Culture

This press release is in support of a presentation by Dr Mostafa Metwally presented online at the 36th Annual Meeting of ESHRE.

8 July 2020: An add-on treatment commonly offered to patients in preparation for IVF has proved ineffective in a large-scale randomised trial of more than 1000 women. Those who had endometrial scratch before their first IVF treatment were found to be no more successful than a control group receiving routine treatment. Endometrial scratch is an adjuvant procedure in which the lining of the uterus is "injured" (usually by a small biopsy) in the hope of improving embryo implantation,

This UK Multicentre Endometrial Scratch Randomised Controlled Trial is the biggest and most powerful study of the add-on so far reported. The results, says chief investigator Mostafa Metwally from Sheffield Teaching Hospitals and the University of Sheffield, UK, "provide conclusive evidence" that endometrial scratch is not beneficial in women having IVF for the first time. "It is time to stop this practice," says Dr Metwally, who will present the results online today at the 36th Annual Meeting of ESHRE.

Although some earlier studies have cast doubt on the efficacy of endometrial scratch, it is still commonly available and offered to IVF patients as an add-on treatment.(1,2) This study, however, because of its size, design and homogeneous population, now leaves no doubt over its findings. The trial was performed at 16 UK centres during 2016 to 2019 and involved more than 1000 women under 37 years of age having their first cycle of IVF. They were randomised equally to endometrial scratch, or no scratch, with primary outcome of the study being a live birth.

Results showed that live birth rate in the intervention group was 38.6% and in the routine treatment group 37.1%, with no statistical difference whatsoever. Secondary outcomes of the trial assessed clinical pregnancy rate, embryo implantation rate and obstetric complications. Again, there were no differences in these secondary outcomes between the scratch and no-scratch groups - with clinical pregnancy rate 42.6% in the former, and 40.6% in the latter.

Dr Metwally says the strength of the study lies in the homogeneous study population, which leaves results less open to bias. All the subjects were having their first cycle of IVF and were expected to be good responders to treatment. The scratch was performed in the mid-luteal phase of the cycle before their IVF began. The study was also powered to detect a 10% difference in outcome (a result considered to be practice-changing) but in these results the intervention was found to be of no value.

The study results come at a time when adjuvant treatments are under increasing scrutiny. A series of recent add-on reviews in one medical journal found that none of several with clinical, endometrial and laboratory applications had a strong enough evidence base for routine use.(3) And in Britain none of those on an official traffic-light list of 11 add-ons (including endometrial scratching) is thought worthy of a green light. Yet the belief persists that a scratch to the lining of the uterus causes an environmental response likely to encourage embryo implantation.

Despite the similarly discouraging results of several earlier studies, Dr Metwally notes that endometrial scratch remains widely offered in IVF clinics throughout the world. Indeed, a 2016 survey found that 83% of clinics in Australia, New Zealand and UK "are recommending endometrial scratching" to their IVF patients.(4)

Dr Metwally described these results as "very reliable for women having their first IVF cycle", a clearly defined study population and different from those in several earlier trials, some of which included patients with unsuccessful previous IVF treatments. "Our study is the largest and most conclusive study in women having first time IVF treatment," says Dr Metwally, "and the findings conclusively indicate that the practice of performing scratch in this group should stop."

* This study is funded by the National Institute for Health Research (NIHR) [Health Technology Assessment programme (project reference 14/08/45)]. The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care.

Brain cancers have long been thought of as being resistant to treatments because of the presence of multiple types of cancer cells within each tumor. A new study uncovers a cancer cell hierarchy that originates from a single cancer cell type, which can be targeted to slow cancer growth.

The research was led by Dr. Kevin Petrecca, a neurosurgeon and brain cancer researcher at The Neuro (Montreal Neurological Institute and Hospital) of McGill University, part of the McGill University Health Centre.

The study, which is the largest ever single cancer cell RNA sequencing project, included 55,000 glioblastoma cells and 20,000 normal brain cells. The team found that there are five main cancer cell types within each tumor, and these cancer cell types are similar to the cell types that are in the normal human brain.

For the first time, researchers detected what they describe as a progenitor glioblastoma stem cell (GSC) -- a cell type from which all other cancer cells develop. They showed a cellular hierarchical organization to the cancer which originates from progenitor GSCs.

The team found that progenitor GSCs divided much more than the mature cancer cells and make up the vast majority of dividing cells in the tumour, despite making up a relatively small proportion of the total tumor. These rapidly dividing cells are the earliest detectable cancer cells in the hierarchy and so make a promising target for therapy.

After identifying molecular vulnerabilities in progenitor GSCs, the researchers then targeted these and found that progenitor GSC survival and proliferation decreased as a result. In preclinical disease models, this reduced tumour growth and increased survival.

"Our work has gone a long way to resolve the complexity of glioblastoma heterogeneity, and provides a new framework to reconsider the nature of glioblastoma," says Dr. Petrecca "As part of this work, our study also shows, in contrast to decades long dogma, that glioblastoma stem cells are the most rapidly dividing cancer cells in the tumor, and we identified new ways to target these cells. There is still much work to be done. Understanding how these cancer cells interact with the cancer microenvironment is not well understood in this disease, but this study serves as a good starting point to begin to understand how glioblastoma originates and evolves prior to treatments."

