11% requiring admission to an intensive care unit and 6.4% requiring intubation. This new study focused on their unborn children and the factors affecting their outcomes.

Adverse outcomes observed during the study included miscarriage, stillbirth or death within the first 28 days after birth. The rate of child mortality among the pregnancies was approximately 4%, mainly related to premature births. However, some trends emerged as risk factors for adverse outcomes.

"The incidence of poor fetal outcomes was significantly higher when COVID-19 infection occurred in the first 3 months of pregnancy," said Dr. Cihat ?en, a researcher involved in the study. "This was also true for children with lower birth weight and when mothers were so ill that they required oxygen treatment."

Strikingly, although all the women in the study had COVID-19, only one baby in the study tested positive for the disease and, thankfully, was asymptomatic, suggesting that transmission from mother to baby is very rare.

"These results could allow doctors to more appropriately tailor the treatment of pregnant women with COVID-19 by helping them to identify risk factors that could increase the chances of an adverse outcome," said ?en.

The results of the current study suggest that minimizing the risk of infection during early pregnancy may be particularly important in decreasing the chances of an adverse outcome. Similarly, doctors should consider closely monitoring babies with low birth weight and those whose mothers required ventilation while pregnant as their risk of an adverse outcome appears to be higher.

Clinical trials are testing whether medications that treat human immunodeficiency virus (HIV) can also treat COVID-19, leading some patients with HIV to believe they might be protected against the coronavirus. But a researcher from the MU School of Medicine not only found patients with HIV are susceptible to the virus, she also discovered which factors increased the risk of hospitalization and death.

Principal investigator Dima Dandachi, MD, assistant professor of clinical medicine, examined data that included 286 adult patients with HIV who were diagnosed with COVID-19 across 36 institutions in 21 states. Within 30 days of COVID-19 diagnosis, 57% of the patients required hospitalization, 16% required ICU admission and 9% did not survive. In the study, more than 94% of patients were actively taking HIV medication.

"We were able to show that patients with HIV who are actively taking their medication are just as susceptible to COVID-19 as the general public," Dandachi said. "And those with low immunity uncontrolled HIV or newly diagnosed HIV are at a higher risk of hospitalization or death. The key message for these patients is to take precautions against contracting the virus while ensuring they are compliant with their HIV medications to raise their immune cell count as high as possible."

Dandachi and her team of researchers found people with HIV older than 60 and those with chronic health issues also had a much higher risk of being hospitalized or dying from COVID-19.

"The medications that prolong the lives of patients with HIV have improved life expectancy, but now we are seeing these patients develop other chronic conditions such as obesity, diabetes and heart disease that we didn't see 15 years ago," Dandachi said. "And when we looked at the data from this study, we found that lung disease, kidney disease, hypertension and older age were associated with higher hospitalization rates, higher ICU admissions and increased mortality from COVID-19."

As a researcher-clinician who treats patients with HIV, Dandachi will use this study to counsel her patients to best protect themselves against COVID-19 while also using it as proof that this patient population should be among the first considered for protection once a vaccine is developed.

"When we have vaccines, our goal is to identify the most vulnerable populations," Dandachi said. "Patients with HIV should be a priority target when we are looking at any measure that could improve outcomes for patients at high risk for complications with COVID-19."

A Cochrane Review into the effectiveness of hospital-based specialist palliative care has found evidence that when compared to usual care, it may slightly improve patient satisfaction and depression, and increase the chances of patients dying in their preferred place (measured by home death).

The effectiveness and cost-effectiveness of hospital-based specialist palliative care for adults with advanced illness and their caregivers was produced by an international group of researchers led by Dr Sabrina Bajwah from the Cicely Saunders Institute of Palliative Care, Policy & Rehabilitation at King's College London and funded by the National Institute for Health Research (NIHR). A Cochrane Review is a study of all the best available evidence generated through research in health care and health policy, which are published in the Cochrane Database of Systematic Reviews.

Most people die in hospital and although the numbers of hospital-based specialist palliative care teams are increasing in response to unmet palliative care needs, there is a lack of clarity around whether they are effective. An earlier Cochrane Review has provided valuable evidence on the effectiveness and cost-effectiveness of home palliative care services (Gomes 2013)1. However, there is no such available evidence for specialist palliative care in hospital.

