Month: November 2022

Categories : AgeingTags :

Hormone Discovery could Predict Longevity of Men

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Old man jogging
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Researchers have discovered that a certain hormone, that develops in males during puberty, could be predictive of the risk of developing age-related disease in later life.

The novel insulin-like peptide hormone, called INSL3, was found by researchers to be consistent over long periods of time and is an important early biomarker for prediction of age-linked disease. Their latest findings have been published today in Frontiers in Endocrinology.

INSL3 is produced in the testes by Leydig cells, which also make testosterone, but unlike testosterone which fluctuates over a man’s life, INSL3 remains consistent, with the level at puberty staying about the same throughout life, decreasing only slightly into old age. This makes it the first clear and reliable predictive biomarker of age-related morbidity as compared to any other measurable parameters.

Blood levels of INSL3 were associated with a range of age-related illnesses, such as bone weakness, sexual dysfunction, diabetes, and cardiovascular disease.

Since the hormone is so consistent, a young man with high INSL3 would still have high INSL3 when he is older. But low levels of INSL3 when young will stay low when older, making a man more likely to acquire typical age-related illnesses. This opens up exciting possibilities for predicting age-related illnesses and finding ways to prevent the onset of these diseases with early intervention.

This study from University of Nottingham was led by Professors Ravinder Anand-Ivell and Richard Ivell and is the latest of three recent studies into this hormone. Prof Anand-Ivell explains: “The holy grail of ageing research is to reduce the fitness gap that appears as people age. Understanding why some people are more likely to develop disability and disease as they age is vital so that interventions can be found to ensure people not only live a long life but also a healthy life as they age. Our hormone discovery is an important step in understanding this and will pave the way for not only helping people individually but also helping to ease the care crisis we face as a society.”

The team analysed blood samples from 3000 men, with two samples taken four years apart and found that unlike testosterone, INSL3 remains at consistent.

The study also showed that there is an almost 10-fold variation in INSL3 levels in the normal male population, even among the young and healthy.

Prof Ivell adds: “Now we know the important role this hormone plays in predicting disease and how it varies amongst men we are turning our attention to finding out what factors have the most influence on the level of INSL3 in the blood. Preliminary work suggests early life nutrition may play a role, but many other factors such as genetics or exposure to some environmental endocrine disruptors may play a part.”

Source: University of Nottingham

Categories : Mental HealthTags :

Psilocybin Shows Promise in Treatment-resistant Depression

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Mushroom
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The largest and most rigorous clinical trial to date of psilocybin (a psychoactive ingredient in magic mushrooms), suggests the possibility that COMP360 psilocybin with psychological support could be a beneficial therapeutic strategy for people with treatment-resistant depression (TRD). The trial results were published in the New England Journal of Medicine.

Prompted by promising preliminary findings, this funded multi-centre, randomised, double-blind, phase 2b clinical trial was launched in 2018 to determine the safety and potential antidepressant effects of a single dose of COMP360 psilocybin (25mg or 10mg), compared to 1mg, with psychological support in people with TRD.

The trial, which included 233 people with TRD across 10 countries who received a single dose of 25mg COMP360 psilocybin experienced a highly statistically and clinically significant rapid reduction in symptoms of depression compared to 1mg at three weeks. This offers hope that COMP360 psilocybin with psychological support could be an effective antidepressant treatment paradigm for some people with TRD, if proven effective and safe in larger studies. COMPASS Pathways, the company that developed the psilocybin formulation., will be running a larger phase 3 programme of COMP360 psilocybin therapy in TRD, which is on schedule to begin in 2022.

KEY RESEARCH FINDINGS

  • 25mg COMP360 psilocybin with psychological support led to a statistically and clinically significantly reduction in symptoms of depression in people with TRD compared to 1mg at week 3.
  • 37% of people with TRD in the 25mg group met criteria for response at week 3 (≥ 50% decrease in depressive symptoms).
  • Approximately 30% of people with TRD in the 25mg group met criteria for remission at week 3 (29.1%).
  • 20% of people with TRD in the 25mg group met criteria for sustained response at week 12.
  • COMP360 psilocybin was generally well-tolerated.

