Researchers at Uppsala University in Sweden have discovered lymph node-like structures close to the tumour in brain cancer patients, where immune cells can be activated to attack the tumour.
In their study published in the journal Nature Communications, the researchers found that immunotherapy enhanced the formation of these structures in a mouse model. This discovery suggests new opportunities to regulate the anti-tumour response of the immune system. Glioma is a deadly brain tumour with a dismal prognosis. One reason why brain tumours are very hard to treat is that our immune system, which is designed to detect and destroy foreign cells including cancer cells, cannot easily reach the tumour site due to the barriers that surround the brain.
To fight a developing tumour, killer immune cells such as T lymphocytes must be activated and primed in our lymph nodes, before travelling to the tumour site to effectively kill the cancer cells. Because of the barriers around the brain, it is a challenging process for T lymphocytes to reach the tumour.
The researchers describe their discovery of structures similar to lymph nodes in the brain where T lymphocytes could be activated. “It was extremely exciting to discover for the first time the presence of lymph node-like structures in glioma patients. These structures are known as tertiary lymphoid structures (TLS) and they are not found in healthy individuals. They have all the components needed to support lymphocyte activation on-site which means that they could have a positive effect on the anti-tumour immune response,” said Alessandra Vaccaro, PhD student at the Department of Immunology, Genetics and Pathology.The researchers also showed that the formation of TLS in the brain can be induced by a type of immunotherapy in glioma-bearing mice. Indeed, when they treated the mice with immunostimulatory antibodies called aCD40, the formation of TLS was enhanced and always occurred in proximity to tumours.“Learning that immunotherapies can modulate the formation of tertiary lymphoid structures in the brain offers exciting opportunities to find new ways of regulating the anti-tumour immune response in glioma,” said Anna Dimberg.aCD40 is currently being tested to treat brain tumours in a number of clinical trials.
In the study now published, the researchers found that while aCD40 boosted TLS formation, it also counterproductively inhibited the tumour-killing ability of the T lymphocytes. The study has therefore provided important insights into the multifaceted effects of aCD40 therapy.
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NEW STUDY REVEALS BEING IN SPACE DESTROYS MORE RED BLOOD CELLS
A world-first study has revealed how space travel can cause lower red blood cell counts, known as space anemia.
Analysis of 14 astronauts showed their bodies destroyed 54 per cent more red blood cells in space than they normally would on Earth, according to a study published in ‘Nature Medicine’.
“Space anemia has consistently been reported when astronauts returned to Earth since the first space missions, but we didn’t know why,” said lead author Dr Guy Trudel, a rehabilitation physician and researcher at The Ottawa Hospital and professor at the University of Ottawa.
“Our study shows that upon arriving in space, more red blood cells are destroyed, and this continues for the entire duration of the astronaut’s mission,” added Dr Trudel.
Before this study, space anemia was thought to be a quick adaptation to fluids shifting into the astronaut’s upper body when they first arrived in space. Astronauts would lose 10 per cent of the liquid in their blood vessels this way. It was thought that astronauts rapidly destroyed 10 per cent of their red blood cells to restore the balance, and that red blood cell control came back to normal after 10 days in space.
Instead, Dr Trudel’s team found that the red blood cell destruction was a primary effect of being in space, not just caused by fluid shifts. They demonstrated this by directly measuring red blood cell destruction in 14 astronauts during their six-month space missions.
On Earth, our bodies create and destroy 2 million red blood cells every second. The researchers found that astronauts were destroying 54 per cent more red blood cells during the six months they were in space, or 3 million every second. These results were the same for both female and male astronauts.
Dr Trudel’s team made this discovery due to the techniques and methods they developed to accurately measure red blood cell destruction. These methods were then adapted to collect samples aboard the International Space Station.
At Dr Trudel’s lab at the University of Ottawa, they were able to precisely measure the tiny amounts of carbon monoxide in the breath samples from astronauts. One molecule of carbon monoxide was produced every time one molecule of heme, the deep-red pigment in red blood cells, was destroyed.
While the team didn’t measure red blood cell production directly, they assumed that the astronauts generated extra red blood cells to compensate for the cells they destroyed. Otherwise, the astronauts would end up with severe anemia, and would have had major health problems in space.
“Thankfully, having fewer red blood cells in space isn’t a problem when your body is weightless,” said Dr Trudel. “But when landing on Earth and potentially on other planets or moons, anemia affecting your energy, endurance, and strength can threaten mission objectives. The effects of anemia are only felt once you land, and must deal with gravity again,” he said.
