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NORTH CHICAGO, IL, July 31, 2020 -- Researchers led by a team at Rosalind Franklin University of Medicine and Science have devised a new therapeutic approach to treating a rare but deadly neurodegenerative genetic disease in children. The study, published this week in Nature Medicine, addresses the urgent need to discover treatments for Batten disease, a fatal neurodegenerative disorder affecting up to four of every 100,000 children in the United States. The disease has no cure, and treatment options are few.

Professor Michelle Hastings, PhD, director for RFU's Center for Genetic Diseases, led the study in collaboration with researchers at Ionis Pharmaceuticals and Sanford Research. Published July 27, "Therapeutic Efficacy of Antisense Oligonucleotides in Mouse Models of CLN3 Batten Disease" demonstrates that symptoms in rodent models with the disease can be treated through the application of antisense oligonucleotides (ASOs) designed to attach specifically to the CLN3 gene product disrupted in CLN3 Batten disease. The researchers also demonstrated that human cells cultured from patients with the disease respond to treatment in a manner that indicates a reversal of cellular defects.

"When rodents were treated with the therapeutic CLN3 corrector, their lifespan was extended, motor skills improved and waste buildup in the brain was lessened," said Dr. Hastings. "It was a surprising demonstration that partial correction of the defective CLN3 gene can lead to meaningful improvements in an animal model with this disease."

"Our work tested a novel approach to therapeutically target the expression of the most common cause of the disease using ASOs -- directed to the mutated form of the gene," said graduate student Jessica Centa, leading author on the paper. "These results are a critical step toward our long-term goal of developing a treatment for CLN3 Batten disease."

The FDA has approved a number of antisense-based therapeutics for genetic diseases in the last few years, including spinal muscular atrophy, another pediatric neurodegenerative disorder. The number of genetic diseases is estimated at more than 7,000, and most have few if any effective treatments. ASO technology offers a potential therapeutic answer to this problem.

"We have work to do before this therapeutic will be ready to test in humans, but the animal studies suggest that our approach may provide an effective treatment in patients," Dr. Hastings said.

Dr. Hastings was recently awarded a $2.3 million grant from the National Institute of Neurological Disorders and Stroke to advance the team's investigation into correcting faulty gene expression associated with CLN3 Batten disease using antisense oligonucleotide technology. ASO is a therapeutic platform with potential applications for a large number of inherited genetic diseases. The grant was awarded in collaboration with colleagues in the Pediatrics and Rare Diseases group at Sanford Research, Sioux Falls, SD, led by neuroscientist Jill Weimer, PhD.

The Center for Genetic Diseases is one of six disease-focused centers within RFU's new Innovation and Research Park that are driving the translation of novel medical discoveries through expanded collaborations with industry and biotech entrepreneurs.

"Dr. Hastings' latest NIH grant is an acknowledgement of her team's seminal work to find therapeutic options for a devastating pediatric neurodegenerative disease and also RFU's strong culture of collaboration, innovation and mentorship," said Executive Vice-President for Research Ronald Kaplan, PhD. "We look forward to the advancement of this study, which offers hope for a healthier future to so many children and their families."

CHAPEL HILL, NC - A study recently published in the journal Circulation looks at temporal trends in the burden of comorbidities and associated risk of mortality among patients with heart failure (HF) with preserved ejection fraction (HFpEF), in which the left ventricle of the heart is not able to relax enough to fill properly with blood, and HF with reduced ejection fraction (HFrEF), in which the left ventricle is not able contract enough to pump out as much blood.

"The medical complexity of patients hospitalized with HFpEF and HFrEF appears to be increasing over time," said Melissa Caughey, PhD, an epidemiologist and instructor in the UNC/NC State Joint Department of Biomedical Engineering, and senior author of the study. "We used data from the surveillance component of the Atherosclerosis Risk in Communities (ARIC) study to examine HF-related hospitalizations from four U.S. areas from 2005 to 2014."

Just over 5,400 hospitalizations were analyzed, with stratification by heart failure type and sex. Caughey says the following comorbidities were extracted from medical records: coronary artery disease, peripheral artery disease, hypertension, pulmonary hypertension, atrial fibrillation, stroke/transient ischemic attack (TIA), valvular heart disease, myocardial infarction, body mass index, diabetes mellitus, serum creatinine, chronic obstructive pulmonary disease (COPD), sleep apnea, depression, anemia, and thyroid disease. Researchers found that over time, the average number of comorbidities increased in both men and women with both heart failure types. However, HFpEF, which is more common in women and is now the predominant form of heart failure, had the worst comorbidity burden.

Of the comorbidities studied, Caughey says there was a decrease in the prevalence of coronary artery disease and an increase in nonatherosclerotic or non-cardiovascular comorbidities.

"This finding is consistent with the hypothesis that the epidemiology of heart failure is evolving - shifting from an ischemic etiology to more of a multi-morbidity heart failure over time," Caughey said.
Ischemic, or atherosclerotic heart disease, is usually caused by the buildup of plaque in arteries over time. This can lead to the narrowing of those arteries, reduced blood flow and weakening of the heart muscle. While heart attacks have declined over time, heart failure arising secondarily to other causes, such as hypertension and obesity, is now more common. Caughey says because many of the comorbidities in the study are manageable or preventable, this highlights the importance of a holistic approach targeting multi-morbidity burden in guiding the management of patients with acute decompensated HF. Because morbidity increases with comorbidities, prevention should be a key focus.

