Day: December 18, 2023

Categories : Immune SystemTags : Leave a comment

Immune Antifungal Protein Exacerbates Autoimmune Diseases

On By ModernMedia
Irritable bowel syndrome. Credit: Scientific Animations CC4.0

An immune system protein that normally guards against fungal infections is also responsible for exacerbating certain autoimmune diseases such as irritable bowel disease (IBS), type 1 diabetes, eczema and other chronic disorders, new research from The Australian National University (ANU) has found.

The discovery, published in Science Advances, could pave the way for new and more effective drugs, without the nasty side effects of existing treatments.

In addition to helping to manage severe autoimmune conditions, the breakthrough could also help treat all types of cancer.

The scientists have discovered a previously unknown function of the protein, known as DECTIN-1, which in its mutated state limits the production of T regulatory cells.

These ‘guardian’ Treg cells are crucial to preventing autoimmune disease because they suppress the effects of a hyperactive immune system.

“Although the DECTIN-1 protein helps to fight fungal infections, in its mutated state it’s also responsible for exacerbating severe autoimmune disease,” lead author Dr Cynthia Turnbull, from ANU, said.

“Understanding how and why the mutated version of this protein causes autoimmunity in patients brings us a step closer to developing more effective drugs and offers new hope to more than one million Australians who suffer from some form of autoimmune disease.”

The scientists believe they can control the immune system by turning the DECTIN-1 protein on and off, like a light switch.

“Turning on the protein would lower the intensity of the immune system’s defensive response which would help to treat conditions such as autoimmune disease,” Professor Carola Vinuesa, from the Francis Crick Institute, said.

“On the other hand, turning off the protein could give the immune system a boost, sending its defensive mechanisms into overdrive and allowing the body to treat an entirely different set of diseases.

“The findings are exciting because there haven’t been many discoveries of so-called modifier proteins such as DECTIN-1, which can change the way the immune system behaves to the extent it can either cause a disease or prevent it.”

According to Dr Turnbull, this means DECTIN-1 could play a key role in treating cancer.

“Cancer cells can disguise themselves by releasing certain proteins and chemicals into the body that essentially render them invisible from the immune system’s natural defences,” she said.

“We think that by using drugs to turn off the DECTIN-1 protein, in combination with existing therapies, we can activate the immune system and help it identify and attack the cancerous cells.”

Current treatments for autoimmune?disease aren’t very effective and have a lot of damaging side effects.

This is because the majority of existing treatments suppress the entire immune system rather than targeting a specific area.

“That means it might not fix the exact problem behind the patient’s disease and could inadvertently make them vulnerable to infections. Many people on these kinds of treatments also get bacterial, fungal and viral infections which can make their autoimmunity worse,” Professor Vinuesa said.

Mutation found in family

By examining the DNA of a Spanish family, the researchers discovered the DECTIN-1 mutation was responsible for exacerbating the severity of a chronic autoimmune disease suffered by the family’s only child.

“We found the family was also carrying a mutated version of another immune system protein known as CTLA-4. The CTLA-4 mutation prevents guardian cells from working properly and is known to cause severe autoimmune disease in about 60 to 70 per cent of people who carry it in their DNA,” Dr Pablo Canete, from the University of Queensland, said.

“Strangely, the remaining 30 to 40 per cent of the population who carry this mutated protein don’t develop disease.

“We discovered the family’s only child had both the DECTIN-1 mutation and the CTLA4 mutation, while his parents had only one of each. This helped us identify why the child, who is now in his twenties, was the only person in the family to develop severe autoimmunity, ending a 20-year-long mystery behind the cause of his disease.

“By discovering the existence of mutated versions of modifier proteins such as DECTIN-1, we finally have an explanation for why some people develop severe autoimmune diseases while others don’t, even if they inherit gene mutations passed down from family members.”

Source: Australian National University

Categories : CancerTags :

New Combination Salvages Immunotherapy Drug for Breast Cancer

On By ModernMedia

Immunotherapy in combination with chemotherapy has become an important therapeutic treatment option in some patients with metastatic breast cancer. Which patients will benefit the most, however, remains unclear; current biomarkers such as PD-L1 that are used to predict response are mediocre at best. Vanderbilt researchers led a clinical trial combining atezolizumab, an immunotherapy, in combination with chemotherapy in patients with metastatic triple-negative breast cancer to both evaluate the efficacy of the treatment combination and to understand biomarkers of response to immunotherapy.

