Body

DUARTE, Calif. -- City of Hope scientists have identified and developed two potent small molecules that appear to suppress tumor growth in multiple cancers even when other treatments cease to work, possibly due to the development of drug resistance.

Called CS1 (or bisantrene) and CS2 (or brequinar), these cancer inhibitor compounds are part of a protein known as "fat mass and obesity-associated protein." Nicknamed FTO, the protein plays a critical role in cancer development and progression, primarily because it regulates cancer stem cells and immune evasion. In other words, FTO promotes the growth, self-renewal, metastasis and immune escape of cancer cells.

"The cancer inhibitors we developed are at least 10 times more effective in killing acute myeloid leukemia cells than several previously reported FTO inhibitors," said Jianjun Chen, Ph.D., the Simms/Mann Family Foundation Chair in Systems Biology at City of Hope and corresponding author of the new study. "In the near future, we should use these two compounds alone or in combination with other therapeutic agents such as targeted therapy, standard chemotherapy, immunotherapy or radiotherapy to treat patients with FTO-high cancers."

Examples of FTO-high cancers include acute myeloid leukemia (AML), an aggressive brain cancer called glioblastoma, pancreatic cancer and breast cancer. The study, published in the journal Cancer Cell on June 11, provides new insight into how cancer stem cells replenish and visibility into how cancer evades our immune system. It highlights the possibility that targeting FTO with potent inhibitors could eventually become a treatment for certain cancers.

In the study, City of Hope scientists demonstrated that the two new FTO inhibitor compounds they created had potent anti-tumor effects and substantially improved overall survival in mice with AML or a solid tumor such as breast cancer.

An estimated 11,200 people are expected to die due to AML in 2020. The five-year survival rate is 29%, according to National Institutes of Health SEER data. Breast cancer is the second most common cancer among U.S. women.

Chen and his colleagues saw the need to address these big problems. The Chen lab has been conducting research on RNA modification in cancer for eight years and is a pioneer in this field -- developing personalized treatments that will enable the practice of precision medicine. The lab began working on the CS1 and CS2 project three years ago when Chen first arrived at City of Hope.

Chen's team noted that many cancer patients either do not respond to treatments that are currently available such as chemotherapy, targeted therapy or immunotherapy, or that they responded to the therapeutics in the beginning but relapse later due to cancer-regenerating stem cells and the escape of cancer cells from our immune surveillance.

It turns out that modifying FTO or using small molecules to inhibit FTO interrupts the supply chain that enables cancer to develop and progress. Studies showed that treatment with a relatively low dose of CS1 or CS2 (5 mg/kg/day 10 times every other day) could, at the very least, double the median survival in mouse models with AML. CS1 became more potent after Chen's lab put a sort of sleeve over it so that it could bypass certain barriers that do not like water-based molecules.

"Our study suggests that combining FTO inhibitor treatment with other therapies will improve patient outcomes because this method will eradicate cancer stem cells and mechanisms that suppress the immune system," said Rui Su, Ph.D., lead author of the study and assistant research professor in the Department of Systems Biology at the Beckman Research Institute of City of Hope.

CS1 and CS2 prevent FTO from connecting with target messenger RNAs, including cancer-causing genes MYC and CEBPA, as well as immune checkpoint gene LILRB4.

Because CS1 (bisantrene) and CS2 (brequinar) have been tested in multiple clinical trials under the guises of other objectives, Chen and his colleagues believe this basic research has access to a freeway entrance that will fast track it into clinical trials. The National Institutes of Health (NIH) has already funded the next step: The Chen lab is working to further optimize CS1 and CS2 to develop improved FTO inhibitor compounds that are more efficacious with minimal side effects for humans.

A new study co-led by Simon Fraser University health sciences professor Scott Lear provides further evidence of the link between depressive symptoms and an increased risk of heart disease and early death.

The global study tracked 145,862 middle-aged participants from 21 countries and found a 20 per cent increase in cardiovascular events and death in people with four or more depressive symptoms. The risks were twice as high in urban areas--where the majority of the global population will be living by 2050-- and more than double in men.

Depression and mental health issues are highly prevalent in Canada. One in five Canadians will experience a mental health problem during their lifetime and eight per cent will experience a major depressive event.

Lear says the results are timely as experts anticipate an increase in the number of people dealing with mental health issues as a result of the COVID-19 pandemic.

The data suggests that depressive symptoms should be considered as important as traditional risk factors such as smoking, high blood pressure and high cholesterol when preventing heart disease and early death.

The study results, published this month in JAMA Psychiatry, lend credibility to existing World Health Organization (WHO) policies to integrate treatment and prevention of mental disorders into primary care.

The study concludes that a greater awareness of the physical health risks associated with depression is needed.

Researchers suggest that a comprehensive approach to tackling non-communicable diseases and mental disorders--to achieve health-related UN Sustainable Development Goals--needs to be a global priority.

DES PLAINES, IL -- Common barriers exist to the use of risk stratification tools in the evaluation of pulmonary embolism in the emergency department and provide insight into where to focus efforts for future implementation endeavors. That is the conclusion of a study to be published in the June 2020 issue of Academic Emergency Medicine (AEM), a journal of the Society for Academic Emergency Medicine (SAEM).