Head and neck cancer is one of the leading causes of cancer-related deaths worldwide, and squamous cell carcinomas (HNSCC) account for the majority of these cases. In a new study, based on preclinical research and published July 29, 2020 in Molecular Cancer Therapeutics, a journal of the American Association for Cancer Research, researchers at University of California San Diego School of Medicine and Moores Cancer Center report that an investigational drug candidate called tipifarnib showed promise in treating HNSCC tumors with mutations in the HRAS gene.

The findings shed new light on the HRAS gene, a member of the RAS family of genes that produce proteins that regulate a variety of cellular processes, including growth, movement and differentiation. In 4 to 8 percent of HNSCC tumors, the HRAS gene is mutated.

"This preclinical research has the potential to extend to the entire HNSCC patient community, whose overall survival rates are limited in recurrent or metastatic disease, and existing therapeutic options that are far from optimal, with response rates of roughly 10 to 20 percent," said senior co-author J. Silvio Gutkind, PhD, Distinguished Professor of Pharmacology and associate director of basic science at UC San Diego Moores Cancer Center.

"These preclinical findings support the idea that HRAS represents a druggable oncogene in HNSCC through tipifarnib's inhibition of a key enzyme. It is a precision therapeutic option for HNSCCs harboring HRAS mutations."

Tipifarnib is a selective inhibitor of farnesyltransferase, an enzyme that plays a critical role in anchoring some RAS family proteins to cellular membranes. Unlike KRAS and NRAS gene mutations, HRAS is dependent on farnesyltransferase activity for function, offering a way to indirectly target an oncogenic RAS isoform using a well-characterized drug with extensive clinical experience.

In the study, UC San Diego researchers found that cell line- and patient-derived HNSCC models harboring HRAS mutations were highly sensitive to tipifarnib, which the authors said has demonstrated encouraging preliminary clinical activity in patients with relapsed or refractory HRAS-mutant HNSCC to date.

Currently, Kura Oncology, a San Diego-based biopharmaceutical company, is conducting a nationwide clinical trial to assess the safety and efficacy of tipifarnib in head and neck cancer with HRAS mutations. Employees of Kura are co-authors of the new paper. UC San Diego is not part of the trial.

Treatment with tipifarnib, wrote study authors, had a multifaceted effect on the biology of HRAS-mutant HNSCC tumors, reducing oncogenic signaling and proliferation, while increasing apoptosis (cell death), blocking angiogenesis (development of new blood vessels in tumors) and driving squamous differentiation of tumors.

Head and neck cancer accounts for approximately 650,000 cases and 330,000 deaths annually worldwide. In the United States, approximately 4 percent of all cancers are head and neck, with an estimated 65,630 persons diagnosed each year, two-thirds of them men and 14,500 deaths, according to Cancer.Net.

A study from Ann & Robert H. Lurie Children's Hospital of Chicago discovered that children younger than 5 years with mild to moderate COVID-19 have much higher levels of genetic material for the virus in the nose compared to older children and adults. Findings, published in JAMA Pediatrics, point to the possibility that the youngest children transmit the virus as much as other age groups. The ability of younger children to spread COVID-19 may have been under-recognized given the rapid and sustained closure of schools and daycare during the pandemic.

"We found that children under 5 with COVID-19 have a higher viral load than older children and adults, which may suggest greater transmission, as we see with respiratory syncytial virus, also known as RSV," says lead author Taylor Heald-Sargent, MD, PhD, pediatric infectious diseases specialist at Lurie Children's and Assistant Professor of Pediatrics at Northwestern University Feinberg School of Medicine. "This has important public health implications, especially during discussions on the safety of reopening schools and daycare."

Dr. Heald-Sargent and colleagues analyzed 145 cases of mild to moderate COVID-19 illness within the first week of symptom onset. They compared the viral load in three age groups - children younger than 5 years, children 5-17 years and adults 18-65 years.

"Our study was not designed to prove that younger children spread COVID-19 as much as adults, but it is a possibility," says Dr. Heald-Sargent. "We need to take that into account in efforts to reduce transmission as we continue to learn more about this virus."

DURHAM, N.C. - A vaccine for HER2-positive breast cancers that is being tested in a clinical trial at Duke Cancer Institute is part of an effective, two-drug strategy for enlisting the immune system to fight tumors, according to a Duke-led study in Clinical Cancer Research, a journal of the American Association for Cancer Research.

The vaccine was developed at Duke and targets the HER2 protein, which is the driver of HER2-positive breast cancer and the cause of about 20 percent of all breast cancer cases.

While the vaccine works to a degree on its own, the tumor can still activate backup strategies for survival. But when combined with existing immune checkpoint inhibitors, the one-two punch proves highly effective, the researchers found.

"This study supports the development of vaccines targeting tumor driver and resistance genes, which we think is critical in establishing effective anti-tumor immune responses," said study leader Zachary Hartman, Ph.D., an assistant professor in the departments of Surgery and Pathology at Duke University School of Medicine.

Hartman and colleagues found that vaccine-induced HER2-specific T-cells were essential for immune responses. Additionally, it was more effective to elicit the T-cells early in tumor development -- a finding that has implications for clinical trial designs that typically enroll patients after standard therapies have failed.

Treatment with the investigational vaccine was significantly enhanced when combined with the checkpoint inhibitor drug pembrolizumab. When used alone, pembrolizumab has shown limited benefit for HER2-positive breast cancers.

By working in tandem, the vaccine primes the immune system and the checkpoint inhibitor then rallies the T-cells to action, resulting in pronounced tumor reduction and long-term tumor-free survival.

