Culture

New research from the Danish psychiatric project, iPSYCH, shows that a specific gene is associated with an increased risk of cannabis abuse. The gene is the source of a so-called nicotine receptor in the brain, and people with low amounts of this receptor have an increased risk of cannabis abuse.

Cannabis is the most commonly used illegal drug in both Denmark and internationally, and around one in ten users becomes addicted to the drug. Researchers from iPSYCH have discovered a gene that they associate with the abuse of cannabis.

"We discovered that the disorder was associated with a genetic variant. This variant affects how much of a certain nicotine receptor is formed in the brain," explains Associate Professor Ditte Demontis from Aarhus University, who is behind the study.

The genetic variant discovered by the researchers affects how much of a specific nicotine receptor is formed. People who have less of this receptor in the brain are at greater risk of becoming cannabis abusers.

Ditte Demontis and her colleagues used a nationwide Danish cohort to analyse the complete genome of more than 2,000 cannabis abusers and the genome of 50,000 control subjects. The researchers subsequently repeated these findings in an analysis of a further 5,500 cannabis abusers and more than 300,000 control subjects.

The researchers also included genetic data from studies in which researchers examined the underlying genetics for cognition such as e.g. the ability to complete an education.

Here, they found that people with a higher number of genetic variants associated with impaired cognition also have an increased risk of cannabis abuse.

"People who abuse cannabis often do worse in the education system, and our results show that this can be partly explained by genetics. That is to say that people with an abuse problem have more genetic variations in the genome which increase the risk of cannabis abuse, while at the same time negatively affecting their ability to get an education," explains Ditte Demontis.

The study is the first of its kind on this scale and represents a step towards understanding the particular biological mechanisms, which lie behind the abuse of cannabis.

"We need to undertake even more research into how the genetic differences in the genome contribute to the development of cannabis abuse, and we need to map out the precise biological mechanisms that lead to one person having a higher risk of becoming a substance abuser than another. Our hope is to be able to improve treatment and perhaps in the long-term even prevent this abuse," says Ditte Demontis.

Singapore, 18 June 2019 - How dormant neural stem cells in fruit flies are activated and generate new neurons is described in a new research study by Duke-NUS Medical School. The findings could potentially help people with brain injury or neuronal loss, if similar mechanisms apply in humans.

Publishing in PLOS Biology, the research team, led by Associate Professor Wang Hongyan, Deputy Director of Duke-NUS' Neuroscience and Behavioural Disorders Programme and lead author of the study, described the process and molecules involved in reactivating fruit flies' (also known by their scientific name, Drosophila) dormant neural stem cells, which can activate and generate new neurons. The ability of neural stem cells to switch from their dormant state and begin to proliferate is crucial in the brain. Until now, very little was known about how dormant neural stem cells become active.

Assoc Prof Wang and colleagues investigated what factors are at play in developing Drosophila brains at the larval stage. They discovered that a protein complex called CRL4 is essential for the reactivation of neural stem cells as it downregulates a pathway that normally keeps neural stem cells in the dormant state. They saw that CRL4 forms a protein complex with the tumour suppressor Warts, a core component of the pathway, and that CRL4 targets Warts for degradation to trigger reactivation.

The ability to awaken dormant neural stem cells could stimulate new neurons to compensate for brain injury or the neuronal loss seen in neurodegenerative diseases, such as Parkinson's or Alzheimer's. Future work is required to confirm that CRL4 and the pathway it regulates works in a similar manner in mammalian brains.

"Mutations of human Cullin4B, a core component of the CRL4 complex, are associated with mental retardation and cortical malformations," said Assoc Prof Wang. "Our work identifies the mechanisms behind CRL4 in fruit fly brain development and we plan to conduct further research to see if the same proteins are in play in mammals. Ultimately, our hope is that greater understanding and stimulation of these cells could eventually lead to therapeutic treatment of neurodevelopmental and neurodegenerative diseases."

Professor Patrick Casey, Senior Vice Dean for Research at Duke-NUS, noted, "The prevalence of neurodegenerative diseases, such as Parkinson's, is projected to increase in Singapore and worldwide in the coming decades, in tandem with increasingly ageing populations. Basic science research to better understand how the brain works, such as this study, is critical to developing new therapeutic strategies to enhance care for such diseases."

Toronto - Canada is stunting its own economy and blocking businesses from reaping the benefits of innovation by clinging to protectionist policies that curb foreign investment, a new study from the University of Toronto's Rotman School of Management says.

Relaxing restrictions to bring Canada more in line with other democratic market economies would significantly boost productivity, it says. Put into hard numbers, that adds up to an extra 137,400 jobs or $9.6 billion in annual earnings -- $648 per worker.

"Canada is far more restrictive than what most people would believe," says Walid Hejazi, an associate professor of economic analysis and policy who co-authored the study with fellow Rotman professor Daniel Trefler, the Douglas and Ruth Grant Canada Research Chair in Competitiveness and Prosperity.

"Our protectionist policies are inhibiting innovation and productivity in the Canadian economy. As a result, Canada is losing its position globally on several metrics," adds Prof. Trefler.

