Culture

There is a broad range of mechanisms associated with chemoresistance, many of which to date are only poorly understood. The so-called cellular stress response - a set of genetic programmes that enable the cells to survive under stressful conditions - plays a key role in the development of numerous diseases and in chemoresistance. A better understanding of the cellular stress response pathways is therefore urgently required to develop new therapeutic concepts to overcome chemoresistance. "In this context, we employed comprehensive analytical approaches to gain deep and molecular insight into the Unfolded Protein Response, a cellular stress reaction induced by unfolded proteins", says Robert Ahrends, group leader at the Department of Analytical Chemistry of the Faculty of Chemistry.

Unfolded proteins cause stress and disease

The Unfolded Protein Response (UPR) contributes to cancer development and progression and plays an important role in diseases such as diabetes and neurodegenerative disorders. For their study of the UPR's molecular biological characteristics, the researchers applied state-to-art analytical tools in the context of a multiomics approach, combining large datasets from genetics, proteomics and metabolomics. This allowed them to define the Unfolded Protein Response regulon, a comprehensive list of genes that are activated to promote cell survival under stress.

"Besides the previously known factors, we identified to our surprise numerous genes that have not previously been implicated in stress response pathways", explain the researchers, "and many of them have key functions in cancer development and cellular metabolism."

Changes in 1C metabolism

Changes in cellular metabolism are characteristic of many cancer types and promote a rapid tumour growth, as Nobel Prize winner Otto Warburg demonstrated already in the 1930s in his ground-breaking work. In their study, the researchers discovered stress-mediated genetic regulation of enzymes involved in one-carbon (1C) metabolism which relies on the vitamin folate as a cofactor. Concomitant to the metabolic re-wiring, the stressed cells became fully resistant against chemotherapeutic agents, which target this specific metabolic pathway. This includes Methotrexate, a drug commonly employed in the treatment of cancer and rheumatic diseases. Detailed biochemical and genetic investigations revealed that resistance is driven by a previously unrecognized mechanism. According to the study authors, its precise molecular characterisation might lead to novel therapeutic concepts aimed at overcoming chemoresistance in cancer therapy.

Stay-at-home orders and "lockdowns" related to the COVID-19 pandemic have had a major impact on the daily lives of people around the world and that includes the way that people sleep, two studies report June 10 in the journal Current Biology. Both studies show that relaxed school and work schedules and more time spent at home has led people to sleep more on average with less "social jetlag" as indicated by a reduced shift in sleep timing and duration on work days versus free days. But, at the same time, one of the studies also finds that the pandemic has taken a toll when it comes to self-reported sleep quality.

"Usually, we would expect a decrease in social jetlag to be associated with reports of improved sleep quality," says sleep researcher and cognitive neuroscientist Christine Blume (@christine_blume) from the University of Basel's Centre for Chronobiology, Switzerland. "However, in our sample, overall sleep quality decreased. We think that the self-perceived burden, which substantially increased during this unprecedented COVID-19 lockdown, may have outweighed the otherwise beneficial effects of a reduced social jetlag."

In their study, Blume and colleagues including Marlene Schmidt and Christian Cajochen explored the effects of the strictest phase of the COVID-19 lockdown on the relationship between social and biological rhythms as well as sleep during a six-week period from mid-March until end of April 2020 in Austria, Germany, and Switzerland. Their data showed that the lockdown reduced the mismatch between social and biological sleep-wake timing as people began working from home more and sleeping more regular hours from day to day. People also slept about 15 minutes longer each night. However, the self-reported data indicated a perception that sleep quality had declined.

In the other study, Kenneth Wright at the University of Colorado, Boulder's Sleep and Chronobiology Laboratory and colleagues asked similar questions by comparing sleep prior to and during Stay-at-Home orders in 139 university students as they shifted from taking their classes in-person to taking them remotely. As the team reports, nightly sleep duration increased by about 30 minutes during weekdays and 24 minutes on weekends. The timing of sleep also became more regular from day to day, and there was less social jetlag.

Students stayed up about 50 minutes later while staying home during weekdays and about 25 minutes later on weekends. Students that tended to sleep less before the effects of COVID-19 took hold showed the greatest increase in the amount of sleep after they stopped going to in-person classes. After the Stay-at-Home orders went into effect, 92 percent of students got the recommended 7 hours or more of sleep per night, up from 84 percent before.

"Insufficient sleep duration, irregular and late sleep timing, and social jetlag are common in modern society and such poor sleep health behaviors contribute to and worsen major health and safety problems, including heart disease and stroke, weight gain and obesity, diabetes, mood disorders such as depression and anxiety, substance abuse, and impaired immune health, as well as morning sleepiness, cognitive impairment, reduced work productivity, poor school performance and risk of accident/drowsy driving crashes," Wright said. "Our findings provide further evidence that poor sleep behaviors are modifiable in university students. A better understanding of which factors during Stay-at-Home orders contributed to changed sleep health behaviors may help to develop sleep health intervention strategies."