The lead author of the study is Lauren M. Westafer DO, MPH, MS, assistant professor, Department of Emergency Medicine, University of Massachusetts Medical School-Baystate. The findings of the study are discussed in a recent AEM podcast, Teacher, Teacher -- Tell Me How to Do It (Diagnose a PE).

According to the study findings, provider-level factors such as risk avoidance and lack of knowledge of the tools dominated as barriers, while inner-setting factors were identified as facilitators.

The authors recommend that future efforts to improve evidence-based diagnosis of pulmonary embolism should focus on implementation strategies targeting these domains.

Commenting on the study is Dr. Kerstin de Wit, an emergency and thrombosis physician and Hamilton Health Sciences and an assistant professor in the department of medicine at McMaster University, Hamilton, Ontario, Canada.

"This important study highlights several common thought processes which act as barriers for emergency physician use of evidence-based pulmonary embolism testing. The authors identified opportunities to promote adherence to evidence-based testing, including leveraging culture and peer pressure."

Older men who have a weak or irregular circadian rhythm guiding their daily cycles of rest and activity are more likely to later develop Parkinson's disease, according to a new study by scientists at the UC San Francisco Weill Institute for Neurosciences who analyzed 11 years of data for nearly 3,000 independently living older men.

The scientists said their discovery of the link between circadian rhythms and Parkinson's -- a disease characterized by loss of control over movement, balance and other brain functions -- suggests these circadian disruptions may reflect neurodegenerative disease processes already affecting the brain's internal clock well before a Parkinson's diagnosis, and that they could be considered an early warning sign of the disease.

"The strength of the circadian rhythm activity seems to have a really important effect on health and disease, particularly in aging. In this latest study we found that even small changes in circadian rhythm in older men were associated with a greater likelihood of getting Parkinson's down the line," said study senior author Kristine Yaffe, MD, the Roy and Marie Scola Endowed Chair and vice chair of the Department of Psychiatry at UCSF, a professor of psychiatry, neurology, and epidemiology and biostatistics, and a member of the UCSF Memory and Aging Center.

The results -- published June 15, 2020 in JAMA Neurology -- merit follow-up, according to the study authors, to investigate whether physiological changes set off by disruptions in circadian rhythms might themselves be a trigger for neurodegeneration, and whether strengthening these rhythms could lower risk for developing Parkinson's.

Parkinson's is the second most common neurodegenerative disorder after Alzheimer's disease. 500,000 individuals in the United States have been diagnosed with Parkinson's disease, and many with the disease are undiagnosed, according to the National Institute of Neurological Disorders and Stroke. Most who have Parkinson's are diagnosed after age 60. There are no drugs known to prevent the disease, but there are a growing number of treatments to relieve symptoms.

Among older adults, weakened or irregular circadian rhythms of rest and activity are common, according to study lead author Yue Leng, MD, PhD, an assistant professor of psychiatry at UCSF. Other conditions -- constipation or deficits in the sense of smell -- have also been associated with increased likelihood of developing Parkinson's later on.

"Parkinson's is a disease that probably takes decades to develop, and apart from changes in movement, earlier signs might be critical in understanding the disease and its mechanisms," Leng said. "This is the first large, long-term study to find that disrupted circadian rhythms might be linked to Parkinson's that emerges years later."

The study, which enrolled 2,930 men with an average age of 76.3 when the research began, was part of the larger, population-based Osteoporotic Fractures in Men Study (MRoS), which began in 2000 and enrolled men at six medical centers nationwide. None of the participants in the subset of the MRoS cohort initially had Parkinson's, and all were living in community-based settings (i.e. not in nursing homes). Their status for many health-related factors was assessed at the start, and they were monitored through follow-up visits and questionnaires.

As part of the study, researchers monitored circadian rhythms of rest and activity over three separate 24-hour periods by having participants wear an actigraph -- a watch-like device that detects and records even slight wrist movements. The data collected from these devices were independently associated with the later development of Parkinson's.

In a previous study, Leng and Yaffe identified an association between daytime napping and the later development of Parkinson's. But the link between circadian rhythms and Parkinson's is not just a matter or disrupted sleep, according to the new study. The association held true even after accounting for indicators of sleep disturbances -- including loss of sleep; sleep inefficiency (time spent asleep after turning off the lights); leg movement during sleep; and the chronic, temporary cessation of breathing known as sleep apnea.

In drawing this conclusion, the researchers took into account numerous other variables collected as part of the MRoS study, including regional differences in study sites and participant demographics, education, baseline cognitive performance, chronic diseases, physical activity, symptoms of depression, body mass index, smoking, and use of benzodiazepines, alcohol, and caffeine.

Leng and Yaffe evaluated four parameters of participants' rest-activity rhythms as measured by actigraph: amplitude, the difference between the period of greatest to least activity; mesor, the average activity; robustness, how well the measured cyclical rest-activity matched a regular curve similar to a cosine wave; and acrophase, a measure of advance or delay in the 24-hour cycle relative to the population average.

During follow-up, 78 of the 2,930 study participants were diagnosed with Parkinson's. Those who scored lowest in actigraph amplitude, mesor or robustness had triple the risk of developing Parkinson's compared to those who scored highest. The researchers did not find an association between acrophase and Parkinson's risk.

Animal models of Parkinson's have shown that cells controlling the brain's circadian rhythm pacemaker often begin to degenerate even before cells in the part of the brain that are traditionally associated with Parkinson's symptoms, suggesting that weakening of circadian rhythm may in some cases represent an early stage of disease.