Researchers looked at evidence from 42 Randomised Controlled Trials involving 6,678 patients and 1101 caregivers/family members. The evidence was found to be low quality and therefore should be interpreted with caution. However, hospital-based specialist palliative care may offer small benefits for several patient-centred outcomes including health-related quality of life, symptom burden, depression and satisfaction with care. The review also showed that those receiving hospital-based specialist palliative care may have 1.63 higher odds of dying in their preferred place (measured by home death). The 1.63 higher odds translate to an increase of 22% in the likelihood of dying in the patient's preferred place (confidence intervals 8% to 39%). While the review found no evidence that hospital specialist palliative care causes serious harms, the evidence was insufficient to draw strong conclusions.

Dr Sabrina Bajwah, Clinical Senior Lecturer at King's College London said: "Population-based projections have indicated that palliative care needs will increase in the future2. Whilst we should interpret the results with caution, our systematic review provides clinicians, policy makers and funders with some clarity on the benefits of hospital palliative care.

"This may help make informed decisions when looking to prioritise further commissioning of hospital-based specialist palliative care. It also provides patients and their care givers valuable information to inform treatment choices on how hospital palliative care may be able to help improve patient centred care and increase the chances of dying in their preferred place, which is often at home. The provision of palliative care is an ethical imperative for those unlikely to survive and may have the advantage of diverting dying people away from overburdened hospitals as well as providing the care that people want. These benefits may be especially clinically relevant during pandemics and at an advanced stage of disease."

Irvine, Calif. - September 30, 2020 - In a new study, published in Current Biology, researchers from the University of California, Irvine School of Medicine reveal how subanesthetic ketamine, which is used for pain management and as an antidepressant in humans, is effective in treating adult amblyopia, a brain disorder commonly known as "lazy eye."

"Our study, demonstrates how a single-dose of subanesthetic ketamine reactivates adult visual cortical plasticity and promotes functional recovery of visual acuity defects resulting from amblyopia," explained Xiangmin Xu, PhD, a professor of anatomy and neurobiology and director of the Center for Neural Circuit Mapping at the UCI School of Medicine.

Subanesthetic ketamine, commonly used to treat depression and pain, evokes rapid and long-lasting antidepressant effects in human patients. There was evidence that ketamine may control how the nervous system makes structural changes in response to internal and external demands, a process called neural plasticity. But, how the drug worked remained elusive, until now.

"Our research team showed that ketamine down-regulates NRG1 expression in PV inhibitory cells, resulting in sustained cortical disinhibition to enhance cortical plasticity in adult visual cortex," said Steven F. Grieco, PhD, a postdoctoral scholar in the Xu lab and lead author.

"Through this neural plasticity-based mechanism, ketamine mediated functional recovery from adult amblyopia." Xin Qiao, PhD, a postdoctoral staff in the Xu lab is a co-first author for the published paper.

Amblyopia is a vision disorder in which the brain fails to process inputs from one eye, favoring the other eye. The condition can result in decreased vision in the affected eye. Each year, between one and five percent of children worldwide, are diagnosed with this condition.

Fast and sustained ketamine actions show promise for therapeutic applications that rely on reactivating adult cortical plasticity. Further testing is needed to determine the full implications of this discovery.

Tumors come in many shapes and forms--curable or deadly, solid or liquid, lodged inside the brain, bone, or other tissues. One thing they all have in common, however, is a knack for molecular deceit. It is often by posing as normal cells, or by hijacking them, that cancer cells advance their takeover of biological systems and learn to grow, survive, and spread to new organs.

Recently, Rockefeller scientists found that breast and lung tumors can appropriate a signaling pathway used by neurons to metastasize. In a report published in Nature, the researchers describe how these cancer cells enlist nearby blood vessels to gain access to this nerve signal, ultimately enabling their escape from the primary tumor and into the bloodstream.

In addition to illuminating previously unseen aspects of tumors' relationship with their surroundings, the findings could lead to new strategies for diagnostics and treatment.

Blood vessels: more than just tumor tubing

The classic example of a tumor's pirate tactics is its ability to attract nearby blood vessels and hook itself up to the body's central oxygen and nutrient supply. Years ago, scientists in Sohail Tavazoie's lab observed that tumors that eventually metastasize tend to recruit more vessels than those that don't, adding fuel to a long-held suspicion that infiltrating vasculature isn't merely helping tumors survive and grow: It might also be participating in the lesser-understood process by which some cancer cells are capable of leaving their site of origin and seed new tumors elsewhere in the body.

