Body

A study by Queen Mary University of London researchers, funded by Cancer Research UK, confirms the role of the oestrogen receptor biomarker in ductal carcinoma in situ and presents a new and more accurate method to predict long term outcomes for this pre-invasive stage of breast cancer. The study is published in Clinical Cancer Research.

Oestrogen receptor (ER), a protein expressed in some breast cancer cells, is routinely tested in invasive breast cancer to predict long-term outcomes select treatment options. Its role in ductal carcinoma in situ (DCIS) has been previously unclear, and it is not generally evaluated in this pre-invasive stage of breast cancer. The new research confirms the role of ER in predicting long-term outcomes in DCIS, and the authors report a new and more accurate method to evaluate ER for predicting long-term outcomes in DCIS.

This is the first study to use samples from a randomised trial (the UK/ANZ DCIS trial) to investigate ER as a prognostic marker in DCIS. The researchers observed multi-clonality in ER expression in 11% of ER-positive DCIS (ie: ER-positive DCIS with distinct ER-negative clones) and investigated the prognostic role of such multi-clonality in ER expression. They found that ER is a strong prognostic factor with greater than 3-fold risk of ipsilateral recurrence in ER-negative DCIS, and therefore conclude that ER should be routinely assessed in DCIS and that the clonal method they report should be considered.

Lead author Mangesh Thorat from Queen Mary University of London said: "It is unlikely that such a study could currently be reproduced elsewhere in the world, and the robustness of these results means we can rely on them to make changes to clinical practice. Routine testing of ER in DCIS will help to avoid both overtreatment and undertreatment in this type of breast cancer. The insights from this study will also help improve future breast cancer research through use of new scientific models, particularly in areas of drug resistance and the use of targeted therapies."

Michelle Mitchell, chief executive of Cancer Research UK, said: "It's currently very difficult to determine whether DCIS will develop into invasive breast cancer, meaning thousands of people undergo unnecessary and intense treatment. This research shows that in the future we might be able make sure patients are getting the right care, potentially saving many from undergoing cancer treatment that is both physically and mentally demanding."

WASHINGTON--Low doses of propylparaben--an estrogen-like chemical used as a preservative in personal care products and foods--can alter pregnancy-related changes in the breast in ways that may reduce the normal protection against breast cancer that pregnancy hormones convey, according to a new study being published in the Endocrine Society's journal Endocrinology.

These results, from an animal study that also will be presented at ENDO 2021, the Endocrine Society's annual meeting, lend evidence that propylparaben is an endocrine-disrupting chemical, the researchers say.

An endocrine-disrupting chemical interferes with the actions of hormones in the body. These chemicals can affect hormone-sensitive organs such as the mammary gland, the milk-producing duct in the breast, said the study's senior author Laura N. Vandenberg of the University of Massachusetts in Amherst, Mass.

"We found that propylparaben disrupts the mammary gland of mice at exposure levels that have previously been considered safe based on results from industry-sponsored studies. We also saw effects of propylparaben after doses many times lower, which are more reflective of human intake," Vandenberg said. "Although our study did not evaluate breast cancer risk, these changes in the mammary tissue are involved in mitigating cancer risk in women."

Hormones produced during pregnancy are not only responsible for reorganizing the breast tissue, allowing it to produce milk for the infant. They also are partly responsible for the reduced risk of breast cancer seen in women who give birth at a younger age.

The researchers tested whether propylparaben exposure during the vulnerable period of pregnancy and breastfeeding adversely alters this mammary gland reorganization. They exposed female mice to environmentally relevant doses of this common preservative during pregnancy and breastfeeding. Five weeks after the chemical exposure ended, they examined the mothers' mammary glands.

Compared with pregnant mice that had not received propylparaben, the exposed mice had mammary gland changes not typical of pregnancy, the researchers reported. These mice had increased rates of cell proliferation, which Vandenberg said is a possible risk factor for breast cancer. Additionally, they had less dense epithelial structures, fewer immune cell types and thinner periductal collagen, the connective tissue in the mammary gland.

"Some of these changes may be consistent with a loss of the protective effects that are typically associated with pregnancy," said co-first author, Joshua Mogus, M.S., a Ph.D. student at the University of Massachusetts.

He said future studies should address whether pregnant females exposed to propylparaben are actually more susceptible to breast cancer.

"Because pregnant women are exposed to propylparaben in many personal care products and foods, it is possible that they are at risk," Mogus said.

Pregnant and breastfeeding women should try to avoid using products containing propylparaben and other parabens, he suggested.

"This chemical is so widely used, it may be impossible to avoid entirely," Mogus added. "It is critical that relevant public health agencies address endocrine-disrupting chemicals as a matter of policy."

This research received funding from the University of Massachusetts Commonwealth Honors College Grant, the Endocrine Society's Summer Research Fellowship, and the National Institutes of Health.

Other authors of the study include: Charlotte D. LaPlante, Ruby Bansal, Klara Matouskova, Shannon J. Silva, Elizabeth Daniele, Mary J. Hagen and Karen A. Dunphy of the University of Massachusetts, Benjamin R. Schneider and Sallie S. Schneider of Baystate Medical Center in Springfield, Mass.; and D. Joseph Jerry of the University of Massachusetts and Pioneer Valley Life Sciences Institute in Springfield, Mass.

The manuscript, "Exposure to Propylparaben During Pregnancy and Lactation Induces Long-term Alterations to the Mammary Gland in Mice," was published online, ahead of print.

The research also will be presented at ENDO 2021, the Endocrine Society's annual meeting, which runs from March 20-23.

SLOW walkers are almost four times more likely to die from COVID-19, and have over twice the risk of contracting a severe version of the virus, according to a team of researchers from the National Institute for Health Research (NIHR) Leicester Biomedical Research Centre led by Professor Tom Yates at the University of Leicester.

The study of 412,596 middle-aged UK Biobank participants examined the relative association of body mass index (BMI) and self-reported walking pace with the risk of contracting severe COVID-19 and COVID-19 mortality.

The analysis found slow walkers of a normal weight to be almost 2.5 times more likely to develop severe COVID-19 and 3.75 times more likely to die from the virus than normal weight fast walkers. (1)

Professor Yates, Lead Researcher for the study and a Professor of Physical Activity, Sedentary Behaviour and Health at the University of Leicester said:-

"We know already that obesity and frailty are key risk factors for COVID-19 outcomes. This is the first study to show that slow walkers have a much higher risk of contracting severe COVID-19 outcomes, irrespective of their weight.