Atezolizumab became the first approved immunotherapy for breast cancer when the Food and Drug Administration granted it accelerated approval in 2019, but two years later, its maker voluntarily withdrew the indication after additional data from a follow-up clinical trial failed to corroborate its efficacy. Atezolizumab had been approved for metastatic PD-L1-positive triple-negative breast cancer in combination with the chemotherapy nab-paclitaxel. Results from Vanderbilt’s clinical trial, published in JAMA Oncology, indicate that this immunotherapy does have a clinically meaningful benefit with a different chemotherapy partner and the correlative analyses provide insight to which patients will respond.

The clinical trial combined atezolizumab with carboplatin – a chemotherapy that works differently than nab-paclitaxel. The new combination significantly improved progression-free and overall survival of patients with metastatic triple-negative breast cancer. Atezolizumab with carboplatin lengthened progression-free survival from a median of 2.2 months to 4.1 months. Overall survival increased from a median of 8.6 months for the control group, who received carboplatin alone, to 12.6 months for those who received the combination therapy.

The phase 2 randomized clinical trial was conducted at six cancer centers through the Translational Breast Cancer Research Consortium and involved 106 patients of diverse ethnicities.

“Triple-negative breast cancer is difficult to treat because we don’t have a clear target, and understanding the underlying factors that affect response to a treatment is key. This study is so important because we were able to collect biopsies in all of the participants and really understand factors that affect response,” said Vandana Abramson, MD, the Donna S. Hall Professor in Cancer Research and co-leader of the Breast Cancer Research Program at Vanderbilt-Ingram Cancer Center.

The researchers hypothesised that atezolizumab would have superior efficacy to carboplatin because the chemotherapy is a platinum agent, which causes structural DNA changes and generates neoantigens that may stimulate an immune response. Nab-paclitaxel chemotherapy works differently: it is a microtubule-stabilising agent that stops cancer cell division.

“The tremendous knowledge gained from our multidisciplinary analyses of the patients and their tumours will continue to be important for clinical decision-making. After our first description of the triple-negative breast cancer subtypes over 10 years ago, more recently, we refined the subtypes further into four, which were analysed in this study: two basal-like subtypes, a mesenchymal subtype and a lumen androgen receptor-expressing subtype. When we refined the triple-negative breast cancer subtypes, we revealed an immune-modulatory descriptor or correlation.

“This JAMA Oncology study and others continue to confirm that lymphocytes, as measured by the immune-modulatory correlation, have predictive value for better relapse-free survival for triple-negative patients. Further, this study provides evidence that the luminal androgen receptor subtype is more like oestrogen receptor-positive (or ER+) disease. Prior studies investigating immunotherapy in breast cancers have shown that patients with ER+ disease have less benefit from immunotherapy, and we found that to be the case with patients with luminal androgen-positive tumours in this trial,” said Jennifer Pietenpol, PhD, the study’s corresponding author.

Interestingly, patients with higher body mass indexes and uncontrolled blood glucose levels had greater benefit from atezolizumab with carboplatin. The researchers noted that these patients may have more immune cells upon which anti-PD1/PD-L1 therapies can act. A lower risk of disease progression was also associated with high mutation burden and increased tumour-infiltrating lymphocytes.

“In this study, we observed that patients received benefit with atezolizumab even if the tumours were PD-L1 negative. We also show that, like prior clinical trials in melanoma and renal and lung cancers, tumours with high mutation burdens and the presence of immune cells within or around the tumour receive greater benefit from immunotherapy. This makes sense because each mutation has the potential to be recognised as non-self by the immune system, increasing the probability of immune cells already positioned around the tumour to recognise and target the cancer,” said Brian Lehmann, PhD, Research Associate Professor of Medicine and lead correlative scientist on the study.

“One surprising finding was the trend toward greater benefit for patients with higher body mass indexes and patients with uncontrolled blood glucose at prediabetic and diabetic levels while on the study. Both obesity and diabetes are linked to systemic inflammation, and the increased benefit may be attributed to higher adipose tissue composition in the breast and augmented by metabolic syndrome conditions such as Type 2 diabetes. Further studies are necessary to validate these findings and delineate the effects of blood glucose and obesity on immunotherapy,”

The combination therapy was generally well-tolerated, and toxic effects were consistent with previous reports for atezolizumab. The most common drug complications on the combination arm of the clinical trial were low blood platelet counts, anaemia, lymphocytopenia, nausea, fatigue and increased liver enzymes. The participants identified as 69% white, 19% African American, 10% unknown and 1% Asian.