Leng also does not rule out the possibility that disruptions in circadian rhythm, already known to cause metabolic changes and inflammation, might themselves contribute to neurodegenerative disease. Leng hopes to investigate whether weakened circadian rhythms trigger inflammation or the abnormal accumulation of proteins seen in affected brain tissue in both Parkinson's and Alzheimer's.

"These neurodegenerative diseases are not reversible," she said. "But if research points to sleep or circadian problems being risk factors for neurodegeneration prior to traditional symptoms, then we may be able to use that information for early detection and diagnosis, or we might be able to intervene in ways that prevent development of neurodegenerative loss of function."

BOSTON - New research from Boston Medical Center shows that providing education and training to pediatric and family medicine providers about the importance of human papillomavirus (HPV) vaccines, in tandem with healthcare systems changes including starting an HPV vaccination series before the age of 11, improves the overall rate of HPV vaccinations among adolescent patients. HPV vaccinations can help reduce rates of HPV-related cancers, as well as play a role in reducing race- and income-related disparities in these diagnoses. Published in Pediatrics, the study results show improvements at each stage in the HPV vaccination series. Importantly, improvements were sustained beyond the conclusion of the intervention period, demonstrating that these types of programs could be used to help produce long term increases in HPV vaccination rates.

According to the Centers for Disease Control and Prevention, HPV affects nearly 80 percent of adults, and while some strains of the virus are low-risk, several strains can lead to cancer. HPV vaccination in early adolescence can prevent HPV infection, and is estimated to prevent up to 90 percent of cervical cancers. Cervical cancer disproportionately affects minority women, with Black women being twice as likely as white women to die from the disease. Because HPV vaccination can stop infections that could lead to cancer, universal HPV vaccination has the potential to reduce these disparities.

DOSE HPV (Development of Systems and Education for HPV) is a multilevel inter-professional provider training program aimed at improving HPV vaccination rates. The program educates providers on how best to communicate with parents and caregivers about HPV vaccinations, as well as how to use data in their practices to address barriers to access and completion rates of the vaccine series for their patients.

"The HPV vaccine has the potential to decrease the rates of six different types of cancer, but rates remain below national goals in the United States," says Rebecca Perkins, MD, MSc, an obstetrician and gynecologist at Boston Medical Center, and principal investigator of this research study. "Programs that produce sustained increases in HPV vaccination rates could help reduce rates of HPV-related cancers nationwide. As a gynecologist, I am particularly interested in the potential of HPV vaccination to reduce racial disparities in cervical cancer incidence and mortality."

In this randomized trial, information from 16,136 individuals between the ages of nine and 17 years-old from five pediatric primary care or family medicine practices was included in the research. At each intervention site, data about the pre and post-intervention HPV vaccination series initiation and completion was analyzed for patients with at least one visit to a clinical site and one HPV vaccination dose or a completed HPV vaccine series. The vaccine series initiation increased from 75 percent before the intervention to 90 percent after the intervention; the entire series completion rate increased from 60 percent before the intervention to 69 percent after the intervention. Importantly, rates continued to rise for 6-18 months after the intervention was completed. Given the routine recommendation of vaccination of 11 to 12 year-olds, this group was analyzed separately, with a vaccine initiation increase from 83 percent before the intervention up to 93 percent afterwards. Vaccine series completion rates increased from 54 percent pre-intervention to 69 percent post-intervention.

"Vaccination rates have significantly decreased due to COVID-19, and interventions to rapidly restore rates are needed to prevent epidemics of other vaccine-preventable diseases," says Perkins, also an associate professor of obstetrics and gynecology at Boston University School of Medicine. "The results of this study can help shed light on the importance of arming providers with the skills necessary to best communicate with families on the importance of getting vaccinations to help decrease the chances of other disease outbreaks in children and young adults." The key program components included educating providers on how to better communicate with families, decreasing missed opportunities for vaccination, and beginning the HPV vaccine series prior to age 11.

Researchers from Nationwide Children's Hospital have published in JAMA Neurology results from the first four patients treated in the first clinical trial of systemic delivery of micro-dystrophin gene therapy in children with Duchenne muscular dystrophy (DMD) - and initial findings suggest that the therapy can provide functional improvement that is greater than that observed under the standard of care.

"We are very pleased to report successful delivery of the micro-dystrophin transgene to the nuclei - corresponding to robust gene expression and proper localization of micro-dystrophin," said Jerry Mendell, MD, the study's co-author and principal investigator with the Center for Gene Therapy in the Abigail Wexner Research Institute at Nationwide Children's Hospital. "This coincides with improvements in functional measurements in study participants who received SRP-9001."

DMD is a fatal neuromuscular disease that occurs in approximately one in every 5,000 males worldwide. It is caused by a mutation in the gene that encodes for dystrophin, and symptoms usually appear in infants and toddlers. The dystrophin gene itself is too large to fit in to the adeno-associated viral vector used in the gene therapy technology utilized by the study. Researchers have developed micro-dystrophin as a microgene that provides function while still fitting in the vector.