"With the pandemic continuing to put unprecedented strain on health care services and communities, identifying individuals at greatest risk and taking preventative measures to protect them is crucial."

A further key finding from this research was that normal weight slow walkers are more at risk for both severe COVID-19 and COVID-19 mortality than fast walkers with obesity. Furthermore, risk was uniformly high in normal weight slow walkers and slow walkers with obesity.

Professor Yates continued:-

"Fast walkers have been shown to generally have good cardiovascular and heart health, making them more resilient to external stressors, including viral infection but this hypothesis has not yet been established for infectious disease.

"Whilst large routine database studies have reported the association of obesity and fragility with COVID-19 outcomes, routine clinical databases do not currently have data on measures of physical function or fitness.

"It is my view that ongoing public health and research surveillance studies should consider incorporating simple measures of physical fitness such as self-reported walking pace in addition to BMI, as potential risk predictors of COVID-19 outcomes that could ultimately enable better prevention methods that save lives."

Durham, NC - Nuclear power offers an efficient, reliable way to provide energy to large populations - as long as all goes well. Accidents involving nuclear reactors such as those that took place in 1986 at Chernobyl and at Fukushima Daiichi after the March 2011 tsunami raise major concerns about what happens if the worst occurs and large numbers of people are simultaneously exposed to high levels of radiation. Currently, there are no effective, safe therapies for total body irradiation (TBI) - a condition known as acute radiation syndrome (ARS). That could change, in the future based on new research published in STEM CELLS Translational Medicine.

Researchers at the University of Pittsburgh Medical Center (UPMC) demonstrated, for the first time, how allogeneic adipose-derived stem cells (ASCs) can mitigate TBI-induced ARS. This would allow for the stockpiling of these cells to be used in case of a radioactive emergency.

"In nearly all instances of TBI exposure, the primary life-threatening damage is inflicted on the hematopoietic system, which primarily consists of the bone marrow, spleen, tonsils and lymph nodes involved in the production of blood. High doses of radiation can cause irreparable damage to the bone marrow, affecting the immune system and potentially causing inflammation and infection," said the study's co-author, Asim Ejaz, Ph.D., from the UPMC Department of Plastic Surgery.

A matched hematopoietic stem cell transplant is the current therapy of choice. Patients are either able to donate their own stem cells for transplantation - called an "autologous" transplant - or a donor whose stem cells are a good match is found. The odds of finding an adequate match is low at about 30 percent and for some populations the odds are even less.

"That fact leads to the major issue with relying on this type of therapy: In a mass population exposure scenario involving several hundred to millions of individuals, hematopoietic stem cell transfusion is an impossible way forward as there is just no way to treat massive numbers of people who are exposed to radiation at the same time. And unfortunately, such a delay in treatment for a large number of individuals would most certainly lead to an increase in their mortality rate," Dr. Ejaz said.

Several drugs are currently being looked at as potential therapies, but none provides complete protection, and all have unwanted side effects. This leaves the need for alternative therapies. Previous studies have reported that mesenchymal stem cells derived from bone marrow, placenta or Wharton's jelly can mitigate the effects of ARS. However, low yield and difficulty in harvest and mass production of these cells for stockpiling are some of their drawbacks.

"There is one attractive cell-based candidate we're looking at," said J. Peter Rubin, M.D., chair of the Department of Plastic Surgery at UPMC and a co-author of the study, "and that is adipose-derived allogeneic stem cells (ASCs). These are mesenchymal stem cells derived from adipose tissue (fat), which can easily be harvested in vast quantities from donors via liposuction.

"Adipose-derived ASCs have been proven to be safe, they have self-renewal capacity and can undergo differentiation to mature cells," he added. "They also are very easy to propagate in cell culture compared to other cell types, which means they can be stockpiled for application at mass levels in case of radiation accidents."

The team's study focused on how treating mice that were exposed to high levels of radiation with injections of allogeneic ASCs measured up to treating them with autologous ASCs. In particular, they wanted to see if the injections would improve the animals' survival rates and repair damage to their hematopoietic systems.

The injections were given 24 hours after the mice were exposed to the radiation. When, 35 days later, the researchers examined the results, they found that the allogeneic ASC-treated groups performed equally to the autologous cells in improving the animals' survival and recovery rates vs. the non-treated control group.

"The ASCs had migrated to the bone marrow and facilitated repair by secreting several factors known to reduce oxidative stress and rescue damaged bone marrow cells from apoptosis," Dr. Ejaz said.

Added Dr. Rubin, "This suggests that allogeneic ASCs therapy may be beneficial for clinical adaptation to treat TBI-induced toxicities. Further studies will help to advocate the scale-up and adaptation of allogeneic ASCs as the radiation countermeasure."

"The data from this pre-clinical study suggesting the ability of fat-derived stem cells as a therapy to effectively mitigate acute radiation syndrome is interesting and potentially useful," said Anthony Atala, M.D., Editor-in-Chief of STEM CELLS Translational Medicine and Director of the Wake Forest Institute for Regenerative Medicine. "Currently, there are no effective and safe approaches to treat mass population exposure to acute radiation syndrome; we welcome future studies that will enable the clinical adaptation of this type of therapy."

CAMBRIDGE, MA -- In the past few years, several medications have been found to be contaminated with NDMA, a probable carcinogen. This chemical, which has also been found at Superfund sites and in some cases has spread to drinking water supplies, causes DNA damage that can lead to cancer.

MIT researchers have now discovered a mechanism that helps explain whether this damage will lead to cancer in mice: The key is the way cellular DNA repair systems respond. The team found that too little activity of one enzyme necessary for DNA repair leads to much higher cancer rates, while too much activity can produce tissue damage, especially in the liver, which can be fatal.

Activity levels of this enzyme, called AAG, can vary greatly among different people, and measuring those levels could allow doctors to predict how people might respond to NDMA exposure, says Bevin Engelward, a professor of biological engineering at MIT and the senior author of the study. "It may be that people who are low in this enzyme are more prone to cancer from environmental exposures," she says.

MIT postdoc Jennifer Kay is the lead author of the new study, which appears today in Cell Reports.