Foreign investment restrictions are typically defended by concerns that domestic industry will be swamped or swallowed up and jobs lost in the face of wide-open foreign competition. But the evidence, says the study, shows foreign investment and competition ultimately lead to higher domestic productivity by introducing and encouraging industries to adopt more efficient and innovative practices.

The study used measures of foreign investment restrictiveness for member countries published by the Organization for Economic Cooperation and Development in 2010.

Focusing on three key business service sectors - financial, telecommunications and air transportation services - the study found that Canada's measure was above the OECD average and the highest in the G7, except for Japan.

Given that those three sectors impact many "downstream" businesses that rely on them to run and grow their own enterprises, such a high level of protectionism poses a serious cramp on productivity throughout the economy, the study points out.

Bringing Canada in line with the OECD average would raise labour productivity by 0.79 percent economy-wide. While that may not sound like much, it's significant in economic terms.

"These are big numbers, from a policy perspective," says Prof. Hejazi. "We anticipated that the numbers would be large, but not this large."

A key contributor to Canada's higher-than-average bar for foreign investment is a review mechanism, in which all foreign investment proposals above a certain threshold are automatically subject to assessment by the Canadian government for their potential net benefit to the country.

Geospatial scientists have developed a new program to monitor street signs needing replacement or repair by tapping into Google Street View images.

The fully-automated system is trained using AI-powered object detection to identify street signs in the freely available images.

Municipal authorities currently spend large amounts of time and money monitoring and recording the geolocation of traffic infrastructure manually, a task which also exposes workers to unnecessary traffic risks.

Results just published in the journal of Computers, Environment and Urban Systems show the system detects signs with near 96% accuracy, identifies their type with near 98% accuracy and can record their precise geolocation from the 2D images.

Study lead author and RMIT University Geospatial Science Honours student, Andrew Campbell, said the proof-of-concept model was trained to see 'stop' and 'give way'(yield) signs, but could be trained to identify many other inputs and was easily scalable for use by local governments and traffic authorities.

"(Municipal authorities) have requirements to monitor this infrastructure but currently no cheap or efficient way to do so," Campbell said.

"By using free and open source tools, we've now developed a fully automated system for doing that job, and doing it more accurately."

The team found during investigations that mandatory GPS location data in existing street sign databases was often inaccurate, sometimes up to 10m off.

"Tracking these signs manually by people who may not be trained geoscientists introduces human error into the database. Our system, once set up, can be used by any spatial analyst - you just tell the system which area you want to monitor and it looks after it for you," Campbell said.

Campbell credited the project's initial concept to his industry mentor at Alpine Shire Council and RMIT Geospatial Science alumnus, Barrett Higman.

RMIT geospatial scientist and project co-lead, Dr Chayn Sun, said the fact that some councils were already attaching cameras onto rubbish trucks to gather street footage showed how valuable visual data were becoming, given what technology could now do with it.

"This imagery is critical for local governments in monitoring and managing assets and with the huge amount of geospatial applications flourishing, this information will only become more valuable," Sun said.

"Ours is one of several early applications for this to meet a specific industry need but a whole lot more will emerge in coming years."

Sun said footage from other sources, like that from rubbish truck cameras or any other geo-referenced imagery of the road network collected by municipal authorities, could also be fed into the system.

"Where footage is already being gathered, our research can provide councils with an economical tool to drive insights and data from this existing resource," she said.

Adequate intake of protein is associated with a reduced risk of frailty and prefrailty in older women, according to a new study from the University of Eastern Finland and Kuopio University Hospital. Adequate protein intake was defined as at least 1.1 g per kg of body weight. The findings were published in European Journal of Nutrition.

Frailty is a multidimensional condition common in older adults, and those affected are at an elevated risk of dependence and mobility loss, fall, fracture, multimorbidity and mortality. Evidence shows a strong link between frailty and malnutrition, and protein may be the most important nutrient at play, mostly through its effect on muscle health. The Nordic Nutrition Recommendations (2012) suggest protein intake of 1.1-1.3 g per kg of body weight as adequate for preserving physical capacity in older adults. However, there is a paucity of data regarding the association of protein intake with frailty. The newly published study examined associations between protein intake and protein sources with frailty status in older women.

Participants were 440 women aged 65--72 years enrolled in the Osteoporosis Risk Factor and Prevention-Fracture Prevention Study. Their protein intake in g per kg of body weight was calculated using a three-day food record at baseline in 2003--2004. At the three-year follow-up in 2006--2007, frailty phenotype was defined as the presence of three or more, and prefrailty as the presence of one or two of the Fried criteria: low grip strength, low walking speed, low physical activity, exhaustion (defined using a low life satisfaction score), and weight loss of more than five per cent.

The study shows that getting the recommended amount of dietary protein was associated with a lower risk of frailty and prefrailty in older women. Moreover, the consumption of animal protein was associated with a lower likelihood of frailty. The recommended protein intake (1.1-1.3 g per kg of body weight) for an older person weighing 70 kg corresponds to a minimum intake of 77 g of protein. To illustrate, the protein content of a chicken breast per portion is 25 g, one boiled egg 6 g, and two slices of whole grain bread 6 g.