Four ambulatory participants, aged 4 to 7 years at time of infusion were treated with a single dose of 2.0 x 1014 vg/kg rAAVrh74.MHCK7. micro-dystrophin (SRP-9001 micro-dystrophin, Sarepta Therapeutics), which was infused through a peripheral limb vein. All treatment-related events were mild to moderate and there were no serious adverse events. The most common treatment-related adverse event was vomiting (9 of 18 events). Three patients had temporarily elevated levels of gamma-glutamyltransferase, which was resolved with corticosteroids.

At 12 weeks post-infusion, gastrocnemius muscle biopsy specimens showed a mean of 81.2% of muscle fibers expressing micro-dystrophin, with a mean intensity of 96% at the sarcolemma. Western blot showed a mean expression of 74.3% without fat or fibrosis adjustment and 95.8% with adjustment.

All of the participants had confirmed vector transduction and showed functional improvement of North Star Ambulatory Assessment (NSAA) scores. The NSAA is a 17-item measure of ambulatory functions with a score range from 0 to 34.

All participants also showed reductions in creatine kinase (CK) levels that were maintained for one year.

Other functional outcomes measured included time to rise, four-stair climb, 100-m timed test and handheld dynamometry for knee extensors and flexors and elbow extensors and flexors, but their results were more varied.

"NSAA score improvement and CK score reduction appear to be the most sensitive measures," said Dr. Mendell. "Different magnitudes of improvement were observed in the other functional measurements, suggesting that a larger sample size and clinical trial are needed to validate improved motor function. Variation in clinical outcomes were associated with many factors, including age and disease severity."

The study is intended to continue until March 2021.

"Duchenne muscular dystrophy is difficult to treat, and gene therapy offers a needed option having the potential to alter the course of the disease," said Dr. Mendell. "Using currently available treatments, the condition is universally fatal, and patients usually succumb to the disease in their twenties."

The safety results, together with biological and clinical markers of efficacy, provide proof-of-concept support for continuation of clinical trials for assessment of SRP-9001 using single-dose gene therapy in participants with Duchenne, he added.

"Following the 9-month update we shared last year, the publication of these results further supports the potential for SRP-9001 to provide clinically meaningful functional improvements in terms of speed and magnitude for DMD patients," said Louise Rodino-Klapac, PhD, senior vice president of gene therapy at Sarepta Therapeutics. "We look forward to advancing our ultimate goal of profoundly improving the lives of as many patients living with DMD as possible."

A new commentary published in Nature Medicine calls for governments to recognize the urgent need to improve their outbreak preparation and response. Noting that many governments are pinning their hopes on a vaccine against COVID-19, Jeffrey Lazarus and co-authors argue that a successful vaccine could take years to develop, and tried and tested public health measure can and must be implemented now. They write, "This pandemic should be a wake-up call for countries to address the most critical shortcomings in their pandemic readiness and health-system resilience in order to prevent and to mitigate the impacts of future catastrophes."

The authors propose six broad actions that governments should to take to improve their responses to COVID-19 and future health crises. The actions, based on the World Health Organization's health systems framework and other national and international public health guidance, include the following: ensuring effective communication with the public, robust surveillance and contact tracing, and investment in healthcare systems.

"The Coronavirus plays no favorites and the likelihood of ongoing waves of infection, which we are already seeing, makes it imperative that we develop a system to measure the effectiveness of governmental response," according to co-author Ayman El-Mohandes, Dean of the CUNY Graduate School of Public Health and Health Policy (CUNY SPH). "This is not an exercise in casting blame; the overall goal is to ensure universal delivery of adequate public health services."

The authors argue there is a need to restore public faith in healthcare systems and to ensure there is credible accountability for government actions. They have designed a COVID-19 Assessment Scorecard, based on those six public-health actions, that can be used by people to rate their local or national government's response to the crisis and assess their pandemic readiness. The scorecard includes 19 statements that can be rated 1-5 and, if used on a large scale, could be useful in guiding government actions, the authors suggest.

"There is no question that this pandemic is one of the greatest threats to human health that we have seen in our lifetimes," says co-author Scott Ratzan, Distinguished Lecturer at CUNY SPH. "We need to manage it with systems consistent with 21st century approaches. This is just a start."

Irvine, CA - June 12, 2020 - A new University of California, Irvine-led study reveals a protein responsible for genetic changes resulting in a variety of cancers, may also be the key to more effective, targeted cancer therapy.

The study, published today in Nature Communications, titled, "Quantification of ongoing APOBEC3A activity in tumor cells by monitoring RNA editing at hotspots," reveals how the genomic instability induced by the protein APOBEC3A offers a previously unknown vulnerability in cancer cells.

Each day, in human cells, tens of thousands of DNA damage events occur. In cancer cells, the expression of the protein APOBEC3A is one of the most common sources of DNA damage and mutations. While the mutations caused by these particular proteins in cancer cells contribute to tumor evolution, they also cause breaks in the DNA, which offer a vulnerability.

"Targeting cancer cells with high levels of APOBEC3A protein activities and disrupting, at the same time, the DNA damage response necessary to repair damages caused by APOBEC3A, could be key to more effective cancer therapies," said Remi Buisson, PhD, senior investigator and an assistant professor in the Department of Biological Chemistry at the UCI School of Medicine. "However, to exploit the vulnerability of the cancer cells, it is critical to first quantitatively measure the protein's activity in tumors."

