NEW INSIGHTS INTO FUNDAMENTAL WORKINGS OF IMMUNE SYSTEM IN RESPONSE TO SKIN CANCER THERAPY - The Daily Guardian
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NEW INSIGHTS INTO FUNDAMENTAL WORKINGS OF IMMUNE SYSTEM IN RESPONSE TO SKIN CANCER THERAPY

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New research led by the University of Birmingham suggests that skin cancer patients could have a better prognosis if their T cells send messages from five specific genes in their immune response to drugs given to treat the disease.

The research, carried out in mice, cells in the laboratory, and using publicly available data from patients with advanced melanoma before and after treatment with Nivolumab therapy, was published in the journal Immunity. T cells are white blood cells that protect the body from harm from viruses, bacteria, and cancer cells and explore their environments by using their T cell receptor (TCR) to recognise fragments – called antigens – of microbes or damaged cancer cells.

The TCR controls the behaviour of the T cell and can send messages to the T cells’ command centre to kick-start an immune response. This process is important for vaccine research and treatment of autoimmune conditions but is particularly of interest for cancer treatments to improve the anti-tumour function of T cells.

The researchers carried out the study to better understand how the amount of antigen controls how the TCR sends messages to the T cells’ command centre, and how this affects the type of immune response. They wanted to explore how antigen amounts control the expression of so-called ‘immune checkpoints’ that act as brakes on immune responses. It is these immune brakes, such as one called PD1, that are the target of drugs that seek to increase the immune response in cancer immunotherapy.

Lead author Dr David Bending, of the University of Birmingham’s Institute of Immunology and Immunotherapy, explained: “Through our research, we discovered that the amount of antigen determined how many immune checkpoints or immune brakes a T cell had on its cell surface.

“When we exposed T cells to the highest amounts of antigen, they stopped sending signals to their command centre, and this was because they had increased the number of immune brakes, which shut down the messengers. This made these T cells unable to respond to antigens for a period.”

By blocking one of the immune brakes, called PD1, the researchers were able to re-awaken some of these ‘unresponsive’ T cells. They found that these re-awakened T cells not only started sending messages to their command centres, but the messages they sent were louder and clearer.

“The response from the command centre was that the T cells started to increase the number of messages from five specific genes,” added Dr Bending. “By looking for the messages from these five genes, we were able to show that these stronger and louder messages were increased in melanoma patients who survived for longer on drugs that block the immune brake PD1. We think that this means that those cancer patients whose immune cells can send messages from these five genes in response to drugs that target PD1, a good outcome is far more likely.”

The researchers said their finding shows that the immune system likely requires an optimal level of stimulation to mount the most effective immune response in skin cancer patients. Dr Bending added: “Our research gives us an interesting insight into fundamental workings of the immune system. It suggests that both the amount of antigen around a T cell and also the number of immune brakes the T cells have at their surface are very important in controlling immune responses. Furthermore, we have shown that we can alter the balance of the immune response through stopping some of these immune brakes, which results in a stronger T cell response.”

The study has generated a new potential readout to monitor patients on drugs targeting PD1 in cancer. It also may be useful for exploring the potential of combinations of drugs that target multiple immune checkpoints to try to further re-awaken T cells in cancer patients.

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Research approves antibiotics for appendicitis

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According to final results of the Comparing Outcomes of antibiotic Drugs and Appendectomy (CODA) trial, and an updated treatment guideline for appendicitis from the American College of Surgeons, antibiotics are now an accepted first-line treatment for most people with appendicitis.

The findings of the study were published in the ‘New England Journal of Medicine’.

“In the first three months after taking antibiotics for the condition, nearly 7 in 10 patients in the antibiotic group avoided an appendectomy. By four years, just under 50 per cent had the surgery,” said Dr David Flum, co-principal investigator and professor and associate chair of surgery at the University of Washington (UW) School of Medicine.

“Other outcomes favoured either antibiotics or surgery. Putting it all together, antibiotics look to be the right treatment for many, but probably not all, patients with appendicitis,” added Dr Flum.

CODA is the largest-ever randomised clinical trial of appendicitis treatment. At 25 hospitals across 14 states, 1,552 patients with appendicitis consented to participate and were randomised to receive antibiotics or to undergo an appendectomy.