Source: Vanderbilt University Medical Center

Categories : Diet and NutritionTags : Leave a comment

People Struggle to Maintain Healthy Habits During the Festive Season

On By ModernMedia

The holiday season is a time for joy and celebration but many Americans admit the endless flurry of activities make it difficult to eat healthy, exercise and get adequate rest, according to a new survey from The Ohio State University Wexner Medical Center.

Two-thirds of those surveyed said they overindulge in food, nearly 45% said they take a break from exercise and more than half report feeling tired and have less time for themselves. Plus, a third admit they drink more alcohol during the holidays.

“Holiday travel, activities with friends and family, and trying to get a bunch of things done can cause people to lose track of their healthy habits,” said Barbara Bawer, MD, family medicine physician at Ohio State Wexner Medical Center and clinical assistant professor of family and community medicine at The Ohio State University College of Medicine.

“If one healthy habit drops off, it can affect other areas very quickly.”

To make it through the holiday season with healthy habits intact, Bawer suggests trying to stick to a normal routine as much as possible while giving yourself some grace.

“Once you’re out of a routine, which typically happens around the holidays, it’s really hard to get back on track partly because the motivation is no longer there,” said Bawer.

When the invitations start to pile up and decadent menus feels tempting, Bawer offers this advice, “Remember that it’s OK to say no.”

To keep healthy habits in check, try the following:

Diet: When it comes to sustaining healthy eating habits, it’s important to plan ahead. If you have an evening event, don’t starve yourself all day. Eat a high protein, low carb meal earlier in the day so you don’t overeat.

You can indulge with a favorite dish or dessert but it’s OK to say no to sampling every entrée or treat so you’re not eating excess calories at each event.

Exercise: Try to keep the same exercise schedule. If an obligation prevents you from going to a fitness centre or going for a run, be flexible. It’s OK to say no to the gym and consider doing an activity with family and friends that keeps you moving like going for a walk or playing a game of basketball.

Sleep: Go to sleep and wake up at your normal times, even when travelling. Limit the use of supplements like melatonin, as long-term use can disrupt healthy sleep-wake cycles. It’s OK to say no to some invitations if you feel like you’re going to overextend yourself.

Alcohol: People may drink more during the holidays but binge drinking is never a healthy choice. Binge drinking is when a man consumes five drinks or a woman consume four drinks in one setting. It’s OK to say no to excessive drinking. If you do drink, try to stick to the recommended two drinks for men or one drink for women. Avoid drinking on an empty stomach and drink plenty of water.

“Small, consistent changes and slowly adding to them can help you reach your health goals,” Bawer said.

Survey results and methodology This survey was conducted on behalf of The Ohio State University Wexner Medical Center by SSRS on its Opinion Panel Omnibus platform. The SSRS Opinion Panel Omnibus is a national, twice-per-month, probability-based survey. Data collection was conducted from Oct. 20-23 among a sample of 1 007 respondents. The survey was conducted via web (n = 977) and telephone (n = 30) and administered in English. The margin of error for total respondents is +/-3.6 percentage points at the 95% confidence level. All SSRS Opinion Panel Omnibus data are weighted to represent the target population of U.S. adults ages 18 or older.

Source: Ohio State University Wexner Medical Center

Categories : Healthcare Politics and RegulationsTags :

NHI Bill Threatens All Citizens’ Constitutional Rights

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HFA outlines presidential petition to prevent decimation of the SA healthcare system

The NHI Bill presented to President Cyril Ramaphosa cannot be permitted, as in its current form, it will infringe the rights of all South Africans by destroying the South African healthcare system. The Health Funders Association (HFA) has petitioned the President to withhold assent of the Bill on constitutional and procedural grounds and intends to take the matter as far as necessary and to the Constitutional Court if need be.

“We have taken a strong stand by respectfully urging the President to withhold assent of the Bill, citing constitutional and procedural concerns that pose a significant threat to the integrity of the country’s healthcare system,” remarks HFA Chairperson Craig Comrie.

