An important new clue for preventing and treating gliomas has been identified in research published in the journal Science, providing a rare window into the biological changes behind glioma development.
In animal models, a team of researchers from Mayo Clinic and Mount Sinai Hospital found that those with a change in DNA known as germline alteration rs55705857 developed gliomas much more frequently and twice as fast compared to animal models without the alteration. In addition to brain tumours, the findings are relevant to other cancers and diseases.
“While we understand much of the biologic function of germline alterations within genes that code for proteins, we know very little about the biologic function of germline alterations outside of genes that code for proteins. In some way, these germline alterations interact with other mutations in cells to accelerate tumour formation,” said co-lead author Robert Jenkins, MD, PhD. “Based on this new understanding of its mechanism of action, future research may lead to novel and specific therapies that target the rs55705857 alteration.”
The study offers new knowledge that may help clinicians determine, pre-surgery, whether a patient has a glioma.
“We expected that rs55705857 would accelerate low-grade glioma development, but we were surprised by the magnitude of that acceleration,” said co-lead author Daniel Schramek, PhD.
There are many alterations, likely thousands, outside of genes associated with the development of cancer and other diseases, but the mechanism of action is only understood for very few, Dr Schramek said.
This study demonstrates that, with the tools of modern molecular/cell biology, it is possible to decipher much of the mechanism of action of such alterations.
Systemic sclerosis, or scleroderma that affects the skin and internal organs, is one of the rarest autoimmune diseases, affecting roughly 100 000 people in the US, mostly women. It has the highest mortality rate among rheumatic diseases.
There are no licensed treatments available for this subset of scleroderma patients, and rheumatology researchers are constantly searching for opportunities to use resources and technology that have proven beneficial in treating other autoimmune and rheumatic diseases.
In a new study published in JCI Insight, researchers found that tofacitinib, a drug approved for rheumatoid arthritis, was well tolerated among patients with early systemic sclerosis, and discovered the drug primarily affected the protein, interferon, both in fibroblasts and keratinocytes cells.
Dinesh Khanna MBBS., MSc, director of the Michigan Medicine Scleroderma Program, explained: “We wanted to understand first, if there was any clinical benefit of tofacitinib to patients, but we were also asking, what are the differences in the cells of healthy skin versus systemic sclerosis cells…how does the drug work?”
The study sample size consisted of 15 patients with early diffuse cutaneous systemic sclerosis — patients with skin hardening and issues with organs. Of the total participants, 10 patients received 5mg of tofacitinib twice a day, and the remaining received placebo in a double-blind randomised placebo-controlled trial.
Over the course of the 24-week trial period, researchers found no patients who exhibited severe adverse effects at or before the trial ended. Measures included the modified Rodnan skin score (mRSS).
These results showed that the average mRSS score and other measures improved over the course of the trial. In addition, patients on placebo went on open label tofacitinib after 24 weeks and there was ongoing improvement during the next 24 weeks, indicating improvement in the measure.
“We are delighted to find that the drug is safe to use and can possibly be repurposed for systemic sclerosis treatment,” said Khanna, “but what made this study innovative was the use of single cell technology.”
Participants in the study had a skin biopsy at the start of the trial and then again six weeks after they received tofacitinib or placebo. Then, clinicians used the relatively new technology — single cell RNA sequencing — to watch the mechanism of tofacitinib at work in the trial participants’ skin cells.
“This work highlights the ability of single-cell RNA-sequencing to determine how disease states are maintained and how various cell populations in the skin, both fibroblasts, skin cells, and immune cells communicate, providing unparallelled power to address disease mechanisms, and how drugs, like tofacitinib, work in a disease where they have not previously been used,” said Johann Gudjonsson MD, PhD, professor of dermatology and a collaborator on this study.
Along with discovering how tofacitinib inhibits fibroblasts and keratinocytes, researchers found that the drug had minimal effect on T cells.
“Because we found that the drug was working on one part (the mechanism of fibroblasts and keratinocytes), we are now considering if we can combine tofacitinib with another drug with complementary mechanism in action, in order to treat early systemic sclerosis without causing toxicity,” explained Khanna.
To understand more about the drug, researchers will need to conduct a more robust study and trial to see if their recent discoveries hold true.
“From this combined effort between Michigan Medicine and University of Pittsburgh, we know that the drug is safe, and we know that the technology (RNA sequencing) is feasible, now we can start to utilise the technology and find out what type of therapies we can mix and match that will add benefit to patients,” Khanna said.