"Not surprisingly, this unprecedented situation of the pandemic and the lockdown increased self-perceived burden and had adverse effects on sleep quality," Blume said. "On a positive note, though, the relaxation of social schedules also led to an improved alignment between external or social factors determining our sleep-wake timing and our body's internal biological signals. This was also associated with overall, more sleep."

From a sleep health perspective, the increase in sleep duration and regularity are welcome changes, say the researchers. For those having trouble with sleep quality, Blume suggests engaging in physical activity under the open sky.

A large international study coordinated by University Hospital Regensburg and Charité - Universitätsmedizin Berlin has demonstrated the safety of new cell therapy approaches for use in kidney transplant recipients. Transplant recipients were shown to require lower levels of immunosuppression in order to prevent organ rejection. This reduces the risk of side effects such as viral infections. Results from this study have been published in The Lancet.*
 

Transplant recipients usually receive immunosuppressants to prevent organ rejection. However, these drugs cannot provide an absolute guarantee that rejection will not occur at a later stage. Furthermore, immunosuppression is often associated with severe side effects such as intolerances, infections, or other problems. Cell therapy offers an alternative treatment approach. This involves the use of specific immune cells, which are isolated and expanded in vitro. Known as 'regulatory cell products', these cells are then infused into the transplant recipient in order to restore their immune system.            
 

Charité was one of a number of institutions involved in the international ONE Study consortium, which was led by Prof. Dr. Edward K. Geissler of University Hospital Regensburg. The Berlin-based members of the consortium were primarily responsible for testing the safety and efficacy of cell therapy in kidney transplant recipients as well as effects on their immune system. Research centers based in several different countries worked to a standardized protocol to develop a range of regulatory cell products, which were then tested in clinical trials. These therapies, which were administered to transplant recipients either before or after their surgery, comprised regulatory T cell and macrophage products, as well as products made of dendritic cells, which produce anti-inflammatory messengers. Results were then combined and compared with a reference patient group who had received standard-of-care immunosuppression. Patients were then followed up for a further 60 weeks.
 

"The new cell therapy was able to reduce the need for immunosuppression in approximately 40 percent of patients, thereby minimizing the risk of side effects," says the study's first author, Prof. Dr. Birgit Sawitzki of the Institute for Medical Immunology on Campus Virchow-Klinikum. The regulatory cells were shown to be just as safe as the drugs used in standard treatment and did not result in higher rejection rates. "Particularly remarkable was the fact that none of the patients given regulatory cells developed herpes infections, which often lead to dangerous complications in transplant recipients," notes Prof. Sawitzki. 
 

Prof. Sawitzki's team was primarily responsible for the development and implementation of standardized immune monitoring, i.e. the monitoring of immune cell populations in the blood. "Before transplantation, patients showed altered immune cell composition, and regulatory cells were better than standard therapy at restoring normal composition," explains Prof. Sawitzki. She adds: "This means there are new, safe treatment options which can help to reduce the dose of conventional immunosuppressants and the risk of viral infections." There are plans for further, larger studies to confirm the efficacy of regulatory cell therapy. 

Stenotrophomonas maltophilia are increasingly recognized as significant opportunistic pathogens in healthcare settings worldwide, the global spread of multidrug-resistant strains of this species being the most serious concern. Epidemiological studies are important to identify particular lineages or strains exhibiting clinically relevant phenotypes and to make knowledge-driven healthcare decisions.

In this context, researchers from the Bacterial Pathogenesis and Antimicrobials group of the Institut de Biotecnologia i de Biomedicina (IBB) and the Department of Genetics and Microbiology at UAB, in collaboration with the Research Center Borstel - Leibniz Lung Center (Germany) and ISGlobal at Hospital Clínic (Barcelona), have discovered the link between the bacterial communication system (quorum sensing) in Stenotrophomonas maltophilia, and virulence and antibiotic resistance phenotypes. Bacterial QS systems are based on small signalling molecules (the so-called autoinducers) which, depending on population density (hence the term quorum sensing), allow them to coordinate gene expression and cope with changes in their environment.

In this work, the correlation between quorum sensing, virulence and resistance was done in a panel of genetically diverse clinical Stenotrophomonas maltophilia isolates from different European countries. In particular, a clonal group of strains were identified that show an increased ability to form biofilms and exhibit higher resistance to the last-resort antibiotic colistin. In addition, new virulence factors exclusive to this lineage have been identified through a comparative genomics study.

The results, published in Frontiers in Microbiology, demonstrate the pivotal role of the quorum sensing system in the pathogenicity and persistence in Stenotrophomonas maltophilia and alert on the potential risk of resistant and virulent clones circulating in European hospitals.

In connection with this study, the UAB group has also participated in an ambitious project aimed to describe the population structure and spread of Stenotrophomonas maltophilia at a global scale, led by the Research Center Borstel. The results of this project have been published in Nature Communications. The analysis of a worldwide collection of 1.305 isolates detected human-associated lineages with higher proportions of key virulence and resistance genes.