Dr John R. Kelly, Psychiatrist and Clinical Senior Lecturer, Trinity College said: “This is the largest and most rigorous clinical trial of psilocybin to date. It shows a promising antidepressant signal for 25mg COMP360 psilocybin with psychological support and has paved the way for phase 3 clinical trials, which will determine whether it translates into a much-needed complementary treatment strategy in the psychiatry clinic.”

Source: Trinity College Dublin

Categories : Surgeries & ProceduresTags :

Better Outcomes with Bypass Surgery in Chronic Limb-threatening Ischaemia

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Performing open bypass surgery to restore circulation for people with a severe form of peripheral artery disease (PAD) resulted in better outcomes for specific patients compared to a less-invasive procedure, according to findings published in the New England Journal of Medicine.

PAD is a condition in which blood flow to one or both legs is reduced by a buildup of fatty plaque in the arteries. One in 10 of patients with this condition develop a severe form of PAD called chronic limb-threatening ischaemia (CLTI), a painful and debilitating condition that can lead to amputation if untreated. Up to about 22 million people worldwide have CLTI, which is also associated with an increased risk of heart attack, stroke, and death.

“Given the projected rise in the number of patients with chronic limb-threatening ischaemia, it is critically important that we understand the full impact of our interventions for this disease,” said Matthew Menard, MD, a study author and associate professor of surgery and co-director of the endovascular surgery program at Brigham and Women’s Hospital, Boston. “These findings help do that and also can assist clinicians and caregivers in providing the best possible care to patients.”

The Best Endovascular versus Best Surgical Therapy for Patients with CLTI (BEST-CLI) trial is a landmark study supported by the National Heart, Lung, and Blood Institute (NHLBI).

To compare effectiveness of two common treatments for CLTI, researchers enrolled 1830 adults who were planning to have revascularisation, a procedure used to restore blood flow in their blocked arteries, and who were eligible for both treatment strategies.

One treatment strategy was an open bypass surgery, in which blood is redirected around the blocked leg artery by using a segment of a healthy vein. The other strategy was an endovascular procedure, where a balloon is dilated and/or a stent is placed in the blocked segment of the artery to improve blood flow. To compare the surgical strategy to the less-invasive endovascular approach, researchers randomised participants into one of two parallel trials between 2014–2021.

The first trial, defined as cohort 1, included 1434 adults who were judged to be the best candidates for the bypass surgery because they had an adequate amount of an optimal vein (the single-segment great saphenous vein) preferred for the procedure. Participants were then randomly assigned to have either a surgical bypass or endovascular procedure. Researchers followed the trial participants for up to seven years.

The second trial, defined as cohort 2, included 396 adults who were not the best candidates for the open bypass because they did not have an adequate amount of the preferred saphenous vein. They were randomised to have either an endovascular procedure or a bypass that used alternate graft material instead of the saphenous vein. Participants were followed-up for up to three years.

At the end of the trial, the researchers found that participants in cohort 1 who received the bypass were 32% less likely to have major medical events related to CLTI than those who had an endovascular procedure. This result was driven by a 65% reduction in major repeat surgeries or procedures to retain blood flow in the lower leg and a 27% reduction in major amputations. No differences were found in death rates between the participants who received the bypass surgery and those who received an endovascular procedure.

Adults in cohort 2 – those who did not have the optimal vein for the bypass – had no major differences in outcomes based on having had an open bypass or an endovascular procedure.

“Our findings support complementary roles for these two treatment strategies and emphasise the need for preprocedural planning to assess patients and inform what treatment is selected,” said co-principal investigator Alik Farber, MD, at Boston Medical Center.

Common symptoms of CLTI include leg and foot pain, foot infections, and open sores on the leg and foot that don’t fully heal. Without having a procedure to redirect or open blocked blood flow to the lower body, about 4 in 10 adults with CLTI have a lower leg or foot amputation.

BEST-CLI is the largest CLTI clinical trial to date and builds on prior research that aims to answer questions about the risks and benefits of revascularisation strategies for CLTI.