Potential hazards

For several years, Engelward's lab, in collaboration with MIT Professor Leona Samson's lab, has been working on a research project, funded by the National Institute of Environmental Health Sciences, to study the effects of exposure to NDMA. This chemical is found in Superfund sites including the contaminated Olin Chemical site in Wilmington, Massachusetts. In the early 2000s, municipal water wells near the site had to be shut down because the groundwater was contaminated with NDMA and other hazardous chemicals.

More recently, it was discovered that several types of medicine, including Zantac and drugs used to treat type 2 diabetes and high blood pressure, had been contaminated with NDMA. This chemical causes specific types of DNA damage, one of which is a lesion of adenine, one of the bases found in DNA. These lesions are repaired by AAG, which snips out the damaged bases so that other enzymes can cleave the DNA backbone, enabling DNA polymerases to replace them with new ones.

If AAG activity is very high and the polymerases (or other downstream enzymes) can't keep up with the repair, then the DNA may end up with too many unrepaired strand breaks, which can be fatal to the cell. However, if AAG activity is too low, damaged adenines persist and can be read incorrectly by the polymerase, causing the wrong base to be paired with it. Incorrect insertion of a new base produces a mutation, and accumulated mutations are known to cause cancer.

In the new study, the MIT team studied mice with high levels of AAG -- six times the normal amount -- and mice with AAG knocked out. After exposure to NDMA, the mice with no AAG had many more mutations and higher rates of cancer in the liver, where NDMA has its greatest effect. Mice with sixfold levels of AAG had fewer mutations and lower cancer rates, at first glance appearing to be beneficial. However, in those mice, the researchers found a great deal of tissue damage and cell death in the liver.

Mice with normal amounts of AAG ("wild-type" mice) showed some mutations after NDMA exposure but overall were much better protected against both cancer and liver damage.

"Nature did a really good job establishing the optimal levels of AAG, at least for our animal model," Engelward says. "What is striking is that the levels of one gene out of 23,000 dictates disease outcome, yielding opposite effects depending on low or high expression." If too low, there are too many mutations; if too high, there is too much cell death.

Varying responses

In humans, there is a great deal of variation in AAG levels between different people: Studies have found that some people can have up to 20 times more AAG activity than others. This suggests that people may respond very differently to damage caused by NDMA, Kay says. Measuring those levels could potentially allow doctors to predict how people may respond to NDMA exposure in the environment or in contaminated medicines, she says.

The researchers next plan to study the effects of chronic, low-level exposure to NDMA in mice, which they hope will shed light on how such exposures might affect humans. "That's one of the top priorities for us, to figure out what happens in a real world, everyday exposure scenario," Kay says.

Another population for which measuring AAG levels could be useful is cancer patients who take temozolomide, a chemotherapy drug that causes the same kind of DNA damage as NDMA. It's possible that people with high levels of AAG could experience more severe toxic side effects from taking the drug, while people with lower levels of AAG could be susceptible to mutations that might lead to a recurrence of cancer later in life, Kay says, adding that more studies are needed to investigate these potential outcomes.

A genetic defect could hold the key to preventing or delaying the onset of a debilitating eye disease that can lead to vision loss and blindness.

MacTel (macular telangiectasia type 2) affects one in 1,000 Australians. Symptoms include slow loss of vision, distorted vision and trouble reading. Because early signs of the disorder are subtle, it is difficult to diagnose.

Researchers have identified an additional seven regions in the human genome that increase the risk of developing the condition, including a rare DNA mutation in the PHGDH gene, which will help clinicians to better diagnose and treat it.

The study builds on earlier WEHI research, which pinpointed that MacTel was associated with low levels of serine, an amino acid used in many pathways of the body.

Led by WEHI Professor Melanie Bahlo in conjunction with Dr Brendan Ansell, Dr Victoria Jackson and Dr Roberto Bonelli and published in Communications Biology, the research provides a new genetic risk calculator for predicting retinal disorders. The research was conducted in collaboration with The Lowy Medical Research Institute, USA and Moorfield's Eye Hospital, UK.

At a glance

MacTel is primarily caused by slight changes to the levels of several fundamental amino acids in an individual's blood

Researchers identified a further, rare, PHGDH gene mutation, which makes people five times more susceptible to developing MacTel, as well as seven other new genetic regions.

Understanding the genetic mutations that cause MacTel will allow clinicians to better screen for the condition and potentially prevent it from developing.

PHGDH increases MacTel risk

Researchers identified that a rare mutation in a gene - called PHGDH - dramatically increases the risk of developing MacTel.

"Amongst our new gene findings, we identified a new rare mutation in the PHGDH gene. These new findings further increase our understanding of retinal biology and the way the eye uses energy," Professor Bahlo said.

"People with this newly discovered PHGDH mutation are five times more likely to develop MacTel than people without this genetic mutation."

Eye disorder often diagnosed late

"MacTel is a really unique eye disease, which is caused by slight changes to levels of fundamental amino acids that have no impact on any other part of the body," she said.

"What we found is that the disease is driven by two factors; metabolic amino acid on one side and then risk factors related to the cellular health of the retina on the other side, which are probably involved in transporting crucial amino acids into the retina. Both of these factors contribute to whether someone is genetically predisposed to getting MacTel in later life."

Findings provide hope for improved diagnosis and treatment
Professor Bahlo said the findings could help improve diagnosis and treatment of MacTel.

"By understanding the causes of the condition, we can tailor treatment to each individual patient to ensure the best outcomes for them," she said.

"This disease is really hard to diagnose, so understanding the risk factors will allow clinicians to better predict and treat the condition."

Retinal disease usually progresses with age so early detection is vital to preserving eyesight in patients with the condition.

"By diagnosing this condition earlier, patients may be able to take mitigating steps to delay or prevent it developing," Professor Bahlo said.

The research team will now carry out further work with collaborators to look at identifying further genes involved in MacTel, with the aim of working towards better treatments and therapeutics.

Females who are fit and healthy tend to burn more fat when they exercise than men, according to new research from a team of sports nutritionists.

The research, comprising two new studies from academics led by the University of Bath's Centre for Nutrition, Exercise & Metabolism, analysed the factors that most influenced individuals' capacity to burn body fat when undertaking endurance sports.