"The public health recommendation is to eat an optimal diet with an adequate intake of protein. Adequate protein intake is important for muscle health and, according to the new results, may also prevent frailty. However, further research is still required in this area," Senior Lecturer Arja Erkkilä from the University of Eastern Finland concludes.

PHILADELPHIA - It's no secret that Americans are politically divided, but a new report offers hope that Democrats and Republicans find common ground on at least one issue: the role of "evidence" in developing and shaping health laws. Strong bipartisan support exists for a greater use of "evidence" - defined as information based on reliable data and produced by statistical methods - in development of health policy in the United States. The study is published today in Translational Behavioral Medicine from a researcher at Drexel University's Dornsife School of Public Health.

In a 2018 public opinion survey, 532 Americans were asked to what extent six factors "should have" and "currently have" influence on health policy decisions made by members of the United States Congress, including industry interests, evidence, and budget costs. The data was weighted to be representative of the U.S. adult population.

"Evidence" as well as "citizens' desires," were the factors most often identified by both Democrats and Republicans as those that should have the most influence. While members of both parties agreed on the most important factors that should shape policy, they were comparably cynical about whether their voices are being acted upon. Although 59 percent of respondents said that evidence should have "a lot of influence" on policy, only 11 percent said that evidence currently has "a lot of influence" on those decisions.

Additionally, more than half of respondents said that desires of citizens should have "a lot of influence," but only 14 percent reported that citizens actually have "a lot of influence" on policy. This disconnect was also found in the role of pharmaceutical companies' lobbying efforts. Just six percent said the interests of pharmaceutical companies should have a lot of influence, but 44 percent said they felt those companies currently have "a lot of influence."

"There is a wide gap between what Americans think should influence health policymaking in U.S. Congress and what they think actually does influence policy," said author Jonathan Purtle, DrPh, MPH, an assistant professor of Health Management and Policy in the Dornsife School of Public Health. "Across the political spectrum, Americans want evidence to play a much stronger role."

Political division has been well-documented. A 2017 Pew Research Center report of 5,000 surveyed Americans notes record levels of division between Democrats and Republicans on many political values, including race, immigration, the environment and other issues.

As prior studies have shown that public opinion can influence decisions made by policymakers, Purtle suggests that members of the U.S. Congress may be held more accountable by efforts to disclose evidence behind specific policy decisions.

Although the findings show no statistically significant difference across party lines on the role of evidence and citizens' desires in health policy, Purtle notes that "evidence" is a flexible idea that can be altered to support an individual's pre-existing policy preferences. He adds that future research should look at how opinions about the influence that evidence should have on policymaking vary when evidence unequivocally supports legislation decisions that are counter to citizens' preferences.

NEW YORK (June 18, 2019) -- Large numbers of healthcare workers risk transmitting respiratory viruses to patients and co-workers by attending work even when they have symptoms, according to a study published today in Infection Control & Hospital Epidemiology, the journal for the Society for Healthcare Epidemiology of America. The study found that 95 percent of people working in healthcare settings have worked while sick, most often because the symptoms were mild or started during their workday.

"We found that physicians and people working in areas that required the most intensive contact with patients were less likely than other workers to stay home or to leave work if symptoms progressed after the start of the day," said Brenda Coleman, PhD, clinical scientist in the Infectious Disease Epidemiology Research Unit at Mount Sinai Hospital, Toronto, and lead author of the study. "Managers and senior staff need to both model and insist on workers staying home when symptomatic as it protects both patients and coworkers from infection."

Hospital-acquired respiratory viral infections are recognized as causing significant illness and even deaths as well as increased healthcare costs. The Centers for Disease Control and Prevention recommends that healthcare workers with fever and respiratory symptoms consider temporary reassignment or exclusion from work for while symptomatic, but working with symptoms of an acute respiratory viral illnesses is common, with as many as 92 percent of healthcare workers reporting to work while symptomatic.

Researchers conducted a four-season prospective cohort study of influenza and other respiratory illnesses in nine Canadian hospitals in Toronto, Hamilton, and Halifax. Healthcare workers in acute care hospitals who worked more than 20 hours a week were asked to complete daily online illness diaries whenever they developed symptoms. Illness diaries collected information about symptoms, possible exposure, attendance at work, reason for work or absence, and medical consultations.

A total of 10,156 illness diaries were completed by 2,728 participants. Diaries of participants that were not scheduled to work were excluded, leaving 5,281 remaining diaries for analysis. Analysis of the diaries found that 69 percent of participants said that they worked during an illness because they had mild symptoms and felt well enough to work, 11 percent said they had things to do at work, 8 percent felt obligated to work, and 3 percent stated that they could not afford to stay home. Half of the participants reported episodes of acute respiratory viral illness during each influenza season, with 95 percent of those who reported an acute respiratory viral illness working one or more days of their illness. Seventy-nine percent said they were entitled to paid sick leave.