"The basic premise is that the immune checkpoint inhibitors work fantastic if the body has already triggered an immune response, but they don't work well in the absence of that," said H. Kim Lyerly, M.D., a professor in the departments of Surgery, Immunology and Pathology at Duke University School of Medicine and an author of this study.

"Our vaccine initiates the anti-tumor response, and in combination with the checkpoint inhibitors, works beautifully," Lyerly said.

What The Study Did: Researchers looked at changes in opioid prescribing rates and level of pain control in patients who had hip or knee replacement in the U.S. from 2014 to 2017.

Authors: Rahul Shah, B.S., of the University of Texas Medical Branch in Galveston, 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.2020.11972)

Editor's Note: The article includes conflicts 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.

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Structures called primary cilia - which act like TV antennas for cells to detect signals - are present in fewer numbers in mice born with Fragile X syndrome, according to researchers from The University of Texas Health Science Center at San Antonio (UT Health San Antonio). Study results were published July 30 in the journal Stem Cell Reports.

Fragile X syndrome is a genetic disorder often accompanied by mild to severe intellectual disability. Autism spectrum disorders frequently occur in the affected children. Understanding the role of primary cilia deficits in Fragile X syndrome and autism and developing novel therapeutics to increase their numbers could lead to reversing these neurodevelopmental disorders, said study senior author Hye Young Lee, PhD, of UT Health San Antonio.

The research team focused on primary cilia located in a brain structure called the dentate gyrus. It is part of the hippocampus, a learning and memory command center. The reduction of primary cilia was specifically noted in the dentate gyrus, Dr. Lee and her colleagues found.

The dentate gyrus is one of two brain structures that contain neuronal stem cells, she said. The dentate gyrus serves as a nursery for newborn neurons, which depend on the primary cilia to enable their maturation.

Primary cilia have not previously been linked to Fragile X syndrome, Dr. Lee said.

"If we get to know how the primary cilia work in the newborn neuron and how they contribute to Fragile X syndrome, the next step would be to promote them," Dr. Lee said.

"There are drugs to do that, and they could be potential therapies for Fragile X syndrome and other neurodevelopmental disorders, because there are multiple studies showing that neurodevelopmental disorders and autism can be reversed in adults," Dr. Lee said.

A new study finds that healthcare workers in the United States are struggling with a suite of mental-health challenges during the COVID-19 pandemic. The study reports that healthcare workers are at greater risk than the general public of experiencing health problems such as depression.

One striking finding is that, on average, healthcare professionals reported enough symptoms of depression to be diagnosed with clinical depression.

"Our goal was to better understand the impact that COVID-19 was having on the mental well-being of healthcare workers," says Ann Pearman, corresponding author of the study and a senior research scientist in the School of Psychology at Georgia Institute of Technology.

"What we learned suggests that anyone who identifies as a healthcare professional - whether it's a physician or a support worker in a hospital - is at risk for mental-health problems that could be devastating if left untreated," says Shevaun Neupert, a professor of psychology at North Carolina State University and co-author of the paper.

"These findings are alarming, and we need additional work to better capture the scope of this problem. What's more, we need to be thinking about how we can help our healthcare workers."

For this study, researchers conducted an online survey of 90 people who identified as healthcare workers. While most respondents were physicians, nurses and medical technicians, some held roles such as hospital administrators. The researchers also surveyed a control group of 90 people who did not work in healthcare, but matched the age and sex of the healthcare workers. The study ran from March 20 through May 14. Study participants came from 35 states.

The survey included demographic questions, as well as questions aimed at capturing various aspects of mental health and well-being.

Healthcare workers reported higher levels of stress, anxiety and tiredness, as well as lower feelings of control over their lives.

"We also found that the healthcare group averaged a depressive symptoms score that would qualify as clinical depression," Neupert says. "It was approximately 30% higher than the depressive symptoms score for the control group. You don't expect to see an entire workforce score like that on a depression diagnostic tool."

The researchers also found that the healthcare workers were less likely to engage in "proactive coping," meaning they were doing less to prepare themselves for future stresses or adverse events.

"Our findings suggest that healthcare workers are at much higher risk right now of negative outcomes, such as depression," Neupert says. "That's not sustainable, and we need to figure out what we're going to do about it."

LOS ANGELES -- Modifying 12 risk factors over a lifetime could delay or prevent 40% of dementia cases, according to an updated report by the Lancet Commission on dementia prevention, intervention and care presented at the Alzheimer's Association International Conference (AAIC 2020).

Twenty-eight world-leading dementia experts added three new risk factors in the new report -- excessive alcohol intake and head injury in mid-life and air pollution in later life. These are in addition to nine factors previously identified by the commission in 2017: less education early in life; mid-life hearing loss, hypertension and obesity; and smoking, depression, social isolation, physical inactivity and diabetes later in life (65 and up).

"We are learning that tactics to avoid dementia begin early and continue throughout life, so it's never too early or too late to take action," says commission member and AAIC presenter Lon Schneider, MD, co-director of the USC Alzheimer Disease Research Center's clinical core and professor of psychiatry and the behavioral sciences and neurology at the Keck School of Medicine of USC.

Dementia affects some 50 million people globally, a number that is expected to more than triple by 2050, particularly in low- and middle-income countries where approximately two-thirds of people with dementia live, according to the report. Women are also more likely to develop dementia than men.

However, in certain countries, such as the United States, England and France, the proportion of older people with dementia has fallen, probably in part due to lifestyle changes, demonstrating the possibility of reducing dementia through preventative measures, Schneider says.

Schneider and commission members recommend that policymakers and individuals adopt the following interventions:

Aim to maintain systolic blood pressure of 130 mm Hg or less from the age of 40.