London, 10 June 2020 - Over the past few months at least half of the world's population has been affected by some form of lockdown due to COVID-19, and many of us are experiencing the impact of social isolation. Loneliness affects both mental and physical health, but counterintuitively it can also result in a decreased desire for social interaction. To understand the mechanics of this paradox, UCL researchers based at the Wolfson Institute and the Sainsbury Wellcome Centre investigated social behaviour in zebrafish. Their results are published in eLife.

Most zebrafish demonstrate pro-social behaviour, but approximately 10% are 'loner' fish who are averse to social cues and demonstrate different brain activity than their pro-social siblings. However, even typically social zebrafish avoid social interaction after a period of isolation. PhD students Hande Tunbak and Mireya Vazquez-Prada, Postdoctoral Research Fellow Thomas Ryan, Dr Adam Kampff and Sir Henry Dale Wellcome Fellow Elena Dreosti set out to test whether the brain activity of isolated zebrafish mimics that of loner fish or whether other forces were at play.

To investigate the effects of isolation, the researchers isolated typically social zebrafish from other fish for a period of two days and then compared their brain activity to zebrafish who demonstrated aversion to social interaction without having been isolated. The isolated fish demonstrated sensitivity to stimuli and had increased activity in brain regions related to stress and anxiety. These effects of isolation were quickly overcome when the fish received a drug that reduces anxiety.

The differences between loner fish and their siblings were found mostly in the hypothalamus, the region of the brain responsible for social rewards. The loner fish hypothalamus did not demonstrate the same pattern of activation during social exposure as its typical counterparts, indicating that loner fish do not experience rewards in the same way as typical fish during social interactions.

By contrast, 'lonely' fish--those that demonstrated typical social behaviour and were isolated--demonstrated hypersensitivity to stimuli and activation of brain regions associated with stress and anxiety. Lonely fish experienced actively negative outcomes from social interaction whereas loner fish simply did not experience reward.

"A detailed view of the zebrafish brain can provide important clues for all of us currently experiencing the effects of social isolation," says Dr Elena Dreosti. Our understanding of the neural mechanisms of social behaviour are limited, but we do know that zebrafish and humans share a fundamental drive for social interaction that is controlled by similar brain structures. Although human behaviour is much more complex, understanding how this basic social drive arises--and how it is affected by isolation--is a necessary step towards understanding the impact of the social environment on human brains and behaviour. The zebrafish, which is completely transparent throughout early development, offers neuroscientists a detailed view of its brain circuitry.

We won't all be loners after lockdown, but we will be anxious upon returning to our normal social lives. As we emerge from lockdown, we should be aware of this new sensitivity and anxiety, but recognise that overcoming it is necessary for returning to a normal, healthy, social existence.

There are currently no licensed vaccines available for COVID-19. While several antiviral drugs have been tested, none has proved to be completely effective against the disease. In a study just published in the journal MDPI Vaccines, researchers from Bar-Ilan University have identified a set of potential immunodominant epitopes from the SARS-CoV-2 proteome. These epitopes are capable of generating both antibody- and cell-mediated immune responses. The findings of this work may thus contribute to developing a peptide vaccine against SARS-CoV-2 infections which can stop the COVID-19 outbreak and future pandemics caused by coronaviruses.

Led by Dr. Milana Frenkel-Morgenstern, Head of the Cancer Genomics and BioComputing of Complex Diseases Lab at Bar-Ilan University's Azrieli Faculty of Medicine, the researchers took an immunoinformatics-based computational approach to mine the protein content of SARS-CoV-2 and subsequently identified immunodominant epitopes of the virus. Immune responses that are based on specific immunodominant epitopes involve the generation of both antibody- and cell-mediated immunity against pathogens presenting such epitopes. Such immunity can facilitate fast and effective elimination of the pathogen.

The team of researchers that also includes Sumit Mukherjee, Dmitry Tworowski, Rajesh Detroja and Sunanda Biswas Mukherjee, identified 15 potential immunogenic regions from three proteins of SARS-CoV-2, and mapped 25 immunodominant epitopes on other SARS-CoV-2 proteins. To confirm that these epitopes could serve to provide immunity to a global population, the percentage of individuals that express a major histocompatibility complex (MHC) capable of recognizing any of these epitopes was determined. Accordingly, seven epitopes were deemed to be present in more than 87% of the worldwide virus-affected population. Further structural molecular docking analyses estimated the binding interaction of these potential epitopes with human MHC. Complete lists of MHC proteins that recognize each epitope have been generated and are presented in both the submitted manuscript and a provisional US patent application (US 63/034.416).

The seven epitopes were tested using multiple tools to verify their non-allergenic and non-toxic natures, as well as to demonstrate that they carry a low risk of triggering any autoimmune responses. Together, such results indicate that these seven epitopes represent potentially effective vaccine candidates. Indeed, the development of vaccines using these immunodominant epitopes could activate both humoral and cellular immune responses in humans comprising a major fraction of the world's population.

Scientists have detected RNA from the new coronavirus, SARS-CoV-2, in the feces of people with COVID-19. So it stands to reason that the viral RNA could end up in city sewage, where it could be used to monitor prevalence of the disease. Now, researchers reporting in ACS' Environmental Science & Technology Letters have detected rising SARS-CoV-2 RNA levels in sewage from several cities in the Netherlands at early stages of the pandemic.