Video games can precipitate life-threatening cardiac arrhythmias in susceptible children whose predisposition may have been previously unrecognised, according to findings published in Heart Rhythm. The investigators documented an uncommon, but distinct pattern among children who lose consciousness while playing video games – particularly among multiplayer war gaming which can have stressful online interactions.
“Video games may represent a serious risk to some children with arrhythmic conditions; they might be lethal in patients with predisposing, but often previously unrecognized arrhythmic conditions,” explained lead investigator Claire M. Lawley, MBBS, PhD. “Children who suddenly lose consciousness while electronic gaming should be assessed by a heart specialist as this could be the first sign of a serious heart problem.”
The investigators performed a systematic review of literature and initiated a multisite international outreach effort to identify cases of children with sudden loss of consciousness while playing video games. Across the 22 cases found, multiplayer war gaming was the most frequent trigger, and some children died following a cardiac arrest. Subsequent diagnoses of several heart rhythm conditions put the children at continuing risk. Catecholaminergic polymorphic ventricular tachycardia (CPVT) and congenital long QT syndrome (LQTS) types 1 and 2 were the most common underlying causes.
There was a high incidence of potentially relevant genetic variants (63%) among the patients, which has significant implications for their families. In some cases, the investigation led to the diagnosis of familial heart problems. “Families and healthcare teams should think about safety precautions around electronic gaming in children who have a condition where dangerous fast heart rhythms are a risk,” noted Dr Lawley.
Adrenergic stimulation related to the emotionally charged electronic gaming environment was attributed as the pathophysiological basis for this phenomenon. At the time of the cardiac incidents, many of the patients were in excited states, having just won or lost games, or were engaging in conflict with companions.
“We already know that some children have heart conditions that can put them at risk when playing competitive sports, but we were shocked to discover that some patients were having life-threatening blackouts during video gaming,” added co-investigator Christian Turner, MBBS. “Video gaming was something I previously thought would be an alternative ‘safe activity.’ This is a really important discovery. We need to ensure everyone knows how important it is to get checked out when someone has had a blacking out episode in these circumstances.”
The study notes that while this phenomenon is not a common occurrence, it is becoming more prevalent. “Having looked after children with heart rhythm problems for more than 25 years, I was staggered to see how widespread this emerging presentation is, and to find that a number of children had even died from it. All of the collaborators are keen to publicize this phenomenon so our colleagues across the globe can recognize it and protect these children and their families,” noted co-investigator of the study, Jonathan Skinner, MBChB, MD, also from Sydney.
In an accompanying editorial Daniel Sohinki, MD, MSc, and coauthors pointed out that, “exertion should be understood to encompass activities outside of traditional competitive athletics. Appropriate counselling regarding the risks of intense video gameplay should be targeted in children with a pro-arrhythmic cardiac diagnosis, and in any child with a history of exertional syncope of undetermined aetiology. Further, any future screening programs aimed at identifying athletes at risk for malignant arrhythmias should encompass athletes being considered for participation in eSports.”
While popular diets discourage midnight snacking, few studies have examined the simultaneous effects of late eating on the weight gain trifecta regulation of calorie intake, the number of calories burnt, and molecular changes in fat tissue. Now, a new study published in Cell Metabolism has found that timing of food intake significantly impacts energy expenditure, appetite, and molecular pathways in adipose tissue.
“We wanted to test the mechanisms that may explain why late eating increases obesity risk,” explained senior author Frank A. J. L. Scheer, PhD, Director of the Medical Chronobiology Program in the Brigham’s Division of Sleep and Circadian Disorders. “Previous research by us and others had shown that late eating is associated with increased obesity risk, increased body fat, and impaired weight loss success. We wanted to understand why.”
“In this study, we asked, ‘Does the time that we eat matter when everything else is kept consistent?'” said first author Nina Vujovic, PhD, a researcher in the Medical Chronobiology Program in the Brigham’s Division of Sleep and Circadian Disorders. “And we found that eating four hours later makes a significant difference for our hunger levels, the way we burn calories after we eat, and the way we store fat.”
Vujovic, Scheer and their team studied 16 patients with a body mass index (BMI) in the overweight or obese range. Each participant completed two laboratory protocols: one with a strictly scheduled early meal schedule, and the other with the exact same meals, each scheduled about four hours later in the day. In the last two to three weeks before starting each of the in-laboratory protocols, participants maintained fixed sleep and wake schedules, and in the final three days before entering the laboratory, they strictly followed identical diets and meal schedules at home. In the lab, participants regularly documented their hunger and appetite, provided frequent small blood samples throughout the day, and had their body temperature and energy expenditure measured. To measure how eating time affected molecular pathways involved in adipogenesis, or how the body stores fat, investigators collected biopsies of adipose tissue from a subset of participants during laboratory testing in both the early and late eating protocols, to enable comparison of gene expression patterns/levels between these two eating conditions.