"We hypothesized that cells in the inner lining of blood-vessels send a signal that instructs cancer cells within the primary tumor to metastasize," Tavazoie says.

Bernardo Tavora, a research associate in the lab and first author of the recent paper, set out to look for that signal using a combination of sophisticated genetic, molecular, and biochemical approaches--including a modified form of TRAP, a technology developed in the lab of Nathaniel Heinz that makes it possible to pinpoint subtle differences between otherwise-similar cells and the proteins they produce. Ultimately, Tavora and his colleagues identified the signal as Slit2, a protein normally produced by neurons. In addition, they were able to explain how cancer cells get their hands on it.

When it first popped up in the search, Slit2 immediately rang a bell. In the nervous system, this signaling molecule is known to help guide nerve-cell extensions as they travel from one part of the brain to the other--for example, previous work in the lab of Rockefeller's Cori Bargmann has revealed that it regulates connectivity among neurons in worms.

The researchers found that breast and lung cancer cells use what Tavazoie calls "an intricate and elegant mechanism" to coax blood-vessel cells into making and releasing Slit2--just enough of a dose to help the cancer cells start migrating. "The cells first activate normally silenced DNA to produce double-stranded RNA, which in turn acts as a signal to trigger their own movement out of the primary tumor and into the blood, from where they can spread to other organs," he says.

Slit2 and other molecules identified in this pathway could potentially serve as diagnostics--for example, by helping physicians identify patients whose cancers have left the primary tumor before it's too late to intervene. "There's also a chance that inhibiting these pathways could open the door to novel cancer drugs that curb metastasis," says Tavora.

A group of Skoltech scientists led by a Skoltech and MSU professor Olga Dontsova discovered a novel liver-specific non-coding RNA. The researchers tracked the RNA amounts in a healthy liver and that affected by carcinogenesis and suggested using the RNA as a biomarker, thus creating a new panel of potential biomarkers for postoperative diagnosis of various liver cancers.

The research was published in the Journal of Cancer Research and Clinical Oncology. The study was supported by the Russian Science Foundation (RSF) grant.

Tumor markers help doctors to determine whether a patient has cancer. Any substances that show different concentrations in sick and healthy individuals can be used as tumor markers: these include non-coding RNA, which are RNA molecules that do not encode proteins but play an important role in regulating the cell activity. Non-coding RNA are grouped into universal RNA present in all body cells and tissue-specific RNA found in certain organs and tissues.

A team of Skoltech scientists discovered a previously undescribed non-coding RNA in the liver that can be used as a biomarker. They named the new molecule HELIS (HEalthy LIver Specific) because, unlike classic tumor markers that are indicators of a disease, it operates as a healthy liver biomarker and can even be called an anti-tumor marker.

Olga Burenina, a research scientist at the Skoltech Center for Life Sciences (CLS) and the first author of the paper, believes that this can be an advantage: "Many classical tumor markers do not always show up in the case of cancer or may have elevated levels due to noncancerous diseases, such as cirrhosis or hepatitis in the case of liver. The "healthy liver" markers can be more informative, because if a "malfunction" occurs in the cancer cells and, for example, HELIS are no longer produced as they should, the problem may not be fixed that easily."

Other organizations involved in the joint research included the Research Institute of Carcinogenesis at the Blokhin Russian Cancer Research Center of the Ministry of Health of the Russian Federation and Petrovsky National Research Centre of Surgery which provided postoperative samples for 6 types of liver tumors. The scientists successfully showed that the HELIS level decreased in all the samples, going well below the normal level, while in several types of malignancies disappearing altogether. The scientists then looked at the behavior of some known non-coding RNAs in these samples and selected 3 additional potential tumor markers. As a result, they obtained a panel of 4 biomarkers which are differentially expressed in various types of liver cancer and, importantly, help distinguish between benign and malignant tumors.

"Currently, there isn't a single good diagnostic marker for liver cancer, so doctors make the diagnosis based mainly on ultrasound or CT tests and remove the entire tumor by surgery regardless of the suspected cancer type. As a biopsy is rarely taken, the final diagnosis is made based on the histology results that become available after 10 to 14 days," explains Olga Burenina.

The new panel of biomarkers can be used for fast preliminary diagnosis based on postoperative liver tumor samples, as well as for additional analysis of ambiguous clinical cases.