These findings suggest the need to educate healthcare workers, managers, workplace health and safety and infection control staff, and administrators about the risk of transmission associated with respiratory viral infection, to clarify what symptoms require exclusion from work, and to develop and implement policies for working while symptomatic, Coleman said.

Though the study was conducted in Canada, researchers believe the results also apply to the United States since hospitals in both countries follow similar recommendations to prevent the spread of disease, including standard, droplet and contact precautions as well as vaccination requirements. "There are likely as many differences between states as there are between Canadian and U.S. institutional recommendations." Coleman said

Amsterdam, June 18, 2019 - Charcot-Marie-Tooth (CMT) disease is the most common inherited neurological disorder affecting peripheral motor and/or sensory nerves in humans. Monogenic disorders like CMT1A, CMT's most prevalent subtype, are caused by a single gene defect. However, its clinical presentation and severity can vary widely, leading doctors to wonder what factors might be responsible for these differences. A study published in the Journal of Neuromuscular Diseases reveals that while all patients with CMT1A share a single gene defect, at least four clinical characteristics were found to be associated with secondary modifying genes.

"Modifier studies offer a significant pathway to additional therapeutic target discovery and underscore that monogenic disorders are a lot more complex than previously thought," explained lead investigator Stephan Züchner, MD, PhD, of the Department of Human Genetics and Hussman Institute for Human Genomics of the University of Miami. "Our study is a first in CMT, and one of the largest in all of rare diseases, to explore - genome wide and unbiased - the correlation of clinical outcome and genetic modifier loci. This study also proves the feasibility of this approach and should encourage scientists to pursue data aggregation and standardized protocols in rare disease in order to obtain a much more complete picture of the genetic architecture of rare disorders."

The study focused on close to 1,000 patients of European ancestry with CMT1A enrolled in a standard protocol over nine years. Researchers genotyped more than 600,000 genomic markers using DNA samples from these patients and performed a case-only genome-wide association study (GWAS) to identify potential genetic association with particular clinical outcomes in a subset of 644 individuals of European ancestry.

Researchers searched for single nucleotide polymorphisms (SNPs), which are specific variations at a single position in a DNA sequence among individuals. Then they investigated whether the SNPs could be statistically associated with any of 14 clinical manifestations of CMT1A, such as disease severity, using the CMT neuropathy score (CMTNS), motor symptoms, sensory symptoms, muscle strength, foot deformity, scoliosis, and hearing loss. "This allowed us to screen genome wide for markers that indicate a correlation with particular clinical outcomes," said Dr. Züchner.

We identified significant genomic loci that contained candidate genes. Four "subphenotypes" of CMT1A (difficulty with using eating utensils, hearing loss, decreased ability to feel, and CMTNS score) were found to be associated with particular SNPs or chromosomal regions. For example, hearing loss affected 16% of 364 individuals. In these individuals, "suggestive associations signals" were found on chromosome 5. The association signal was supported by multiple SNPs around a lead SNP. Other nearby genes were also found to be affected, none of which had previously been implicated in hearing loss.

"This is still a high-level statistical exploration and the benefit for individual patients is not yet fully understood. In the best-case scenario, we will be able to use such modifier genetic information to predict more precisely the natural course of disease in a single person," commented Dr. Züchner. "As new genetic therapies and small molecular screening technologies mature, such targets can be exploited much faster."

The investigators anticipate that GWAS analysis can be applied to other inherited disorders in order to provide a more nuanced understanding of all genetic anomalies that might contribute to the disease.

According to the Muscular Dystrophy Association, CMT1A accounts for around 60% of CMT1 cases. It is an autosomal dominant demyelinating form of CMT. CMT1 is characterized by muscle weakness, atrophy, and changes in sensation, mostly in the periphery of the body -- particularly in the feet, lower legs, hands and forearms. CMT1A patients usually present with CMT symptoms during adolescence but remain ambulatory with no reduced life expectancy.

Temporary bans on fishing can be better than permanent ones as a way of allowing fish stocks in an area to recover, while still providing enough to eat, a research team has found.

A new study published in the Journal of Applied Ecology by researchers from the California Polytechnic State University San Luis Obispo (Cal Poly), WCS (Wildlife Conservation Society), Swansea University, the University of Rhode Island (URI) and other groups has revealed that the challenge of keeping fish in the sea while putting fish on the plate might be best achieved through fishing grounds with closures that are periodically subject to pulse harvests.

The new research could help revolutionize fisheries management and settle a long-running debate between fisheries management and conservation sectors about the role of marine protected areas (MPAs) in balancing potential for stock recovery and maintaining yields.

At the crux of the matter is the current model of fishing closures. Conservationists have argued that permanently closed, no-take MPAs are an effective means of mediating overfishing and allowing stock replenishment, and many global conservation agencies are thus calling on high levels of protection in 30% of the world's oceans.

However, MPAs can shift fishing effort into remaining fishing grounds. More crowded fishing grounds can make it harder to find fish, thus reducing catch efficiency and driving up costs for the industry to maintain steady yields. Therein lies a wicked tradeoff, where managers seemingly need to balance competing objectives for keeping fish in the sea and fish on the dinner plate.