Durham, NC - Results of a clinical trial released today in STEM CELLS Translational Medicine indicates that breast augmentation in patients treated with fat grafts enriched with autologous adipose-derived stem cells (ASCs) had significantly superior results compared to those treated with non-enriched grafts.

The clinical trial, conducted by a multi-institutional group of researchers led by Stig-Frederik T. Kølle, M.D., Ph.D., chief surgeon in the Department of Plastic Surgery at Aleris Hamlet Hospitals in collaboration with the stem cell research and production facility Stemform (Copenhagen), was designed to examine whether ex vivo-expanded ASC-enriched fat grafts for breast augmentation could improve the results of conventional lipofilling while offering a safe procedure. It is the first study to investigate the effect of expanded ASCs on large-volume fat grafting in a clinically relevant setting.

"The repair of disfiguring volume defects of the female breast following cancer resection and congenital anomalies are secondary to the aging process and breast feeding represents a large and growing patient population with an increasing demand for natural solutions to address their surgical needs," Dr. Kølle said. "Silicone implants are the gold standard for correcting breasts aesthetically, but they can have significant complications, and some have been associated with lymphoma. With the goal of an aesthetic and natural appearance, patient safety and satisfaction, an alternative strategy for breast augmentation and correction is autologous fat grafting."

Autologous fat is gaining acceptance as an ideal soft tissue filler because it is biocompatible, versatile, non-immunogenic, and readily available. Also, harvesting fat through liposuction involves minimal trauma. However, clinical outcomes have varied extensively, and reported retention rates for transferred fat range from 25 to 80 percent, regularly necessitating repeated procedures.

Methods to increase graft retention are needed to make the procedure a reliable and attractive alternative to implants, especially in slim patients with limited fat resources. In this respect, cell enrichment has been shown to have promise. Animal and human studies have demonstrated that enrichment with ex vivo-expanded ASCs markedly improved the residual volume and histological appearance of fat grafts.

In the study reported here, 12 healthy women with small breasts who had a desire for augmentation were divided into two groups. Six received ASC-enriched fat grafts, while the control group (also six patients) received conventional, non-enriched fat grafts. The patients were followed for a minimum of 18 months and will also be given a five-year follow-up safety evaluation.

Total breast volume was determined by MRI both preoperatively and again after four months. Clinical results were also evaluated by 10 independent board-certified plastic surgeons. Photos of the patients before the operation, at four months and 18 months after the operation, were presented blinded and at an equal profile to each surgeon and assessed by the question: "If you performed one fat transplantation for breast augmentation, how satisfied would you be with the retention/survival and the cosmetic result?"

"Both the MRI and the plastic surgeons' assessments showed significantly better clinical results in the ASC-treated group than in the controls receiving non-enriched fat grafts," Dr. Kølle reported. "With a median survival of 80.2 percent of the total injected volume in the ASC group (compared to 45.1 percent in the control group), and a median enlargement of 2.6 times the initial breast volume, no second augmentation procedure was needed.

"This study demonstrates a safe profile for the usage of adipose-derived stromal cells," he added. "The results are likely transferable to most soft tissue augmentations and may, therefore, be beneficial to a broad spectrum of patients."

"The outcomes of this first clinical trial comparing breast augmentation in patients treated with fat grafts enriched with adipose-derived stromal cells to those treated with fat grafts alone are encouraging and indicate this procedure is safe and effective," said Anthony Atala, M.D., Editor-in-Chief of STEM CELLS Translational Medicine and director of the Wake Forest Institute for Regenerative Medicine. "Such procedures could someday offer a valid alternative for patients who currently are treated with silicone breast implants."

Hearing is widely thought to be the last sense to go in the dying process. Now UBC researchers have evidence that some people may still be able to hear while in an unresponsive state at the end of their life.

This research, published recently in Scientific Reports, is the first to investigate hearing in humans when they are close to death.

Using electroencephalography (EEG), which measures electrical activity in the brain, the researchers analyzed data collected from healthy control participants, from hospice patients when they were conscious, and from the same hospice patients when they became unresponsive. The patients were receiving palliative care at St. John Hospice in Vancouver.

"In the last hours before an expected natural death, many people enter a period of unresponsiveness," says study lead author Elizabeth Blundon, who was a PhD student in the department of psychology at the time of the study. "Our data shows that a dying brain can respond to sound, even in an unconscious state, up to the last hours of life."

This new insight into the dying brain's response to sound can help family and friends bring comfort to a person in their final moments.

The researchers introduced study participants to various patterns of common and rare sounds that changed frequency. When the rare tone pattern occurred, both groups responded by giving a pre-arranged signal.

The researchers monitored the brain's response to those tones using EEG and found that some dying patients responded similarly to the young, healthy controls--even when they were hours away from death.

"We were able to identify specific cognitive processes from the neuro-typical participants as well as the hospice patients," says Lawrence Ward, a professor in the department of psychology at UBC. "We had to look very carefully at the individual control participants' data, to see if each one of them showed a particular type of brain response before we felt confident that the unresponsive patient's brain reacted similarly."