“While there were advantages and disadvantages to each treatment, we found that both treatments are safe, and patients will likely value these outcomes differ based on their unique symptoms, concerns and circumstances,” Flum said.

Patients with an appendicolith, a calcified deposit found in about 25 per cent of cases of acute appendicitis, were associated with more complications and a higher chance of appendectomy in the first 30 days. At 90 days out, however, there was no greater chance of appendectomy in patients with an appendicolith.

“Given these results and new treatment guidelines, it is important for surgeons and patients to discuss the pros and cons of both surgery and antibiotics in deciding on the treatment that’s best for that person at that time,” said Dr Giana Davidson. She is a UW associate professor of surgery and director of the CODA trial’s clinical coordinating centre.

To foster those conversations, CODA investigators created an online decisionmaking tool for patients. It includes a video (currently in English and Spanish, with other languages to come) and a mechanism to help patients choose a direction that may better suit their individual circumstances.

“In the emergency setting, patients with appendicitis can make a treatment d e c i s i o n h u r r i e d l y, ” Davidson said.

“This online tool was built to help communicate the CODA results in laymen’s terms, and to spur a conv e r s a t i o n b e t w e e n patients and surgeons about potential benefits and harms of each approach,” Davidson concluded.

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Polyphenol-rich diet helps leaky gut syndrome in elderly

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According to a new study, a polyphenol-rich diet can improve intestinal permeability in old people. The findings of the study were published in the journal ‘Clinical Nutrition’.

The study is led by Cristina Andres-Lacueva, professor at the Faculty of Pharmacy and Food Sciences and head of the Research Group of Biomarkers and Nutritional Metabolomics of Food of the University of Barcelona and the Biomedical Research Center of Fragility and Healthy Ageing (CIBERFES), also part of the Catalan Food Innovation Network (XIA).

This European study, conducted within the framework of the Joint Programming Initiative – A Healthy Diet for a Healthy Life (JPI HDHL), was carried out in people aged over sixty who underwent a polyphenol-rich diet for eight weeks.

The results have shown that including up to three daily portions of apple, cocoa, dark chocolate, green tea, cranberries, oranges or pomegranate juice, improves intestinal permeability when making specific changes in the intestinal microbiota.

According to the experts Gregorio Peron and Tomas Merono (UB-INSA and CIBERFES), “we studied the existing relationship between the metabolism of the elements of the diet, microbiota and intestinal permeability, by analysing the changes that are caused by a polyphenol-rich diet in the microbiota of the participants in our study and testing the resulting improvement of their gut barrier”.

The analysis of plasmatic and faecal samples showed an increase of the serum metabolome related to the polyphenol intake.

“For instance, theobromine and methylxanthine – derived from cocoa and green tea- are positively correlated with butyrate-producing bacteria (a fatty acid in the intestinal flora), and inversely with zonulin, a protein related to the intestinal permeability”, noted the authors.

According to Professor Andres-Lacueva, “the study of the relationship between intestinal permeability, microbiota composition and food metabolism has to be the base for establishing customized diets for every life stage, especially for the elderly”. Andews-Lacueva noted that higher intake of fruits, vegetables and foods that provide fibre and polyphenols could help counterbalance the damaging of permeability due to ageing.

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MEN, WOMEN RIDE SAME EMOTIONAL ROLLER COASTER: STUDY

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Contrary to widely held gender stereotypes, women are not more emotional than men, according to researchers at the University of Michigan.

Feelings such as enthusiasm, nervousness, or strength are often interpreted differently between the two genders. It’s what being “emotional” means to men vs. women that is part of a new University of Michigan study that dispels these biases.

For instance, a man whose emotions fluctuate during a sporting event is described as “passionate.” But a woman whose emotions change due to any event, even if provoked, is considered “irrational,” says the study’s senior author Adriene Beltz, U-M assistant professor of psychology.

Beltz and colleagues Alexander Weigard, U-M assistant professor of psychiatry, and Amy Loviska, a graduate student at Purdue University, followed 142 men and women over 75 days to learn more about their daily emotions, both positive and negative. The women were divided into four groups: one naturally cycling and three others using different forms of oral contraceptives.

The researchers detected fluctuations in emotions in three different ways, and then compared the sexes. They found little-to-no differences between the men and the various groups of women, suggesting that men’s emotions fluctuate to the same extent as women’s do (although likely for different reasons).

