Culture

The cover for issue 62 of Oncotarget features Figure 7, "Proposed model of the hyperploid pathway as a salvage survival strategy regulated by the G2-M checkpoint," by Yeung, et al.

Subpopulations of tumor cells may exhibit diverging behaviors from the bulk tumor due to an alternate stress response that diverts tumor cells from apoptotic death.

In this study, the researcher identified a salvage survival pathway in which G2-arrested tumor cells bypassed apoptosis and progressed through aberrant mitotic events to then emerge as a distinct subpopulation of viable large hyperploid cells but with uncertain long-term propagation potential.

Dr. Robert Rottapel and Dr. Andras Kapus said "High grade serous carcinoma (HGSC) of tubal-ovarian origin is an aggressive epithelial tumor with poor survival outcomes. Platinum drugs are used as part of first-line therapy and exert genotoxic effects to tumor cells"

For tumor cells lacking a functional G1-S checkpoint such as in high grade serous carcinoma where the retinoblastoma and p53 pathways are perturbed, an arrest in cell cycle at the G2 phase is critical for DNA damage repair.

The entry to mitosis with residual DNA damage often results in mitotic catastrophe-mediated cell death but occasional tumor cells may circumvent mitotic death by failure to complete telekinesis and revert back to a single cell state termed mitotic slippage .

While chemotherapy treatment induces apoptotic cell death in the tumor, there are additional morphologic changes within the treated tumor field that suggest alternate mode of cell death or occasional survival via non-canonical response to treatment.

The cell cycle and DNA ploidy status are then additionally correlated with markers of key cellular programs such as the DNA damage response and G2-M cell cycle checkpoint pathway via immunofluorescence staining.

As this approach analyzes all tumor cells within a population at the single cell level, distinct subpopulational responses to treatment within the bulk tumor cell line can be revealed.

Using this refined technical approach, here we demonstrate that platinum treatment induces nuclear enlargement in the surviving cell population of several HGSC cell line models, and this in-vitro observation resembles closely to the morphologic changes seen in-vivo in patient tumors after neoadjuvant chemotherapy treatment.

The Rottapel/Kapus Research Team concluded, "The efficacy of this pathway to produce viable progenies was low and highly contingent on the initial platinum concentration that generated the hyperploid cells.

Potentially, the coupled process of hyperploidization and de-polyploidization might increase the genomic diversity of the recovering tumor cell line and contribute to acquired platinum resistance."

Full text - https://doi.org/10.18632/oncotarget.27330

Correspondence to - Robert Rottapel - rottapel@uhnresearch.ca and Andras Kapus - andras.kapus@unityhealth.to

Journal

Oncotarget

DOI

10.18632/oncotarget.27330

CAMBRIDGE, MA -- When your immune system is exposed to a vaccine, an allergen, or an infectious microbe, subsets of T cells that can recognize a foreign intruder leap into action. Some of these T cells are primed to kill infected cells, while others serve as memory cells that circulate throughout the body, keeping watch in case the invader reappears.

MIT researchers have now devised a way to identify T cells that share a particular target, as part of a process called high-throughput single-cell RNA sequencing. This kind of profiling can reveal the unique functions of those T cells by determining which genes they turn on at a given time. In a new study, the researchers used this technique to identify T cells that produce the inflammation seen in patients with peanut allergies.

In work that is now underway, the researchers are using this method to study how patients' T cells respond to oral immunotherapy for peanut allergies, which could help them determine whether the therapy will work for a particular patient. Such studies could also help guide researchers in developing and testing new treatments.

"Food allergies affect about 5 percent of the population, and there's not really a clear clinical intervention other than avoidance, which can cause a lot of stress for families and for the patients themselves," says J. Christopher Love, the Raymond A. and Helen E. St. Laurent Professor of Chemical Engineering and a member of MIT's Koch Institute for Integrative Cancer Research. "Understanding the underlying biology of what drives these reactions is still a really critical question."

Love and Alex K. Shalek, who is the Pfizer-Laubach Career Development Associate Professor at MIT, an associate professor of chemistry, a core member of MIT's Institute for Medical Engineering and Science (IMES), and an extramural member of the Koch Institute, are the senior authors of the study, which appears today in Nature Immunology. The lead authors of the paper are graduate student Ang Andy Tu and former postdoc Todd Gierahn.

Extracting information

The researchers' new method builds on their previous work developing techniques for rapidly performing single-cell RNA sequencing on large populations of cells. By sequencing messenger RNA, scientists can discover which genes are being expressed at a given time, giving them insight into individual cells' functions.

Performing RNA sequencing on immune cells, such as T cells, is of great interest because T cells have so many different roles in the immune response. However, previous sequencing studies could not identify populations of T cells that respond to a particular target, or antigen, which is determined by the sequence of the T cell receptor (TCR). That's because single-cell RNA sequencing usually tags and sequences only one end of each RNA molecule, and most of the variation in T cell receptor genes is found at the opposite end of the molecule, which doesn't get sequenced.

"For a long time, people have been describing T cells and their transcriptome with this method, but without information about what kind of T cell receptor the cells actually have," Tu says. "When this project started, we were thinking about how we could try to recover that information from these libraries in a way that doesn't obscure the single-cell resolution of these datasets, and doesn't require us to dramatically change our sequencing workflow and platform."

In a single T cell, RNA that encodes T cell receptors makes up less than 1 percent of the cell's total RNA, so the MIT team came up with a way to amplify those specific RNA molecules and then pull them out of the total sample so that they could be fully sequenced. Each RNA molecule is tagged with a barcode to reveal which cell it came from, so the researchers could match up the T cells' targets with their patterns of RNA expression. This allows them to determine which genes are active in populations of T cells that target specific antigens.