The researchers considered a third management strategy that is commonly implemented by small-scale fishers across the Pacific, who periodically open their fisheries closures to pulse harvests, similar to a rotational harvest model. Like permanent no-take MPAs, these "periodic closures" temporarily displace fishing effort and thus can promote stock recovery during the intervals while they are closed.

Most importantly, however, many of the fish protected within the closure become less wary of fishing gear, giving large boosts to harvest efficiency when the closures are temporarily opened.

The researchers developed innovative bioeconomic fisheries models that incorporated this documented fish behavioral response to protection. They found that in a well-managed fishery, simulated fishing grounds with periodic closures outperformed those with non-spatial management and permanently closed MPAs for achieving the triple bottom-line objectives of simultaneously supporting high yields, stock abundance and harvest efficiency. The outcomes were maximized with closures for 1-2 year periods, followed by pulse harvests within a single year.

Lead author Paul Carvalho, formerly of CalPoly and presently at URI, says, "We were impressed by how well periodic closures continued to perform under different scenarios. Across a large range of closure durations, closure sizes, fish population growth rates and movement patterns, fishing grounds with periodic closures consistently gave the best combined outcomes for stock, yield and catch efficiency."

Dr. Fraser Januchowski-Hartley at Swansea University further explained, "While recreational and small-scale fishers across the world know that fish behavior can change because of fishing and protection, it normally isn't included in management models. These results show the importance of considering changing fish behavior and its impact on catch when designing fisheries management regimes."

In fact, the only scenarios where periodic closures did not come out on top were under extreme overfishing, where the harvest efficiency benefit was too small for the periodic closure strategy to best meet the three objectives compared with permanent no-take MPAs.

"Less than 25% of global fisheries are currently characterized by this extreme level of overfishing," explains Prof. Crow White of CalPoly. "For these fisheries, permanent no-take MPAs may be critical for any chance at stock recovery. For the remaining three-fourths, periodic closures should be considered as an option to balance conservation and sustainable development needs for the fishing sector."

These sentiments are echoed by Dr. Stacy Jupiter, WCS Melanesia Regional Director, "For many years, we have been arguing that management undertaken by small-scale fishers in the Pacific Islands is more than just a niche practice. This study validates that conclusion, and provides credence to a management tool that is incredibly important for local cultural practice. I believe these findings will have real impacts on how people around the globe implement fisheries management so that they can have their fish in the water and eat them too."

Repeat coral bleaching caused by rising sea temperatures has resulted in lasting changes to fish communities, according to a new long-term study in the Seychelles.

Large predator fish such as snappers and very small fish such as damselfish dramatically reduced in number and were largely replaced by seaweed-loving fish like rabbitfish.

Publishing in the journal Global Change Biology, researchers show clear evidence that coral bleaching back in 1998 has led to changes in biodiversity and permanent shifts in the range of fish species coexisting on coral reefs, which still remain in place today.

While some of the coral reefs surveyed, bounced back and recovered following the bleaching event, other reefs shifted to fields of seaweeds.

Changes in fish communities were most apparent on these seaweed dominated reefs, but the 'herbivore' fish that feed on seaweeds became a dominant part of the community on all the reefs in the study.

Researchers believe these same changes are likely to be found in similarly damaged reefs around the world and could be described as the 'new normal' state for post bleached reefs.

The Lancaster University-led research tracked reef recovery in the Seychelles for 16 years, before another major coral-bleaching event impacted the reefs in 2016. Despite the length of time between these two major coral bleaching events, fish populations failed to recover to their pre-bleaching condition.

Where previously there were greater numbers of large predator fish such as snappers and groupers and also a large amount of very small fish such as damselfish and butterflyfish, after bleaching a new community, dominated by algal-feeding parrotfish and rabbitfish and invertebrate-feeding fish such as emperors and wrasses, has taken over.

These changes occurred because the fish's habitat structure - corals - collapsed. Where corals did not recover and seaweeds took over the space, the number and composition of fish changed substantially.

Surprisingly, even on the reefs where the corals gradually recovered between the bleaching events, the number of fish species recovered, but did not return to their original species composition.

Other studies have shown that the time between bleaching periods is now reducing, and is typically less than 10 years. In this study the time frame from the 1998 coral bleaching event to the next major one was longer -18 years - yet the fish communities were still unable to recover. This leads researchers to conclude other reefs will suffer similar shifts, especially given bleaching events are becoming more frequent.

Dr James Robinson, of Lancaster University, the lead author of the study, said: "Although the 18-year period between major mass bleaching events allowed corals to recover on some reefs, we found evidence that fish populations were not able to return to their pre-bleaching levels, and they were substantially altered on the reefs that become dominated by seaweeds. The Seychelles case study suggests under current levels of ocean warming - where the average frequency of bleaching events is less than 10 years - permanent changes to reef fishes are likely on most coral reefs globally."