This study was adapted from a European study that explored brain responses to sound in individual healthy participants, and in minimally conscious and unresponsive brain-injured patients. The UBC researchers applied a similar paradigm to actively dying unresponsive patients.

Blundon and Ward collaborated with Dr. Romayne Gallagher, a palliative care physician at St. John Hospice who has since retired. The research required patients to give their consent in advance. Thirteen families participated and brain recordings were obtained from five patients when they were unresponsive.

In Gallagher's 30 years of treating dying patients, she has witnessed positive reactions in people when loved ones spoke to them in their final moments. Gallagher and her colleagues often wondered if hearing was the last sense to go. She contacted Ward to see if this theory could be proven.

"This research gives credence to the fact that hospice nurses and physicians noticed that the sounds of loved ones helped comfort people when they were dying," says Gallagher. "And to me, it adds significant meaning to the last days and hours of life and shows that being present, in person or by phone, is meaningful. It is a comfort to be able to say goodbye and express love."

Blundon says what while the evidence of brain activity supports the idea that a dying person might be hearing, they can't confirm whether people are aware of what they're hearing.

"Their brains responded to the auditory stimuli, but we can't possibly know if they're remembering, identifying voices, or understanding language," says Blundon. "There are all these other questions that have yet to be answered. This first glimpse supports the idea that we have to keep talking to people when they are dying because something is happening in their brain."

Knee replacements are a huge burden on society and individuals from all walks of life. A major global systematic review has identified the common jobs - paid and unpaid - that may be putting people unknowingly at risk.

A study by the Universities of Sydney, Oxford and Southampton reveals there is a need for targeted work health and safety practices to extend beyond physically burdensome jobs; regulators and insurance companies should take account of the high number of medium-risk occupations and that unpaid roles also rate highly.

It is the biggest meta-analysis and systematic review of the potentially debilitating knee osteoarthritis (OA) - comprising 71 studies and almost one million people - and the first systematic review into the association between job 'titles' and knee OA.

Increased risk was found in agriculture workers, construction workers, miners, service workers, houseworkers (i.e. housewives) and cleaners.

The findings are published today in the prestigious journal Arthritis Care and Research.

The senior author, Professor David Hunter, of the University of Sydney's Florance and Cope Chair of Rheumatology, Institute of Bone and Joint Research in the Kolling Institute, said the research, while not focusing on the important role of exercise in combatting this common lifestyle ailment, identified the jobs that placed high-to-moderate stress on vulnerable knees.

"Knee osteoarthritis is a leading cause of loss of work and disability worldwide and can necessitate invasive surgery including total knee replacement, so preventing occupational hazards is critical," Professor Hunter said.

"The burden is increasing, with projections of osteoarthritis that affects one in eight people jumping 50 percent within 15 years , in large part attributable to lifestyle issues such as growing rates of obesity and reduced exercise."

Lead author Dr Xia Wang, also from the Institute of Bone and Joint Research, Faculty of Medicine and Health, said although research has previously identified frequent kneeling, squatting and heavy lifting - particularly in agriculture and construction - as risk factors, this comprehensive study highlighted occupational risks generally.

"With people working and living longer knee osteoarthritis is an area of concern even in service-focused developed nations, including in mid-risk occupations such as cleaning and full-time, unpaid housework and caring," she said.

Findings include:

- Floor-layers, bricklayers and carpenters have ~2.5 times increased odds compared to sedentary workers.

- Agricultural workers had up to 64% increased odds; builders and construction workers had increased odds of 63%.

- Houseworkers (unpaid) have up to 93% increased odds.

- Occupations like commerce, forestry or fishery workers, machine operators, plumbers, electricians, technicians, postmen were not found to be statistically significantly associated with knee OA.

- The following activities were identified as increased risk: excessive kneeling, squatting, standing, lifting and climbing stairs.

Dr Thomas Perry, co-lead author and postdoctoral researcher at the Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, said: "Our collaborative work has been critical in understanding the relationship between work-place physical activities and knee osteoarthritis. We hope these findings will help guide the future development of work-place personal protective equipment."

Professor Cyrus Cooper, director of the MRC Lifecourse Epidemiology Unit, University of Southampton, said: "Further evaluation of this issue will ensure that occupational risks of knee osteoarthritis - the commonest joint disorder worldwide - are minimised."

Meconium--the earliest stool of an infant--is composed of materials ingested during the time the infant spends in the uterus. A new study published in Pediatric Obesity found that the types of normal bacteria found in the meconium may predict an infant's likelihood of later developing obesity.

In the study of 212 newborns, children who became overweight at 3 years of age differed in their meconium bacterial makeup from those with normal weight, having a higher proportion of bacteria in the Bacteroidetes phylum (29% versus 15%).

The concept of fetal microbiome is controversial and the colonization process after birth is better understood than the possible fetal colonization; however, there are many prenatal factors affecting the microbial composition of the baby's first stool, such as the mother's use of antibiotics during pregnancy and biodiversity of the home environment during pregnancy," said corresponding author Katja Korpela, MD, of the University of Oulu, in Finland. "It is very interesting that the microbiome formed before birth is possibly linked to a child's subsequent weight status."