"To put the function of T cells into context, you have to understand what it is they're trying to recognize," Shalek says. "This method lets you take existing single-cell RNA sequencing libraries and pull out relevant sequences you might want to characterize. At its core, the approach is a straightforward strategy for extracting some of the information that's hidden inside of genome-wide expression profiling data."

Another advantage of this technique is that it doesn't require expensive chemicals, relies on equipment that many labs already have, and can be applied to many previously processed samples, the researchers say.

Analyzing allergies

In the Nature Immunology paper, the researchers demonstrated that they could use this technique to pick out mouse T cells that were active against human papilloma virus, after the mice had been vaccinated against the virus. They found that even though all of these T cells reacted to the virus, the cells had different TCRs and appeared to be in different stages of development -- some were very activated for killing infected cells, while others were focused on growing and dividing.

The researchers then analyzed T cells taken from four patients with peanut allergies. After exposing the cells to peanut allergens, they were able to identify T cells that were active against those allergens. They also showed which subsets of T cells were the most active, and found some that were producing the inflammatory cytokines that are usually associated with allergic reactions.

"We can now start to stratify the data to reveal what are the most important cells, which we were not able to identify before with RNA sequencing alone," Tu says.

Love's lab is now working with researchers at Massachusetts General Hospital to use this technique to track the immune responses of people undergoing oral immunotherapy for peanut allergies -- a technique that involves consuming small amounts of the allergen, allowing the immune system to build up tolerance to it.

In clinical trials, this technique has been shown to work in some but not all patients. The MIT/MGH team hopes that their study will help identify factors that could be used to predict which patients will respond best to the treatment.

"One would certainly like to have a better sense of whether an intervention is going to be successful or not, as early as possible," Love says.

This strategy could also be used to help develop and monitor immunotherapy treatments for cancer, such as CAR-T cell therapy, which involves programming a patient's own T cells to target a tumor. Shalek's lab is also actively applying this technique with collaborators at the Ragon Institute of MGH, MIT and Harvard to identify T cells that are involved in fighting infections such as HIV and tuberculosis.

Berkeley -- Teen girls in South Africa face an extraordinary threat of HIV: By the time they reach adulthood, one in four South African girls will have contracted the virus, and most are first infected during adolescence.

Experiencing depression puts these girls at even higher risk of HIV infection, reveals analyses led by researchers at the University of California, Berkeley, and based on a longitudinal study led by colleagues at the University of North Carolina and the University of the Witwatersrand, South Africa.

The findings, which appear online in the American Journal of Epidemiology, suggest that interventions targeted at improving mental health among adolescent girls may help stem the spread of HIV in South Africa and throughout the rest of sub-Saharan Africa.

"We've known that depression and HIV go together for decades, but no one has known which way the arrow goes: Does depression lead to HIV or does HIV lead to depression?" said Jennifer Ahern, professor of epidemiology at UC Berkeley and senior author on the study. "Probably it goes both ways, but we were able to show that, at least in this population, the arrow certainly goes one way, which is depression leads to HIV. This could have important implications for where interventions might lie."

As part of the study, the team looked at which aspects of teens' social lives and behaviors might explain the relationship between depression and HIV incidence. Teen girls who experienced symptoms of depression were later more likely to report not having close relationships with their parents, and having a partner who would hit her if she asked him to wear a condom. These factors appeared to be part of the pathway to contracting HIV.

"Partner violence in response to condom negotiations, and a lack of parental monitoring, had the strongest association with both depression and HIV, which indicates that the majority of the relationship between depression and HIV may be influenced through those factors," said Dana Goin, a postdoctoral scholar in the Department of Obstetrics, Gynecology, and Reproductive Sciences at the University of California, San Francisco, and lead author of the study.

"The results illustrate how so much of infection among this population has to do with structural factors," said Goin, who completed the work as a PhD candidate in epidemiology at UC Berkeley.

The study drew on data collected from 2,533 women between the ages of 13 and 21 living in rural Mpumalanga Province, South Africa. Each teen was screened for symptoms of depression at the beginning of the study, and then tested for HIV annually for six years.

A little more than 18% of the adolescents had depression at the outset of the study -- about twice the national average of South Africa. Of those with depression, nearly 11 percent went on to contract HIV, while only 6.5% of those without depression eventually became infected.

While a previous study has shown that depression can lead to higher incidence of HIV in men who have sex with men in the U.S., this is the first study to examine the relationship among girls and young women in sub-Saharan Africa.

Though residents in rural South Africa have limited access to mental health services, Ahern and Goin's collaborators at Oxford University and at the University of the Witwatersrand in South Africa are currently working to develop community-based interventions that can help identify and support girls who are experiencing depression.

"There is increasing evidence that proven psychological treatments for depression, such as behavioral activation, can be delivered by lay counsellors and community healthcare workers, which provides a feasible way of delivering treatment for depression in the community," said Alan Stein, a professor of child and adolescent psychiatry at the University of Oxford. "There is also the possibility of delivering these kinds of treatments using the internet or mobile phones, with the support of phone calls from peer mentors, and this is something we are working on."

"Many low- and middle- income settings, including much of Africa, lack skilled mental health personnel," added Kathleen Kahn, a professor and senior scientist at the Medical Research Council / Wits University Rural Public Health and Health Transitions Research Unit (Agincourt) at the School of Public Health, University of the Witwatersrand and co-author on the paper. "Interventions that can be delivered by non-specialist workers -- lay health workers or community health workers -- and that are appropriate across different cultures should be vigorously pursued. This is what our work now focuses on."