“We also didn’t find meaningful differences between the groups of women, making clear that emotional highs and lows are due to many influences- not only hormones,” she said.

The findings have implications beyond everyday people, the researchers say.

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TUMOUR REASONS WHY CANCERS THRIVE IN CHROMOSOMAL CHAOS

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Researchers at the University of California San Diego School of Medicine and Moores Cancer Center at UC San Diego Health describe how a pair of fundamental genetic and cellular processes are exploited by cancer cells to promote tumour survival and growth.

The findings appear in the journal European Molecular Biology Organisation. Cancer is driven by multiple types of genetic alterations, including DNA mutations and copy number alterations ranging in scale from small insertions and deletions to whole-genome duplication events.

Collectively, somatic copy number alterations in tumours frequently result in an abnormal number of chromosomes, termed aneuploidy, which has been shown to promote tumour development by increasing genetic diversity, instability, and evolution. Approximately 90 per cent of solid tumours and half of the blood cancers present some form of aneuploidy, which is associated with tumour progression and poor prognoses.

In recent years, it has become apparent that cells cohabiting within a tumour microenvironment are subject not only to external stressors (mainly of metabolic origin, such as lack of nutrients) but also to the internal stressor aneuploidy. Both activate a stress response mechanism called the unfolded protein response (UPR), which leads to an accumulation of misfolded proteins in the endoplasmic reticulum (ER) of cells — an organelle that synthesises proteins and transports them outside the cell.

When this primary transport/export system is disrupted, UPR attempts to restore normal function by halting the accumulation of misfolded proteins, degrading and removing them and activating signalling pathways to promote proper protein folding.

If homeostasis or equilibrium is not re-established quickly, non-tumour cells undergo cell death. Conversely, cancer cells thrive in this chaos, establishing a higher tolerance threshold that favours their survival.

“In these circumstances, they also co-opt neighbouring cells in a spiral of deceit that progressively impairs local immune cells,” said co-senior author Maurizio Zanetti, MD, professor of medicine at UC San Diego School of Medicine and a tumour immunologist at Moores Cancer Center with Hannah Carter, PhD, associate professor of medicine and a computational biologist. Zanetti had previously introduced the hypothesis in a Science commentary.

The researchers hypothesized that aneuploidy, UPR and immune cell dysregulation could be linked together in a deadly triangle. In the new study, Zanetti, Carter and colleagues analyzed 9,375 human tumour samples and found that cancer cell aneuploidy intersects preferentially with certain branches of the signalling response to stress and that this finding correlates with the damaging effects of aneuploidy on T lymphocytes, a type of immune cell.

“This was an ambitious goal not attempted before,” said Zanetti. “It was like interrogating three chief systems together — chromosomal abnormalities in toto, signalling mechanisms in response to endogenous stress and dysregulation of neighbouring immune cells — just to prove a bold hypothesis.

“We knew the task would be challenging,” added Carter, “and that we would need to create and refine new analytical tools to test our hypotheses in heterogeneous human tumour data, but it was a worthwhile risk to take.”

The findings show that the stress response in cancer cells serves as an unpredicted link between aneuploidy and immune cells to “diminish immune competence and anti-tumour effects.” It also demonstrates that molecules released by aneuploid cells affect another type of immune cells by subverting their normal function to turn them into tumour-promoting actors.

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Lack of sleep affects your walk: Study

The fewer sleep students got, the less control they had when walking during a treadmill test. For students who pulled an all-nighter before the test, this gait control plummeted even further.

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A new study, by researchers at MIT and the University of Sao Paulo in Brazil, reports that walking and specifically, how well we can control our stride, or gait, can indeed be affected by lack of sleep.

In experiments with student volunteers, the team found that overall, the fewer sleep students got, the less control they had when walking during a treadmill test. For students who pulled an all-nighter before the test, this gait control plummeted even further. The findings were published in the journal.

Interestingly, for those who didn’t stay up all night before the test, but who generally had less-than-ideal sleep during the week, those who slept in on weekends performed better than those who didn’t.