In this study, five out of 13 astronauts were clinically anemic when they landed –one of the 14 astronauts did not have blood drawn on landing. The researchers saw that space-related anemia was reversible, with red blood cells levels progressively returning to normal three to four months after returning to Earth.
Interestingly, the team repeated the same measurements one year after astronauts returned to Earth, and found that red blood cell destruction was still 30 per cent above pre-flight levels. These results suggest that structural changes may have happened to the astronaut while they were in space that changed red blood cell control for up to a year after long-duration space missions.
The discovery that space travel increases red blood cell destruction had several implications. First, it supported the screening of astronauts or space tourists for existing blood or health conditions that are affected by anemia. Second, a recent study by Dr Trudel’s team found that the longer the space mission, the worse the anemia, which could impact long missions to the Moon and Mars. Third, increased red blood cell production would require an adapted diet for astronauts. And finally, it was unclear how long the body could maintain this higher rate of destruction and production of red blood cells.
These findings could also be applied to life on Earth. As a rehabilitation physician, most of Dr Trudel’s patients were anemic after being very ill for a long time with limited mobility, and anemia hindered their ability to exercise and recover. Bedrest had been shown to cause anemia, but how it did this was unknown.
“If we can find out exactly what’s causing this anemia, then there is a potential to treat it or prevent it, both for astronauts and for patients here on Earth,” said Dr Trudel.
He was further quoted saying, “This is the best description we have of red blood cell control in space and after return to Earth. These findings are spectacular, considering these measurements had never been made before and we had no idea if we were going to find anything. We were surprised and rewarded for our curiosity.”
SCIENTISTS FIND BIOMARKERS IN PLATELETS FOR DEPRESSION, ANTIDEPRESSANT RESPONSE
A new study has found biomarkers for depression in platelets that track the extent of the disorder.
Published in a new proof of concept study, researchers led by Mark Rasenick, University of Illinois Chicago distinguished professor of physiology and biophysics and psychiatry, have identified a biomarker in human platelets that tracks the extent of depression.
The research builds off of previous studies by several investigators that have shown in humans and animal models that depression is consistent with decreased adenylyl cyclase — a small molecule inside the cell that is made in response to neurotransmitters such as serotonin and epinephrine.
“When you are depressed, adenylyl cyclase is low. The reason adenylyl cyclase is attenuated is that the intermediary protein that allows the neurotransmitter to make the adenylyl cyclase, Gs alpha, is stuck in a cholesterol-rich matrix of the membrane — a lipid raft — where they don’t work very well,” Rasenick said.
The new study has identified the cellular biomarker for translocation of Gs alpha from lipid rafts. The biomarker can be identified through a blood test.
“What we have developed is a test that can not only indicate the presence of depression but it can also indicate therapeutic response with a single biomarker, and that is something that has not existed to date,” said Rasenick, who is also a research career scientist at Jesse Brown VA Medical Centre.
The researchers hypothesized that they will be able to use this blood test to determine if antidepressant therapies are working, perhaps as soon as one week after beginning treatment. Previous research has shown that when patients showed improvement in their depression symptoms, the Gs alpha was out of the lipid raft. However, in patients who took antidepressants but showed no improvement in their symptoms, the Gs alpha was still stuck in the raft — meaning simply having antidepressants in the bloodstream was not good enough to improve symptoms.
A blood test may be able to show whether or not the Gs alpha was out of the lipid raft
after one week.
“Because platelets turn over in one week, you would see a change in people who were going to get better. You’d be able to see the biomarker that should presage successful treatment,” Rasenick said.
Currently, patients and their physicians have to wait several weeks, sometimes months, to determine if antidepressants are working, and when it is determined they aren’t working, different therapies are tried.
“About 30 per cent of people don’t get better — their depression doesn’t resolve. Perhaps, failure begets failure and both doctors and patients make the assumption that nothing is going to work,” Rasenick said.
“Most depression is diagnosed in primary care doctor’s offices where they don’t have sophisticated screening. With this test, a doctor could say, ‘Gee, they look like they are depressed, but their blood doesn’t tell us they are. So, maybe we need to re-examine this,” he added.
Working with his company, Pax Neuroscience, Rasenick aims to develop the screening test after further research.
The Study has been published in the ‘Molecular Psychiatry Journal ‘.
A small molecule inside the cell that is made in response to neurotransmitters such as serotonin and epinephrine.
Study finds long-term exposure to air pollution may increase virus risk
Long term exposure to ambient air pollution may heighten the risk of COVID-19 infection, suggests recent research.