How the body burns fat is important to all of us for good metabolic health, insulin sensitivity and in reducing the risk of developing Type II diabetes. But, for endurance sport competitions, such as running or cycling, how the body burns fat can make the difference between success and failure.

Previous research from the same team has shown how, for endurance athletes competing in distance events, the body's carbohydrate stores deplenish quickly when exercising. This means that that an athletes' ability to tap into their fat reserves to fuel them on becomes essential to their performance.

The first study, published in the International Journal of Sport Nutrition & Exercise Medicine, involved 73 healthy adults aged 19-63 (41 men; 32 women). It tested the lifestyle and biological factors for optimal fat burning by asking participants to take part in a cycling fitness test and measuring key indicators.

Their results found that females and those who were physically fitter, right across the age ranges, burnt fat more efficiently when exercising.

The second related paper, published in the journal Experimental Physiology, took this a stage further to explore what molecular factors in our muscles and fat tissue determine how fat is burnt. This experiment involved the researchers taking fat and muscle biopsies from participants to analyse how differences in the proteins in fat and muscle tissue might affect their ability to burn fat.

It found that the proteins in muscle that are involved in breaking down stored fat into the smaller fatty acids, and proteins involved in transporting those fatty acids into the mitochondria in muscle (the powerhouse of the cells) consistently correlated with a greater ability to burn fat. The molecular factors explored did not explain why females burned more fat than males, however.

Lead author on both papers, Ollie Chrzanowski-Smith from the University of Bath explains: "Our study found that females typically have a greater reliance upon fat as a fuel source during exercise than males. Understanding the mechanisms behind these sex differences in fuel use may help explain why being female seems to confer a metabolic advantage for insulin sensitivity, an important marker of metabolic health."

The researchers note that the ability to burn fat as a fuel appears to protect against future weight gain, ensuring good weight management. However, they caution that the body's ability to burn fat should not be equated with an ability to lose weight. Losing weight is primarily produced by an energy deficit (ie. consuming fewer calories than we expend). For weight loss, in particular where individuals might be overweight, they stress the importance of diet and exercise.

Dr Javier Gonzalez, also from the University of Bath's Department for Health, added: "Weight management is mainly about energy balance, so to lose weight we need to eat fewer calories than we expend through our resting metabolism and physical activity. However, people with a higher ability to burn fat as a fuel seem to be somewhat protected against future weight gain, which might be related to how fat burning affects food intake and energy expenditure.

"Ultimately, a greater capacity to burn fat as a fuel has potential benefits for endurance athletes, by delaying the timepoint when they run out of precious carbohydrate stores."

Low doses of propylparaben - a chemical preservative found in food, drugs and cosmetics - can alter pregnancy-related changes in the breast in ways that may lessen the protection against breast cancer that pregnancy hormones normally convey, according to University of Massachusetts Amherst research.

The findings, published March 16 in the journal Endocrinology, suggest that propylparaben is an endocrine-disrupting chemical that interferes with the actions of hormones, says environmental health scientist Laura Vandenberg, the study's senior author. Endocrine disruptors can affect organs sensitive to hormones, including the mammary gland in the breast that produces milk.

"We found that propylparaben disrupts the mammary gland of mice at exposure levels that have previously been considered safe based on results from industry-sponsored studies. We also saw effects of propylparaben after doses many times lower, which are more reflective of human intake," Vandenberg says. "Although our study did not evaluate breast cancer risk, these changes in the mammary tissue are involved in mitigating cancer risk in women."

Hormones produced during pregnancy not only allow breast tissue to produce milk for the infant, but also are partly responsible for a reduced risk of breast cancer in women who give birth at a younger age.

The researchers, including co-lead author Joshua Mogus, a Ph.D. student in Vandenberg's lab, tested whether propylparaben exposure during the vulnerable period of pregnancy and breastfeeding adversely alters the reorganization of the mammary gland. They examined the mothers' mammary glands five weeks after they exposed the female mice to environmentally doses of propylparaben during pregnancy and breastfeeding.

Compared with pregnant mice that had not received propylparaben, the exposed mice had mammary gland changes not typical of pregnancy, the researchers report. These mice had increased rates of cell proliferation, which Vandenberg says is a possible risk factor for breast cancer. They also had less-dense epithelial structures, fewer immune cell types and thinner periductal collagen, the connective tissue in the mammary gland.

"Some of these changes may be consistent with a loss of the protective effects that are typically associated with pregnancy," says Mogus, who was chosen to present the research, deemed "particularly newsworthy" by the Endocrine Society, at the international group's virtual annual meeting, ENDO 2021, beginning March 20.

Mogus says future studies should address whether pregnant females exposed to propylparaben are actually more susceptible to breast cancer. "Because pregnant women are exposed to propylparaben in many personal care products and foods, it is possible that they are at risk," Mogus says, adding that pregnant and breastfeeding women should try to avoid using products containing propylparaben and other parabens.

"This chemical is so widely used, it may be impossible to avoid entirely," Mogus adds. "It is critical that relevant public health agencies address endocrine-disrupting chemicals as a matter of policy."

The continuous improvement of imaging technology holds great promise in areas where visual detection is necessary, such as with cancer screening. Three-dimensional imaging in particular has become popular because it provides a more complete picture of the target object and its context.

"More doctors and radiologists are looking at these 3D volumes, which are new technologies that allow you to look not just at one image, but a set of images," said UC Santa Barbara psychology professor Miguel Eckstein(link is external), whose expertise lies in the field of visual search. "In some imaging modalities this gives doctors information about volume and it allows them to segment what they're interested in."

Common wisdom is that with all this additional information provided, the rate of detection success should increase considerably. However that's not always the case, Eckstein said. In a study(link is external) published in the journal Current Biology, he, lead author Miguel Lago and their collaborators point out an odd foible of human vision: We're actually worse at finding small targets in 3D image stacks than if they were in a single 2D image.

"For those type of small targets, what happens is that they become harder to find in these 3D volumes," Eckstein explained. Unlike humans, machine observers (e.g., deep neural networks) did not show this deficit with small targets in 3D search, suggesting that the effect is related to some human visual-cognitive bottleneck.

It's a phenomenon that could have important implications in the medical field, particularly in the realm of breast cancer screening with the growing popularity of breast tomosynthesis (3D mammography) to detect not just large, unusual masses but also microcalcifications that could signal the beginnings of cancer development. According to the study, searching through 3D renderings led to high small target miss rates and a significantly decreased decision confidence on the part of the observer.