Although infectious SARS-CoV-2 has been detected in stool samples, the virus spreads primarily through respiratory droplets when an infected person coughs, sneezes, laughs, speaks or breathes, according to recent studies. However, if the new coronavirus is present at high levels in sewage at treatment plants, it could pose risks to workers at the facilities. Gertjan Medema and colleagues wanted to see if they could detect SARS-CoV-2 in the domestic wastewater of cities in the early stages of the COVID-19 pandemic in the Netherlands. They also wanted to determine if levels of the virus's RNA correlated with the COVID-19 prevalence in each city. If so, sewage surveillance could be a helpful tool to monitor the circulation of SARS-CoV-2 in communities, especially since clinical testing likely underestimates the actual number of people infected with the virus.

As the new coronavirus took hold in other parts of the world, the researchers collected sewage samples from wastewater treatment plants that serve six cities in the Netherlands to see if the virus could be detected in this way. Samples were taken 3 weeks before the first reported COVID-19 case in the Netherlands, and then at 1, 2.5 and 4 weeks after the first case. The team measured SARS-CoV-2 levels in the sewage using a technique called quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR). Then, the researchers correlated viral RNA levels with the number of COVID-19 cases reported in each city on the day of sampling. SARS-CoV-2 was undetectable in sewage from all cities 3 weeks before the first reported case, but as the outbreak progressed, the concentration of SARS-CoV-2 RNA in sewage increased with the number of reported COVID-19 cases in each city. Although more research is needed, this study and similar ones in different locations suggest that sewage surveillance of SARS-CoV-2 RNA could serve as a sensitive early warning system for increased virus circulation in the population, the researchers say.

With summer on the way, and some beaches reopening after COVID-19 shutdowns, people will be taking to the ocean to cool off on a hot day. But those unlucky enough to encounter the giant jellyfish Nemopilema nomurai (also known as Nomura's jellyfish) might wish they had stayed on shore. Now, researchers reporting in ACS' Journal of Proteome Research have identified the key toxins that make the creature's venom deadly to some swimmers.

Found in coastal waters of China, Korea and Japan, Nomura's jellyfish can grow up to 6.6 feet in diameter and weigh up to 440 pounds. This behemoth stings hundreds of thousands of people per year, causing severe pain, redness, swelling, and in some cases, even shock or death. The jellyfish's venom is a complex brew of numerous toxins, some of which resemble poisons found in other organisms, such as snakes, spiders, bees and bacteria. Rongfeng Li, Pengcheng Li and colleagues wanted to determine which of the many toxins in the jellyfish's venom actually cause death. The answer could help scientists develop drugs to counteract jellyfish stings.

The researchers captured N. nomurai jellyfish off the coast of Dalian, China, and collected their tentacles, which contain the venom. They extracted venom proteins and separated them into different fractions using chromatography. By injecting each protein fraction into mice, the team identified one that killed the animals. Autopsies revealed damage to the mice's heart, lungs, liver and kidneys. The researchers used mass spectrometry to identify 13 toxin-like proteins in this lethal fraction. Some of the jellyfish proteins were similar to harmful enzymes and proteins found in poisonous snakes, spiders and bees. Instead of any one toxin being lethal, it's likely that multiple poisons work in concert to cause death, the researchers say.

Washington, DC - Up to 76 percent of all outpatient antibiotic prescriptions in the United States may be inappropriate, with peak prescribing associated with the flu season. Evidence suggests that influenza vaccines may reduce overall and inappropriate antibiotic use by reducing the burden of influenza-like illness commonly mistreated with antibiotics, as well as preventing secondary bacterial infections. While flu vaccines have been proven to reduce severe illness, evidence is lacking on the link between flu vaccination and antibiotic prescribing at the population level in the US.

To examine this association, researchers analyzed state-level data from IQVIA and the US Centers for Disease Control and Prevention's FluVaxView on antibiotic prescribing rates and influenza vaccine coverage between January and March of each year from 2010 to 2017.

"Getting the flu vaccine doesn't guarantee you will not get sick, but it is effective at reducing both the likelihood and the severity of disease at the individual level, which for individuals would translate into fewer trips to the doctor and less chance of being prescribed antibiotics. Since people who don't get sick don't transmit the disease to others, we believed that the more people who got a vaccine in an area, the less illness there would be and the fewer antibiotic prescriptions there would be," said Eili Klein, lead study author and CDDEP Senior Fellow.

Utilizing fixed-effects regression analysis adjusted for socioeconomic differences, access to health care, childcare centers, climate, vaccine effectiveness, and state-level differences, the study found that a ten percent increase in influenza vaccination coverage was associated with a 6.5 percent reduction in antibiotic use, or 14.2 fewer antibiotic prescriptions per 1,000 individuals. Increased vaccination rates were tied to significant reductions in antibiotic prescribing rates among pediatric (6 percent), elderly (5.2 percent), and adult populations (4.2 percent). Specifically, the researchers found that across all ages, flu vaccine coverage was significantly and negatively associated with prescribing rates for macrolides, tetracyclines, narrow-spectrum penicillins, and aminoglycosides- all of which are antibiotic classes commonly prescribed for upper respiratory tract infections or severe infections, which flu vaccines prevent.