The association was strongest for particulate matter, with an average annual raise of 1 ug/m3 linked to a 5 per cent increase in the infection rate. This equates to an extra 294 cases/100,000 people a year, according to the findings, which focus on the inhabitants of one Northern Italian city.
While further research is needed to confirm cause and effect, the findings should reinforce efforts to cut air pollution, say the researchers.
Northern Italy has been hit hard by the coronavirus pandemic, with Lombardy the worst affected region in terms of both cases and deaths. Several reasons have been suggested for this, including different testing strategies and demographics. But estimates from the European Union Environmental Agency show that most of the 3.9 million Europeans residing in areas where air pollution exceeds European limits live in Northern Italy.
Recent research has implicated airborne pollution as a risk factor for COVID-19 infection, but study design flaws and data capture only up to mid-2020 have limited the findings, say the researchers.
To get around these issues, they looked at long term exposure to airborne pollutants and patterns of COVID-19 infection from the start of the pandemic to March 2021 among the residents of Varese, the eighth-largest city in Lombardy.
Among the 81,543 residents as of 31 December 2017, more than 97 per cent were
successfully linked to the 2018 annual average exposure levels for the main air pollutants, based on home address.
Regional COVID-19 infection data and information on hospital discharge and outpatient drug prescriptions were gathered for 62,848 adults yet to be infected with SARS-CoV-2, the virus responsible for COVID-19 at the end of 2019 until the end of March 2021.
Official figures show that only 3.5 per cent of the population in the entire region were fully vaccinated by the end of March 2021.
Estimates of annual and seasonal average levels of five airborne pollutants were
available for 2018 over an area more than 40 km wide: particulate matter (PM2.5, PM10); nitrogen dioxide (NO2); nitric oxide (NO); and ozone (O3).
The average PM2.5 and NO2 values were 12.5 and 20.1 ug/m3, respectively. The
corresponding population-weighted average annual exposures in Italy for the same year were 15.5 and 20.1 ug/m3, respectively.
Some 4408 new COVID-19 cases, which were registered between 25 February 2020 and March 13, 2021, were included in the study. This equates to a rate of 6005 cases/100,000 population/year. The population density wasn’t associated with a heightened risk of infection. But living in a residential care home was associated with a more than 10-fold heightened risk of the infection. Drug treatment for diabetes, high blood pressure, and obstructive airway diseases, as well as a history of stroke, were also associated with, respectively, a 17 per cent, 12 per cent, 17 per cent, and 29 per cent, heightened risk. After accounting for age, gender, and care home residency, plus concurrent long term conditions, averages, both PM2.5 and PM10 were significantly associated with an increased COVID-19 infection rate.
Every 1 ug/m3 increase in long term exposure to PM2.5 was associated with a 5 per cent increase in the number of new cases of COVID-19 infection, equivalent to 294 extra cases per 100,000 of the population/year.
Applying seasonal rather than annual averages yielded similar results, and these findings were confirmed in further analyses that excluded care home residents and further adjusted for local levels of deprivation and use of public transport. Similar findings were observed for PM10, NO2 and NO.
The observed associations were even more noticeable among older age groups,
indicating a stronger effect of pollutants on the COVID-19 infection rate among 55-64 and 65-74-year-olds, suggest the researchers.
This is an observational study, and as such, can’t establish cause. And although the researchers considered various potentially influential factors, they weren’t able to account for mobility, social interaction, humidity, temperature and certain underlying conditions, such as mental ill-health and kidney disease.
BOOSTER DOSE NEUTRALISES COVID-19 OMICRON VARIANT, SAYS EU RESEARCH
Aim of study was to characterise efficacy of therapeutic antibodies and scientists concluded that many mutations in spike protein of variant enabled it to largely evade immune response
An international team of researchers recently studied the sensitivity of Omicron to antibodies compared with the currently dominant Delta variant.
The new COVID-19 Omicron variant is more transmissible than the Delta variant. However, its biological characteristics are still relatively unknown.
In South Africa, the Omicron variant replaced the other viruses within a few weeks and led to a sharp increase in the number of cases diagnosed. Analyses in various countries indicate that the doubling time for cases is approximately 2 to 4 days. Omicron has been detected in dozens of countries, including France, and became dominant by the end of 2021.
In a new study supported by the European Union’s Health Emergency Preparedness and Response Authority (HERA), scientists from the Institut Pasteur and the Vaccine Research Institute, in collaboration with KU Leuven (Leuven, Belgium), Orleans Regional Hospital, Hospital Europeen Georges Pompidou (AP-HP) and Inserm, studied the sensitivity of Omicron to antibodies compared with the currently dominant Delta variant.