Source: NIH/National Heart, Lung and Blood Institute

Categories : Gastrointestinal Obstetrics & GynaecologyTags :

Even in Remission, IBD is a Risk Factor for Preterm Birth

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Inflammatory bowel disease is a risk factor for giving birth preterm even when in apparent disease remission, according to a study published in the journal eClinicalMedicine. If corroborated, the results may eventually affect recommendations for women with ulcerative colitis wishing to conceive.

Inflammatory bowel disease (IBD) is chronic inflammatory disease with a prevalence of approximately 0.5%. IBD, which includes ulcerative colitis and Crohn’s disease, and – unlike irritable bowel syndrome (IBS) – causes visible damage to the mucosa lining the intestines. IBD is characteristic for its recurrent tendency for symptoms to relapse, followed by periods of remission.

Onset of IBD commonly occurs at age 15–30, so questions about its impact on pregnancy and the foetus are common. IBD has previously been linked to negative birth outcomes, such as preterm birth (< 37 weeks of pregnancy), mainly in women showing signs of active disease.

Also, women without obvious IBD activity often have microscopic inflammation in the intestinal mucosa. Until now, however, it has been unknown whether even microscopic inflammation may be associated with risks in pregnancy.

Higher risk of preterm birth

The present study, shows that microscopic inflammation in IBD, especially ulcerative colitis, is linked to an elevated risk of giving birth prematurely.

Among babies born to women with microscopic inflammation due to IBD, 9.6% were preterm, while 6.5% of children were born preterm to women without microscopic inflammation of IBD. This corresponds to a relative risk increase of 46 percent. Microscopic inflammation was not clearly associated with other adverse pregnancy outcomes, such as growth restriction.

The results are based on register data on women in Sweden, diagnosed with IBD in 1990–2016, in whom information was available on the microscopic appearance of the intestine shortly before pregnancy. The study included 1223 children of women with microscopic IBD inflammation of the intestine and 630 children of women with IBD but with microscopically healed intestinal mucosa.

Through register linkages, data were also retrieved from several national health registers, such as the Swedish Medical Birth Register and the Swedish Quality Register for Inflammatory Bowel Desiease (SWIBREG).

Prospect of new treatment targets

“Our results suggest that IBD treatment aimed at not merely alleviate symptoms of IBD, but also microscopically heal the intestine, can reduce the risk of giving birth preterm,” sayd first author and corresponding author is Karl Mårild, associate professor of paediatrics at Sahlgrenska Academy, University of Gothenburg. “If our results hold up in future studies, they may therefore be the basis for recommendations to confirm microscopic healing before pregnancy, to reduce such risks.”

“Even a modestly increased relative risk of preterm birth is important, given that preterm birth can greatly affect the child’s health in both the short and the long term. Preterm birth is still one of the most common causes of death for children under the age of five in Sweden,” Karl Mårild concludes.

Source: University of Gothenburg

Categories : Diseases, Syndromes and ConditionsTags :

New Monoclonal Antibody Prevents Malaria Infection in African Adults

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Mosquito, a malaria parasite vector
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One dose of a new monoclonal antibody safely protected healthy, non-pregnant adults from malaria infection during the malaria season in Mali. The antibody was up to 88.2% effective at preventing infection over a 24-week period, demonstrating for the first time that a monoclonal antibody can prevent malaria infection in an endemic region. These findings were published in The New England Journal of Medicine.

The only WHO-recommended vaccine against vaccine, RTS,S (Mosquirix), provides partial protection against clinical malaria during the early years of life when given to children aged 5 to 17 months in four doses over a 20-month period. Other drugs consisting of small chemical compounds that effectively prevent malaria infection are also available for infants and young children as well as travellers. The requirement for frequent dosing of these drugs can limit adherence, however, and the emergence of drug resistance may also limit their usefulness. Thus, there is an urgent need for new, fast-acting, infrequently dosed interventions that safely provide strong protection against malaria infection.

Malaria is caused by Plasmodium parasites, which mosquitos inject into into the skin and bloodstream in a form called sporozoites. These travel to the liver, where they mature and multiply before spreading throughout the body via the bloodstream to cause illness. P. falciparum is the Plasmodium species most likely to result in severe malaria infections, which, if not promptly treated, may lead to death.