"Another thing we found out was that when you ask people searching these 3D volumes how much they explored, they tended to overestimate quite a bit how much they thought they explored," he added. Based on results from eye-tracking software, subjects conducting the 3D search were looking through only about half of the search area while reporting up to more than 80% image exploration.

Much of the reason for this diminished performance, according to the paper, is how we use our vision when we search. We use both focused and peripheral vision to analyze the object before us and decide where next to fix our attention. People searching through a 2D image tended to rely more on their fovea (the part of the retina that brings objects into sharp, direct focus) and more exhaustively move their focus around the image. Those searching through 3D renderings -- composites of many images -- were found to move their gaze less and rely on peripheral visual processing.

"What happens is when doctors are looking through these 3D images, they basically underexplore the whole data set," said Eckstein, whose collaborators in the Department of Radiology at University of Pennsylvania reproduced the effect with some radiologists. "They're not looking at every single spot on every single image, because it takes a long time." The lack of eye movement in 3D searches could also be a matter of strategy, he added, in which clinicians fix on the same spot in every image as they flip back and forth through the stack.

Small targets, Eckstein explained, were highly detectable at or near the point of fixation but became much less noticeable as they moved toward the periphery. This fundamental visual limitation, the eye movement under-exploration and reliance on peripheral vision resulted in a high number of errors in the 3D searches.

The same couldn't be said for large targets, which followed the common wisdom about the benefits of 3D images; their detection was improved in the 3D searches.

The findings of this paper illustrate the gaps that sometimes arise between the technology we invent and our ability to make the best use of it, according to Eckstein.

"We're good at making technology, but sometimes we don't really connect with it that well," he said. "And we don't know that we don't connect with it that well."

In the case of radiologists combing through 3D images for small targets, this bottleneck of human vision and cognition, once recognized, could be improved with practice and extended search times. In some cases, clinicians already lean on synthesized 2D images for the small targets while using 3D renderings for the large objects. Performance may also be improved with the use of computer vision, artificial intelligence and/or having multiple observers scrutinizing images.

Even though a fruit fly doesn't have ears, it can hear with its antennae. In a new study published in the journal Development, USC Stem Cell scientists describe how adult flies can regenerate sensory hearing cells in their antennae, and how studying flies can provide a new way to understand and develop treatments for the hundreds of millions of patients worldwide who live with hearing and balance disorders.

"Flies provide a powerful way to study the biology of hearing and balance at cellular, circuitry and behavioral levels. We can quickly and inexpensively perform sophisticated experiments on large swarms of flies, and we already possess a detailed map of their genomes and neural circuitry," said postdoctoral fellow Ismael Fernández-Hernández, who led the study, along with co-author Evan Marsh and corresponding author Michael Bonaguidi.

In the fly, the sensory hearing cells are neurons located in a segment of their antennae known as the Johnston's Organ, or JO. Despite differences in form, the genetic programs and function of these neurons are extremely similar in flies and mammals. The scientists were able to label, trace and view newborn JO neurons in live flies under microscopes.

In healthy flies, JO neurons were naturally turning over. The scientists set out to discover a distinct "cell type of origin." Instead, they observed JO neurons proliferate and produce more of themselves--although this doesn't rule out the potential for other types of cells to also produce JO neurons.

In flies given the chemotherapy drug cisplatin, which is known to kill sensory hearing cells, JO neurons compensated for the damage by proliferating even more. In flies given a different drug, known to enhance the generation of neurons in the brain, JO neurons similarly increased their proliferation.

The scientists also observed the JO neurons developing hair-like extensions known as cilia, and extending long nerve fibers called axons into hearing- and balance-related circuits in the brain. These features indicate that new JO neurons mature and may functionally remodel existing circuitry.

"Flies have the potential to provide many insights into how to promote the regeneration of sensory hearing cells," said Bonaguidi, who is an assistant professor of stem cell biology and regenerative medicine at the Keck School of Medicine of USC. "This is such an important area of research, given that one in three people can expect to develop a hearing or balance disorder by the age of 80. Our results establish a new in vivo platform to expedite the search for compounds promoting their recovery."

Philadelphia, March 15, 2021 - Biomarker testing surveys specific disease-associated molecules to predict treatment response and disease progression; however its use has complicated the diagnosis of non-small-cell lung cancer (NSCLC). In a new study in The Journal of Molecular Diagnosis, published by Elsevier, investigators provide for the first time a complete overview of biomarker testing, spanning multiple treatment lines, in a single cohort of patients.

Using exploratory data analysis and process-mining techniques in a real-world setting, investigators identified significant variation in test utilization and treatment. They also found that while whole-genome sequencing, in which a patient's unique DNA is mapped at once, may not be a cost saving alternative to biomarker testing, as some have suggested, it may have other benefits for patients, such as decreasing the time between testing and therapy.

"While there is a lot of interest in the use of real-world data to analyze treatment variation and outcomes, this study demonstrates the importance of identifying variation in the use of molecular tests as the gateway to most cancer treatments," explains lead investigator Professor Maarten IJzerman, Health Technology and Services Research, TechMed Center, University of Twente, Enschede, the Netherlands; and the University of Melbourne Centre for Cancer Research in Melbourne, Australia.

The investigators had access to the complete biomarker testing history of 102 stage IV NSCLC patients who had been referred to a comprehensive cancer center in the Netherlands. Patients are referred to such a facility when they have a complex case, enroll in a clinical trial, or have exhausted treatment options at the referring hospital. Eligible patients were identified using linked pathology data from the referring hospitals to ensure analysis of their complete diagnostic pathways. Process mining allows for the discovery of the actual ordering of care processes and for the evaluation of the characteristics of testing, such as turnaround times and costs.

This study is the first to provide a comprehensive report that includes tested genes, utilized techniques, costs, and turnaround times on the entire sequence of tests received by patients with stage IV NSCLC.

Ninety-nine unique biomarker-test combinations were found in 102 patients; almost none underwent the same tests in the same order. The most common biomarkers were typically tested in the first few tests, and emerging biomarkers were typically tested later. The number of tests per patient also showed substantial variation. Tests were completed at different times in each patient, and in most patients more than one test was completed.