"The flu is more common in children and the elderly, and thus this is fairly suggestive that the vaccine is limiting the severity of disease in these populations leading to lower rates of antibiotic prescribing," said Klein.

Overall, results indicate that flu vaccination is associated with reduced antibiotic use in the United States, which suggests that expanding flu vaccine coverage could reduce inappropriate antibiotic prescribing. The study titled, "The Impact of Influenza Vaccination on Antibiotic Use in the United States, 2010-2017" was published on June 6, 2020 in Open Forum Infectious Diseases.

Power plants that burn coal and other fossil fuels emit not only planet-warming carbon dioxide, but also pollutants linked to breathing problems and premature death. Policies proposed to mitigate climate change, however, often fail to fully account for the health benefit of switching to cleaner technologies. In a new study published in ACS' Environmental Science & Technology, researchers show that emphasizing health concerns in such policies can alter the optimal locations of these upgrades. 

Location matters little for carbon dioxide emissions -- no matter where the gas is emitted, it eventually mixes into the atmosphere and contributes to global climate change. However, location makes a big difference for air pollutants such as sulfur dioxide and nitrogen oxides, since those emissions tend to concentrate near their source and can impact the health of people living nearby. Studies have been exploring the connection between reducing climate-warming emissions and healthier air, and how that plays out at a local level. But Brian Sergi, Inês Azevedo and colleagues wanted to take an even more granular, county-by-county approach to assess how a combined climate-and-health-driven strategy for the U.S. electricity system might play out compared to one prioritizing only climate. 

In the study, the researchers started out with a goal of reducing carbon dioxide emissions by 30%. Using computer models, they examined the effects of two approaches: one in which reducing carbon dioxide is the only goal, and another in which reducing both carbon dioxide and local air pollution are prioritized equally. These two scenarios produced markedly different results for some states. When undertaken with only climate implications (carbon dioxide levels) in mind, the transition to cleaner power required retiring many coal-powered plants in the West and Southwest. However, when health (pollution levels) was also considered, it was better to retire more coal-powered plants in the Midwest and Mid-Atlantic regions. The combined approach could help states better determine how to prioritize upgrades for power plants within their borders, the researchers say. 

An autism diagnosis can present a number of challenges for families from learning about the neurodevelopment disorder and accessing support services and resources to financial struggles. A new report from the A.J. Drexel Autism Institute at Drexel University highlighted the financial challenges facing households of children with autism spectrum disorder (ASD) in the United States. According to the report, households of children with ASD experience higher levels of poverty, material hardship and medical expenses than households of children with other special health care needs.

The report also found that over half of children with autism live in low-income households (household income below 200% of the federal poverty level, or FPL, with an income of $48,500 four a family of four) and 30% live in very low-income households (household income below 100% of the FPL, $24,250 for a family of four).

Families living in poverty have fewer resources to spare and are especially vulnerable in the face of burdens like care-related expenses, reduced earnings from taking time off work to cope with caregiving, and disconnection from services and supports.

"I have talked with countless families of children with autism over the past 20 years who are struggling with the dual challenge of parenting a child with special needs AND covering the basic needs of the entire family," said Paul Shattuck, PhD, director of the Autism Institute's Life Course Outcomes Program and co-author of the report. "Our hope for this Indicators Report is that it will raise awareness and spark discussion about the ways in which families are struggling and need our collective societal support."

Safety net programs can help to offset financial challenges through the provision of monetary support and increased access to social services and programs. However, the current understanding of safety net program use among households of children with ASD is limited. And few population-level studies have described the characteristics of children with ASD from low-income households.

"We need exploratory and descriptive research that can chart the types of safety net programs low-income households of children with ASD report using, and how they compare to households of children without ASD," said Kristy Anderson, associate researcher in the Autism Institute and lead author. "Such analyses could help to unveil specific conditions and characteristics that are unique to the subpopulation of children with ASD living in poverty."

The report found households of children with ASD experienced material hardships (not being able to consume goods and services that are deemed minimally necessary) much more often than parents of children with other special health care needs and children with no special health care needs. Nearly half reported difficulty paying for basics like food or housing. Almost one-third had to reduce work to care for their child with autism. About one in five families had problems paying for their child's health care and roughly 15% had difficulty affording food for the family.

Young children with ASD (ages 3-5 years) and those from minority groups faced an increased risk of material hardship. This was especially common for the subset of households living below 200% the federal poverty level, despite high levels of participation in safety net programs. More than two-thirds of low-income households of children with ASD reported that someone in their family received cash assistance; help from the Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) and Supplemental Nutrition Assistance Program (SNAP); and/or free and reduced-price meals during the previous year.