When we pass through an art gallery, what determines our idea of beauty? A University of Sydney study of how people rate the aesthetics of each artwork shows part of our aesthetic assessment is due to the painting you saw a few moments before.

The research, led by PhD student Ms Sujin Kim in the School of Psychology, is published in the Journal of Vision. It shows that we don't appreciate every painting in isolation. Instead, we carry a bias from the artwork just seen.

This bias is not the contrast effect you might intuitively think. A beautiful painting does not make the next one look less attractive but makes it more attractive.

The study, completed under the supervision of Professor David Alais from the University of Sydney and Professor David Burr from the University of Florence, Italy, involved presenting a sequence of 40 paintings to 24 observers who were asked to rate each one using a slider to indicate how aesthetically appealing or attractive it was. The paintings were depicting scenery or still life.

"While it is often said that beauty is in the eye of the beholder, this is not the whole story - it partly depends on what was recently seen," Professor Alais said.

The first question the 24 observers were asked to respond to was whether they rated each painting independently of what they had just seen. To do this, the sequence was presented 20 times with each run having a different random order. In this way, a given painting was rated 20 times, but with a different random sequence preceding it. The data was clear: observers don't rate each painting consistently but are biased by what they just saw.

"Many people naively suppose a kind of 'contrast effect' whereby a painting may look more attractive if it follows an unattractive painting," Professor Alais said. "The surprising result was that the bias was a positive one: paintings were rated higher following an attractive painting, or lower, following unattractive ones."

The research refers to this effect as "serial dependence", which describes a systemic bias towards recent past experience. Previous studies have found, many stimulus attributes - including orientation, numerosity, facial expression and attractiveness, and perceived slimness - are systematically biased towards recent past experience.
"Perhaps art curators have known all along about the bias towards the recent past," Professor Alais said. "They often keep the best pieces for last and build up to it. Our study shows this would ensure an accumulating effect and guarantee a big finish."

Researchers of Sechenov University together with their colleagues from several Russian institutes studied the dynamics of microtubules that form the basis of the cytoskeleton and take part in the transfer of particles within a cell and its division. The computer model they developed describes the mechanical properties of protofilaments (longitudinal fibers that compose microtubules) and suggests how they assemble and disassemble. All the details of the study can be found in PLOS Computational Biology.

Microtubules are long hollow cylinders with walls consisting of tubulin molecules arranged helix-wise. Each cycle contains 13 pairs of α- and β-tubulin, so a microtubule is composed of 13 longitudinal fibers, protofilaments. Microtubules grow by addition of tubulin from the cytoplasm. The protein binds more actively to one end (plus-end) of the microtubule and dissociates from the other one (minus-end) quicker. Both processes take place simultaneously, but their rate changes: when the concentration of tubulin is sufficient, microtubules grow faster than degrade, and when the concentration is low - vice versa. Between the phases of growth and shrinking there is a period of stability, but it is very short.

Though the mechanisms of microtubule's growth and shortening are well-studied, there are still quite a few questions about how the structure and properties of tubulin change. It is known that both molecules of tubulin (α- and β-tubulin) are connected to a molecule of guanosine triphosphate (GTP). GTP of β-tubulin can hydrolyse and turn into guanosine diphosphate (GDP) that causes the double tubulin molecule (dimer) to dissociate from a microtubule. The authors of the paper tried to understand how the properties of tubulin dimers and protofilaments depend on GTP hydrolysis and what provides the difference between plus- and minus-ends of microtubules. Above all, microtubules take part in cell division, and studies of these mechanisms will contribute to the search for yet unknown ways to suppress the replication of cancer cells. In particular, microtubules serve as molecular targets for an important anti-tumour drug, paclitaxel, that inhibits microtubule disassembly.

Existing studies offer several models of possible changes in protein structure taking place upon GTP hydrolysis: a slight curving of tubulin dimers or weakening of longitudinal bonds between dimers without significant changes in their shape. Some researchers also suggest that hydrolysis may affect interactions between neighbouring protofilaments. According to the authors, it was impossible to prove or refute any of these claims for a long time because of the lack of precise experimental data. In this research they verified the first hypothesis and computed the 'behaviour' of molecules using the latest of available experimental structures obtained by cryo-electron tomography. They examined bonds between dimers as well as between α- and β-tubulin within them.

Scientists modelled the bending of the tubulin dimer and the whole protofilament, with GTP and GDP bound to them, throughout one millisecond, watching the angle and direction of the curvature and assessing the strength of bonds within and between dimers. The results showed that protofilaments with GTP and GDP-bound tubulin were bent almost to the same extent, so the first hypothesis was disproved. But it turned out that GTP influences the flexibility of the bonds between dimers: protofilaments made of tubulin connected with GTP were much more bendable compared with those containing GDP.

Using the revealed difference in bond rigidity between GTP and GDP-connected protofilaments, the authors concluded that more flexible bonds ease the straightening of protofilaments and thus facilitate the assembly of the microtubule.

'Based on simulations, we developed a simple model of dynamic instability of microtubules, i.e. their assembly and disassembly. A deeper understanding of this process on the molecular level would enable a targeted development of medicines able to affect the stability of microtubules and thus prevent the reproduction of tumour cells', said Philipp Orekhov, co-author of the paper and senior scientist at the Institute for Personalized Medicine, Sechenov University.

While the diagnoses and treatment of sport-related concussion have well-established guidelines and protocols, a new study from UBC's Okanagan campus is looking at what has previously been an understudied group--women survivors of intimate partner violence (IPV).

Their hope is to develop a simple screening tool to help front-line services, like women's shelters, identify traumatic brain injury (TBI) earlier, says Paul van Donkelaar, lead researcher and professor with the School of Health and Exercise Sciences.