Encourage use of hearing aids for hearing loss and reduce hearing loss by protecting ears from high noise levels.

Reduce exposure to air pollution and second-hand tobacco smoke.

Prevent head injury (particularly by targeting high-risk occupations).

Limit alcohol intake to no more than 21 units per week (one unit of alcohol equals 10 ml or 8 g pure alcohol).

Stop smoking and support others to stop smoking.

Provide all children with primary and secondary education.

Lead an active life into mid-life and possibly later life.

Reduce obesity and the linked condition of diabetes.

The report also advocates for holistic, individualized and evidenced-based care for patients with dementia, who typically have more hospitalizations for conditions that are potentially manageable at home and are at greater risk for COVID-19. In addition, it recommends providing interventions for family caregivers who are at risk for depression and anxiety.

The commission members conducted a thorough investigation of all the best evidence in the field, including systematic literature reviews, meta-analyses and individual studies, to reach their conclusions.

Philadelphia, July 30, 2020 - In a report in the Journal of Molecular Diagnostics, published by Elsevier, researchers at Augusta University and PerkinElmer Genomics describe a cheaper, rapid, and accurate pooling strategy for the RT-PCR-based detection of SARS-CoV-2 in clinical samples. This assay has a significant impact on large-scale population screening in the wake of the current COVID-19 pandemic.

The COVID-19 pandemic has caused a massive strain on global healthcare systems, governance, and economies. Testing for SARS-CoV-2 has lagged in many countries due to various bottlenecks including but not limited to the failure of the reagent supply chain, lack of adequate test kits, and hindrances in the analytical and regulatory processes.

"We have proposed a mass population screening approach based on sample pooling strategy for rapid and wide-scale population screening that may be adopted by laboratories currently using RT-PCR-based methods to test for SARS-CoV-2," explained Ravindra Kolhe, MD, PhD, Vice-Chair for Translational Research in the Department of Pathology, Medical College of Georgia, Augusta University, Augusta, GA, USA.

According to Dr. Kolhe, this strategy would lead to an approximately 5- to 10-fold reduction in the cost of testing of SARS-CoV-2. PerkinElmer's FDA-EUA (Emergency Use Authorization) RT-PCR kit for SARS-CoV-2 detection (with a limit of detection of 5-20 copies/mL) has been implemented in the laboratory by Dr. Kolhe since March 2020.

The investigators analyzed approximately 1,000 samples using this pooled sampling approach and achieved 91.6 percent PPA (positive percent agreement) and 100 percent NPA (negative percent agreement) compared to the routine screening approach. The study demonstrates the clinical utility and accuracy of sample pooling strategy and presents a carefully planned layout for mass population testing that can be executed by laboratories using RT-PCR-based methods for detecting SARS-CoV-2. The proposed methodology has the potential to allow institutions to ramp up their testing needs in a cost-efficient manner with minimal turnaround times. This testing allows for the timely isolation and treatment of COVID-19-positive patients, specifically in populations with a lower prevalence of the disease, for example, screening large numbers of students returning to college campuses.

"In terms of cost analysis, one million individuals can be tested for around US$9.1 million with the proposed mass population screening approach compared to approximately US$58 million with current routine diagnostic methods. These cost projections highlight significant savings of healthcare dollars that could be achieved in both high- and low/middle-income countries," said Amyn Rojiani, MD, PhD, Chair of the Department of Pathology, Augusta University, Augusta, GA, USA. The global impact of these enormous savings has the potential to enhance laboratory operations throughout the pandemic and can be deployed to laboratories that are facing dire constraints in supplies.

CHICAGO, July 30, 2020 -- Risk factors for Alzheimer's dementia may be apparent as early as our teens and 20s, according to new research reported at the Alzheimer's Association International Conference® (AAIC®) 2020.

These risk factors, many of which are disproportionately apparent in African Americans, include heart health factors -- such as high blood pressure, high cholesterol and diabetes -- and social factors like education quality. According to the Alzheimer's Association Alzheimer's Disease Facts and Figures report, older African Americans are about twice as likely to have Alzheimer's or other dementias as older whites.

"By identifying, verifying, and acting to counter those Alzheimer's risk factors that we can change, we may reduce new cases and eventually the total number of people with Alzheimer's and other dementia," said Maria C. Carrillo, Ph.D., Alzheimer's Association chief science officer. "Research like this is important in addressing health inequities and providing resources that could make a positive impact on a person's life."

"These new reports from AAIC 2020 show that it's never too early, or too late, to take action to protect your memory and thinking abilities," Carrillo said.

The Alzheimer's Association is leading the U.S. Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk (U.S. POINTER), a two-year clinical trial to evaluate whether lifestyle interventions that simultaneously target many risk factors protect cognitive function in older adults who are at increased risk for cognitive decline. U.S. POINTER is the first such study to be conducted in a large, diverse group of Americans across the United States.

African American Youth At Higher Risk of Dementia

In a population of more than 714 African Americans in the Study of Healthy Aging in African Americans (STAR), Kristen George, Ph.D., MPH, of the University of California, Davis, and colleagues found that high blood pressure and diabetes, or a combination of multiple heart health-related factors, are common in adolescence and are associated with worse late-life cognition. Study participants were adolescents (n=165; ages 12-20), young adults (n=439; ages 21-34) and adults (n=110; ages 35-56). Mean age at cognitive assessment was 68.

Cognition was measured using in-person tests of memory and executive function. The researchers found that, in this study population, having diabetes, high blood pressure, or two or more heart health risk factors in adolescence, young adulthood, or mid-life was associated with statistically significantly worse late-life cognition. These differences persisted after accounting for age, gender, years since risk factors were measured, and education.