The Phase 2 NIAID-USTTB trial evaluated the safety and efficacy of a one-time, intravenous infusion of a monoclonal antibody called CIS43LS. This antibody was previously shown to neutralise the sporozoites of P. falciparum in the skin and blood before they could infect liver cells. Researchers led by Robert A. Seder, MD, isolated a naturally occurring form of this antibody from the blood of a volunteer who had received an investigational malaria vaccine, and then modified the antibody to extend the length of time it would remain in the bloodstream.

The study team for the Phase 2 trial enrolled 369 healthy, non-pregnant adults aged 18 to 55 years in the rural communities of Kalifabougou and Torodo in Mali, where intense P. falciparum transmission typically occurs from July through December each year.

The first part of the trial assessed the safety of three different intravenous doses of CIS43LS – 5mg/kg of body weight, 10 mg/kg and 40 mg/kg – in 18 study participants, with six participants per dose level. The study team followed these participants for 24 weeks and found the antibody infusions were safe and well-tolerated.

The second part of the trial assessed the efficacy of two different doses of CIS43LS compared to a placebo. Three hundred and thirty participants were assigned at random to receive either 10mg/kg of the antibody, 40mg/kg, or a placebo by intravenous infusion. No one knew who was assigned to which group until the end of the trial. The study team followed these individuals for 24 weeks, testing their blood for P. falciparum weekly for the first 28 days and every two weeks thereafter. Any participant who developed symptomatic malaria during the trial received standard treatment from the study team.

The investigators analysed the efficacy of CIS43LS two ways. Based on the time to first P. falciparum infection over the 24-week study period, the high dose (40 mg/kg) of CIS43LS was 88.2% effective at preventing infection and the lower dose (10 mg/kg) was 75% effective. An analysis of the proportion of participants infected with P. falciparum at any time over the 24-week study period found the high dose was 76.7% at preventing infection and the lower dose was 54.2% effective.

“These first field results demonstrating that a monoclonal antibody safely provides high-level protection against intense malaria transmission in healthy adults pave the way for further studies to determine if such an intervention can prevent malaria infection in infants, children, and pregnant women,” Dr Seder said. “We hope monoclonal antibodies will transform malaria prevention in endemic regions.”

Dr Seder and colleagues have developed a second antimalarial monoclonal antibody, L9LS, that is much more potent than CIS43LS and therefore can be administered in a smaller dose as a more convenient subcutaneous injection. An early-phase NIAID trial of L9LS in the United States found that the antibody was safe and prevented malaria infection for 21 days in 15 out of 17 healthy adults exposed to P. falciparum in a carefully controlled setting. Two larger, NIAID-sponsored Phase 2 trials assessing the safety and efficacy of L9LS in infants, children and adults are underway in Mali and Kenya.

Source: NIH/National Institute of Allergy and Infectious Diseases

Categories : COVID NeurologyTags :

Delayed COVID Recovery could be a Protective Mechanism against Hypoxia

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COVID patients placed on ventilators can take a long time to regain consciousness. New research published the Proceedings of the National Academy of Sciences now shows that these delays may serve a purpose: protecting the brain from oxygen deprivation.

The existence of such a brain-preserving state could explain why some patients wake up days or even weeks after they stop receiving ventilation, and it suggests that physicians should take these lengthy recovery times into account when determining a patient’s prognosis.

In their study, investigators connect the pattern seen among those who have survived severe COVID with similar delays known to occur in a small fraction of cardiac arrest patients.

“The delayed recoveries in COVID patients are very much like the rare cases we’ve documented in previous research. In this new paper, we describe a mechanism to explain what we’re seeing in both types of patients,” said study co-senior author Dr Nicholas D. Schiff, a neurology professor at Weill Cornell Medicine.

He suggests that this mechanism is the brain protecting itself, pointing to animals, most notably painted turtles, that can tolerate extended periods without oxygen.

More than a decade ago, Dr Schiff and his colleagues first observed these delays among comatose cardiac arrest patients who received cooling therapy to reduce brain damage caused by a loss of blood flow. In one such case, a 71-year-old patient took 37 days to awaken, before ultimately making a near-complete recovery.

During the pandemic, Dr Schiff performed neurology consultations for COVID patients, and he soon began seeing similar, delayed awakenings occurring when patients were taken off ventilators and stopped receiving movement-limiting sedatives.