"It is widely known survivors of intimate partner violence face many short- and long-term consequences from abuse which can have profound impacts on both their mental and physical health," says van Donkelaar. "But there is currently very little direct evidence for the potential link between this violence and traumatic brain injury-induced brain dysfunction."

Despite the abundance of research and public awareness around brain injury in athletes, van Donkelaar says traumatic brain injuries suffered by survivors of IPV are largely ignored. In fact, his most recent research, which is hoping to establish the incidence and effects of TBI on these women, is only the fourth study he knows of that deals specifically with this issue.

"IPV happens behind closed doors and usually there are no witnesses--if there are witnesses they are generally the children and they are traumatized," says van Donkelaar, adding that if a survivor does seek medical help after an attack it is often for other traumatic injuries. "In many cases, survivors of IPV don't necessarily know they have had a traumatic brain injury and yet they are suffering from chronic symptoms including headaches, dizziness, and difficulty remembering," he says.

"If a brain injury is diagnosed, it might be several months or even years after the initial damaging blow took place. And was it caused by one blow, multiple attacks over several months, or from being shaken or even strangled?"

While diagnosis is a challenge, there also remains a social stigma with IPV. Van Donkelaar says many women who do seek medical help, may not tell the truth when asked how the injury occurred. For these reasons alone, van Donkelaar and his research team, including former UBCO postdoctoral fellow Jonathan Smirl, want to make concussion assessments and care for survivors of IPV accessible and straightforward.

"Although the health care system is a good place for TBI diagnoses in the context of IPV, many survivors do not feel comfortable accessing care in this manner so this leaves staff at women shelters as the first line of defense," says Smirl. "Yet these staff members aren't necessarily aware TBI can be part of their client's experience and currently do not have appropriate screening tools available to them."

For this latest research, the team used two brain injury questionnaires--the Brain Injury Severity Assessment tool (BISA) and the Sport Concussion Assessment Tool (SCAT5)--to get a better sense of the symptoms experienced by survivors of IPV. Eighteen women who had experienced IPV took the part in the study.

The research, published in Brain Injury, determined that by using the BISA test, which asks questions about symptoms resulting from episodes of IPV, more brain injuries were reported by the survivors. The study determined that each of the participants have suffered at least one previous TBI, and most had suffered many.

"It's estimated that several hundred thousand Canadian women a year experience a TBI, an even greater number than hockey or football players," says Smirl. "And yet, due to the perceived stigma around IPV, many of these women don't seek medical support. Unfortunately, living in this situation is their normal, waking up in a daze because she was punched again is her normal. Not only is it going undiagnosed, it's going untreated."

The findings from the current investigation can help develop TBI-informed screening tools to help front-line staff at women's shelters identify a brain injury as a possible factor in the symptoms experienced by IPV survivors.

"What we're hoping to do is implement a simple informed screening tool, just a few questions that front-line staff can ask which can help reveal whether a woman has potentially experienced an IPV-related TBI," he says. "We will then be able to use it as a means to refer them to appropriate supports in the community."

Van Donkelaar says providing these practical support resources to IPV survivors will improve their chances of breaking the cycle and enable them to move forward into an abuse-free future for themselves and their children.

MAYWOOD, IL - The past 25 years have seen a significant increase in student participation in high school athletics. Studies have revealed that 2 million injuries, 500,000 doctor visits and 30,000 hospitalizations occur each year among high school athletes. This has led to strong recommendations from the National Athletic Trainers' Association (NATA), the American Academy of Family Physicians and the American Medical Association for physician sideline coverage at high school games and practices.

In addition to this recommendation, providing proper training to athletic directors and coaches, having a defibrillator on the sidelines, having a concussion protocol in place and teaching proper tackling progressions can all impact the overall health and safety of student athletes.

Researchers at Loyola Medicine recently completed a follow-up study to reassess the state of medical sideline coverage during football games and practices at the 99 Chicago public high schools. The team is led by Nathaniel Jones, MD, sports medicine specialist, who collaborated with Pietro Tonino, MD, Chief of Sports Medicine, who published a similar study in 2003.

Through the use of an online survey, researchers requested information about the personnel available to assess medical problems at home football games and at practices as well as CPR and first aid certification of these Chicago public high school staffers.

Of most concern are concussions, catastrophic events, cervical spine injuries and sudden cardiac events, for which players' outcomes can be impacted by having a physician present. "The impact," Dr. Jones says, "is that immediate and appropriate medical care saves lives. Properly trained medical professionals know when to prioritize a serious injury.

For instance, head injuries should be handled differently and more urgently than an ankle sprain." Dr. Tonino notes that concussions are a significant issue. "If an athlete gets a concussion that is not diagnosed, this may impact his or her performance at school which can have long-term effects," he says.

Sixty-six Chicago public high schools responded to the recent survey, revealing a greater proportion of schools with athletic trainers and ambulances on the sidelines at home football games as compared to responses in 2003. By contrast, a smaller proportion of responding schools had a physician or paramedic on the sidelines.

Additionally, the proportion of head coaches certified in CPR and first aid decreased. "Practices are a big issue," says Dr. Tonino, "just as you can get a concussion in a game, the same thing can happen in practice. Often the coach is the only person there. It's important that the coach has some training and basic knowledge."

With regard to practical implications, Dr. Jones notes that Chicago public high schools share stadiums throughout the city. Ideally, Chicago medical centers would commit attending physicians, fellows and residents in primary care and sports medicine to cover stadiums during football games. "If Chicago's medical centers agreed to share coverage, we could offer comprehensive coverage for Chicago public high school student athletes," says Dr. Jones.