Before this report, little was known about whether cardiovascular disease (CVD) risk factors developed prior to mid-life were associated with late-life cognition. This is an important question because African Americans have a higher risk of CVD risk factors compared to other racial/ethnic groups from adolescence through adulthood.

According to the researchers, these findings suggest that CVD risk factors as early as adolescence influence late-life brain health in African Americans. Efforts to promote heart and brain healthy lifestyles must not only include middle-aged adults, but also younger adults and adolescents who may be especially susceptible to the negative impact of poor vascular health on the brain.

Early Adult BMI Associated With Late Life Dementia Risk

In what the authors say is the first study to report on the issue, higher early adulthood (age 20-49) body mass index (BMI) was associated with higher late-life dementia risk.

Relatively little is known about the role of early life BMI on the risk of Alzheimer and other dementias. The scientists studied a total of 5,104 older adults from two studies, including 2,909 from the Cardiovascular Health Study (CHS) and 2,195 from the Health, Aging and Body Composition study (Health ABC). Of the total sample, 18% were Black and 56% were women. Using pooled data from four established cohorts spanning the adult life course, including the two cohorts under the study, the scientists estimated BMI beginning at age 20 for all older adults of CHS and Health ABC.

For women, dementia risk increased with higher early adulthood BMI. Compared to women with normal BMI in early adulthood, dementia risk was 1.8 times higher among those who were overweight, and 2.5 times higher among those who were obese. Analyses were adjusted for midlife and late life BMI.

They found no association between midlife BMI and dementia risk among women.

For men, dementia risk was 2.5 times higher among those who were obese in early adulthood, 1.5 times higher among those who were overweight in mid-life and 2.0 times higher among those who were obese in mid-life, in models also adjusted for late life BMI.

For both women and men, dementia risk decreased with higher late life BMI.

Adina Zeki Al Hazzouri, Ph.D. of Columbia University and colleagues found that high BMI in adulthood is a risk factor for dementia in late life. The researchers suggest that efforts aimed at reducing dementia risk may need to begin earlier in life with a focus on obesity prevention and treatment.

Quality of Early-Life Education Influences Dementia Risk

In a diverse group of more than 2,400 people followed up to 21 years, higher quality early-life education was associated with better language and memory performance, and lower risk of late-life dementia. Results were somewhat different between men and women, and between Blacks and Whites in the study.

The study included 2,446 Black and White men and women, age 65 and older, enrolled in the Washington Heights/Inwood Columbia Aging Project who attended elementary school in the United States. A school quality variable based on historical measures included: mandatory school enrollment age, minimum dropout age, school term length, student-teacher ratio, and student attendance.

People who attended school in states with lower quality education had more rapid decline in memory and language as an older adult. Black women and men and White women who attended schools in states with higher quality education were less likely to develop dementia. According to the scientists, the results were explained, in part, because people who attend higher quality schools end up getting more years of school.

Justina Avila-Rieger, PhD, a postdoctoral research scientist at Columbia University Irving Medical Center and colleagues say the findings provide evidence that later life dementia risk and cognitive function is influenced by early-life state educational policies.

More than 200 genes with novel and known roles in glioblastoma - the most aggressive type of brain cancer - offer promising new drug targets. Researchers from the Wellcome Sanger Institute, Addenbrooke's Hospital and their collaborators engineered a new mouse model to show for the first time how a mutation in the well-known cancer gene, EGFR initiates glioblastoma, and works with a selection from more than 200 other genes to drive the cancer.

The results, published today (30 July) in Genome Biology present the first mouse model of its kind, which is available for the research community to advance new treatments for this lethal form of brain cancer.

Glioblastoma is an aggressive form of brain cancer. It is treated with surgery followed by chemotherapy or radiotherapy, however glioblastoma cells can evade treatment and tumours return. The prognosis is poor - the average patient survives for 12-18 months following diagnosis*.

New, targeted treatments and immunotherapies are currently being developed to help glioblastoma patients. It is still not known exactly why glioblastomas begin to grow.

In a new study, researchers from the Wellcome Sanger Institute and their collaborators created a new mouse model with glioblastoma to investigate which genes were implicated in the cancer.

The model showed that the well-known cancer gene, EGFR (epidermal growth factor receptor) can alone initiate the brain tumours to grow in mice, resulting in tumours that were highly representative of human glioblastomas.

Dr Imran Noorani, a corresponding author previously from the Wellcome Sanger Institute, and now based at Addenbrooke's Hospital and the University of Cambridge, said: "We have created a new mouse model for studying the lethal human brain cancer, glioblastoma. For the first time, we showed that the familiar cancer gene, EGFR is capable of initiating glioblastoma and we identified new driver genes, whose potential for therapeutic targeting deserves further exploration."

To identify which genes help EGFR to drive the cancer, the team used the PiggyBac transposon technique - a small section of DNA inserted into different parts of the genome to introduce mutations. This revealed more than 200 known and novel mutations in tumour suppressor genes that were working with EGFR to drive brain tumour growth, many of which present new drug targets.

The team compared the results with human genome sequences from glioblastoma patients and uncovered many genetic mutations found in both humans and mice. Human genomic data contains many mutations implicated in glioblastoma, without clear indication of which specific mutations drive the cancer. With the new mouse model, the team were able to narrow down on which mutations drive glioblastoma, which will focus future drug development.