Children with ASD who participated in at least one safety net program fared worse on three indicators of material hardship (difficulty paying bills, parents reduced/stopped work and inability to afford food) and had higher out-of-pocket expenditures than children who were disconnected from the safety net. Families of children who had public health insurance reported lower out-of-pocket expenditures and were less likely to report problems paying for their child's medical care than children with private health insurance.

"Findings from this report indicate that younger children with ASD from minority backgrounds might be particularly vulnerable to the effects of poverty and hardship," said Anderson. "Given what we know about the effects of poverty on the developing brain, and the importance of intervening early to improve outcomes for children with autism, there is a vital need for new resources and programs with targeted support for these families."

The recently published "2020 National Autism Indicators Report: Children on the Autism Spectrum and Family Financial Hardship" uses data from the 2016-2017 National Survey of Children's Health (NSCH) to examine family financial hardship among families of children with ASD (ages 3-17 years) and their participation in four safety net programs: 1) cash assistance for poor families with children; 2) the Special Supplemental Nutrition Program for Women, Infants, and Children; 3) the Supplemental Nutrition Assistance Program (also known as "food stamps"); 4) free and reduced-price meals in schools. The NSCH is a survey of child and family health, health care and wellbeing conducted yearly by the U.S. Census Bureau.

This report builds on the 2018 National Autism Indicators Report that found many low-income families of teenagers on the autism spectrum rely on federal safety net programs to help with things like health insurance and paying for food.

Volume 11, Issue 23 of @Oncotarget reported that the authors have previously established that mi R-151a functions as an onco-mi R in non-small cell lung cancer cells by inducing partial EMT and enhancing tumor growth.

Here, the authors identify anti-mi R-151a as a molecule that promotes endothelial cell contacts and barrier properties, suggesting that mi R-151a regulates cell-cell junctions.

They find that induced mi R-151a expression enhances endothelial cell motility and angiogenesis and these functions depend on mi R-151a-induced Slug levels.

Moreover, The authors show that mi R-151a overexpression enhances tumor-associated angiogenesis in 3D vascularized tumor spheroid assays.

Their results suggest that mi R-151a plays multi-faceted roles in the lung, by regulating multiple functions in distinct cell types.

Dr. Irene Munk Pedersen from The University of California as well as The Scintillon Institute said, "Angiogenesis, or the growth of new networks of blood vessels from existing vessels, is an important natural process used for growth, healing, and reproduction."

"The authors find that anti-mi R-375 and anti-mi R-151a strengthen cell-cell contact and endothelial cell barrier in primary lung endothelial cells, relative to control samples"

Proper regulation of angiogenesis is essential not only for developing an adult's healthy organs to support growth and metabolism but also for disease progression since abnormal vessel growth and/or function are hallmarks of cancer, ischemic and chronic inflammatory diseases.

Slug and Snail may regulate a distinct but overlapping set of genes and therefore Snail may compensate for Slug in the Slug-knock-out context.

There is a need to characterize the repertoire of master mi R regulators in normal and diseased microenvironments to further understand how to restore the delicate balance of cell homeostasis when it has been lost.

The authors find that anti-mi R-375 and anti-mi R-151a strengthen cell-cell contact and endothelial cell barrier in primary lung endothelial cells, relative to control samples.

The Munk Pedersen Research Team concluded in their Oncotarget Priority Research Paper, "Our results show that increased miR-151 expression, significantly promotes endothelial cell motility and angiogenesis in 2D and 3D models and that miR-151a-induced Slug expression is required for these endothelial cell properties. Our findings provide a new avenue to the understanding of the processes in the lung niche environment, and may facilitate the development of potential therapeutics against lung cancer."

PHILADELPHIA -- Prostate cancer is a leading cause of death from cancer in the US and especially in the Philadelphia region. Consistently, Philadelphia has outpaced the state of PA and the nation in diagnoses and death from prostate cancer. A key area impacting prostate cancer risk and treatment is germline genetic testing, which involves testing for hereditary cancer genes. Genes such as BRCA2, BRCA1 and many other genes have been reported to raise the risk for prostate cancer and are increasingly informing treatment and management approaches. However, genetic testing of men for prostate cancer is still not common practice due to inconsistent guidelines and challenges to implementation of genetic counseling.

To address these challenges, experts at Sidney Kimmel Cancer Center - Jefferson Health and the Department of Urology at Thomas Jefferson University hosted the international Philadelphia Prostate Cancer Consensus Conference 2019 entitled Implementation of Germline Testing for Prostate Cancer. The Consensus Conference, co-chaired by Drs. Veda Giri, Karen Knudsen, and Leonard Gomella, had representation from many major Philadelphia healthcare institutions, such as University of Pennsylvania and Fox Chase Cancer Center, as well as centers around the United States, Europe, and Australia. Importantly, the conference addressed key gaps or areas in need of clarity regarding genetic testing for prostate cancer including: which men should undergo genetic testing for prostate cancer, which genes should be tested, how genetic results impact precision medicine and precision management across the stage spectrum, and the impact of genetic testing for cancer risk and screening for men and their families.