Education is also a key component. To that end, Loyola Medicine offers a sports medicine update conference annually, which shares the latest research in sports medicine, updates on best practices, gender differences in sports injuries, and education on a variety of injuries that can occur on the field. This conference is available to medical professionals, coaches and other school staff.

"Sports keep kids out of trouble," says Dr. Jones. "We don't want students to stop playing sports, but rather, we want athletes to have access to appropriate medical care during games and practices. We want parents and students to know the risks of contact sports, but also know that sports are important for kids to participate in. It keeps kids healthy, teaches teamwork, and kids learn how their performance effects the whole team."

It is generally known that viruses, with their cell-invading capabilities, can be responsible for a number of different cancers. What is less broadly discussed are the cancer-causing capabilities of bacteria, or the processes by which they may cause malignancy.

In a review article appearing in the November 18 issue of Trends in Molecular Medicine, University of North Carolina at Charlotte, cancer biologists Pinku Mukherjee and Mukulika Bose discuss a mechanism that, they suggest, may implicate bacterial infections in a wide variety of cancers - a cause that science has yet to fully understood.

The article, "Microbe - MUC1 Crosstalk in Cancer-Associated Infections," makes the case for the likely implication of microbial (especially bacterial) interactions with the glycoprotein known as MUC1 in cancers involving epithelial cells, including cancers of the colon, lungs, stomach, liver and pancreas.

Epithelial cells are cells that are frequently specialized for absorption or secretion purposes, and to form linings or barriers in organs, including the intestines, lungs, stomach, liver and reproductive organs. MUC1 is a "transmembrane" protein - extending outside, through and inside the cell membrane to the cytoplasm - and is present in nearly all glandular epithelial cells. It is one of a group of proteins known as "mucins" for their involvement in protective mucous layers, whose gel-forming features are caused by sugar molecules coating part of the protein's length ("glycosolation"). The sugars, essentially, interact with water molecules, creating a slippery, slimy barrier, protecting cell layers against pathogens and environmental damage.

Mukherjee, Irwin Belk Distinguished Professor of Cancer Research and chair of UNC Charlotte's Department of Biological Sciences, has done considerable past research on the surprisingly negative roles MUC1 can play in a variety of cancers. The association of the protein with cancer is very strong -- as the article notes, "the National Cancer Institute ranked MUC1 as the second best target antigen for the development of cancer vaccines."

Mukherjee also does work on the interaction of cancer and pathogen infections. "Now it is known that about 20% of all malignancies, especially epithelial malignancies, are associated with some sort of infection, viral or bacterial, persistent inflammation being the root cause" she notes.

Mukherjee explains that a lot is now known about viruses and the biological mechanisms involved - the association of HPV with cervical cancer, for example.

"But there is very little known about what causes cancers associated with bacterial infections... not much is known about this. But when there are bacterial infections that have definitely been linked to cancer -- like H. pylori with stomach cancer and ulcers - that appears to have to do with the basic persistence of the bacteria," she said.

Persistent infections may be different because of the effects of their long-term attacks on cellular defense mechanisms.

"But if these persistent bacterial infections cause aberrations on the epithelial layers, mucins must be involved because every glandular epithelial cell has mucins and we know that mucins are the first protective layer in any bacterial infection."

Imbedded in the epithelial cell membrane, with its outside end coated with attached sugars and its inside end floating largely naked in the cell's cytoplasm, MUC1 serves a largely protective role, Mukherjee explains. Molecules on the surface of bacterial cells bind to the mucosal layer or to the glycosolated end of MUC1, but the cell is ready for the attack and responds.

"Attachment by the bacteria triggers MUC1 to shed its extracellular domain (the glycosolated section) with the bacteria attached, and the whole thing goes to the mucous layer, where the bacteria is removed," she said. "It thus works as an anti-inflammatory by pushing the attacking bacteria out and engulfing it into the sugary molecule."

However, the process can have side-effect, she explains: "That's mainly how MUC1 works, but what happens sometimes when MUC1 sheds, its remaining outside and cytoplasmic tail (the protein's inner segment) gets activated. A persistent bacterial barrage on a cell activates some cytoplasmic tail and we know that when the cytoplasmic tail is activated it can trigger signaling pathways that cause cancer."

MUC1 can thus play a dual role during infection, either being anti-inflammatory by staving off bacterial attack, or pro-inflammatory, triggering inflammation processes, which, in turn, can cause malignancy.

"The dual role of MUC1 as protective and oncogenic in the presence of microbial infection is, in a nutshell, what this article is about," she said. "There are pieces of research out there that point to this, but we are trying to pull them together."

The article surveys studies on a dozen common infections by bacteria and viruses that are known to involve MUC1 and notes a limited number of examples where the protein is known to play a pro-inflammatory role.

"The field has only looked at these mechanisms in small number of infection-associated cancers, and even fewer where bacteria are involved," she noted. "We hope our hypothesis leads to people looking at this in a more scientific manner."

Mukherjee's hypothesis stresses the central role of MUC1 and mucins in targeting future research. Because of strong connections between the protein and cancer processes in epithelial cells and the protein's strong involvement in combating microbial infections, it is an obvious, yet understudied connection between infection and cancer.

"The idea is that at some point we are going to have to start studying mucins more seriously," she said. "Rather than only studying mucins in already transformed cancer cells, we need to be studying them before the cells transform and see what is going on. The work being done on the cancer side needs to be connected with the work on the bacterial side, and the role of infection in triggering inflammation."

Adolescent binge drinking modifies gene expression in a fashion that increases susceptibility to anxiety and alcohol use disorders in adulthood, according to research in rats recently published in eNeuro. Targeting the microRNAs responsible could be a new route for undoing the damage of alcohol use caused during adolescence.