In a recent study from Singapore, early access to pension wealth was associated with improved health status. The findings are published in Economic Inquiry.

Singapore has a unique policy that allows individuals to withdraw a proportion of their pension savings after their 55th birthday, which relaxes individuals' borrowing constraints. To examine its health impacts, investigators analyzed monthly survey data from 2015 to 2019, comparing individuals' self-reported health status before and after their 55th birthday.

The results indicated that early access to pension wealth improves overall health status. Detailed analyses of underlying mechanisms showed that early access to pension wealth might boost health by improving psychological well-being.

"Since allowing the early partial withdrawal of pension balances does not necessarily increase the fiscal burden of the government, our results imply that flexible access to pension wealth could be a cost-effective policy to improve the health of middle-aged individuals," said co-author Kanghyock Koh, PhD, of Korea University.

When it comes to soils, proper identification is key. Identification allows scientists to determine the story behind the soil: how it formed, how it behaves in different scenarios, and how valuable it may be to certain plants and animals.

Soil classification, or scientific identification, can also help determine if the soil needs extra attention and resources for protection. For example, certain soils may not be safe for hiking, could be home to an endangered species, or foster a unique ecosystem like wetlands.

However, soil classification is complex. Soil characteristics include color, texture, mineral composition, air and water content, and much more. Each of these characteristics can give added details to solve the story behind the soil.

Many soils are simple for trained soil scientists to identify. But Karen Vaughan of the University of Wyoming and her team dug in to investigate an area of soil along the central coast of California that had some peculiar characteristics.

"The reason for this research site really comes from long ago in a wetlands field lab," she says. "Students kept saying the soil didn't meet all the field indicators of hydric -- or wetter -- soils. I thought, it has to. It's wet and there's plenty of water-loving vegetation. Then I realized it must be a problematic soil, so we set up this experiment to figure it out."

Vaughan's experiment consisted of studying how dark the color of the soil was, as well as its water content, vegetation, and chemical composition. Looking at how wet the soils seemed, the vegetation that grew there, and microbes that lived there, a scientist would think they were wetland soils.

However, other characteristics of the soil, such as its dark color, confused the researchers because it was so similar to the surrounding drier soil. This is where a way to analyze soil color more precisely, called the profile darkness index, was helpful. It allowed them to properly classify the soils.

Soil classification is usually a pretty exact science. Hydric soils have a specific set of characteristics. One of the key characteristics of hydric soil is a pale, light greyish color. As a result of the uniquely dark color, they could be mistakenly identified as drier soils and not meet the requirements of wetlands.

More clues for soil classification can sometimes be found in the landscape. Landslides are common on these cliffs, which cause soil to fall and be deposited in other areas. Often, these landslides result in depressions where a soil might be wetter than its surroundings.

"We get these situations where the soil characteristics don't match features we usually see in wetter soils," Vaughan explains. "This is, for example, because the transported soils inherited darker colors from the parent material. If someone looked at these soils, they would assume they are not as wet as they are. They then would not classify these areas as wetlands, despite them performing as wetlands."

"This kind of proper identification is important so the wetlands can be better conserved," Vaughan says. "If researchers don't know about them, they can't be protected."

This is because wetlands are so beneficial to the environment. They can help store water to protect against floods and erosion, as well as improve water quality. They also serve as a place for important plants and animals to live. Of course, they are also beautiful to observe when hiking out in nature.

"Soils tells the story of an ecosystem," she says. "If we look to the soil, we can understand ecosystem function."

New research from the UBC Sauder School of Business shows that people are 30 per cent more likely to donate their assets when faced with their own mortality.

The study examines how people respond to "mortality salience" -- that is, the uniquely human awareness that they're going to die.

Earlier studies have shown that some people console themselves by acquiring more material possessions -- in other words, they subscribe to the notion that "He who dies with the most toys wins."

But the new research shows that people can also express a desire to pass important possessions on to others, because it gives them a kind of immortality the researchers call "transcendence."

"It sounds dramatic, but it's the idea that you can live on longer, symbolically through something else," says study co-author and UBC Sauder Professor Katherine White, who co-authored the study with UBC Sauder Professor Darren Dahl and Lea Dunn, assistant professor of marketing at the Foster School of Business at the University of Washington. "So, if a product or a possession is somehow linked to your identity and you pass that on to others, it could potentially have this ability to transcend the self."

The researchers first launched the study several years ago, long before the threat of COVID-19 had people more closely considering their mortality, and updating wills and planning estates.

"For many people, that mortality salience is much higher now, for better or for worse. People are just more aware of how fragile life can be," says Dahl. As a result, adds White, more people are likely thinking about the idea of symbolic immortality and where their possessions will go when they pass on.

To conduct the experiment, 512 participants were asked to arrive at the lab with a book they might consider giving away. One group was then given a task that made them contemplate their deaths, while the other considered what their typical day was like.