Results revealed that eating later had profound effects on hunger and appetite-regulating hormones leptin and ghrelin, which influence our drive to eat. Specifically, levels of the hormone leptin, which signals satiety, were decreased across the 24 hours in the late eating condition compared to the early eating conditions. When participants ate later, they also burned calories at a slower rate and exhibited adipose tissue gene expression towards increased adipogenesis and decreased lipolysis, which promote fat growth. Notably, these findings convey converging physiological and molecular mechanisms underlying the correlation between late eating and increased obesity risk.
Vujovic explained that these findings are not only consistent with a large body of research suggesting that eating later increases risk of developing obesity, but they shed new light on how this might occur. By using a randomised crossover study, and tightly controlling for behavioural and environmental factors such as physical activity, posture, sleep, and light exposure, investigators were able to detect changes the different control systems involved in energy balance, a marker of how our bodies use the food we consume.
Future studies will include more female participants. Despite only five female participants, the study was set up to control for menstrual phase, reducing confounding but making recruiting women more difficult. Going forward, Scheer and Vujovic are also interested in better understanding the effects of the relationship between meal time and bedtime on energy balance.
“This study shows the impact of late versus early eating. Here, we isolated these effects by controlling for confounding variables like caloric intake, physical activity, sleep, and light exposure, but in real life, many of these factors may themselves be influenced by meal timing,” said Scheer. “In larger scale studies, where tight control of all these factors is not feasible, we must at least consider how other behavioural and environmental variables alter these biological pathways underlying obesity risk. “
Blocking calcium signalling in immune cells suppresses allergic asthma, but without compromising the immune defence against flu viruses, according to the findings of a new study published in Science Advances.
The researchers showed that, in a mouse model, removing the gene for a certain calcium channel reduced asthmatic lung inflammation caused by house dust mite faeces, a common cause of allergic asthma. Blocking signals sent through this channel, the calcium release-activated calcium (CRAC) channel, with an investigational inhibitor drug had a similar effect.
The study revolved human cells’ use of signalling and switch-flipping ions, mainly calcium. When triggered by viral proteins or allergens, T cells open channels in their outer membranes, allowing calcium in to activate signalling pathways that control cell division and secretion of cytokine molecules.
Past work had found that CRAC channels in T cells regulate their ability to multiply into armies of cells designed to fight infections caused by viruses and other pathogens.
The new study showed that the CRAC channel inhibitor reduced allergic asthma and mucus build-up in mice without undermining their immune system’s ability to fight influenza, a main worry of researchers seeking to tailor immune-suppressing drugs for several applications.
“Our study provides evidence that a new class of drugs that target CRAC channels can be used safely to counter allergic asthma without creating vulnerability to infections,” said senior study author Stefan Feske, MD, a professor at NYU Langone Health. “Systemic application of a CRAC channel blocker specifically suppressed airway inflammation in response to allergen exposure.”
Allergic asthma, which is the most common form of the disease, is characterised by increased type 2 (T2) inflammation, which involves T helper (Th) 2 cells, the study authors noted. Th2 cells produce cytokines that play important roles in both normal immune defences, and in disease-causing inflammation that occurs in the wrong place and amount. In allergic asthma, cytokines promote the production of IgE antibodies and the recruitment to the lungs of inflammation-causing immune cells called eosinophils, the hallmarks of the disease.
In the new study, the research team found that deletion of the ORAI1 protein in T cells, which makes up the CRAC channel, or treating mice with the CRAC channel inhibitor CM4620, thoroughly suppressed Th2-driven airway inflammation in response to house dust mite allergens.
Treatment with CM4620 significantly reduced airway inflammation when compared to an inactive control substance, with the treated mice also showing much lower levels of Th2 cytokines and related gene expression. Without calcium entering through CRAC channels, T cells are unable to become Th2 cells and produce the cytokines that cause allergic asthma, the authors say.
Conversely, ORAI1 gene deletion, or interfering with CRAC channel function in T cells via the study drug, did not hinder T cell-driven antiviral immunity, as lung inflammation and immune responses were similar in mice with and without ORAI1.
“Our work demonstrates that Th2 cell-mediated airway inflammation is more dependent on CRAC channels than T cell-mediated antiviral immunity in the lung,” said study co-first author Yin-Hu Wang, PhD. “This suggests CRAC channel inhibition as a promising, potential future treatment approach for allergic airway disease.”