Previous researchers found that microRNA, small bits of RNA that modify how genes are expressed rather than coding for a protein, are involved in how early-life alcohol exposure changes the brain, but the exact mechanism was unknown.

Kyzar et al. exposed adolescent rats to alcohol and measured the resulting levels of miR-137, one type of microRNA, in the rats' amygdalae. The rats exposed to alcohol displayed increased levels of miR-137, resulting in lower expression of proteins necessary for healthy neuron growth and branching. In adulthood, the rats displayed higher levels of anxiety behaviors and a higher preference for alcohol compared to control rats. Inhibiting miR-137 in the amygdala reversed the anxiety and alcohol preference in the rats with an adolescent drinking history.

The drug ketamine decreases alcohol consumption in male, but not female, rats, according to new research published in eNeuro. The findings suggest that ketamine may be a viable treatment option for male patients with an alcohol use disorder.

Prior studies found that ketamine reduces alcohol use disorder symptoms in both rats and humans, but the drug was administered once, rather than over a more realistic treatment time period. Ketamine is itself an addictive drug, so it is critical to examine how it affects patients over extended use.

Strong et al. divided male and female rats into groups based on how much alcohol they were prone to consume. The rats were allowed unrestricted access to alcohol three times a week. Three weeks later, ketamine treatments began.

Ketamine administration reduced alcohol consumption in high-consumption male rats, and the effects lasted at least three weeks after the ketamine treatments ended. Ketamine did not affect the habits of high-consumption female rats and increased drinking in low-consumption females. The female rats also displayed a higher risk of abusing ketamine compared to the male rats.

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The overall rate of new cancer cases is decreasing in men but increasing in women younger than 80 years, and obesity-related cancers are increasing in young people, according to a study on cancer trends in Canada from 1971 to 2015 published in CMAJ (Canadian Medical Association). http://www.cmaj.ca/lookup/doi/10.1503/cmaj.190355.

"The most striking results from these analyses relate to increasing incidence trends among younger adults for breast, colorectal, pancreatic, endometrial and kidney cancers," writes Dr. Darren Brenner, Cumming School of Medicine, University of Calgary, with coauthors. "Obesity is a risk factor for these cancer sites, and the rising incidence runs parallel to the growing prevalence of obesity in recent decades."

The study, which included almost 5.2 million cancer cases diagnosed in Canada between 1971 and 2015, looked at cancer trends by age and birth cohort (patients grouped by year/decade of birth). Cancer incidence -- the rate of new cases -- is well documented in Canada, but less is known about trends by age groups.

"The trend among younger adults is of greater concern because they are ineligible for most cancer screening programs," write the authors.

Other key findings:

There has been an overall increase in cancers not normally occurring at younger ages, particularly breast and colorectal cancer.

The highest increase in cancer incidence is for women aged 30-39 years.

Cancer incidence has decreased in women aged 80-89 years.

The most recent trends show statistically significant decreases in the incidence of cervical, lung, bladder and prostate cancer, across most age categories.

The overall recent decrease in cancer incidence is due to declines in cancer in people older than 50 years.

The reductions in cancer incidence across age groups for several cancer types are most likely the result of primary and secondary prevention activities, including smoking cessation programs, which have decreased lung cancer, and sun safety behaviours, which have led to lower rates of melanoma in women younger than 40 and in men younger than 50 years. Endoscopy and fecal-based screening programs for colorectal cancer and screening for cervical cancer have contributed to declining rates in these cancers.

However, a rise in the use of prostate-specific antigen (PSA) testing resulted in sharp increases in prostate cancer diagnoses between 1990 and 2007, and thyroid cancer has also been over-diagnosed.

Age-specific cancer rates over time help identify the impact of changes in practice such as screening programs, better diagnosis and changing risk factors. Further efforts to reduce obesity, promote additional cancer prevention programs and further research into risk factors that may be causing cancer in younger age groups are essential.

ANN ARBOR, Mich. -- Telling the difference between a teen's normal ups and downs and something bigger is among top challenges parents face in identifying youth depression, a new national poll suggests.

Though the majority of parents say they are confident they would recognize depression in their middle or high school aged child, two thirds acknowledge barriers to spotting specific signs and symptoms, according to the C.S. Mott Children's Hospital National Poll on Children's Health at the University of Michigan.

Forty percent of parents struggle to differentiate between normal mood swings and signs of depression, while 30% say their child is good at hiding feelings.

"In many families, the preteen and teen years bring dramatic changes both in youth behavior and in the dynamic between parents and children," says poll co-director Sarah Clark. "These transitions can make it particularly challenging to get a read on children's emotional state and whether there is possible depression."

Still, a third of parents polled said nothing would interfere with their ability to recognize signs of depression in their child.

"Some parents may be overestimating their ability to recognize depression in the mood and behavior of their own child," Clark says. "An overconfident parent may fail to pick up on the subtle signals that something is amiss."

The poll also suggests that the topic of depression is all too familiar for middle and high school students. One in four parents say their child knows a peer or classmate with depression, and 1 in 10 say their child knows a peer or classmate who has died by suicide.

Indeed, rates of youth suicide continue to rise. Among people ages 10 to 24 years old, the suicide rate climbed 56% between 2007 and 2017, according to the Centers for Disease Control and Prevention.

"Our report reinforces that depression is not an abstract concept for today's teens and preteens, or their parents," Clark says.

"This level of familiarity with depression and suicide is consistent with recent statistics showing a dramatic increase in suicide among U.S. youth over the past decade. Rising rates of suicide highlight the importance of recognizing depression in youth."

Compared to the ratings of their own ability, parents polled were also less confident that their preteens or teens would recognize depression in themselves.