To understand the role of APOBEC3A in tumor evolution and to target the APOBEC3A -induced vulnerabilities, the researchers developed an assay to measure the RNA-editing activity of APOBEC3A in cancer cells. Because APOBEC3A is difficult to quantify in tumors, developing a highly sensitive assay for measuring activity was critical. Using hotspot RNA mutations, identified from APOBEC3A-positive tumors, the team developed an assay using droplet digital PCR and demonstrated its applicability to clinical samples from cancer patients.

"Our study presents a new strategy to follow the dysregulation of APOBEC3A in tumors, providing opportunities to investigate the role of APOBEC3A in tumor evolution and to target the APOBEC3A-induced vulnerability in therapy," said Buisson. "We anticipate that the RNA mutation-based APOBEC3A assay will significantly advance our understanding of the function of the protein in tumorigenesis and allow us to more effectively exploit the vulnerabilities it creates in cancer therapy."

A new modeling study evaluating unfolding COVID-19 epidemics among different income countries reports that, in lower income countries, even if risk is reduced because populations are younger, this benefit is largely negated by limited health system capacity and closer inter-generational contact. In these places, efforts to mitigate the virus will need to be maintained or triggered more frequently, say the authors. The results offer insight into how differences in demography, social structure and healthcare availability and quality combine to influence the impact of virus mitigation measures. The COVID-19 epidemic places intense pressure on national health systems. To date, this has sometimes outstripped availability of resources even in relatively highly resourced settings. Many lower income, resource-poor countries have acted while transmission remains at low levels, which is likely to have substantially slowed the spread of the virus, but questions remain about future virus spread. To better understand the factors that could result in a differential impact of the COVID-19 pandemic in low- and middle-income countries (LMICs), Patrick Walker and colleagues calibrated a global model with country-specific data on demography, contact patterns, disease severity, and healthcare capacity. In lower income countries, despite risk being reduced by a younger population, they say, overall risk is still higher due to a limited health system capacity coupled with closer inter-generational contact. In these locations, mitigation strategies that slow but do not interrupt transmission will still lead to COVID-19 epidemics rapidly overwhelming health systems. A short-term priority in such locations should be to increase the availability of oxygen support to mitigate the health impact. In the longer-term, ensuring equitable provision of pharmaceutical interventions, once they are developed, should be a global focus. "While our results illustrate the challenges that many countries will face in attempting to mitigate the impact of local COVID-19 epidemics, it is important to bear in mind that even moderate levels of changes in behavior can avert many infections and hence save millions of lives."

Genetics could help diagnose diabetes in Indians, study shows

A new way of using genetics to diagnose diabetes could pave the way for better diagnosis and treatment in Indians, new research has concluded.

Misdiagnosis of diabetes could be an issue in India because of features of diabetes in Indians which might vary from the standard western textbooks. Until recently, it was widely believed that type 1 diabetes appeared in children and adolescents, and type 2 diabetes in obese and older (typically after 45 years of age). However, recent findings have shown that type 1 diabetes can occur later in life, while type 2 diabetes is on the rise among younger and thinner Indians. Distinguishing the two types of diabetes has therefore, become more complex. The two types follow different treatment regimes with type 1 diabetes needing lifelong insulin injections but type 2 diabetes often being managed with diet or tablet treatment. Misclassification of the type of diabetes may lead to sub-standard diabetes care and possible complications.

A new publication conducted between researchers at the KEM Hospital, Pune, CSIR-Centre for Cellular and Molecular Biology (CCMB), Hyderabad, and the University of Exeter in the UK shows that a genetic risk score is effective in diagnosing type 1 diabetes in Indians.

The genetic risk score, developed by the University of Exeter, takes into account detailed genetic information known to increase the chance of developing type 1 diabetes. The score may be used at the time of diabetes diagnosis to help decide if someone has type 1 diabetes.

Up to now, the bulk of research in this field has been conducted in European populations. Now, in a paper published in Scientific Reports, researchers have analysed whether the European risk score is effective in diagnosing type 1 diabetes in Indians. The team studied people with diabetes from Pune, India. The team analysed 262 people with type 1 diabetes, 352 people with type 2 diabetes, and 334 people without diabetes. All were of Indian (Indo-European) ancestry. Outcomes from the Indian populations were compared with those of Europeans from the Wellcome Trust Case Control Consortium study.

The research, supported by Diabetes UK, the KEM Hospital Research Centre, Pune and the Council of Scientific and Industrial Research (CSIR) in India, found that the test is effective in diagnosing the right type of diabetes in Indians, even in its current form, which is based on European data. Authors also found genetic differences between the populations which mean the test could be further improved to enhance outcomes for Indian populations.

Dr Richard Oram, of the University of Exeter Medical School, said: "Diagnosing the right diabetes type is an increasingly difficult challenge for clinicians, as we now know that type 1 diabetes can occur at any age. This task is even harder in India, as more cases of type 2 diabetes occur in people with low BMI. We now know that our genetic risk score is an effective tool for Indians, and can help get people on the treatment they need to avoid life threatening complications such as diabetic ketoacidosis and to achieve the best health outcomes."