Professor Allan Bradley, previously Director of the Wellcome Sanger Institute, and now Chief Scientific Officer of Kymab and Professor in the Department of Medicine, University of Cambridge, said: "Glioblastoma patients urgently require new, targeted therapies. Unfortunately, glioblastoma tumours can become highly resistant to therapies that target specific molecules, as there are many other genetic drivers that can 'take over' progressing the cancer. This new mouse model provides the missing link to translate findings from new potential treatments tested on mice to clinical trials."

A new technique that can spot a potential preterm birth in asymptomatic high-risk women, with up to 73% accuracy months before delivery, has been developed by scientists at the University of Warwick.

Utilising cutting-edge volatile organic compound analysis technology, designed to characterise airborne chemicals, the scientists 'trained' the device using machine-learning techniques to identify the chemical vapour patterns from preterm birth using vaginal swabs taken during routine examinations.

Their technique is detailed in a paper for Scientific Reports and could lead to a cost-effective, non-invasive, point-of-care test that could form part of routine care for women identified as being at risk of delivering prematurely. This could enable healthcare staff to better support those women during pregnancy and birth and help to reduce the risks to their baby.

Preterm birth is the leading cause of death in children under five and at present there are few accurate tools to predict who is going to deliver preterm.

The researchers initially analysed volatile organic compounds (VOCs) present in the vagina for a condition called bacterial vaginosis, in which the bacteria of the vagina have become imbalanced. Previous research has shown that bacterial vaginosis in early pregnancy is associated with an increased risk in having a preterm birth, although treating bacterial vaginosis doesn't decrease that risk.

The technology they used works by separating the vapour molecules by combining two techniques that first pre-separates molecules based on their reaction with a stationary phase coating (a gas-chromatograph), followed by measuring their mobility in a high-electric field (an Ion Mobility Spectrometer). Using machine learning techniques, the team 'trained' the technology to spot patterns of VOCs that were signs of bacterial vaginosis.

The researchers then analysed vaginal swabs taken from pregnant women attending a preterm prevention clinic as part of their routine care. These women either had prior histories of preterm births or a medical condition that makes it more likely that they would deliver preterm but had shown no other indications that they would deliver preterm and were considered asymptomatic.

Vaginal swabs were taken during the second and third trimesters of pregnancy and the outcome of all pregnancies followed up. The first test had an accuracy of 66% while the second, closer to the time of delivery, had an accuracy of 73%. The test results means that 7/10 women with a positive test went on to deliver preterm. 9/10 women with a negative test delivered after 37 weeks.

Lead author Dr Lauren Lacey of Warwick Medical School and an obstetrics and gynaecology registrar at University Hospitals Coventry and Warwickshire NHS Trust said: "We've demonstrated that the technology has good diagnostic accuracy, and in the future it could form part of a care pathway to determine who would deliver preterm.

"Although the first test taken earlier in pregnancy is diagnostically less accurate, it could allow interventions to be put in place to reduce the risk of preterm delivery; for the test towards the end of pregnancy, high risk women can have interventions put in place to optimise the outcome for baby.

"There are a number of different factors that could cause a woman to go into preterm labour. Because of that, prediction is quite difficult. There are lots of things we can look at - the patient's history, the examination, ultrasound scan, various other biomarkers that are used in clinical practice. No single test fits all.

"VOC technology is really interesting because it reflects both the microbiome and the host response, whereas other technologies look for a specific biomarker. It's the beginning of looking at the association of VOCs with preterm delivery. We want to develop this and look at whether these patterns could be implemented into a care pathway."

The next stage of research would see a small VOC analysis device stored at a hospital so samples could be analysed on site. The hope is that it could eventually be developed for use in a labour ward triage so tests can be administered and results obtained rapidly.

Professor James Covington from the University of Warwick School of Engineering said: "There is a strong interest around the world in the use of vapours emanating from biological waste for the diagnosis and monitoring of disease. These approaches can non-invasively measure the health of a person, detect an infection or warn of an impending medical need. For the need described in the paper, the technology can be miniaturised and be easily located in a maternity ward. The analysis only takes few minutes, the instrument needs no specialised services (just power) and is easy to use. We believe that the analysis of odours will become commonplace for this and many other diseases in the near future."

The researchers behind this study are part of the newly established Centre for Early Life, based at Warwick Medical School at the University of Warwick, which launches on 31 July. The new Centre builds on the University's existing expertise in early life research by aiming to pioneer research into the formative factors in our lives such as this latest research.

Professor Siobhan Quenby, Co-Director of the new Centre and Honorary Consultant at University Hospital Coventry and Warwickshire NHS Trust said: "I am delighted that the new Centre for Early Life will facilitate further interdisciplinary collaborations, to the benefits of my patients."

A study led by Charité - Universitätsmedizin Berlin and the Max Planck Institute for Molecular Genetics (MPIMG) shows that some healthy individuals possess immune cells capable of recognizing the novel coronavirus, SARS-CoV-2. The reason for this might be found in prior infections with 'common cold' coronaviruses. Whether or not this cross-reactivity has a protective effect on the clinical course in individuals infected with SARS-CoV-2 will now be addressed by the 'Charité Corona Cross' study.

Why is it that some people develop severe symptoms following infection with the novel coronavirus, while others hardly notice the infection? The answer to this question is multilayered and is the subject of intensive research. One potentially crucial factor has now been identified by a team of researchers from Charité and the MPIMG: prior exposure to harmless 'common cold' coronaviruses. This insight is based on research involving T-helper cells, a type of specialized white blood cell which is essential to the regulation of our immune response. The researchers found that one in three people with no prior exposure to SARS-CoV-2 nonetheless have T-helper cells capable of recognizing the virus. The likely reason for this is that SARS-CoV-2 shares certain structural similarities with coronaviruses which are responsible for the common cold.