“Scientifically, it wasn’t clear that almost automatic activities like walking would be influenced by lack of sleep,” says Hermano Krebs, a principal research scientist in MIT’s Department of Mechanical Engineering. “We also find that compensating for sleep could be an important strategy. For instance, for those who are chronically sleep-deprived, like shift workers, clinicians, and some military personnel, if they build in regular sleep compensation, they might have better control over their gait.”

The act of walking was once seen as an entirely automatic process, involving very little conscious, cognitive control. Animal experiments with a treadmill suggested that walking appeared to be an automatic process, governed mainly by reflexive, spinal activity, rather than more cognitive processes involving the brain.

Indeed, since those experiments, scientists including Krebs have shown that the act of walking is slightly more involved than once thought. Over the last decade, Krebs has extensively studied gait control and the mechanics of walking, in order to develop strategies and assistive robotics for patients who have suffered strokes and other motion-limiting conditions.

In previous experiments, he has shown, for instance, that healthy subjects can adjust their gait to match subtle changes in visual stimuli, without realizing they are doing so. These results suggested that walking involves some subtle, conscious influence, in addition to more automatic processes.

In 2013, he struck up a collaboration with Forner-Cordero through a grant from the MIT-Brazil MISTI program, and the team began to explore whether more subtle stimuli, such as auditory cues, might influence walking. In these initial experiments, volunteers were asked to walk on a treadmill as researchers played and slowly shifted the frequency of a metronome. The volunteers, without realizing it, matched their steps to the subtly changing beat.

Forner-Cordero and Krebs continued to investigate the mechanics of walking and general motor control, mostly enlisting student volunteers in their experiments. Cordero in particular noticed that, toward the end of the semester, when students faced multiple exams and project deadlines, they were more sleep-deprived and happened to do worse in the team’s experiments.

In their new study, the team enlisted students from the University of Sao Paulo to take part in an experiment focused on the effects of sleep deprivation on gait control.

The students were each given a watch to track their activity over 14 days. This information gave researchers an idea of when and how long students were sleeping and active each day. The students were given no instruction on how much to sleep so that the researchers could record their natural sleep patterns. On average, each student slept about six hours per day, although some students compensated, catching up on sleep over the two weekends during the 14-day period.

On the evening before the 14th day, one group of students stayed awake all night in the team’s sleep lab. This group was designated the Sleep Acute Deprivation group or SAD. On the morning of the 14th day, all students went to the lab to perform a walking test.

Each student walked on a treadmill set at the same speed, as researchers played the metronome. The students were asked to keep step with the beat, as the researchers slowly and subtly raised and lowered the metronome’s speed, without telling the students they were doing so. Cameras captured the students’ walking, and specifically, the moment their heel struck the treadmill, compared with the beat of the metronome.

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Learning second language boosts cognitive function

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A new study that was jointly conducted by Baycrest and York University has reported that learning a second language is an effective and enjoyable way to improve brain health.

Researchers found that older adults who studied Spanish showed similar improvements in certain critical cognitive skills as did those who engaged in brain training activities that targeted those skills. The findings were published in the journal Aging Neuropsychology and Cognition.

“These results are exciting because they indicate that older adults can reap cognitive benefits from an enjoyable activity in which they might want to participate, regardless of these benefits,” says Dr. Jed Meltzer, Baycrest’s Canada Research Chair in Interventional Cognitive Neuroscience, a neurorehabilitation scientist at Baycrest’s Rotman Research Institute (RRI) and the lead author on this study.

In the study, the researchers recruited 76 older adults aged 65-75. All participants spoke only one language, were cognitively healthy, had never formally studied Spanish before and had not studied any other language in the past 10 years.

Participants were randomly assigned to one of three groups: language learning, brain training or a waitlist (with no language learning or brain training), which served as the control group. For 1

6 weeks, those in the language learning group spent 30 minutes a day, five days a week learning Spanish using Duolingo, an online language learning app. Those in the brain training group spent the same amount of time but used BrainHQ by Posit Science.

The researchers assessed participants’ performance on specific cognitive tasks before and after the 16 weeks. These tasks were similar to the exercises in BrainHQ. At the end of the intervention, they also measured participants’ adherence to the learning schedule and their enjoyment of the program they followed (language learning or brain training).

They found that participants in the language learning group showed similar improvements as the brain training group in two areas of cognition: working memory and executive function – that is, the ability to manage conflicting information, stay focused and avoid distractions.

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