Dr Chittaranjan Yajnik of the KEM Hospital & Research Centre, Pune agrees with Dr Oram. He said, that the escalating epidemic of diabetes in young Indians makes it imperative that we diagnose the type of diabetes correctly to avoid mistreatment and its long term biological, social and economic implications. The new genetic tool will be a great help in this. It will help decide when diabetes is mainly caused by autoimmune destruction of pancreatic beta cells (type 1 diabetes), and when diabetes is mainly caused by reduced action of insulin due to excess fat and smaller muscle mass in the body of Indians ('thin-fat Indians'), as is the case in type 2 diabetes. He said, "we look forward to using this test in diabetic patients from different parts of India where the physical characteristics of diabetic patients differ from the standard description".

The authors found nine genetic areas (called the SNPs) that correlate with type 1 diabetes both in Indian and European populations, and can be used to predict the onset of type 1 diabetes in Indians. Dr GR Chandak, Chief Scientist leading the study at the CSIR-Centre for Cellular and Molecular Biology (CCMB), said: "It's interesting to note that different SNPs are more abundant among Indian and European patients. This opens up the possibility that environmental factors might be interacting with these SNPs to cause the disease."

Given the genetic diversity of the population of India, the study's results need to be validated in other ethnic groups of the country too. Dr Rakesh K Mishra, Director of the CSIR-Centre for Cellular and Molecular Biology (CCMB), said: "Since more than 20 per cent of people with type 1 diabetes below the age of 15 years of age are in India, developing a genetic test kit to reliably detect type 1 from type 2 diabetes holds a lot of significance for the country."

During the COVID-19 pandemic, patients with multiple sclerosis (MS) and their clinicians have had questions and concerns about whether immunotherapies for MS could influence risk for infection or lead to an unfavorable outcome.

In the Journal of Neurology, Rohit Bakshi, MD, a senior neurologist at Brigham and Women's Hospital, and international co-authors present the cases of five MS patients who developed COVID-19 infection while taking the oral disease-modifying therapy teriflunomide and continued taking the medication. All five patients had favorable outcomes, with their COVID-19 taking a mild course and without experiencing relapse of their MS.

"Managing MS during the COVID-19 pandemic has raised many questions," said Bakshi, the corresponding author of the paper. "Our observations in these five patients suggest that teriflunomide may not need to be discontinued in patients with MS who develop an active COVID-19 infection. We also discuss potential direct anti-viral effects of teriflunomide."

Investigating Teriflunomide's Role in COVID-19 Outcomes

In the current international, multicenter study, Bakshi and co-authors, including lead author Amir Hadi Maghzi, MD, a clinical and research fellow in the Brigham's Neurology Department, report on five patients, ranging in age from 52 to 79, who had been taking teriflunomide for at least six months. The patients continued their teriflunomide therapy after COVID-19 diagnosis and had self-limiting illness without experiencing MS relapse.

Treatment for MS usually requires long-term therapy, often with immunomodulating or immunosuppressing drugs. Teriflunomide modulates the immune response by selectively reducing the level of activated T and B lymphocytes without suppressing the body's full immune response. One possibility, the authors write, is that teriflunomide could prevent an excessive immune response while maintaining an adequate defense against the virus. The authors also discuss pre-clinical data suggesting that the drug may reducing reduce viral nucleotide synthesis in infected cells.

The case series was small, retrospective, open-label, uncontrolled, and non-randomized, and the authors state that future studies are necessary to understand what role, if any, teriflunomide therapy may play in COVID-19 infection since patient recovery may be unrelated to the treatment.

"A delicate balance may be necessary in the host immune response to successfully confront COVID-19 infection," said Bakshi. "Additional studies are warranted to further understand the relationship between treatment with teriflunomide and outcomes for MS patients with COVID-19."

LA JOLLA, CA--An extraordinary percentage of people infected by the virus behind the ongoing deadly COVID-19 pandemic never show symptoms of the disease, according to the results of a Scripps Research analysis of public datasets on asymptomatic infections.

The findings, published in Annals of Internal Medicine, suggest that asymptomatic infections may account for as much as 45 percent of all COVID-19 cases, playing a significant role in the early and ongoing spread of COVID-19. The report highlights the need for expansive testing and contact tracing to mitigate the pandemic.

"The silent spread of the virus makes it all the more challenging to control," says Eric Topol, MD, founder and director of the Scripps Research Translational Institute and professor of Molecular Medicine at Scripps Research. "Our review really highlights the importance of testing. It's clear that with such a high asymptomatic rate, we need to cast a very wide net, otherwise the virus will continue to evade us."

Together with behavioral scientist Daniel Oran, Topol collected information from testing studies on 16 diverse cohorts from around the world. These datasets--gathered via keyword searches of PubMed, bioRxiv and medRxiv, as well as Google searches of relevant news reports--included data on nursing home residents, cruise ship passengers, prison inmates and various other groups.

"What virtually all of them had in common was that a very large proportion of infected individuals had no symptoms," says Oran. "Among more than 3,000 prison inmates in four states who tested positive for the coronavirus, the figure was astronomical: 96 percent asymptomatic."

The review further suggests that asymptomatic individuals are able to transmit the virus for an extended period of time, perhaps longer than 14 days. The viral loads are very similar in people with or without symptoms, but it remains unclear whether their infectiousness is of the same magnitude. To resolve that issue, we'll need large-scale studies that include sufficient numbers of asymptomatic people.