Clark says parents should stay vigilant on spotting any signs of potential depression in kids, which may vary from sadness and isolation to anger, irritability and acting out. Parents might also talk with their preteen or teen about identifying a "go to" adult who can be a trusted source if they are feeling blue, Clark says.

Most parents also believe schools should play a role in identifying potential depression, with seven in 10 supporting depression screening starting in middle school.

"The good news is that parents view schools as a valuable partner in recognizing youth depression," Clark says.The bad news is that too few schools have adequate resources to screen students for depression, and to offer counseling to students who need it."

Clark encourages parents to learn whether depression screening is taking place at their child's school and whether counseling is available for students who screen positive. Given the limited resources in many school districts, parents can be advocates of such efforts by talking to school administrators and school board members about the importance of offering mental health services in schools.

The nationally representative Mott Poll report is based on responses from 819 parents with at least one child in middle school, junior high, or high school.

Our expert's guide for parents on how to talk to children and teens about depression and suicide.

Opening Medicare to Americans aged 50 to 64 would lower health care premiums for the group, but also drive up costs for younger people who buy health insurance on exchanges created under the federal Affordable Care Act, according to a new RAND Corporation study.

Under most scenarios examined, the study estimates that the premium to buy into Medicare would be about $10,000 per year in 2022. For many potential enrollees, this amount is a good deal compared to the ACA-compliant individual insurance market, in which older adults are charged up to three times as much as younger adults.

While older exchange enrollees currently pay higher premiums, the analysis finds that, as a group, their care is less expensive relative to their high premiums. Younger people in the exchange tend to be less healthy and their care is more expensive than the premiums they pay.

As a result, the analysis finds that enabling adults aged 50 to 64 to move to Medicare could increase premiums for those remaining in the individual health insurance market by between 3% and 9%.

"Our findings suggest that Medicare buy-in could offer significantly more-affordable health care coverage to older adults, while potentially leading to higher premiums for the pool of people remaining on the individual market," said Christine Eibner, the study's lead author and the Paul O'Neill Alcoa Chair in Policy Analysis at RAND, a nonprofit research organization.

For a typical 50-year-old, buying into Medicare would cost about $2,500 less than buying a gold-level plan on the insurance exchanges, but be about $500 more than a bronze-level plan. Medicare offers significantly better coverage than bronze-level insurance plans, but unlike exchange plans, it does not have a maximum limit on the total amount of out-of-pocket spending a beneficiary might have to pay.

For a typical 60-year-old, the savings would be greater. For this group, buying into Medicare would cost about $8,000 less per year as compared to a gold-level plan on the insurance exchanges and $3,700 less than buying a bronze-level plan.

The analysis finds that opening Medicare to Americans aged 50 to 64 would not substantially change the number of Americans with health insurance. While such a move likely would increase the number of Americans aged 50 to 64 who have health insurance, the higher costs on insurance exchanges is likely to mean that fewer younger Americans would buy coverage.

Under all the scenarios studied, a Medicare buy-in for Americans aged 50 to 64 would have no effect on the Medicare Trust Fund or on outcomes for current Medicare beneficiaries.

Policymakers have long discussed allowing people under the age of 65 to buy into Medicare, primarily as a way to provide older adults with access to insurance without regard to coverage denial or preexisting condition exclusions.

Following the passage of the ACA and its requirement that coverage be offered regardless of health status, discussions about expanding Medicare eligibility have focused on creating alternative coverage options that include access to Medicare's provider payment rates, reducing premiums on the ACA's marketplaces by moving older people into a separate risk pool and increasing overall insurance enrollment.

The RAND study used a microsimulation model to estimate the effects of allowing older adults to buy into Medicare under a number of scenarios. Researchers assumed that eligible individuals can apply their marketplace advanced premium tax credits to the buy-in plan.

The study's finding that allowing 50- to 64-year-olds to buy into Medicare would drive up insurance costs for individuals in the marketplace runs counter to conventional wisdom, which argues that older adults drive up individual market premiums because they tend to have more medical problems.

The RAND model accounts for the fact that low-cost older adults are more likely to enroll in the insurance exchanges than low-cost young adults, and these healthy older people act as a stabilizing force. The model also accounts for the fact that Medicare payment rates are lower than commercial rates, and administrative costs are lower in Medicare than in private plans.

The report was developed with the support of funding by AARP. Any opinions, findings, conclusions and recommendations are those of the authors and do not necessarily reflect the views of AARP.

Given consumer concern that statins may be associated with memory or cognitive decline, a new study published today in the Journal of the American College of Cardiology may offer reassurance, as no difference was found in the rate of memory or cognitive decline of elderly statin-users compared to never-users.

"Not only are statins one of the most prescribed medications in the world, there is strong evidence that they reduce mortality in our patients with heart disease, stroke, diabetes, renal disease and other lipid disorders. Most importantly, statins aren't associated with a risk for major adverse health advents," said Katherine Samaras, MBBS, PhD, an endocrinologist at St. Vincent's Hospital in Australia and the study's lead author. "These findings will hopefully go a long way toward reducing consumers' concerns about memory and cognition from statins, so they don't stop taking these lifesaving medications."

The researchers examined changes in the memory and global cognition regarding statin-use over a six-year observation period and two years of brain volume studies using the Sydney Memory and Ageing Study, a longitudinal observation study of cognition of community-dwelling, non-demented elderly participants conducted at the Centre for Healthy Brain Ageing (CHeBA), University of New South Wales, Sydney, Australia. Data were collected every two years on four occasions over the six-year period by psychologists and nurses. Clinicians diagnosed the presence of heart disease, cerebrovascular disease, hypertension and Type 2 diabetes.