Later, participants were asked if they wanted to donate their book to charity; some were also offered the chance to write an inscription in the book and sign it, making the offering more personal. No researchers were present when participants made their decision to ensure there was no pressure to donate.

"The people who had contemplated their death were more than 30 per cent more likely to give away the product -- particularly when they had connected it to themselves," says White.

"They're much more likely to donate it after they have somehow connected it to their identity."

However, the effect goes away if the item may be broken up or recycled, thereby losing its perceived potential for transcendence.

"Let's say you're passing on a car or a motorcycle. If it's broken up into pieces and sold off as parts, it's not the same as if your specific car or your specific product was left to endure," says Dahl. "The specialness of it, and the fact that it represents you, is broken up, and you're not a whole entity sticking around."

The effect also didn't work on people who had already satisfied that desire for transcendence through other channels.

White says the findings could be helpful to charitable organizations looking for people to donate a portion of their estates. "Anything they can do to connect the self to something that's more lasting will help," says White. "So, it could be something like a plaque or a mural or a somewhat permanently displayed list of donors -- just a tangible representation of the self that's going to continue to exist."

Companies can also use transcendence as a selling point by marketing products as having high emotional value or being precious and irreplaceable family heirlooms.

PHOENIX, Ariz. -- July 8, 2020 -- A groundbreaking study published today and led by the Translational Genomics Research Institute (TGen), an affiliate of City of Hope, identifies unique lung cells that may drive Idiopathic Pulmonary Fibrosis (IPF), a deadly lung disease that affects hundreds of thousands of Americans, and for which there is no cure.

This is one of the first comprehensive looks at lung cells using a technology called single-cell RNA sequencing. Instead of examining a mash-up of many cells from a tissue sample, single-cell sequencing allowed researchers in this study to closely examine the individual cells that make up the lungs; to identify their function, and ultimately understand the molecular changes that may be driving the disease.

Using this method, researchers identified five unique cells types associated with lung fibrosis, which could potentially lead to earlier diagnosis and therapeutic drug targets.

The study's initial findings, published today as the cover story for the journal Science Advances, are the first under a combined $6.1 million in federal grants aimed at uncovering the origins of lung disease, including IPF, the nation's most common and severe form of fibrotic lung disease. An estimated 50,000 Americans, mostly middle-aged and older adults, are diagnosed each year with IPF. Most die from respiratory failure within five years.

In collaboration with Vanderbilt University Medical Center (VUMC), researchers analyzed tissue samples from 20 lungs with pulmonary fibrosis provided by the Norton Thoracic Institute and VUMC, and tissue samples from 10 healthy lungs provided by the Donor Network of Arizona and the Tennessee Donor Services.

Dr. Nicholas Banovich, an Assistant Professor in TGen's Integrated Cancer Genomics Division and co-senior author of the study, said the most interesting finding is the characterization of cells called KRT5-/KRT17+, which appeared in the epithelium, or protective lining of the lungs, but only in individuals with pulmonary fibrosis.

"These cells are incredibly unique as they are clearly epithelial, but are also producing collagen and components of extra-cellular matrix (ECM), which make scar tissue," Dr. Banovich said, "They are directly contributing to fibrosis." These cells also share characteristics of both the airway and alveolar epithelium, the respiratory membrane that allows the exchange of gases.

Another of the study's most interesting findings is the high degree of plasticity, the ability of a cell to share characteristics with multiple classically defined cell types, in the lung epithelium.

"Classically, the field used a small number of genes to determine cell types. With the single cell RNA sequencing approach, we find that it is often hard to draw a firm line between different types of cells," Dr. Banovich said. "Instead of thinking of them as discrete cell types, we should think of them more along a continuum, and given the right stimulus, these cells can change their state."

In addition to the KRT5-/KRT17+ cells, the study identified a cell type marked by the gene SCGB3A2. These cells are similar to club cells -- an epithelial cell that lines the airways -- yet are found almost exclusively in in pulmonary fibrosis. Unlike other airway epithelial cells, it appears these cells are able to transform into type 1 alveolar cells (AT1) -- the cells where oxygen is taken into the body, and through which carbon dioxide is expelled -- in an effort to repair damage to the lung.

"In addition to becoming AT1 cells, our results suggest the SCGB3A2+ cells can also become the KRT5-/KRT17+ cells. It actually appears that, during the transformation into AT1 cells, the process is being hijacked and instead of helping repair the lungs these cells are pushed toward this weird pro-fibrotic epithelial cell that continues to drive fibrosis," Dr. Banovich said.

Two other cells unveiled by the study are distinct subsets of fibroblasts, the cells that form normal connective tissue and scar tissue in the lungs, marked by high levels of the genes PLIN2 or HAS1. These cells are also limited to pulmonary fibrosis.

IPF is a progressive and irreversible disease characterized by a dry cough, fatigue, aching muscles and joints, and ever worsening shortness of breath. IPF and PF both scar and stiffen the interstitium -- the delicate lace-like network that supports the lungs' tiny air sacs. IPF has both genetic and environmental risk, but the exact cause is unknown and current treatments short of a lung transplant only slow disease progression. Lung transplants are radical surgeries that usually require months of waiting for available organs, and often require a long and sometimes agonizing recovery.