For their study, the researchers isolated immune cells from the blood of 18 COVID-19 patients receiving treatment at Charité and confirmed PCR positive for SARS-CoV-2. They also isolated immune cells from the blood of 68 healthy individuals who had never been exposed to the novel coronavirus. The researchers then stimulated these immune cells using small, synthetic fragments of SARS-CoV-2 'spike proteins', the characteristic, crown-like protrusions on the outer surface of coronaviruses which enable the virus to enter human cells. The researchers subsequently tested whether the T-helper cells would be activated by contact with these protein fragments. They found that this was the case in 15 out of 18 patients with COVID-19 (85%). "This was exactly what we had expected. The immune system in these patients was in the process of fighting this novel virus, and therefore showed the same reaction in vitro," explains one of the study's three lead authors, Dr. Claudia Giesecke-Thiel, head of the Flow Cytometry Facility at the MPIMG. She adds: "The fact that not all patients with COVID-19 showed this T-helper cell response to viral fragments is probably due to fact that T cells cannot be activated outside the human body during an acute or particularly severe phase of an illness."

The team were, however, surprised to find memory T-helper cells capable of recognizing fragments of SARS-CoV-2 in the blood of healthy individuals. They were found in a total of 24 out of 68 healthy individuals tested (35%). In fact, the researchers noticed that the immune cells of COVID-19 patients reacted to different fragments of the viral envelope than the immune cells of healthy individuals. While the T-helper cells of patients recognized the spike protein in its full length, the T-helper cells isolated from healthy individuals were primarily activated by sections of the spike protein which showed similarity to corresponding sections found in the spike proteins of harmless 'common cold' coronaviruses. "This suggests that the T-helper cells of healthy individuals react to SARS-CoV-2 because of previous exposure to the endemic 'common cold' coronaviruses," says Dr. Giesecke-Thiel. She goes on to explain: "One of the characteristics of T-helper cells is that they are not only activated by a pathogen with an 'exact fit', but also by pathogens with 'sufficient similarity'." Notably, the researchers were able to show that the T-helper cells isolated from healthy participants who reacted to SARS-CoV-2 were also activated by various 'common cold' coronaviruses - displaying what is known as 'cross-reactivity'.

What effects this cross-reactivity might have on a previously healthy person infected with SARS-CoV-2 was not addressed in the current study. "Generally speaking, it is possible that cross-reactive T-helper cells have a protective effect, for instance by helping the immune system speed up its production of antibodies against the novel virus," explains co-lead author Prof. Dr. Leif Erik Sander of Charité's Medical Department, Division of Infectious Diseases and Respiratory Medicine. He adds: "In this case, a recent bout of the common cold would probably result in less severe COVID-19 symptoms. However, it is also possible that cross-reactive immunity could lead to a misdirected immune response and potentially negative effects on the clinical course of COVID-19. We know this can occur with dengue fever, for instance."

Prospective studies will be needed in order to conclusively determine whether previous 'common cold' coronavirus infections confer protection against subsequent infection with SARS-CoV-2 - and whether this might explain the high variability in clinical manifestations. One such study, which will be led by Charité and conducted in collaboration with Technische Universität Berlin and the MPIMG, has just been launched. Funded by the Federal Ministry of Health (BMG) and the Federal Institute for Drugs and Medical Devices (BfArM), the 'Charité Corona Cross Study' will investigate the impact of cross-reactive T-helper cells on the course of COVID-19.

In Germany, coronaviruses are responsible for up to 30 percent of all seasonal colds, says Prof. Dr. Andreas Thiel, a Charité researcher based at both the Si-M ('Der Simulierte Mensch - literally 'The Simulated Human', a joint research space of Charité and Technische Universität Berlin) and the BIH Center for Regenerative Therapies (BCRT). "Current estimates suggest that the average adult will contract an infection caused by one of the four endemic coronaviruses approximately every two to three years," explains Prof. Thiel, who is the article's third co-lead author and responsible for coordinating the Charité Corona Cross Study. He adds: "If we assume that these cold viruses are capable of conferring a certain level of immunity against SARS-CoV-2, this would mean that people who have had frequent exposure to such infections in the past, and who test positive for cross-reactive T-helper cells, should have better protection. This group of people will therefore be a particular focus of the 'Charité Corona Cross Study'." The researchers will simultaneously follow COVID-19 risk populations over several months. Ultimately, the study aims to help predict the clinical course of COVID-19, both in people with and without previous SARS-CoV-2 infections. "This is of paramount importance, both in terms of people's day-to-day lives and the treatment of patients," explains Prof. Thiel.

The study includes a comprehensive immunological investigation of child daycare staff, pediatric practice staff and care home residents, which will last well into next year. Swabs collected from participants will be tested for SARS-CoV-2 using PCR-based testing. Additional tests will include tests for antibodies against the virus and for T cell reactivity. Should study participants subsequently contract SARS-CoV-2, the researchers will be able to establish links between the course of the disease and individual patients' immunological parameters.

The researchers also plan to collect blood samples from a minimum of 1,000 recovered COVID-19 patients. These will then be tested for a range of immunological factors in order to study how they correlate with symptoms. The team hope to be able to identify other potential parameters which influence COVID-19 severity and clinical course. The researchers are currently looking for individuals who were confirmed cases of COVID-19 and subsequently recovered from the illness. They would also like to hear from individuals who, at some point over the past few years, developed infections subsequently confirmed as caused by 'common cold' coronaviruses like 229E, C43, NL63 or HKU1. Those interested should contact the research team on 030/314 279 12 (Mondays to Fridays between 10 AM and 5PM) or email studie@si-m.org.