Professor Nick Graham, of Lancaster University, added: "The new normal for coral reefs will be reef fish communities which have fewer species and are dominated by herbivores and invertebrate feeding fish. This will alter the way coral reefs function, and the fishery opportunities for coastal communities adjacent to coral reefs."

BOSTON - A growing body of evidence suggests that traditional cancer treatments can paradoxically promote new tumor growth. Now, a team of scientists led by Dipak Panigrahy, MD, and Allison Gartung, PhD, of the Cancer Center at Beth Israel Deaconess Medical Center (BIDMC), has demonstrated that administration of anti-inflammatory treatments that prevent inflammation as well as proresolution treatments that tamp down the body's inflammatory response to surgery or chemotherapy can promote long-term survival in experimental animal cancer models. The paper was published online in The Journal of Clinical Investigation and has been named the Editor's Pick for the month of July.

"Cancer therapy is a double-edged sword, as dying cancer cells can trigger inflammation and promote the growth of microscopic cancerous cells," said Panigrahy. "Surgery, chemotherapy and radiation can all induce the body's inflammatory/immunosuppressive injury response. Even anesthetics can impair the resolution of inflammation."

Panigrahy and colleagues, including Charles N. Serhan, PhD, DSc, director of the Center of Experimental Therapeutics and a member of the Department of Anesthesiology, Perioperative and Pain Medicine at Brigham and Women's Hospital and Vikas P. Sukhatme, MD, ScD, Dean of Emory University School of Medicine, hypothesized that an early blockade of the inflammatory cascade and/or accelerating the resolution of inflammation could overcome the tumor-promoting unintended consequences of cancer surgery. Physiologic stress, including from therapeutic procedures such as surgery and anesthesia, can prompt these microscopic cancers to grow into palpable tumors.

Using a well-established animal model, the scientists found that preoperative but not postoperative administration of a nonsteroidal anti-inflammatory drug called ketorolac eliminated the spread of cancer cells in multiple tumor-resection models, resulting in significantly prolonged survival. The team also showed that preoperative administration of resolvins - naturally occurring anti-inflammatory factors produced by the human body first discovered by Serhan and colleagues at Brigham and Women's Hospital in 2002 - produced the same result. Moreover, they found that together, ketorolac and resolvins exhibited synergistic anti-tumor activity, preventing surgery or chemotherapy from converting dormant tumor cells into a growing tumor in animal models.

This novel approach of blocking inflammation and/or accelerating the resolution of inflammation before a surgical procedure may also benefit the more than 30 percent of patients who do not have cancer but harbor microscopic cancers - small clusters of cancer cells that don't produce a growing tumor. Physiologic stress, including from therapeutic procedures such as surgery and anesthesia, can prompt these microscopic cancers to grow into palpable tumors.

“Collectively, our findings suggest a potential paradigm shift in our approach to resectable cancers,” says Sukhatme. “Clinical trials are now urgently needed to validate these animal studies.”

Researchers have developed a new class of drugs to tackle a common hereditary kidney disease

The disease affects 12 million people worldwide

The compound tested successfully in cell lines cultured from kidney patients

Scientists from the University of Sheffield are part of an international collaboration to develop a new class of drugs to treat a common genetic kidney disease which is a major cause of kidney failure.

Working with Glasgow-based biotech company Mironid and colleagues in the US, the Sheffield researchers have carried out successful laboratory tests of a compound developed by Mironid to treat autosomal dominant polycystic kidney disease (ADPKD), a hereditary, progressive disease which affects over 60,000 people in the UK and around 12 million people worldwide.

ADPKD is caused by a genetic fault that disrupts the normal development of kidney cells and causes cysts to form inside the kidneys. The cysts, which are like fluid-filled blisters, grow and eventually destroy normal kidney tissue causing the kidneys to stop working properly. This leaves patients needing life-saving treatments, such as dialysis or a kidney transplant.

In ADPKD cells, cysts develop and grow because they express higher than normal levels of a 'messenger molecule' called cyclic AMP (or cAMP). One of the many known functions of cAMP is to tell cells when to divide and when to secrete fluid.

The new compound discovered by Mironid activates an enzyme called PDE4, whose natural role is to break down cAMP. Researchers at Mironid Ltd describe how the novel small molecule activators of PDE4 enzymes act to supress disease driving cAMP signalling.

Using cell lines and patient tissues derived from ADPKD patient kidneys, researchers at Sheffield and in the US confirmed that when the Mironid compound switched PDE4 on, levels of cAMP in the disease cells were reduced and the number and growth of the cysts were suppressed. The findings are published today (18 June 2019) in the prestigious US journal Proceedings of the National Academy of Sciences (PNAS).

Moreover, the reversible nature of the compound means that PDE4 activity may be rapidly and accurately controlled in patients, according to the dose decided by the clinician. This suggests that a future treatment for ADPKD could be tailored to an individual patients' needs and the severity of their disease without the side effects seen with other approaches. In theory, the compound could also suppress cyst formation due to ADPKD in other organs apart from the kidney, especially in the liver.