“Should the need arise, the HFA is prepared to escalate the matter to the courts. Our goal is to meticulously align the legislation with the authentic objectives of Universal Health Coverage and the principles enshrined in the South African Constitution.

“Our action in opposing the NHI Bill being signed into law protects the interests of ALL South Africans who will require healthcare in future, including the people we are duty-bound to safeguard through the medical schemes and healthcare administrators we represent,” Comrie says.

While expressing unwavering support for achieving Universal Health Coverage (UHC) in South Africa, the HFA questions Parliament’s endorsement of a bill that raises significant constitutional and procedural concerns and fundamentally cannot achieve a sustainable system of UHC.

Some of the primary concerns outlined in the letter include:

  • Constitutional concerns: The NHI Bill’s clear infringement on constitutional rights, particularly the right to access healthcare and freedom of choice for South Africans, and by implication, the right to life. The Bill is seriously flawed in that regard, undermining the rule of law.
  • Procedural concerns: Questioning the extent and effectiveness of public consultation during the drafting and review of the NHI Bill, where thousands of submissions resulted in no meaningful changes to the Bill, the HFA advocates for a more inclusive and consultative approach.

The letter implores President Ramaphosa to exercise the powers granted by the Constitution to refer the NHI Bill back to Parliament for review.

“In addition to petitioning the President directly as guardian of the Constitution, the HFA will oppose the NHI Bill in its current form through every possible avenue, including approaching the courts to set aside the Bill on constitutional and procedural grounds.

“The HFA will also seek a High Court interdict against implementation of the NHI Act until the merits of our case have been heard and ruled upon by the High Court.

Craig Comrie concludes, “It is with a heavy heart that we make this plea, urging the President to secure the rights and wellbeing of our people. We will persist to ensure that what is right triumphs in our nation. South Africa deserves leadership that prioritises the welfare of all of its citizens, above all.”

Categories : Cardiovascular Disease Diet and NutritionTags :

Times of Meals are Important for Cardiovascular Health, Large Study Finds

On By ModernMedia
Photo by Richard Bell on Unsplash

A study published in Nature Communications has revealed that the time at which we eat could influence our risk of developing cardiovascular disease. This study, suggests that eating a late first or last meal is associated with a higher risk of cardiovascular disease. It also appears that a longer night-time fasting duration is associated with a reduced risk of cerebrovascular disease such as stroke. The findings, suggest the importance of daily meal timing and rhythm in reducing cardiovascular disease risk.

The study was led by scientists from INRAE, the Barcelona Institute for Global Health, Inserm, and the Université Sorbonne Paris Nord.

Diet plays a major role in the development and progression of cardiovascular diseases. The modern lifestyle of Western societies has led to specific eating habits such as eating dinner late or skipping breakfast. In addition to light, the daily cycle of food intake (meals, snacks, etc) alternating with periods of fasting synchronizes the peripheral clocks, or circadian rhythms, of the body’s various organs, thus influencing cardiometabolic functions such as blood pressure regulation. Chrononutrition is emerging as an important new field for understanding the relationship between the timing of food intake, circadian rhythms and health.

Scientists used data from 103,389 participants in the NutriNet-Santé cohort (79% of whom were women, with an average age of 42) to study the associations between food intake patterns and cardiovascular disease. To reduce the risk of possible bias, the researchers accounted for a large number of confounding factors, especially sociodemographic factors (age, sex, family situation, etc.), diet nutritional quality, lifestyle and sleep cycle.

The results show that having a first meal later in the day (such as when skipping breakfast), is associated with a higher risk of cardiovascular disease, with a 6% increase in risk per hour delay. For example, a person who eats for the first time at 9 am is 6% more likely to develop cardiovascular disease than someone who eats at 8 am When it comes to the last meal of the day, eating late (after 9 pm) is associated with a 28% increase in the risk of cerebrovascular disease such as stroke compared with eating before 8 pm, particularly in women. Finally, a longer duration of night-time fasting – the time between the last meal of the day and the first meal of the following day – is associated with a reduced risk of cerebrovascular disease, supporting the idea of eating one’s first and last meals earlier in the day.

These findings, which need to be replicated in other cohorts and through additional scientific studies with different designs, highlight a potential role for meal timing in preventing cardiovascular disease. They suggest that adopting the habit of eating earlier first and last meals with a longer period of night-time fasting could help to prevent the risk of cardiovascular disease.

Source: INRAE