The mean cost per patient of biomarker testing was US$2258.52 / €1881.23. The number of patients for whom biomarker testing would be equally or less expensive if their entire test sequence had been replaced by whole-genome sequencing ranged from 2 to 29, depending on the assumed cost.

"We have shown that it is currently unlikely that replacing the current practice of molecular testing in lung cancer with whole-genome sequencing will be cost saving," notes first author Michiel van de Ven, PhD candidate, TechMed Center, University of Twente, Enschede, The Netherlands. "Yet, for whole-genome sequencing to be routinely used there are other aspects where it adds value, such as the discovery of other driver mutations not routinely tested for and the potential to streamline diagnostic workflows."

Multiple biomarker tests for NSCLC can result in unnecessary delays in treatment. The substantial variation of biomarker tests in patients suggests the possibility of inequities in access to the tests and subsequently in access to targeted therapy or immunotherapy. "Whole-genome sequencing may reduce the complexity of the diagnostic pathway, but it has not yet been explored in detail. It could be an exciting avenue for future research," concludes Professor IJzerman.

BOSTON - Researchers at Massachusetts General Hospital (MGH) have uncovered new clues that add to the growing understanding of how female mammals, including humans, "silence" one X chromosome. Their new study, published in Molecular Cell, demonstrates how certain proteins alter the "architecture" of the X chromosome, which contributes to its inactivation. Better understanding of X chromosome inactivation could help scientists figure out how to reverse the process, potentially leading to cures for devastating genetic disorders.

Female mammals have two copies of the X chromosome in all of their cells. Each X chromosome contains many genes, but only one of the pair can be active; if both X chromosomes expressed genes, the cell couldn't survive. To prevent both X chromosomes from being active, female mammals have a mechanism that inactivates one of them during development. X chromosome inactivation is orchestrated by a noncoding form of RNA called Xist, which silences genes by spreading across the chromosome, recruiting other proteins (such as Polycomb repressive complexes) to complete the task.

Jeannie Lee, MD, PhD, an investigator in the Department of Molecular Biology at MGH and the paper's senior author, has led pioneering research on X chromosome inactivation. She believes that understanding the phenomenon could lead to cures for congenital diseases known as X-linked disorders, which are caused by mutations in genes on the active X chromosome. "Our goal is to reactivate the inactive X chromosome, which carries a good copy of the gene," says Lee. Doing so could have profound benefits for people with conditions such as Rett syndrome, a disorder brought on by a mutation in a gene called MECP2 that almost always occurs in girls and causes severe problems with language, learning, coordination and other brain functions. In theory, reactivating the X chromosome could cure Rett syndrome and other X-linked disorders.

In this study, Lee and Andrea Kriz, a PhD student and first author of the paper, were interested in understanding the role of clusters of proteins called cohesins in X inactivation. Cohesins are known to play a critical role in gene expression. Imagine a chromosome as a long piece of string with genes and their regulatory sequences being far apart, says Lee. For the gene to be turned "on" and do its job, such as producing a specific protein, it has to come in contact with its distant regulator. Chromosomes allow this to happen by forming a small loop that brings together the gene and regulator. Ring-shaped cohesins help these loops form and stabilize. When the gene's work is done and it's time to turn off, a scissor-like protein called WAPL snips it, causing the gene to disconnect from its regulator. An active chromosome has many of these loops, which are continually forming and dissociating (or separating).

These small loops, which are essential for gene expression, are relatively suppressed on an inactivated X chromosome. One reason, as Lee and her colleagues have already shown, is that Xist "evicts" most cohesins from the inactive X chromosome and that this cohesin depletion may be necessary to reorganize the shape and structure of the chromosome for silencing.

In the current study, Lee and Kriz used embryonic stem cells from female mice to find out what happens when cohesin or WAPL levels are manipulated during X chromosome inactivation by using protein-degradation technology. "We found that if cohesin levels build up too high, the X chromosome cannot inactivate properly," says Lee. Normally, retaining cohesins (which are normally supposed to be evicted) prevented the X chromosome from folding into an inactive shape and gene silencing was affected. "You need a fine balance between eviction and retention of cohesins during X chromosome inactivation," says Lee.

Next, the authors asked what happens when cohesin is manipulated in an active X chromosome. The short answer: It takes on some peculiar qualities of an inactivated X chromosome. First, when there is insufficient cohesin, the active X develops structures called "superloops" that are usually only seen on the inactive X. Second, when there is too much cohesin, the active X develops "megadomains," which Lee calls two "big blobs," and are also ordinarily unique to the inactive X. "The fact that we can confer some features of the inactive X chromosome onto the active X chromosome just by toggling cohesin levels is intriguing," says Lee. She and her colleagues are trying to understand how and why that happens.

These findings suggests that shape and structure of the X chromosome play a vital role in allowing Xist to spread from one side to the other and achieve inactivation. "The more we learn about what's important for silencing the X chromosome," says Lee, "the more likely we'll be to find ways to reactivate it and to treat conditions like Rett syndrome."

March 15, 2021 - After arthroscopic surgery on the meniscus of the knee, patients using telemedicine for postoperative follow-up are just as satisfied with their care as those making in-person visits, reports a study in The Journal of Bone & Joint Surgery. The journal is published in the Lippincott portfolio in partnership with Wolters Kluwer.

"Patient satisfaction with overall care is equivalent between telemedicine and office-based follow-up after an arthroscopic meniscal surgical procedure in the immediate postoperative period," according to the randomized trial report by Christina P. Herrero, MD, and colleagues of NYU Langone Health, New York , and colleagues.

Telemedicine is 'a reasonable alternative' for postoperative visits

The study included 122 patients who underwent arthroscopic surgery of the meniscus - sometimes called the "shock absorber" of the knee. About 88 percent of patients underwent removal of the meniscus (meniscectomy), and the rest underwent meniscal repair procedures. Arthroscopic meniscal surgery is one of the most common orthopaedic surgical procedures.

Patients were randomly assigned to either office-based or telemedicine follow-up, scheduled for 5 to 14 days postoperatively. During both types of follow-up visits, the surgeon talked to the patient about the surgical findings, the patient's pain, and the postoperative recovery period and performed a physical examination that included range-of-motion testing.