The aim of the study was to characterize the efficacy of therapeutic antibodies, as well as antibodies developed by individuals previously infected with SARS-CoV-2 or vaccinated, in neutralizing this new variant.
The scientists from KU Leuven isolated the Omicron variant of SARS-CoV-2 from a nasal sample of a 32-year-old woman who developed moderate COVID-19 a few days after returning from Egypt. The isolated virus was immediately sent to scientists at the Institut Pasteur, where therapeutic monoclonal antibodies and serum samples from people who had been vaccinated or previously exposed to SARS-CoV-2 were used to study the sensitivity of the Omicron variant.
The scientists used rapid neutralization assays, developed by the Institut Pasteur’s Virus and Immunity Unit, on the isolated sample of the Omicron virus. This collaborative multidisciplinary effort also involved the Institut Pasteur’s virologists and specialists in the analysis of viral evolution and protein structure, together with teams from Orleans Regional Hospital and Hospital Europeen Georges Pompidou in Paris.
The scientists began by testing nine monoclonal antibodies used in clinical practice or currently in preclinical development. Six antibodies lost all antiviral activity, and the other three were 3 to 80 times less effective against Omicron than against Delta.
The antibodies Bamlanivimab/Etesevimab (a combination developed by Lilly), Casirivimab/Imdevimab (a combination developed by Roche and known as Ronapreve), and Regdanvimab (developed by Celtrion) no longer had any antiviral effect against Omicron. The Tixagevimab/Cilgavimab combination (developed by AstraZeneca under the name Evusheld) was 80 times less effective against Omicron than against Delta.
“We demonstrated that this highly transmissible variant has acquired significant resistance to antibodies. Most of the therapeutic monoclonal antibodies currently available against SARS-CoV-2 are inactive,” commented Olivier Schwartz, co-last author of the study and Head of the Virus and Immunity Unit at the Institut Pasteur.
The scientists observed that the blood of patients previously infected with COVID-19, collected up to 12 months after symptoms, and that of individuals who had received two doses of the vaccine, taken five months after vaccination, barely neutralized the Omicron variant. But the sera of individuals who had received a booster dose of Pfizer, analyzed one month after vaccination, remained effective against Omicron.
Five to 31 times more antibodies were nevertheless required to neutralize Omicron, compared with Delta, in cell culture assays. These results help shed light on the continued efficacy of vaccines in protecting against severe forms of the disease.
“We now need to study the length of protection of the booster dose. The vaccines probably become less effective in offering protection against contracting the virus, but they should continue to protect against severe forms,” explained Olivier Schwartz.
“This study shows that the Omicron variant hampers the effectiveness of vaccines and monoclonal antibodies, but it also demonstrates the ability of European scientists to work together to identify challenges and potential solutions. While KU Leuven was able to describe the first case of Omicron infection in Europe using the Belgian genome surveillance system, our collaboration with the Institut Pasteur in Paris enabled us to carry out this study in record time,” commented Emmanuel Andre, co-last author of the study, a Professor of Medicine at KU Leuven (Katholieke Universiteit Leuven) and Head of the National Reference Laboratory and the genome surveillance network for COVID-19 in Belgium.
“There is still a great deal of work to do, but thanks to the support of the European Union’s Health Emergency Preparedness and Response Authority (HERA), we have clearly now reached a point where scientists from the best centres can work in synergy and move towards a better understanding and more effective management of the pandemic,” added Emmanuel.
The scientists concluded that the many mutations in the spike protein of the Omicron variant enabled it to largely evade the immune response. Ongoing research is being conducted to determine why this variant is more transmissible from one individual to the next and to analyze the long-term effectiveness of a booster dose.
The Study about this variant has been published in the ‘Nature Journal ‘
INNER LANGUAGE DECODED
A research team from the University of Geneva (UNIGE) and the Hopitaux Universitaires de Geneve (HUG) has succeeded in identifying certain signals produced by our brain when we speak to ourselves.
Findings were published in the journal Nature Communications. When human beings speak, different areas of their brain must be activated. However, the function of these regions can be seriously impaired after damage to the nervous system. For example, amyotrophic lateral sclerosis (or Charcot’s disease) can completely paralyze the muscles used to speak.
In other cases, following a stroke, for example, areas of the brain responsible for language can be affected: this is called aphasia. However, in many of those cases, the ability of patients to imagine words and sentences remains partly functional.