In a separate analysis of a large cohort of COVID patients from Weill Cornell Medicine and two other major U.S. medical centres, Dr Schiff and his colleagues, including co-author of the current paper, Dr Emery N. Brown, professor of anaesthesia at Harvard Medical School, found that a quarter of patients who survived ventilation took 10 days or longer to recover consciousness. The more oxygen deprivation they suffered while on the ventilator, the longer that delay.

In the prior study of cardiac patients, the researchers recorded a distinctive pattern in brain activity, one also seen in patients under deep anaesthesia. (Recordings from COVID patients are extremely limited.) Dr Schiff read that a similar pattern had been seen in the brains of painted turtles, which can withstand up to five months without oxygen under ice in the winter. To do so, they activate the same inhibitory system within the brain targeted by anaesthetics given to human cardiac and COVID patients but in novel ways developed by evolutionary specialisations.

Drs Schiff and Brown propose that, by chance, the same protective response emerges in the patients.

“It is our theory that oxygen deprivation as well as practices in the ICU, including commonly used anaesthetics, expose elements of strategies that animals use to survive in extreme conditions,” Dr Schiff said.

“These observations may offer new insights into the mechanisms of how certain anaesthetics produce unconsciousness and new approaches for ICU sedation and for fostering recovery from disorders of consciousness,” Dr Brown added.

When patients fail to regain consciousness for an extended time, physicians may recommend withdrawing life-supporting care. This threshold is typically set at 14 days or less for cardiac patients, while no such guidelines exist for COVID.

In light of this new research, however, so long as they lack brain injuries, physicians should avoid making negative projections about these patients’ potential to recover, note the researchers.

Source: Weill Cornell Medicine

Categories : NeurologyTags :

Brain Changes in Autism More Widely Spread than Previously Believed

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In autism, brain changes are spread throughout the cerebral cortex instead of in areas thought affect social behaviour and language, according to a new study that significantly refines scientists’ understanding of how autism spectrum disorder (ASD) progresses at the molecular level.

The study, published in Nature, represents a comprehensive effort to characterise ASD at the molecular level. While neurological disorders like Alzheimer’s disease or Parkinson’s disease have well-defined pathologies, autism and other psychiatric disorders have had a lack of defining pathology, challenging efforts to develop more effective treatments.  

The new study finds brain-wide changes in virtually all of the 11 cortical regions analysed, regardless of whether they are higher critical association regions – those involved in functions such as reasoning, language, social cognition and mental flexibility – or primary sensory regions.  

“This work represents the culmination of more than a decade of work of many lab members, which was necessary to perform such a comprehensive analysis of the autism brain,” said study author Dr Daniel Geschwind, the Gordon and Virginia MacDonald Distinguished Professor of Human Genetics, Neurology and Psychiatry at UCLA. “We now finally are beginning to get a picture of the state of the brain, at the molecular level, of the brain in individuals who had a diagnosis of autism. This defines a molecular pathology, which similar to other brain disorders such as Parkinson’s, Alzheimer’s and stroke, provides a key starting point for understanding the disorder’s mechanisms, which will inform and accelerate development of disease-altering therapies.” 
 
Just over a decade ago, Geschwind led the first effort to identify autism’s molecular pathology by focusing on two brain regions, the temporal lobe and the frontal lobe. Those regions were chosen because they are higher order association regions involved in higher cognition – especially social cognition, which is disrupted in ASD.  
 
For the new study, researchers examined gene expression in 11 cortical regions by sequencing RNA from each of the four main cortical lobes. They compared brain tissue samples obtained after death from 49 people with ASD against 54 controls individuals.  
 
While each profiled cortical region showed changes, the largest changes in RNA levels were in the visual cortex and the parietal cortex, which processes information like touch, pain and temperature. The researchers said this may reflect the sensory hypersensitivity that is frequently reported in people with ASD. Researchers found strong evidence that the genetic risk for autism is enriched in a specific group of genes expressed in neurons that has lower expression across the brain, indicating that these correlated RNA changes in the brain are likely the cause of ASD rather than a result of the disorder. 