Of course, surgeons could not feel or touch the knee during telemedicine follow-ups - but they were still able to perform a visual assessment of wound healing, drainage, and swelling. Telemedicine follow-ups were performed using the patient's home computer or mobile device via a telemedicine program that was compliant with privacy rules.

In patient surveys, overall satisfaction ratings were almost identical between groups. Average patient satisfaction scores (on a 0-to-10 scale) were 9.77 with office-based follow-up and 9.79 for telemedicine follow-up. In both groups, only about 20 percent of patients said they would have preferred the other type of visit. Pain scores also showed similar improvement between groups: from about 5 (out of 10) on the day of the surgery to 3 at the follow-up visit.

Both groups had low complication rates. Two patients in each group had pain and swelling, raising concern about a possible blood clot-related complication (venous thromboembolism, or VTE). All four patients were sent for same-day Doppler ultrasound scans, which found no evidence of VTE. "All potential complications were identified, and there were no subsequent or missed complications identified on subsequent chart review," Dr. Herrero and colleagues write.

Telemedicine is a promising approach to delivering "direct, long-range care" to patients with many different conditions. During the COVID-19 pandemic, the use of telemedicine in routine medical care has greatly accelerated; the researchers began their study well before the start of the pandemic.

Although studies have reported a wide range of benefits from telemedicine visits, there are mixed data regarding satisfaction with telemedicine visits among patients undergoing common orthopaedic procedures. The new study is the first to directly compare telemedicine with standard office-based follow-up after orthopaedic surgery.

"Telemedicine may be a reasonable alternative to office-based follow-up after knee arthroscopy," Dr. Herrero and coauthors conclude. "[Our] study only evaluated the first postoperative visit, but future studies may benefit from expanding the use of telemedicine to longer-term follow-ups or to additional surgical procedures."

HSE University researchers together with specialists from the Humanitarian Action Charitable Fund (St. Petersburg) and the University of Michigan School of Public Health (USA) studied the specifics of remote work with Russian people who use drugs to reduce the harm of drug use. They discovered that the use of online platforms increases the § who use drugs to seek help. Online platforms also serve as a kind of 'gateway' for people with problematic drug use to receive a wider range of qualified help. The authors concluded that remote work in this field should be developed and built upon in an ongoing systematic way even when the threat of coronavirus recedes. The results of the study are published in the Harm Reduction Journal.

All over the world, people who use drugs face many health hazards. These include, for example, contracting HIV, hepatitis C, vein damage, overdoses, and numerous psychological problems.

Drug-related harm reduction programmes, often run by NGOs, are aimed at combating that harm. Humanitarian Action is one such non-governmental organisation in Russia. Founded in 1997, Humanitarian Action provides accessible services for people with substance use disorders, that are designed to reduce the severity of the negative consequences of drug use. These services include:

exchange and disposal of used syringes and needles;

provision of motivational packages containing sterile syringes, alcohol wipes, water for injections, ointments, bandages;

help with express testing for HIV, HCV, HBV, and syphilis;

support and referral of clients to medical centres for HIV diagnosis confirmation and initiation of antiretroviral therapy (ART);

assistance in accessing treatment for opioid drug overdose;

case management in accessing social, medical, and legal services.

These services are provided at no cost to individuals when they visit the NGO's mobile units. The NGO has recently added web outreach work to its activities in order to increase the programmes' accessibility, including for people who use drugs who do not attend the mobile units.

One of the main online services that the NGO actively uses to interact with people who use drugs is Telegram instant messaging. As of June 2020, the platform had 30 million active users in Russia.

The researchers used the example of a St. Petersburg NGO to analyse the most frequent requests received via Telegram from people who use drugs, the difficulties they face with people who use drugs and the specialists assisting them, and the prospects for the development of a remote format of working in the field of drug use harm reduction.

Researchers have analysed the working reports of NGO staff in 301 cases of web outreach work. The period of contact with people who use drugs in these cases was from November 2019 to June 2020. These included a description of the clients' needs as well as the nature of the assistance provided.

In addition, the researchers conducted four semi-structured interviews with the NGO staff and the deputy director in June 2020, to study the process of web outreach in terms of organisational processes. A thematic analysis method was used in the study. The study was approved by the Ethical Committee of the St. Petersburg Association of Sociologists.

It turned out that the most frequent online requests for help from people who use drugs concern:

minor complications arising from injecting drugs;

information regarding harm reduction, HIV, and HCV;

information regarding detoxification at home;

information regarding the COVID-19 pandemic;

psychological support.

The study provides a comprehensive picture of how the NGO works with people who use drugs. As a rule, NGO clients direct their question to a group chat. If the answer to a question may be important for all participants in the group chat, then the NGO specialist responds in the chat itself. If the question is of a sensitive nature and/or private communication is required, then the NGO staff member contacts the client privately.
Sometimes other participants may provide answers in the general group chat. The NGO staff will then moderate the discussions in order to maintain a safe and comfortable space.

The most frequent enquiries concern minor complications related to drug use. These fall into the category of minor complications when face-to-face medical care is unnecessary. In fact, they refer to such unpleasant consequences of injecting drugs as collapsed veins, venous bleeding, varicose veins, venous ulcers, and rashes. People who use drugs describe their problems text and/or with photos. The specialists' answers are verified by medical professionals before they are sent. In cases where a web outreach worker feels that more skilled medical assistance is needed, the client will be directly contacted by a doctor working at the NGO.

Other common requests for help relate to information on how to reducing the harm and risk of contracting HIV or hepatitis -- for example, centres where antiretroviral therapy (ART) is available. Some clients enquire through the NGO staff about the ways in which HIV and hepatitis are transmitted.

A less common, yet still important topic of enquiry is detoxification at home. Only a few clients have shown interest in this topic, the researchers noted. NGO staff informed people who use drugs about the potential risks, as well as providing general information on how detoxification is carried out in medical settings and contact information of specialists with whom clients can get in touch.

Since April 2020, a number of COVID-19 pandemic-related needs have emerged. Specifically, clients have asked how they can get help during the pandemic, such as details of rehabilitation programmes or detoxification services.

Another frequent reason people who use drugs ask for help via Telegram is the need for psychological support. Among the most common requests are: difficulties in combatting drug addiction, anxiety about the repercussions of quarantine measures (e.g. drug shortages), anxiety about the death of a partner, worries about possible infection. If the clients do not request the help of a certified psychologist, the web outreach workers provide them with advice based on their personal experience and the contact information of the NGO staff who can be contacted for additional help.