The study acknowledges the help of: 10x Genomics and the Chan Zuckerberg Initiative in developing technology optimizations of the single-cell RNA sequencing; and the patients and organ donors who made this work possible.

Below please find a summary and link(s) of new coronavirus-related content published today in Annals of Internal Medicine. The summary below is not intended to substitute for the full article as a source of information. A collection of coronavirus-related content is free to the public at http://go.annals.org/coronavirus.

Quantifying and Interpreting Treatment Effects in COVID-19 Studies

Trials evaluating treatments for COVID-19 often use the time to a positive outcome as a key end point. In the presence of death as a competing risk, commonly used survival analysis techniques may not be appropriate. Using examples from two recent trials of treatments for COVID-19, the authors from Harvard University discuss issues with the current practice and present alternative, more clinically interpretable approaches. Read the full text: https://www.acpjournals.org/doi/10.7326/M20-4044.

Media contacts: PDFs for these articles is not yet available. Please click the link to read the full text. The lead author, Jason Lyell Vassy, MD, MPH, can be contacted directly at jvassy@partners.org.

Burkholderia pseudomallei is a bacterium in the soil that causes melioidosis, a tropical disease with high morbidity and mortality. Recently, researchers at the NUS Yong Loo Lin School of Medicine discovered that Burkholderia infection sets off a series of events that provoke the host's immune system and cause the infected cells to self-destruct. The work was published on 22 June in the prestigious journal Proceedings of the National Academy of Sciences U.S.A.

When Burkholderia pseudomallei infects cells, it can cause the infected cells to fuse with other cells around them, forming giant cells with many nuclei. Dr Joanne Wei-Kay Ku and Associate Professor Gan Yunn Hwen, both from the Department of Biochemistry and the NUSMed Infectious Disease Programme, as well as their co-authors found that this cell fusion event stimulated the type 1 interferon (IFN) signaling pathway, which modulates the immune system to fight against invading pathogens such as bacteria and viruses.

Interestingly, the act of the cells fusing, rather than the bacterial infection, was the trigger to the immune system because the type 1 IFN signaling pathway was also stimulated when cell fusion was induced by the addition of a chemical. The researchers found that the giant cells did not behave like normal cells. Firstly, they started to divide but could not complete the process (Images 1 and 2; Video). Secondly, the DNA in the giant cells was damaged, making it more unstable (prone to changes such as mutations). These are ripe conditions for the cells to transform into cancer cells.

One of the hallmarks of damaged, unstable DNA is the presence of micronuclei, which form when bits of DNA fail to segregate properly during cell division. When these micronuclei rupture (which they are prone to do), the DNA is made accessible to factors in the cytosol. A/Prof Gan and team observed micronuclei in the giant cells and a corresponding activation of the cGAS-STING pathway of the immune system, which senses the out-of-place DNA and is known to lead to type 1 IFN signaling.

However, under the onslaught of extensive cell fusion, the activated cGAS-STING pathway turns on an unusual death program known as autophagy instead of producing type 1 IFN. This causes these abnormal giant cells to self-destruct. Since unnatural cell fusion is often accompanied with DNA damage and instability, the killing mechanism could be a powerful way to destroy cells before they become cancerous.

The ability of our immune system to "sense" different forms of danger such as viral or bacterial invaders is well known. However, it took an unusual pathogen like Burkholderia bacteria for researchers to discover that abnormal cell fusion is a novel danger signal sensed by the immune system. These findings add to our understanding of how the immune system resists abnormally fused cells, whether a result of infections or through exposure to chemicals, from turning into cancer cells.

A/Prof Gan further explained the importance of knowing your enemy, "Our microbial adversaries are often our best teachers. Learning how to cure and control infections are critically important. However, understanding the interactions between pathogen and host is equally important, because it allows us to discover what our immune system is capable or incapable of, and these fundamental discoveries can give us new perspectives in maintaining health and treating disease."

The cover for issue 27 of Oncotarget features Figure 4, "(A) Bimodal imaging examples of control and treated tumors (red) before and after the treatment period," by Browning, et al. and reported that the authors developed a 3-dimensional bioprinted skin model of cutaneous squamous cell carcinoma (cSCC) tumors together with a microscopy assay to test chemotherapeutic effects in tissue.

Fluorescence-derived imaging biomarkers indicated that 50% of cancer cells were killed in the tissue after 1μM 5-Fluorouracil 48-hour treatment, compared to a baseline of 12% for untreated controls.

The imaging biomarkers also showed that normal keratinocytes were less affected by treatment than the untreated tissue, which had no significant killing effect.

Data showed that 5-Fluorouracil selectively killed cSCC cells more than keratinocytes.

The authors' 3DBPS assay platform provides the cellular-level measurement of cell viability and can be adapted to achieve non-destructive high-throughput screening in bio-fabricated tissues.