One of the next steps is to determine whether researchers can use computational approaches to develop therapies based on reversing gene expression changes the researchers found in ASD, Geschwind said, adding that researchers can use organoids to model the changes in order to better understand their mechanisms.  

Source: University of California, Los Angeles

Categories : Uncategorized

Probing why Vaccine Responses Vary among Individuals

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Many factors dictate whether a vaccine provokes an immune response, including specific biomarkers within a person’s immune system, but until now there has been no evidence showing whether these factors were universal across a wide range of vaccines.

New findings from a meta-analysis published in Nature Immunology examine the biological mechanisms responsible for why some people’s immune systems respond differently to vaccinations, which could have global implications for the development and administration of vaccines.

As part of a series of studies for The Human Immunology Project Consortium (HIPC), a network of national research institutions studying the range of responses to different infections and vaccinations, Emory researchers analysed the molecular characteristics of 820 healthy young adults who were immunised with 13 different vaccines to identify specific biomarkers that generate antibody response to vaccines.

The participants were separated into three endotypes, or groups with a common gene expression, based on the level of inflammatory response prior to vaccination – a high inflammatory group, a low inflammatory group, and a mid-inflammatory group. After studying the immunological changes that occurred in participants following vaccination, researchers found the group that had the highest levels of inflammation prior to vaccine had the strongest antibody response.

“We were surprised because inflammation is usually depicted as something that is bad,” says Slim Fourati, PhD, bioinformatic research associate at Emory University and first author on the paper. “These data indicate that some types of inflammation can actually foster a stronger response from a vaccine.”

Fourati, Dr Rafick-Pierre Sekaly, professor and senior author of the paper, and the HIPC team identified specific biomarkers among this group and cellular features that characterised the pre-vaccination inflammatory signature, information that can be used to predict how well an individual will respond to a vaccine.

“With the knowledge we now have about what characteristics of the immune system enable a more robust response, vaccines can be tailored to induce this response and maximize their effectiveness,” says Fourati. “But we still have more questions to answer.”

More research is needed to determine the cause of this inflammation in otherwise healthy adults. Additionally, Fourati suggests future studies should look at how these biomarkers facilitate vaccine protection in older age groups and among populations who are immunocompromised.

These findings can serve to improve vaccine response across all individuals. Better understanding of how various pre-vaccine immune states impact antibody responses opens the possibility of altering these states in more vulnerable individuals. For example, scientists may give patients predicted to have a weaker immune response an adjuvant with the vaccine to trigger the inflammatory genes associated with greater protection.

This work will help enable improved, more efficient clinical trials for the development of new vaccines.

Source: Emory Health Sciences

Categories : Immune SystemTags :

Study Reveals a Possible Secret to Viral Infection Resistance in Humans

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Colourised scanning electron microscope image of a natural killer cell. Credit: National Institutes of Health

Studying resistance to viral infections in humans is difficult because it’s virtually impossible to disentangle resisting being infected from simply not being exposed. By studying women who were accidentally exposed to hepatitis C (HCV) over 40 years ago, scientists in Ireland have uncovered a secret that may explain why some people are able to resist viral infections.

The extraordinary work, published in Cell Reports Medicine, has wide-ranging implications from improving our fundamental understanding of viral resistance to the potential design of therapies to treat infected people.

From 1977–79, several thousand women in Ireland were exposed to the hepatitis C virus through contaminated anti-D, a medication made using plasma from donated blood and given to Rhesus negative women who are pregnant with a Rhesus positive foetus. The medication prevents the development of antibodies that could be dangerous in subsequent pregnancies. Some of the anti-D used during the 1977–79 period was contaminated with hepatitis C.

Infected women fell into three groups: those who were chronically infected; those who cleared the infection with an antibody response; and those who appeared protected against infection but yet produced no antibodies against hepatitis C.

“We hypothesised that women who seemed to resist HCV infection must have an enhanced innate immune response, which is the ancient part of the immune system that acts as a first line of defence,” said senior author Cliona O’Farrelly, Professor of Comparative Immunology in Trinity’s School of Biochemistry and Immunology.

“To test this we needed to make contact with women exposed to the virus over forty years ago and ask them to help us by allowing us to study their immune systems to hunt for scientific clues that would explain their differing responses.