The authors also conclude that the absence of symptoms may not imply an absence of harm. CT scans conducted on 54 percent of 76 asymptomatic individuals on the Diamond Princess cruise ship, appear to show significant subclinical lung abnormalities raising the possibility of SARS-CoV-2 infection impacting lung function that might not be immediately apparent. The scientists say further research is needed to confirm the potential significance of this finding.

The authors also acknowledge that the lack of longitudinal data makes distinguishing between asymptomatic and presymptomatic individuals difficult. An asymptomatic individual is someone who is infected with SARS-CoV-2, but never develops symptoms of COVID-19, while a presymptomatic person is similarly infected, but will eventually develop symptoms. Longitudinal testing, which refers to repeated testing of individuals over time, would help differentiate between the two.

"Our estimate of 40 to 45 percent asymptomatic means that, if you're unlucky enough to get infected, the probability is almost a flip of a coin on whether you're going to have symptoms. So to protect others, we think that wearing a mask makes a lot of sense," Oran concludes.

Researchers at Massachusetts General Hospital (MGH) have identified a key mechanism in X chromosome inactivation, a phenomenon that may hold clues that lead to treatments for certain rare congenital disorders.

Their findings, published in the journal Developmental Cell on June 11, 2020, may also aid in the creation of novel medicines for certain cancers.

Female humans and other mammals have two copies of the X chromosome in each of their cells. Both X chromosomes contain many genes, so only one of the pair can be active; having both X chromosomes expressing genes would be toxic to the cell.

For this reason, female mammals developed a mechanism called X chromosome inactivation, which silences one chromosome, explains Jeannie Lee, MD, PhD, of the Department of Molecular Biology at MGH, senior author of the Developmental Cell study.

Learning how to inactivate and reactivate an X chromosome would have important implications for medicine. A notable category of beneficiaries could be people with certain congenital diseases known as X-linked disorders, which are caused by mutations in genes on the X chromosome.

One example is Rett syndrome, a disorder brought on by a mutation in a gene called MECP2 that almost always occurs in girls and results in profound problems with language, learning, coordination, and other brain functions.

In theory, it may be possible to treat a disorder like Rett syndrome by reactivating the X chromosome. "Why don't we put the dormant X chromosome to work and rescue the cells that are lacking a proper copy of MECP2?" asks Lee.

The goal of X chromosome reactivation has led scientists to focus on epigenetic factors, which turn genes "on" or "off" without altering the genetic code. Silencing genes on the X chromosome occurs when a form of noncoding RNA called Xist spreads across the X chromosome, explains Lee.

However, Xist doesn't act alone: It must attract proteins called Polycomb repressive complexes (PRC) 1 and 2 to complete inactivation of the X chromosome.

But how Xist pulls in PRC1 and PRC2 had been unclear and the subject of debate. Research indicates that repeating sequences of nucleotides on Xist called Repeat A and Repeat B appear to act as magnets for these proteins. Yet some recent research suggests that Repeat A plays no role.

In the new study, Lee and her colleagues showed that both Repeat A and Repeat B are needed to attract PRC1 and PRC2 and complete X chromosome inactivation. By deleting Repeat A from Xist in mouse embryonic stem cells, they found that X chromosome inactivation is not only thwarted, but one X chromosome is eliminated entirely in order for the cells to survive in culture.

In human females, when one X chromosome is missing, the result is Turner syndrome, which affects stature, fertility, and other physical traits.

Understanding how Xist "recruits" PRC1 and PRC2 could have far-reaching implications, especially since the latter plays a key role in maintaining overall cell health.

"We think that through interfering with the Xist recruitment of Polycomb and other silencing complexes, we may eventually be able to treat X-linked diseases like Rett syndrome and perhaps even cancer," says Lee.

BALTIMORE, MD (June 12, 2020) - A new University of Maryland study found fentanyl tops the list of drugs detected in overdose patients at two Baltimore hospital emergency departments. The finding suggests that hospitals and medical systems throughout the United States consider adding fentanyl, a potent synthetic opioid linked to most fatal overdoses in Maryland, to their routine drug testing panels. That is the conclusion of researchers at the University of Maryland School of Medicine (UMSOM) and the Center for Substance Abuse Research (CESAR) at the University of Maryland, College Park. Currently, fentanyl is not routinely included in these panels nationwide. The study is based on de-identified urinalysis results and other data collected through the new Maryland Emergency Department Drug Surveillance (EDDS) system, launched to support improved patient outcomes.

UMSOM researchers collaborated with investigators at CESAR to analyze drugs identified in urine samples taken at both University of Maryland Medical Center (UMMC) Midtown and Downtown campuses from January 2016 through December 2019. Fentanyl testing was incorporated for all patients undergoing urine screens as a routine test at these hospitals in January 2019.

"The overdose cases we see in our emergency departments stem from a wide variety of substances that may not be known and present increasingly complex treatment challenges," said the study's lead author Zachary D.W. Dezman, MD, Assistant Professor of Emergency Medicine, UMSOM. "In the case of fentanyl, without knowing its true role in these overdoses, public health officials and policy makers will find it difficult to implement the correct measures to improve patient care and help prevent substance abuse."

Fentanyl was the most prevalent drug identified in the study. It was detected in 73 to 87 percent of specimens that were tested for the substance in each of the four calendar quarters in 2019 when fentanyl testing was first implemented. Sixty-one percent of the fentanyl positive specimens contained other drugs in addition to fentanyl, while 13 percent contained fentanyl only. The researchers noted that these results are specific to these two Baltimore hospitals and that the rate of fentanyl positives could vary in other hospitals and states.