"The authors' 3DBPS assay platform provides the cellular-level measurement of cell viability and can be adapted to achieve non-destructive high-throughput screening in bio-fabricated tissues"

Dr. Daniel S. Gareau from The Laboratory for Investigative Dermatology at The Rockefeller University, New York said, "Global incidence of cSCC is 2.2 million people and accounts for most of the ~10,000 annual non-melanoma skin cancer deaths in the United States."

Drug discovery for small molecule therapies to treat locally advanced/inoperable or metastatic cSCC and other cancers can be accelerated using patient-specific, physiologically relevant models amenable to high-throughput screening.

Models should mimic the tumor microenvironment, given its influence on tumor progression and metastasis, and should reproduce in vivo tumor cell physiochemical signaling and mechanical cues from the surrounding tissue extracellular matrix.

Animal models may not be readily translatable to human cancer treatment, and three-dimensional tissue culture models offer a viable alternative for pre-clinical screening of small molecule therapeutics.

3D models using human-derived cell lines offer increased complexity and physiological fidelity compared with two-dimensional monocultures and have been developed for several cancer models, including melanoma, pancreatic cancer, and cervical cancer.

In the disease model presented here, A431 cSCC spheroids were introduced into the tissue, and histopathology and cDNA microarray analysis was used to confirm the biological fidelity of the cancer model.

The authors' objective was to quantify the therapeutic efficacy of a standard of care treatment for a cSCC skin tissue model that recapitulates the microenvironment in which this cancer grows.

The Gareau Research Team concluded in their Oncotarget Research Paper that the model described provides a higher degree of clinical relevance because it enables the testing of chemotherapeutics against tumor cell growth in a tissue-specific context, thus capturing any potential interactions between the tumor and its microenvironment.

They envision that this model could be adopted in a “bedside” manner and applied to cells from cSCC patient tumor biopsies.

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DOI - https://doi.org/10.18632/oncotarget.27570

Full text - https://www.oncotarget.com/article/27570/text/

Correspondence to - Daniel S. Gareau - dgareau@rockefeller.edu.

Keywords -
squamous cell carcinoma,
screening,
3D printing,
in vitro model,
confocal microscopy

About Oncotarget

Oncotarget is a weekly, peer-reviewed, open access biomedical journal covering research on all aspects of oncology.

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Oncotarget is published by Impact Journals, LLC please visit http://www.ImpactJournals.com or connect with @ImpactJrnls

Journal

Oncotarget

DOI

10.18632/oncotarget.27570

Oncotarget Volume 11, Issue 27 published "Epigenetic feedback and stochastic partitioning during cell division can drive resistance to EMT" by Jia et al. which reported that Epithelial-mesenchymal transition (EMT) and its reverse process mesenchymal-epithelial transition are central to metastatic aggressiveness and therapy resistance in solid tumors.

While molecular determinants of both processes have been extensively characterized, the heterogeneity in the response of tumor cells to EMT and MET inducers has come into focus recently, and has been implicated in the failure of anti-cancer therapies.

Recent experimental studies have shown that some cells can undergo an irreversible EMT depending on the duration of exposure to EMT-inducing signals.

While the irreversibility of MET, or equivalently, resistance to EMT, has not been studied in as much detail, evidence supporting such behavior is slowly emerging.

Here, the authors' identify two possible mechanisms that can underlie resistance of cells to undergo EMT: epigenetic feedback in ZEB1/GRHL2 feedback loop and stochastic partitioning of biomolecules during cell division.

Identifying the ZEB1/GRHL2 axis as a key determinant of epithelial-mesenchymal plasticity across many cancer types, the authors' use mechanistic mathematical models to show how GRHL2 can be involved in both the above mentioned processes, thus driving an irreversible MET. This study highlights how an isogenic population may contain subpopulation with varying degrees of susceptibility or resistance to EMT, and proposes a next set of questions for detailed experimental studies characterizing the irreversibility of MET/resistance to EMT.

Dr. Herbert Levine from The Center for Theoretical Biological Physics at Rice University as well as The Department of Physics at Northeastern University and Dr. Mohit Kumar Jolly from The Centre for BioSystems Science and Engineering at The Indian Institute of Science said "Epithelial-Mesenchymal Transition (EMT) is a cell biological process involved in driving cancer metastasis and therapy resistance?the two grand clinically unsolved challenges."

These hybrid E/M phenotypes may drive collective cell migration as clusters of tumor cells and can be more aggressive than cells in pure epithelial or mesenchymal phenotypes.

Recent experiments decoding the dynamics of EMT/MET using live-cell imaging and/or induction and withdrawal of various EMT-inducing external signals such as TGF? or tuning the levels of EMT-specific transcription factors have provided important insights into the reversibility of EMT and MET. Cells induced to undergo EMT for shorter durations may revert to an epithelial state after withdrawal of the signal/stimulus.

However, similar investigations about the irreversibility of MET, or in other words, the resistance of epithelial cells to undergo EMT in response to EMT-inducing signals, remain to be done.

Here, the authors' propose two independent mechanism that may explain the resistance of epithelial tumor cells to undergo EMT:

1) epigenetic feedback mediated via GRHL2?an MET-inducing transcription factor ; and
2) stochastic partitioning of parent cell biomolecules among the daughter cells at the time of cell division.