CAMBRIDGE, MA -- Yellow fever, a hemorrhagic disease that is common in South America and sub-Saharan Africa, infects about 200,000 people per year and causes an estimated 30,000 deaths. While there is a vaccine for yellow fever, it can't be given to some people because of the risk of side effects, and there are no approved treatments for the disease.

An international team of researchers, led by MIT Professor Ram Sasisekharan, has now developed a potential treatment for yellow fever. Their drug, an engineered monoclonal antibody that targets the virus, has shown success in early-stage clinical trials in Singapore.

This class of antibodies holds promise for treating a variety of infectious diseases, but it usually takes several years to develop and test them. The MIT-led researchers demonstrated that they could design, produce, and begin clinical trials of their antibody drug within seven months.

Their approach, which condenses the timeline by performing many of the steps necessary for drug development in parallel, could also be applied to developing new treatments for Covid-19, says Sasisekharan, the Alfred H. Caspary Professor of Biological Engineering and Health Sciences and Technology. He adds that a potential Covid-19 antibody treatment, developed using this approach in a process that took just four months, has shown no adverse events in healthy volunteers in phase I clinical trials, and phase 3 trials are expected to start in early August in Singapore.

"Traditional drug development processes are very linear, and they take many years," Sasisekharan says. "If you're going to get something to humans fast, you can't do it linearly, because then the best-case scenario for testing in humans is a year to 18 months. If you need to develop a drug in six months or less, then a lot of these things need to happen in parallel."

Jenny Low, a senior consultant in infectious diseases at Singapore General Hospital, is the lead author of the study, which appears today in the New England Journal of Medicine. Researchers from the Singapore-MIT Alliance for Research and Technology (SMART), Duke-National University of Singapore Medical School, and the biotechnology company Tysana Pte also contributed to the study.

Speeding up the process

Several types of monoclonal antibodies have been approved to treat a variety of cancers. These engineered antibodies help to stimulate a patient's immune system to attack tumors by binding to proteins found on cancerous cells.

Many researchers are also working on monoclonal antibodies to treat infectious diseases. In recent years, scientists have developed an experimental cocktail of three monoclonal antibodies that target the Ebola virus, which has shown some success in clinical trials in the Democratic Republic of Congo.

Sasisekharan began working on a "rapid response" to emerging infectious diseases after the Zika outbreak that started in 2015. Singapore, which experienced a small outbreak of the Zika virus in 2016, is home to the SMART antimicrobial resistance research group, where Sasisekharan is a principal investigator.

The Sasisekharan lab antibody design process uses computational methods to target functionally important, and evolutionarily stable, regions on the virus. Building blocks from a database of all known antibody elements are selected based on several criteria, including their functional importance, to build candidate antibodies to evaluate. Testing these candidates provides valuable feedback, and the design loop continues until an optimized antibody that fully neutralizes the target virus is identified.

The group also explored new approaches to compress the timeline by performing many of the necessary steps in parallel, using analytical techniques to address regulatory risks associated with drug safety, manufacturing, and clinical study design.

Using this approach, the researchers developed a candidate Zika treatment within nine months. They performed phase 1a clinical trials to test for safety in March 2018, but by the time they were ready to test the drug's effectiveness in patients, the outbreak had ended. However, the team hopes to eventually test it in areas where the disease is still present.

Sasisekharan and his colleagues then decided to see if they could apply the same approach to developing a potential treatment for yellow fever. Yellow fever, a mosquito-borne disease, tends to appear seasonally in tropical and subtropical regions of South America and Africa. A particularly severe outbreak began in January 2018 in Brazil and lasted for several months.

The MIT/SMART team began working on developing a yellow fever antibody treatment in March 2018, in hopes of having it ready to counter an outbreak so that it could be made available for potential patients in late 2018 or early 2019, when another outbreak was expected. They identified promising antibody candidates based on their ability to bind to the viral envelope and neutralize the virus that causes yellow fever.

The researchers narrowed their candidates down to one antibody, which they called TY014. They then developed production methods to create small, uniform batches that they could use to perform necessary testing phases in parallel. These tests include studying the drugs' effectiveness in human cells, determining the most effective dosages, testing for potential toxicity, and analyzing how the drug behaves in animal models. As soon as they had results indicating that the treatment would be safe, they began clinical trials in December 2018.

"The mindset in the industry is that it's like a relay race. You don't start the next lap until you finish the previous lap," Sasisekharan says. "In our case, we start each runner as soon as we can."

Clinical trials

TY014 was clinically tested in parallel to address safety through dose escalation in healthy human volunteers. Once an appropriate dose was deemed safe, the researchers began a phase 1b trial, in which they measured the antibody's ability to clear the virus. Even though the 1b trial had begun, the 1a trial continued until a maximum safe dose in humans was identified.

Because there is a vaccine available for yellow fever, the researchers could perform a type of clinical trial known as a challenge test. They first vaccinated volunteers, then 24 hours later, they gave them either the experimental antibody drug or a placebo. Two days after that, they measured whether the drug cleared the weakened viruses that make up the vaccine.

The researchers found that following treatment, the virus was undetectable in blood samples from people who received the antibodies. The treatment also reduced inflammation following vaccination, compared to people who received the vaccine but not the antibody treatment. The phase 1b trial was completed in July 2019, and the researchers now hope to perform phase 2 clinical trials in patients infected with the disease.