During the study, the authors identified a separate block of enquiries that cannot be fully handled online because they require the client to be physically present. Such requests occurred in nearly a third of the cases analysed. For example, clients needed personal assistance in obtaining ART at a specialised centre, receiving ART in a home setting, personal assistance with hospitalisation for detoxification and rehabilitation, support from a certified psychologist, assistance with obtaining documents or confirming incapacity to work. In such cases, people who use drugs were invited to the NGO's mobile units for face-to-face assistance.

Other requests that could not be processed online included severe complications from intravenous drug use, such as severe venous bleeding and lesions, swelling, and skin abscesses. In addition, people who use drugs sought help via Telegram related to HIV and hepatitis testing. In these cases, clients received instructions on how they could be tested.

The smallest number of enquiries was related to overdose. For these requests, the NGO created a special Telegram bot that provided clients with the necessary information about symptoms, treatment options, and the contact information of a doctor who could provide online assistance. In two of the four cases, clients had to call an ambulance. The centre's staff stayed in touch with clients until the paramedics arrived.

The researchers determined the difficulties that arose during communication between people who use drugs and the professionals assisting them online. These include, for example, sending voice messages when the staff member cannot listen to them or messages at night when the staff member is not available. Sometimes clients send illegible messages because they cannot formulate the request correctly. The centre's staff then offer to call them back, but further dialogue may not take place.

Some staff noted that phone calls are the next step in communication between the client and the NGO specialist.

Nevertheless, as the research has shown, Telegram serves as a kind of gateway to harm reduction for people who use drugs. From the point of view of the NGO's staff, it is a convenient 'first step' that clients can take to receiving assistance. Importantly, the availability of such services increases the likelihood that people who use drugs, who are not ready to discuss their drug-related problems face-to-face, will contact specialists.

Researchers have concluded that existing online services aimed at reducing the harm of drugs could be improved. One of the possible solutions, they believe, is to automate some of the work, for example by using more bots that clients could use, including at night. 'However, not all services can be automated; therefore, it may be necessary to hire employees who can respond to clients during the night. This is especially important when it comes to critical situations such as overdose,' says the study.

The researchers also suggest that an effective way to develop online harm reduction services could be to increase their presence on darknet forums.

Every year in Russia, thousands of people die and suffer critical complications related to drug use. For example, according to data provided in a report by the State Anti-Drug Committee, 4,569 people died from drug use in Russia in 2019, an increase of 2.8% compared to 2018. There were also 18,053 cases of drug poisoning, an increase of 10.5% compared to 2018. Meanwhile, about half a million people (423,400) with mental and behavioural disorders related to drug use were registered in Russia in 2018, according to the Ministry of Health of the Russian Federation. Among them, 5,400 were minors.

During the pandemic, many services, including those related to healthcare, have become difficult to access -- especially for stigmatised groups. In this context, online services aimed at reducing the harm of drug use are of particular importance.

The findings of the study show how effective web outreach work with people who use drugs can be. However, according to the authors, further research in this area is needed. It is important, for example, to understand the motivations behind the refusal of drug addicts to continue communicating with specialists by phone, to clarify their needs, and to develop new ways to reduce the harm of drug use.

Exercise during pregnancy may let mothers significantly reduce their children's chances of developing diabetes and other metabolic diseases later in life, new research suggests.

A study in lab mice has found that maternal exercise during pregnancy prevented the transmission of metabolic diseases from an obese parent - either mother or father - to child. If the finding holds true in humans, it will have "huge implications" for helping pregnant women ensure their children live the healthiest lives possible, the researchers report in a new scientific paper.

This means that one day soon, a woman's first trip to the doctor after conceiving might include a prescription for an exercise program.

"Most of the chronic diseases that we talk about today are known to have a fetal origin. This is to say that the parents' poor health conditions prior to and during pregnancy have negative consequences to the child, potentially through chemical modification of the genes," said researcher Zhen Yan, PhD, a top exercise expert at the University of Virginia School of Medicine. "We were inspired by our previous mouse research implicating that regular aerobic exercise for an obese mother before and during pregnancy can protect the child from early onset of diabetes. In this study, we asked the questions, what if an obese mother exercises only during pregnancy, and what if the father is obese?"

Exercise and Pregnancy

Scientists have known that exercise during pregnancy helps lead to healthy babies, reducing the risk of pregnancy complications and premature delivery. But Yan, the director of the Center for Skeletal Muscle Research at UVA's Robert M. Berne Cardiovascular Research Center, wanted to see if the benefits continued throughout the children's lives. And his work, both previous and new, suggests it does.

To determine that, Yan and his collaborators studied lab mice and their offspring. Some of the adult mice were fed typical mouse chow before and during pregnancy, while other were fed a high-fat, high-calorie diet to simulate obesity. Some receiving the high-fat diet before mating had access to a voluntary running wheel only during pregnancy, where they could run all they liked, while others did not, meaning they remained sedentary.

The results were striking: Both mothers and fathers in the high-fat group could predispose their offspring to metabolic disorders. In particular, male offspring of the sedentary mothers on high-fat diets were much more likely to develop high blood sugar and other metabolic problems in adulthood.

To better understand what was happening, the researchers looked at the adult offspring's metabolism and chemical (epigenetic) modification of DNA. They found there were significant differences in metabolic health and how active certain genes were among the different groups of offspring, suggesting that the negative effects of parental obesity, although different between the father and the mother, last throughout the life of the offspring.

The good news is that maternal exercise only during pregnancy prevented a host of "epigenetic" changes that affect the workings of the offspring's genes, the researchers found. Maternal exercise, they determined, completely blocked the negative effects of either mother's or father's obesity on the offspring.

The results, they say, provide the first evidence that maternal exercise only during pregnancy can prevent the transmission of metabolic diseases from parent to child.

"The take-home message is that it is not too late to start to exercise if a mother finds herself pregnant. Regular exercise will not only benefit the pregnancy and labor but also the health of the baby for the long run," Yan said. "This is more exciting evidence that regular exercise is probably the most promising intervention that will help us deter the pandemic of chronic diseases in the aging world, as it can disrupt the vicious cycle of parents-to-child transmission of diseases."