Key recommendations which were published in Journal of Clinical Oncology on June 9th include a strong endorsement to perform genetic testing of all men with metastatic prostate cancer to inform precision medicine or clinical trial eligibility, as well as men with a family history suggesting hereditary prostate cancer as well as other cancers such as breast, ovarian, pancreatic, and colon cancers, to inform active surveillance or screening discussions. Recommended priority genes for testing include BRCA2, BRCA1, and DNA mismatch repair genes in metastatic prostate cancer.

The Consensus recommendations come on the heels of two very important FDA approvals for drugs that target metastatic prostate cancer in men who carry BRCA mutations or mutations in other DNA repair genes. Two medications, rucaparib and olaparib, were granted FDA approval recently for treatment among men with specific genetic mutations due to clinical benefit, thus expanding precision medicine for prostate cancer. Therefore, the Conference results have significant impact for treatment decision-making for men with metastatic prostate cancer.

The Conference also addressed how genetic testing may impact management of early-stage prostate cancer. BRCA2 testing was recommended to inform active surveillance discussions and may help men and their doctors make decisions for management of early-stage disease. The Conference also focused on prostate cancer screening strategies such as age to begin screening and which genes to factor into screening discussions between men and their doctors to make an informed and shared decision. For example, BRCA2 and HOXB13 were recommended for testing to inform prostate cancer early detection discussions. The panel also recommended that BRCA2 carriers should begin early PSA screening, such as at age 40 or 10 years prior to the youngest prostate cancer diagnosis in a family. Since genetic testing may uncover hereditary cancer risk, the Conference also addressed genetic testing for male and female relatives of men who test positive for genetic mutations, factoring in family cancer history and other factors.

This was the first conference to propose a model for how to implement genetic testing in medical practices. The Conference included experts in oncology, urology, genetic counseling, primary care, Veterans Affairs, and patient stakeholders. Their guidance was used to develop genetic-evaluation processes that include seeing men in-person, using telehealth, or using videos to provide genetic information to make an informed decision for genetic testing. In this era of COVID-19, remote health services such as telehealth, are increasingly needed to keep ahead of cancer development and to provide high-level cancer care.

Genetic testing is very conducive the telehealth genetic counseling, with at-home sample collection for genetic testing, and discussion of results through telehealth.

Finally, the Consensus Conference addressed approaches to increase knowledge of genetics among doctors and the public along with priorities for research. Many currently available resources were highlighted, with additional patient and public resources under development.

Overall, genetic testing for prostate cancer is now increasingly informing treatment, management, and screening for this potentially lethal disease at high rates in our region. The 2019 Philadelphia Consensus Conference was a major effort to provide guidance to doctors, men, and their families regarding how best to consider and undergo genetic testing to impact prostate cancer care. Importantly, the results can also provide information on other cancer risks impacting males and females in families such as breast cancer, prostate cancer, pancreatic cancer, ovarian cancer, and colon cancer.

This Father's Day, men may consider approaching their doctors and families regarding genetic testing for prostate cancer to be proactive in treatment and screening which may be life-saving from this potentially fatal disease.

Washington - (June 10, 2020) - A new set of expert consensus-based recommendations lays out how best to study possible neurodevelopmental impacts of pubertal suppression treatment in transgender youth. Developed by a consensus panel of 24 international scientists, the recommendations were published in the journal Transgender Health.

While early evidence suggests suppressing puberty has positive effects on the mental health of transgender adolescents, little is known about how this standard of care treatment affects an adolescent's brain development.

"We don't know how stopping puberty for a year or more affects a transgender adolescent's neurocognitive development. Clearly, pubertal suppression is important for many transgender youth, but at this time, we can't speak to a family's questions about how this medical treatment might affect brain development," said Diane Chen, Ph.D., co-lead author of the study and Behavioral Health Director for the Potocsnak Family Division of Adolescent and Young Adult Medicine at the Ann & Robert H. Lurie Children's Hospital of Chicago.

John Strang, Psy.D., co-lead author and director of Research for the Children's National Hospital Gender Development Program, continued, "We need high quality research to understand the impacts of this treatment - impacts which may be positive in some ways and potentially negative in others. This information about benefits and risks will help young people make informed decisions and assist providers in knowing how best to provide this treatment for optimal outcomes."

Transgender youth, who are on the verge of developing sex-based characteristics that don't align with their gender identity, often work with their care providers to suppress pubertal development via gonadotropin releasing hormone agonists (GnRHa). This medication approach suspends the production of gonadal (sex) hormones for as long as GnRHa is administered, which is often 1-2 years.

Employing a Delphi consensus method that included 24 international experts from the fields of adolescent neurodevelopment, gender development, neuroendocrinology and measurement science, the authors identified three primary domains of neurodevelopment that should be measured in these studies: mental health, executive function/cognitive control and social awareness/functioning.

In addition, the authors identified 44 study design elements, that all experts agreed were crucial components, out of the original 160 identified at study start. The consensus elements include:

Measuring neurodevelopment domains repeatedly over time, before and during treatment

Identifying an individual's stage of puberty prior to treatment

Applying analytical approaches that account for the heterogeneity, or broad range of differences that exist between transgender individuals

Incorporating comparisons between multiple groups, including untreated transgender youth at the same pubertal stage, cisgender youth at the same pubertal stage and an independent sample from available largescale youth databases.