Professor Albert Ong, a consultant nephrologist and professor of renal medicine who led the experiments conducted at the University of Sheffield said: "Drug development usually focuses on looking for ways to block molecular and chemical processes, not switch them on, so this is a rare mode of action. As a researcher, it's very exciting to be involved in the early stage development of a completely new class of drugs.

"It's also very heartening for me as a clinician since like most genetic diseases, ADPKD cannot be cured. This discovery gives me hope for the many patients I see in my clinics that there could be another effective new treatment in the future to keep the disease in check for much longer, either on its own or in combination with other drugs such as tolvaptan.

"I would love to think that ADPKD could one day be a disease that people can successfully manage throughout their natural lives, rather than one that could shorten their lives."

Mironid's next step is to refine the compounds in anticipation of being able to develop a new medicine to treat ADPKD patients.

Dr David Henderson, Senior Investigator at Mironid added: "This exciting publication highlights the innovative science behind our LoAc® PDE4 activator technology. These first-in-class small molecules have the potential to address unmet clinical need in Autosomal Dominant Polycystic Kidney Disease (ADPKD), and potentially have further utility across different therapeutic areas where unbalanced cellular signalling drives disease progression. Looking to the future, we are excited and enthusiastic in our continued collaboration to translate this novel approach into real therapeutic benefit."

Kidney Research UK has funded work on ADPKD at the University of Sheffield for several years, helping to develop vital knowledge on the mechanism of the disease and ways in which it might be managed.

Chief executive of the charity, Sandra Currie, said: "We are proud to have supported several ADPKD studies led by Professor Ong and his team at Sheffield over the years. Most recently, we funded Professor Ong's investigations into how to control the 'messenger molecule', cyclic AMP, which affects the rate at which cysts grow and expand in the kidneys.

"It is really encouraging news that this collaboration with Mironid has now successfully laboratory-tested a compound which reduces levels of the cyclic AMP molecule. This could bring new hope to the 12 million people living with ADPKD worldwide - we look forward to further developments."

The mysterious function of a key protein has been revealed following a breakthrough by University of Dundee scientists.

HOIL-1 is a component of the Linear Ubiquitin Assembly Complex (LUBAC) which lies at the heart of the mechanism that determines whether the cells of our body will survive or die. Now researchers working in the laboratory of Professor Sir Philip Cohen in the University's Medical Research Council Protein Phosphorylation Unit (MRC-PPU) have found that HOIL-1 operates in tandem with a second component of LUBAC to form ubiquitin chains.

The research, which has just been published in the journal Proceedings of the National Academy of Sciences (PNAS), has also revealed that the ubiquitin chains are joined to other proteins by an unusual mechanism.

Sir Philip said, "It's been known since its discovery that HOIL-1 looks like an E3 Ligase, but nobody knew what it actually did in cells. Now we know.

"One thing it does is to start new ubiquitin chains. HOIL-1 puts the first ubiquitin on, while a second component of LUBAC, called HOIP, attaches additional ubiquitins to form a ubiquitin chain.

"Remarkably, it turns out that HOIL-1 joins ubiquitin to proteins by forming ester bonds. It is only the second time that this type of ubiquitin linkage has been detected, the first example being discovered here in Dundee only last year by Dr Satpal Virdee. It is incredible that two people working next to each other have come across the first two examples of this type of protein connection."

Since its discovery in Japan around 13 years ago, LUBAC has turned out to be a regulator of the body's defence system that allows it to combat infection by microbes, such as bacteria and viruses. A key role of LUBAC is to suppress two forms of cell death called apoptosis and necroptosis, thereby ensuring cell survival.

Sir Philip says that although his lab's new findings represent a significant breakthrough, more research is needed before it becomes clear whether new drugs can be developed to treat diseases by modulating the activity of LUBAC.

DALLAS - June 17, 2019 - The increasing sophistication of cancer treatments threatens to outpace the ability of health care providers to enroll patients in clinical trials to test those therapies. That's a key finding by researchers in UT Southwestern's new Department of Population and Data Sciences.

The authors of the study published this month in the Journal of Clinical Oncology investigated why many cancer clinical trials fail to enroll enough patients. The researchers sought to identify potential interventions - i.e., solutions - to improve the situation.

Research in the Department of Population and Data Sciences investigates ways to improve health care delivery on a population level. Its studies often involve breaking a problem into its component steps, identifying potential barriers at each step, and developing a list of possible interventions for future study. In this specific project, the researchers approached suboptimal clinical trial enrollment - a significant national concern - as a health care delivery issue.

"Cancer clinical trials are meant to result in treatment advances. However, their potential benefits are diminished by suboptimal trial participation, both by patients and by clinicians and their organizations," said Dr. Celette Sugg Skinner, Chair and Professor of Population and Data Sciences and corresponding author of the study. Dr. Skinner is also a member of the Harold C. Simmons Comprehensive Cancer Center and holds the Parkland Community Medicine Professorship.

Nearly half - 40 percent - of cancer trials fail to reach targets for accrual, the medical term for the number of patients who have completed or will complete the trial. Fewer than 2 percent of adults with cancer enroll in trials, and last year no trials were offered in 36 percent of physician-owned and 14 percent of hospital-owned oncology practices, she said.