“After a nationwide campaign over 100 women came forward and we have gained some unique and important insights. That so many women – many of whom have lived with medical complications for a long time – were willing to help is testament to how much people want to engage with science and help pursue research with the potential to make genuine, positive impacts on society. We are deeply grateful to them.”

The scientists ultimately recruited almost 40 women from the resistant group, alongside 90 women who were previously infected.

In collaboration with the Institut Pasteur in Paris they then invited almost 20 women in each group to donate a blood sample that they stimulated with molecules that mimic viral infection and lead to activation of the innate immune system.

“By comparing the response of the resistant women to those who became infected, we found that resistant donors had an enhanced type I interferon response after stimulation,” said first author Jamie Sugrue, PhD Candidate. Type I interferons are a key family of antiviral immune mediators that play an important role in defence against viruses including hepatitis C and SARS-CoV-2, or COVID.

“We think that the increased type I interferon production by our resistant donors, seen now almost 40 years after the original exposure to hepatitis C, is what protected them against infection.

“These findings are important as resistance to infection is very much an overlooked outcome following viral outbreak, primarily because identifying resistant individuals is very difficult – since they do not become sick after viral exposure, they wouldn’t necessarily know that they were exposed. That’s why cohorts like this, though tragic in nature, are so valuable – they provide a unique opportunity to study the response to viral infections in an otherwise healthy population.”

The lab’s efforts are now focused on leveraging these biological findings to unpick the genetics of viral resistance in the HCV donors. Their work on HCV resistance has already helped ignite international interest in resistance to other viral infections such as SARS-CoV-2.

The O’Farrelly lab has expanded its search for virus-resistant individuals by joining in the COVID human genetic effort and by recruiting members of the public who have been heavily exposed to SARS-CoV-2 but never developed an infection.

Source: Trinity College Dublin

Categories : CancerTags :

A Shot of Vitamin C Gives Dendritic Cells a Potent Cancer-fighting Boost

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Vitamin C pills and orange
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New research published in Nucleic Acids Research has shown that vitamin C improves the immunogenic properties of dendritic cells, activating genes involved in the immune response. This discovery could help the development of potent new dendritic cell-based immunotherapies.

Since the onset of anticancer cell therapies, many types of immune cells have been used. The best-known of these cell therapies use lymphocytes, as in the highly successful CAR-T therapies. Recently, researchers have to turned to dendritic cells, known as the ‘master regulators of the immune system‘, for their ability to uptake and present antigens to the T-lymphocytes and induce an antigen-specific potent immune activation. This approach entails loading dendritic cells with specific antigens to create immune memory to make dendritic cell (DC)-vaccines.

To study dendritic cells in the lab, researchers differentiate them from monocytes using a particular set of molecular signalling. This differentiation is accomplished through a complex set of gene activation processes in the nucleus, mostly thanks to the activity of the chromatin remodelling machinery spearheaded by the TET family of demethylases, proteins that act upon the DNA epigenetic marks.

Vitamin C was already known to interact with several TET proteins to enhance its activity, but the specific mechanism was still poorly understood in human cells. In this study, a team lead by Dr Esteban Ballestar hypothesised that treating monocytes in vitro while differentiating into dendritic cells, would help the resulting cells be more mature and active.

The results obtained show that vitamin C treatment triggers an extensive demethylation at NF- kB/p65 binding sites compared with non-treated cells, promoting the activity of genes involved in antigen presentation and immune response activation. Vitamin C was also found to increase the communication of the resulting dendritic cells with other components of the immune system and stimulates the proliferation of antigen-specific T cells.

The researchers proved that vitamin C-stimulated dendritic cells loaded with antigens specific for the SARS-CoV-2 virus were able to activate T cells in vitro more efficiently than non-treated cells.

Overall, these new findings support the hypothesis that treating monocyte-derived dendritic cells with vitamin C may help generate more effective DC-vaccines. After consolidating these results in preclinical models and, hopefully, in clinical trials, a new generation of cell therapies based on dendritic cells may be used in the clinic to fight cancer more efficiently.

Source: Josep Carreras Leukaemia Research Institute