"This is a critical topic for transgender youth and their families. It is also a difficult topic to study because we would never randomly assign transgender youth to treatment and no treatment groups - that would be harmful and unethical," says Dr. Strang.

Dr. Chen concludes, "Instead, we gathered the world's experts in relevant fields to work together and design the best possible research approaches to study the effects of this treatment without relying on a randomized treatment design."

The global effort to quickly develop drugs and vaccines for COVID-19 has been hampered by limited numbers of laboratory mice that are susceptible to infection with SARS-CoV-2, the virus that causes COVID-19. Now, researchers at Washington University School of Medicine in St. Louis report they have developed a mouse model of COVID-19 that replicates the illness in people. Further, the same approach could be adopted easily by other scientists to dramatically accelerate the testing of experimental COVID-19 treatments and preventives.

The mouse model is described in a paper published online June 10 in the journal Cell. In addition to drug and vaccine testing, scientists can use the model with mice bred to develop health conditions such as obesity, diabetes or chronic lung disease to investigate why some people develop life-threatening cases of COVID-19 while others recover on their own.

"There's been a huge push to develop vaccines and therapeutics as quickly as possible, and since animal models have been limited, these investigational drugs and vaccines have been put directly into humans, and many of them haven't panned out," said principal investigator Michael S. Diamond, MD, PhD, the Herbert S. Gasser Professor of Medicine and an expert on viral infections. "Mice are useful because you can study a large number of them and observe the course of the disease and the immune response in a way that is hard to do in people. It would be more cost-effective and efficient and safer for people if we could get more information about how these potential drugs and vaccines work and how effective they are before we move to more challenging non-human primate and ultimately human studies."

Mice do not naturally get infected with the virus that causes COVID-19. To infect people, the virus latches onto a protein called angiotensin converting enzyme-2 (ACE2) on the surface of cells in the respiratory tract. But the human ACE2 protein is different from the mouse ACE2 protein, and the virus is unable to attach to the mouse version.

The virus that caused the SARS epidemic in 2003 is closely related to the one causing the COVID-19 pandemic, and the SARS virus also infects cells by latching onto the human ACE2 protein. During the SARS epidemic, researchers created a strain of genetically modified mice with the human ACE2 protein so they could study SARS. After the epidemic ended, however, interest in SARS waned and the mouse colonies were closed. The emergence of COVID-19 earlier this year triggered a frantic rush to begin breeding the mice again, but even now there are not nearly enough mice for all of the researchers who want to study the disease and to test potential vaccines and therapeutics.

Diamond, who previously had led an effort to develop a mouse model of Zika infection, realized they needed a faster way to obtain mice that could be used for COVID-19 studies. Diamond and colleagues - including co-first authors Ahmed Hassan, DVM, PhD, and Brett Case, PhD, both postdoctoral researchers, and Emma Winkler, an MD/PhD graduate student, as well as several other key members of the COVID-19 team from Diamond's laboratory - decided to introduce the human ACE2 protein into mice temporarily. To accomplish this, they inserted the gene for human ACE2 into a mild respiratory virus known as an adenovirus. They also removed genes that the adenovirus needs to replicate, so the virus could infect cells once but not multiply. Then, the researchers infected mice with the modified adenovirus. The animals produced human ACE2 in their respiratory tracts for a few days, making them vulnerable to infection with the virus that causes COVID-19.

To see whether mice develop an illness similar to the one in people, the researchers infected mice with the modified adenovirus, and then five days later gave them the COVID-19 virus through the nose. The virus quickly spread along the respiratory tract and especially to the lungs, where it replicated to high numbers and caused pneumonia with marked inflammation, much as it does in people. The researchers also found lower levels of virus in the heart, spleen and brain - all organs that can be targets of the virus in people. The mice lost 10% to 25% of their body weight during their illnesses but ultimately recovered.

"The mice develop a similar lung disease to what we see in humans," said Diamond, who is also a professor of molecular microbiology, and of pathology and immunology. "They get quite sick for a while but eventually recover, like the vast majority of people who get COVID-19. You can use this technique with almost any strain of laboratory mouse to make them susceptible to SARS-CoV-2 and then do whatever kind of study you want: test vaccines or drugs, study the immune response, and many other things related to how the virus causes disease."

The model also can be used to better understand the factors that put some people at risk of severe COVID-19 disease. Advanced age, male sex, and conditions such as obesity, diabetes, and heart, kidney or lung disease all increase risk of severe COVID-19 for reasons that are not fully understood.

"It would be easy to study, for example, older mice or obese mice and see how they respond to infection," Diamond said. "I'd expect that they would do substantially worse, but the real question is why. Do they have more virus in the early stages? Is their condition weakening the immune response, or perhaps exacerbating a detrimental inflammatory response? With this model, we can begin to look at some of those factors that are very hard to study in people."