Decoding our internal speech is therefore of great interest to neuroscience researchers. But the task is far from easy, as Timothee Proix, the scientist in the Department of Basic Neuroscience at the UNIGE Faculty of Medicine, explains “Several studies have been conducted on the decoding of spoken language, but much less on the decoding of imagined speech. This is because, in the latter case, the associated neural signals are weak and variable compared to explicit speech. They are therefore difficult to decode by learning algorithms.”
That is, through computer programmes.
When a person speaks aloud, he or she produces sounds that are emitted at certain precise moments. Researchers can thus relate these tangible elements to the brain regions involved. In the case of imagined speech, the process is much less easy.
Scientists have no obvious information on the sequencing and tempo of the words or sentences formulated internally by the individual. The areas recruited in the brain are also less numerous and less active.
In order to perceive the neural signals of this very particular type of speech, the UNIGE team used a panel of thirteen hospitalized patients, in collaboration with two American hospitals. They collected data through electrodes implanted directly into patients’ brains in order to assess their epileptic disorders.
“We asked these people to say words and then to imagine them. Each time, we reviewed several frequency bands of brain activity known to be involved in language”, explains Anne-Lise Giraud, a professor in the Department of Basic Neuroscience at the UNIGE Faculty of Medicine, and newly appointed director of the Institut de l’Audition in Paris.
The researchers observed several types of frequencies produced by different brain areas when these patients spoke, either orally or internally.
“First of all, the oscillations called theta (4-8Hz), which correspond to the average rhythm of syllable elocution. Then the gamma frequencies (25-35Hz), observed in the areas of the brain where speech sounds are formed. Thirdly, beta waves (12-18Hz) related to the cognitively more efficient regions solicited, for example, to anticipate and predict the evolution of a conversation. Finally, the high frequencies (80-150Hz) that are observed when a person speaks out” explains Pierre Megevand, assistant professor in the Department of Clinical Neurosciences at the Faculty of Medicine of the UNIGE and associate physician at the HUG.
Thanks to these observations, the scientists were able to show that the low frequencies and the coupling between certain frequencies (beta and gamma in particular) contain essential information for the decoding of imagined speech.
Their research also reveals that the temporal cortex is an important area for the eventual decoding.
Detection of ADHD more accurately: Study
A new study has identified a new neurological marker for attention deficit disorder with or without hyperactivity. The research has been published in the ‘Biological Psychiatry Cognitive Neuroscience and Neuroimaging Journal’. Supported by the national research centre Synapsy, neuroscientists from the University of Geneva (UNIGE), the Centre for Biomedical Imaging (CIBM), and the University Hospital of Geneva (HUG) focused their attention on a new electroencephalographic approach called microstates to identify ADHD’s neurological signatures.
The microstates technique is used to look at the combined spatial and temporal aspects of cerebral activity. Using this technique, the research team discovered that a certain cerebral activity state associated with sleep and attention lasted longer among people with ADHD. The results provided evidence of a more robust ADHD biomarker and thus contributed towards helping psychiatry become a more precise medical discipline.
ADHD affects five per cent of adults, making it one of the most common psychological disorders. Current clinical diagnosis is based only on questionnaires that focus mainly on the inattention and impulsivity symptoms. However, neuroscientists speculate that ADHD’s causes, while still not well known, have a biological and genetic basis, suggesting that there may exist biomarkers that could help in its diagnosis. This was the scope of this new study supported by Synapsy, a research centre that has combined psychiatry and the neurosciences over the past twelve years to understand the neural basis of different psychological disorders in the hope of creating better means for diagnosing and treating them.
The study of the human brain is a difficult endeavour because we cannot directly access the brain to look at its cellular and molecular mechanisms. Hence, non-invasive investigative methods such as brain scans or electroencephalograms (EEG) are used. The latter test uses a network of electrode sensors placed on the subject’s scalp to measure the electrical fields generated by large-scale neural networks.
Recent studies have revealed abnormal EEG activity among patients affected by ADHD, suggesting that abnormal cerebral development may be the cause of ADHD. Unfortunately, the data vary too much from one study to another, making them unreliable markers for ADHD. “These variations are due either to the wide heterogeneity of ADHD’s causes or to the fact that traditional EEG analyses are not a good tool for looking into the matter because they do not take into account the Spatio-temporal aspects of cerebral states,” said Tomas Ros, a researcher at the Department of Psychiatry and Neuroscience at the UNIGE Faculty of Medicine.
Brain activity fluctuated successively from one state to another while at rest, manifesting different spatial configurations in the EEG’s electrical field. Neuroscientists speak most often of five “micro” states or main configurations, lettered from A to E.
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