In order to help ensure results will reach statistical significance, clinical trials are designed to enroll a calculated number of patients, she explained. "Before we can figure out how to improve accrual in trials, we need to better understand the entire process and challenges along the way."

To gain this understanding, lead author Dr. Simon Craddock Lee, Associate Professor in the Department, conducted in-depth interviews with 10 key oncology physicians, nurses, and research staff in leadership positions across nine states.

"Nationally, we know there are large numbers of cancer patients and relatively few of them are in clinical trials," Dr. Lee said. "Most of the research to date has focused on the idea that the problem must be that patients don't know about clinical trials."

That mindset led to a research emphasis on improving communication so that patients are aware of trials and understand the risks and benefits as well as reaching out to underrepresented populations and ensuring messages are culturally appropriate - all worthy goals. However, this study identifies another group of problems, he explained.

The researchers found that emerging therapies and the changing landscape of oncology have introduced complexity, he continued. Specifically, oncology practices encounter barriers to (1) staying aware of available trials, (2) identifying eligible patients, (3) introducing the idea of trial participation vs. standard treatment to those patients, and (4) enrolling and caring for them throughout clinical trials.

These steps have become more complicated due to emerging discoveries in the realm of precision oncology, which seeks to determine the best treatment based on patient genetic, environmental, or lifestyle factors. For example, whereas trials in the past would enroll all patients with stage 2 breast cancer, current trials often are designed to enroll only patients with certain biomarkers.

"As eligibility criteria become more numerous and specific, the likelihood of any patient meeting all criteria goes down," Dr. Lee explained. "Because oncology practices are not reimbursed for determining and documenting enrollment, trial accrual is threatened as these tasks become more costly and time-consuming."

The authors suggest that addressing challenges to trial accrual may involve changes in trial-specific reimbursement, as well as incentives for administrative and infrastructure costs.

"Our next goal must be to enhance logistic, infrastructure, and policy support to translate oncology discoveries into high-quality cancer care," said co-author Dr. David Gerber, a Professor of Internal Medicine and Population and Data Sciences. Dr. Gerber serves as Associate Director for Clinical Research and co-Leader of the Experimental Therapeutics Program in the Simmons Cancer Center.

The researchers will use this study to guide future investigations. Most immediately, they have surveyed more than 1,000 oncology providers, asking in-depth questions about the barriers identified in this study. Findings from that survey will help to identify strategies to ensure that clinical trials enroll the targeted number of patients.

Engineered tissues and organs have been grown with various degrees of success in labs for many years. Many of them have used a scaffolding approach where cells are seeded onto biodegradable supportive structures that provide the underlying architecture of the organ or tissue desired.

But scaffolds can be problematic -- ultimately, they should degrade and disappear, but timing that decomposition to coincide with the maturation of the organ is tricky, and sometimes degradation byproducts can be toxic. Scaffolds also can interfere with the development of cell-to-cell connections, which are important for the formation of functional tissues.

Now, a research team led by Eben Alsberg, the Richard and Loan Hill Professor of Bioengineering and Orthopaedics at the University of Illinois at Chicago, has developed a process that enables 3D printing of biological tissues without scaffolds using "ink" made up of only stem cells. They report their results in the journal Materials Horizons.

"Our cell only printing platform allows for the 3D printing of cells without a classical scaffold support using a temporary hydrogel bead bath in which printing takes place," Alsberg said.

The micron-scale hydrogel beads allow the nozzle of the 3D printer to move through it and deposit cells with minimal resistance to that nozzle movement or the ejection of the cells. The gel beads support the cells as they are printed and keeps them in place and preserves their shape.

Once the cells are printed into the hydrogel bead matrix, it is exposed to UV light, which cross-links the beads together, in effect freezing them in place. This lets the printed cells connect with each other, mature and grow within a stable structure. The media that bathes the cells flows easily through the cross-linked gel beads and can be changed out as needed to provide fresh nutrients and dispose of waste products made by the cells. The hydrogel beads can be removed through gentle agitation, or controlling their degradation, leaving the intact tissue behind.

"The hydrogel bead bath has unique properties which allow for both printing of the cell-only bioink in complex architectures, and subsequent temporary stabilization of these cell-only structures to allow for cell-cell junctions to form," Alsberg said. "Using chemistry we can then regulate when the beads go away."

The cells Alsberg's team used are stem cells -- those that can differentiate into a wide variety of other cell types. They used the stem cells to 3D print a cartilage ear and a rodent-sized "femur" in the hydrogel bead bath. The cells they printed were able to form stable, cell-cell connections through specialized proteins.

"For the first time, cell-only constructs can be printed in intricate forms that are made up of different cell types without a hydrogel carrier or traditional scaffold that can then be stabilized for a period of a day to weeks. We've demonstrated that cell aggregates can be organized and assembled using this strategy to form larger functional tissues, which may be valuable for tissue engineering or regenerative medicine, drug screening and as models to study developmental biology," Alsberg said.