September 29, 2020 - Nutley, NJ - A one-two punch of changing gene expression, then deploying immune checkpoint inhibitors, shows promise in battling one of the most treatment-resistant types of cancer in preclinical models, according to a new publication including authors from the Hackensack Meridian Center for Discovery and Innovation (CDI).

Their research findings published Aug. 14 in the journal Cancer Research suggest that since some cancer treatments can be undermined by epigenetic changes (altered DNA methylation affecting gene expression) in cancer cells before the treatments are even administered, a worthwhile strategy is to administer an epigenetically-acting drug - which can pave the way for more effective subsequent use of immune-acting cancer treatments, the authors found.

"Overall, these findings in a model of aggressive pancreatic cancer have clear and promising implications for the design of future studies, both in mice and in human patients, to improve the effectiveness of epigenetic modulation, in combination with immune checkpoint inhibition," said Benjamin Tycko, M.D., Ph.D., the CDI lab director who oversaw the study, along with his longtime colleague Tamas Gonda, M.D. "They also suggest a clear path forward for making further improvements."

The tumor type - pancreatic ductal adenocarcinoma - is among the most deadly cancer types, since it has proven to be stubbornly resistant both to standard chemotherapy and more recent immunotherapies.

The researchers tested four protocols, which included the sequential use of decitabine, a DNA-hypomethylating drug, followed by immune checkpoint inhibitors. Among the effects documented in the data: the increase in crucial, and tumor-infiltrating, effector T cells, with this one-two punch.

Compared against the control group, there were no adverse side effects of adding decitabine, and the one-two punch of decitabine and the immune-acting agents doubled the average survival time in the model.

However, treatment was still not a cure, and the cancers ultimately progressed - perhaps partly because of a decitabine-induced increase in M2 macrophages, immune system cells which can inhibit therapeutic responses.

The researchers' work continues, with further strategies including adding other epigenetic drugs, and also discovering ways to reduce the number of M2 macrophages - to potentially improve the response.

In a world first, a young man suffering from severe aplastic anemia who could not be helped by standard treatments has been given a life-saving blood transplant with the made-in-Canada UM171 molecule.

The procedure was done by a medical team at the Institute of Hemato-oncology and Cellular Therapy (iHOTC) of Maisonneuve-Rosemont Hospital and the Institute for Research in Immunology and Cancer, both affiliated with Université de Montréal.

The young man's case history, including the lifesaving transplant, was recently published in the scientific journal European Journal of Haematology, highlighting the unique and revolutionary properties of the UM171 molecule.

An autoimmune disease, severe aplastic anemia destroys stem cells in bone marrow and leads to a halt in the production of red blood cells, white blood cells and platelets. For allografting (grafting between individuals) for this disease, the donor's stem cells must be as compatible as possible with those of the recipient to avoid the risk of immunological complications.

No donor option

If no compatible family or unrelated donor can be found, stem cells from a semi-identical family donor, also known as a haplo-identical donor, may be considered, under certain conditions, as an alternative source of cells. However, a family member must be healthy and available for such a procedure; the young man in this case did not have that option.

Cord blood transplantation, which is less demanding in terms of compatibility, is a good option for many patients requiring a stem cell transplant. On the other hand, cord blood generally does not contain enough stem cells for an adult patient weighing more than 70 kg; it produces a slow rise in white blood cells with an increased risk of often fatal infections.

In addition, the rate of graft rejection - the destruction of infused cord cells by the recipient's immune system - is very high in patients with severe aplastic anemia who have received multiple blood transfusions.

"It was after having exhausted all our treatment options that UM171, which had already proven itself in a clinical trial in blood cancer patients, came into play," said UdeM medical professor Jean Roy, a hematologist and clinical researcher at the MRH.
35-fold increase

"As well as increasing the number of stem cells in a unit of umbilical cord blood by an average of 35 times, it greatly reduces the risk of a frequent long-term immunological complication (graft-versus-host disease) requiring years of use of toxic immunosuppressive drugs."

The researchers' success confirms the excellent performance of UM171, which has already been demonstrated in two other studies conducted by iHOTC research teams with very encouraging results. A third study is now underway.

"This young man's story and the other studies with UM171 clearly demonstrate how innovative clinical research, set up by local investigators, can create a culture of excellence and improve care to save more lives," said IHOTC director Denis Claude Roy.

"The future will certainly bring us more such accomplishments, and that's very encouraging."