Conversely, here, the authors' show that incorporating this epigenetic feedback loop acting on the inhibition of ZEB1 by GRHL2 can cause an irreversible MET. Cells undergoing irreversible MET may exhibit resistance in undergoing EMT when exposed to EMT-inducing signals.

The Levine/Jolly Research Team concluded in their Oncotarget Research Paper that their results offer mechanistic insights into two possible mechanisms that may drive varying degrees of susceptibility and resistance to undergoing EMT in response to an EMT-inducing signal in a given isogenic population.

"Results offer mechanistic insights into two possible mechanisms that may drive varying degrees of susceptibility and resistance to undergoing EMT in response to an EMT-inducing signal in a given isogenic population."

Future efforts should decode the molecular mechanisms of any such epigenetic feedback of GRHL2 on ZEB1 expression as well as track the distribution of molecules during cell divisions happening while cells are being induced to undergo EMT/MET. Moreover, this study calls for concerted efforts to map the single-cell dynamics of MET induction.

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DOI - https://doi.org/10.18632/oncotarget.27651

Full text - https://www.oncotarget.com/article/27651/text/

Correspondence to - Herbert Levine - h.levine@northeastern.edu and Mohit Kumar Jolly - mkjolly@iisc.ac.in.

Keywords -
epithelial-mesenchymal transition,
mesenchymal-epithelial transition,
GRHL2,
epigenetics,
asymmetric cell division

About Oncotarget

Oncotarget is a weekly, peer-reviewed, open access biomedical journal covering research on all aspects of oncology.

To learn more about Oncotarget, please visit https://www.oncotarget.com or connect with:

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Oncotarget is published by Impact Journals, LLC please visit http://www.ImpactJournals.com or connect with @ImpactJrnls

Journal

Oncotarget

DOI

10.18632/oncotarget.27651

Oncotarget Volume 11, Issue 27 published "Australian experience of peptide receptor radionuclide therapy in lung neuroendocrine tumours" by Lim et al. which reported peptide receptor radionuclide therapy (PRRT) is an approved treatment modality for gastroenteropancreatic neuroendocrine tumours, although Phase III randomised clinical trial data is not available for NETs of other site of origin, in practice, PRRT is used more widely in clinical practice, based on its mechanism of targeting the somatostatin receptor.

A retrospective chart review of patients with TC and AC who received 177Lu-dotatate PRRT between January 2002 and June 2019 in six hospitals across Australia was undertaken.

Forty-eight patients received a median of four 177Lu-dotatate treatments.
The response rate to 177Lu-dotatate was 33%, with a median overall survival of 49 months, at a median follow up of 33 months.
177Lu-dotatate PRRT in patients with lung NETs is used in real world practice, where it appears well-tolerated with some efficacy.

Dr. Lisi Elizabeth Lim from The Department of Medical Oncology at Monash Health said "Neuroendocrine tumours (NETs) are uncommon malignancies, comprising 0.5% of all cancers."

Lung is the primary site for approximately 20?25% of NETs; conversely NETs comprises about 2% of all lung malignancies.

New trials have demonstrated that adequate numbers of patients can be recruited through global collaborations, both for protocols specific to lung NETs and those recruiting patients with NETs from a variety of sites.

PRRT is a firmly established treatment modality for advanced GEP NETs following the publication of the landmark NETTER-1 trial, where patients with progressive midgut NET were randomised to receive 177Lu-dotatate with ongoing octreotide long-acting repeatable therapy, or high dose octreotide LAR alone.

The significant benefit for PRRT in midgut NETs has provoked debate about whether randomised trials are required to prove its efficacy in NETs of other site of origin.

"The significant benefit for PRRT in midgut NETs has provoked debate about whether randomised trials are required to prove its efficacy in NETs of other site of origin."

NET consensus guidelines either omit specific comment on the use of PRRT in lung NETs, or state that imaging with SSTR-PET can assist in identifying patients who may benefit from PRRT. The Lim Research Team concluded in their Oncotarget Research Paper that further data will be forthcoming also from studies of PRRT in patients with SSTR-expressing tumours of histologies other than NET. The randomised phase II LUTHREE trial is inclusive of all SSTR positive tumour types, and is not restricted to NETs. The POLNETS trial is also extending the use of PRRT to paraganglioma and pheochromocytoma, in addition to advanced NETs of any site of origin.

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DOI - https://doi.org/10.18632/oncotarget.27659

Full text - https://www.oncotarget.com/article/27659/text/

Correspondence to - Lisi Elizabeth Lim - elizabeth.lisi.lim@gmail.com.

Keywords -
lung,
carcinoid,
atypical,
neuroendocrine,
peptide receptor radionuclide therapy

About Oncotarget

Oncotarget is a weekly, peer-reviewed, open access biomedical journal covering research on all aspects of oncology.

To learn more about Oncotarget, please visit https://www.oncotarget.com or connect with:

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Oncotarget is published by Impact Journals, LLC please visit http://www.ImpactJournals.com or connect with @ImpactJrnls

Journal

Oncotarget

DOI

10.18632/oncotarget.27659