Results from the study appear in the current issue of the Morbidity and Mortality Weekly Report (MMWR), from the Centers for Disease Control and Prevention. The researchers turned to fentanyl testing after previous EDDS observations at four Baltimore hospitals showed that even in the midst of the opioid epidemic, fewer patients were testing positive for opiates. The opiate screen primarily detects morphine and codeine (most frequently indicating the presence of heroin) but does not detect fentanyl.

"The EDDS system represents an important partnership between University of Maryland researchers and hospitals," said Eric D. Wish, PhD, Director of CESAR and Director of the Maryland EDDS. "It can enable faster, more accurate identification of changing trends in substance use and, ultimately, aims to improve patient care."

Nationwide, hospital laboratory testing is routine for a number of substances including opiates, cocaine, and methadone, but not fentanyl, according to Dr. Dezman. "Fentanyl was rarely a cause of overdoses, so routine fentanyl testing was not typically performed. However, through our regular fentanyl testing and EDDS collaboration, we have addressed a gap in our patient care, allowing us to better inform our patients of the risks associated with continued use, assist with buprenorphine induction in the emergency department, and help us connect patients to substance use treatment programs," he said.

Dr. Dezman, together with CESAR, had previously conducted a small pilot study at UMMC Midtown Campus to test for fentanyl in a subset of 76 drug overdose specimens. The findings suggested that the opiate screen was, in fact, missing many of the patients who had tested positive for fentanyl. As a result, Dr. Dezman encouraged both UMMC Downtown and UMMC Midtown hospitals to initiate routine fentanyl screening for all ED patients who undergo urine testing, including psychiatric evaluations, emergency petitions, and labor and delivery patients. The MMWR article presents the first findings for fentanyl from the EDDS system for the four quarters of 2019.

"This study finding makes an important case for including fentanyl in routine drug overdose testing," said UMSOM Dean E. Albert Reece, MD, PhD, MBA, University Executive Vice President for Medical Affairs and the John Z. and Akiko K. Bowers Distinguished Professor. "It highlights the important role and function of the newly created Maryland EDDS system, which helps to better guide patient treatment and more effective overdose prevention programs."

Scientists of Far Eastern Federal University (FEFU), together with German and Russian colleagues, have developed a lead compound to fight chemotherapy-resistant prostate cancer. The original design comes out as scientists combine biologically active molecules from the chemically modified pigment of sea urchins with glucose molecules to deliver the active drug substance inward the tumor cells. A related article recently was published in Marine Drugs.

To cure prostate cancer scientists decided to capitalize on the Warburg effect, which turns as tumor cells inclination to eat lots of "sugar", i.e. consume glucose compounds more intensively comparing to the majority of normal cells.

Researchers took active molecules analogous to the molecules isolated from sea urchins pigment and "sewed" on a sugar tail to them using Sulfur linker to tie up. The resulted compound was introduced to the cell culture of prostate cancer sustainable to Docetaxel, a standard chemotherapeutic drug. The outcome was cancer cells died more efficiently.

The scientific breakthrough comes out as the result of the close cooperation of teams from Russia and Germany that includes collaborators from FEFU School of Natural Sciences (Vladivostok Russia), University Medical Center Hamburg-Eppendorf (Germany), G.B. Elyakov Pacific Institute of Bioorganic Chemistry (PIBOC FEB RAS, Vladivostok, Russia), and University of Greifswald (Germany).

The Russian-German scientific paper was recognized as a best research article of the current issue of Marine Drugs.

"In our study, we benefit from the chance to combine the ideas and experience of specialists from different countries," says one of the authors of the research, Dr. Sergey Dyshlovoy, senior researcher at the Laboratory of Biologically Active Compounds of FEFU School of Natural Science. "Firstly, we had at our disposal analogues of biologically active compounds from sea urchins which antitumor potential had been increased via chemical modification by Far Eastern colleagues from PIBOC FEB RAS. Secondly, we used the broad experience of German colleagues in the field of prostate cancer to establish and explain the mechanism that makes tumor cells more sensitive to glucose-related molecules. It turned out that prostate cancer cells have a large number of receptors responsible for the uptake of glucose and associated molecules into the cell."

The scientist went on that although new drug compound effectively targets prostate cells culture there is a good prospect it might cure other types of cancer if the outcome of the first clinical trials is positive. The majority of tumor cells consume more glucose than healthy cells of the body.

The research outcomes not only in the new compound of sea urchins molecules tagged with glucose but also in the new way of conjugating them via Sulfur, instead of Oxygen, as it used to be early. The reason for the new method of molecules connection is a looking for the drug not breaking up by enzymes in the bloodstream before it hits a tumor target. Previous experiments confirm that compounds joined via Oxygen molecules are not as stable as needed.

Fall 2020, researchers plan to start the study possible side effects of the new drug, first on mice and then on other laboratory animals. Before this, the molecule of the drug compound will be further modified to assure its even greater stability in the bloodstream. The patent will secure the rights to a new generation molecule.

Considering the time spent on laboratory and subsequent clinical trials, as well as in case of these trials' success, a new on-the-shelf drug should approach the market in the next 10 years.

Prostate cancer is the second most deadly cancer for men living in developed countries.