Participants' medications and duration of use were categorized as statin ever-use versus never-use; continuous statin-use during observation versus never-use; specific statins (simvastatin, pravastatin and atorvastatin) versus never-use; and statin initiation during observation period versus never-use.

The 1,037 participants were aged 70 to 90 years and were 98% Caucasian and Australian- (67%) or European- (18%) born. There were 395 statin never-users and 642 statin ever-users, which included ever-users at baseline and those who commenced taking statins during the study period. On average, participants had been on statins for nine years.

To measure their primary endpoints--memory and global cognition--a comprehensive assessment of global cognition and memory was developed. Five memory tests were employed by the researchers to assess new learning and short and long-term recall using verbal and visual memory tasks. Global cognition evaluated memory plus processing speed, language, visuospatial ability and executive function.

All participants were offered brain magnetic resonance imaging (MRI) at baseline, with 529 patients accepting and 408 undergoing a repeat MRI two years later. Statin ever-users and never-users were found to have similar total brain volume, hippocampal and parahippocampal brain volumes at baseline with no significant differences two years later.

Statin ever-users and never-users were similar at baseline for both memory and global cognition, the researchers found no significant difference in rate of decline in either memory or global cognition. Participants who took statins continuously over the study period had significantly higher baseline performance in memory and global cognition compared to never-users; the rate of decline in memory and global cognition for this subgroup was similar over the six-year observation period. When researchers compared the 99 participants who started statins during the study period, they found statin initiation was associated with a lessening in the rate of decline of memory. Overall, no associations between statin use and cognition were found between baseline and the six years of observation.

The researchers did find a protective interaction between statin ever-use, heart disease and the six-year change in the total learning memory test score. Among patients with heart disease, statin ever-users displayed a slower rate of decline on this test compared to never-users. However, in patients without heart disease, there was a comparable rate of decline between statin ever-users and never-users. The study also found a protective interaction between statin ever-use and the rate of decline in long-delayed recall performance for patients carrying the APOE-4 genotype. Carriers of this genotype are at high risk of Alzheimer's disease. In secondary analyses, male statin users did display a significantly faster logical memory decline compared to male never-users, but there was no significant difference between female statin users and never-users.

"We must acknowledge some limitations of the study, in particular the observational design and potential for selection and survivor bias," said Perminder Sachdev, MBBS, PhD, senior author who, along with Henry Brodaty, MBBS, MD, leads the Sydney Memory and Ageing Study. "Additionally, as participants with more advanced cognitive impairment were excluded from the study, no conclusions can be made for statin benefits in that group."

In an accompanying editorial, Costantino Iadecola, MD, and Neal S. Parikh, MD, MS, from Weill Cornell Medicine in New York City said, "These data support the view that worries about cognitive impairment should not limit statin use and raise the possibility that statins may favorably alter cognitive trajectories in a group of elders at high risk of Alzheimer's disease."

A parasitic wasp was recently discovered in Guanajuato, Mexico, where it was found to parasitize the eggs of an invasive stink bug, known as the bagrada bug, which is a major pest of cruciferous vegetables. A research team from Colegio de Postgraduados (Mexico), Agriculture and Agri-Food Canada (AAFC) and the Florida State Collection of Arthropods (FSCA) collaborated to publish a study on the biology this species, Idris elba, and describe it as a species new to science.

The genus Idris was described in 1856 and now contains over 300 species and many more species are still undescribed. Species of Idris were previously known to only parasitize spider eggs. It was thus very unexpected when specimens of Idris were found to emerge from eggs of the bagrada bug by Dr. Refugio Lomeli-Flores and his team in Guanajuato. Advanced methods in molecular forensics were used by Dr. Tara Gariepy (AAFC) to match the DNA of the adult wasp with DNA left behind in the stink bug egg from which it emerged, independently confirming the results. The specimens were then sent to taxonomist, Dr. Elijah Talamas (FSCA), who determined that it was an undescribed species.

The discovery of this wasp marks an important step toward the development of efficient and natural control of the stink bug species Bagrada hilaris in North America. Commonly known as the bagrada bug, it is native to Africa, but is already an established and important pest of over 74 plant species in India, southern Europe, southern Asia and the Middle East. Across the Atlantic, it has been known since 2008, when it was reported from Los Angeles, California (USA), followed by records from Coahuila state, Mexico, in 2014. Three years later, it was also found in the state of Guanajuato, which is responsible for over 70% of the country's broccoli production, as well as the major import of broccoli and cauliflower in the USA and Canada. So far, measures to halt the bug's invasion have proven largely ineffective, and its distribution is expected to reach new ecosystems of economical importance.

While not unheard of, it is uncommon for native parasitoids to attack an introduced host. Idris elba is exceptional because it demonstrates that these wasps can make the leap from parasitizing the eggs of spiders to the eggs of stink bugs. Having rejected the possibility of the species having been introduced alongside its host, the scientists note that the unexpected association could be either the result of a broad host range, or a case of lucky confusion, where the parasitoid tends to mistake the eggs of the stink bug for those of a spider.

It is no coincidence that this wasp has the species name "elba". Dr. Talamas explained that explicitly naming the species after Idris Elba (the actor), also known as a patronym, would have to follow Latin grammar and become Idris elbai. By treating the second name as an arbitrary combination of letters, the grammar was avoided.

Four-time Golden Globe nominee for Best Actor, Idris Elba is a famous British actor, producer, writer, singer, DJ and producer, best known for a long list of blockbusters, including a good number of superhero movies, such as the Marvel series inspired by the myths of the Norse god Thor. There, Elba stars as Heimdall, whose almost namesake: Heimdallr, is a Norse deity believed to be the sole protector of the bridge linking the human world and the realm of the gods.