Year: 2021

Categories : Immune SystemTags :

Mystery Protein is an Immune System Component

On By ModernMedia

A protein called ITIH4, the function of which was largely a mystery, has been shown to a as a protease inhibitor, and a component of the innate immune system.

The discovery was made by Professor Steffen Thiel and PhD student Rasmus Pihl at Aarhus University, with the help of a mass spectrometry team led by Professor Jan J Enghild.

Proteases are enzymes which cleave other proteins, and usually occur in cascade networks where proteases cleave each other in a chain reaction. One example of this is blood clotting.

There is also the complement system in the body, which is responsible for eliminating pathogens, and cancerous or dying cells. Immunoglobin G (IgG) and M (IgM) antibodies activate complement proteins which work with them, hence the name “complement”. This system of enzymes is kept in check by protease inhibitors.

The researchers wanted to find out which other proteins in our blood the “MASP” proteases from the complement cascade interact with. They found to their surprise that two MASP proteases formed a strong complex with the ITIH4 protein, about which very little is known, especially its function.

“I was highly surprised when I saw the first data from our partners, showing that ITIH4 could form a complex with the MASP-1 and MASP-2 enzymes. At Biomedicine, we have been studying these two proteases for 25 years, and ITIH4 has simply never been on the radar. But it made good sense, as proteins similar to ITIH4 act as inhibitors of other proteases,” said Rasmus Pihl.

It was also discovered that when ITIH4 formed a complex with MASP-1 and MASP-2, they could still cleave small proteins, but when ITIH4 inhibited them, they could not cleave large proteins.The researchers discovered that ITIH4 performs an inhibitory enzyme function similar to that of one discovered in the 1980s called AM2, but it accomplished it in a new, entirely different manner.

“There is very little knowledge about ITIH4, but it is known that under various pathological conditions, the protein can be cleaved. Our results show that such a cleavage is absolutely necessary for the way ITIH4 can function as an enzyme inhibitor,” Professor Steffen Thiel explained.

Their colleague Gregers R Andersen added: “By using cryo-electron microscopy, we now try to understand in detail how ITIH4 inhibits MASP-1 and MASP-2 via this new inhibition mechanism. We already know that when ITIH4 is cleaved, it forms a complex with both MASP-1 and another ITIH4 molecule. We are very excited to see how it takes place.”

Source: Medical Xpress

Journal information: Rasmus Pihl et al, ITIH4 acts as a protease inhibitor by a novel inhibitory mechanism, Science Advances (2021). DOI: 10.1126/sciadv.aba7381

Categories : Addiction Mental HealthTags :

Happier Memories in Teens Linked to Less Alcohol and Marijuana Use

On By ModernMedia

A study of teenage American students has found that happy childhood memories, along with a positive view of the present and outlook for the future are associated with reduced alcohol use, binge drinking and marijuana use. 

Researchers say that action is needed because COVID restrictions have left teenagers isolated and vulnerable. Quarantining results in anxiety, stress and feelings of loneliness in children and adolescents, and the closure of schools has also taken away mental health support systems which some teenagers may rely on.

John Mark Froiland of Purdue University said: “School often seems a source of stress and anxiety to students. This puts them at greater risk of not participating in lessons, getting lower grades and of substance misuse. Many teenagers also aren’t engaging with online learning during Covid or have lower engagement levels.

“But they’re more likely to be enthusiastic learners and not use drink and drugs if teachers take time to build more positive relationships with them. They can help students see that everything they’re learning is truly valuable. Parents have a role to play too.”

The study was based on questionnaires completed by 1961 student participants in San Francisco, of which 53% were female. The researchers examined how happy the students believed their childhood was, how happy they were currently and how optimistic they were about their futures.

In addition, they looked at alcohol and marijuana use over the past 30 days and binge use, as well as academic grades, behaviour during lessons and motivation.

Positive attitudes towards the past, present and future was associated with lower alcohol use, binge drinking and marijuana use, while the reverse was true for negative attitudes.

An optimistic outlook increased the likelihood that they would be motivated and focus on learning. Other findings included drinking being associated with marijuana use, and that girls had better behavioural engagement than boys.

Source: News-Medical.Net

Journal information: Froiland, J.M., et al. (2020) Positive and negative time attitudes, intrinsic motivation, behavioral engagement and substance use among urban adolescents. Addiction Research & Theory. doi.org/10.1080/16066359.2020.1857740.

Categories : Cardiovascular DiseaseTags :

Blood Vessels Self-Reinforce After Aneurysms

On By ModernMedia

Immediately following an aneurysm, blood vessels reinforce themselves by adapting collagen fibres to spread out the load, a study has found. 

An aneurysm is an abnormal bulge in the artery wall that can form in brain arteries. Brain aneurysms that rupture are fatal in nearly 50% of cases. In a rabbit model, the researchers used cutting-edge high-resolution microscopes to observe changes within the aneurysm, and observed that new collagen fibres laid down to deal with the strain and existing ones were re-oriented. Blood vessels had already been known to be able to reform and restructure over time, but this kind of primary restructuring is the first time that it has been observed, happening immediately after an event.  Instead of forming along the same direction, the blood vessels adapt to the different directions the new loads are in. 

Professor Anne Robertson at the University of Pittsburgh’s Swanson School of Engineering explained: “Imagine stretching a rubber tube in a single direction so that it only needs to be reinforced for loads in that direction. However, in an aneurysm, the forces change to be more like those in a spherical balloon, with forces pulling in multiple directions, making it more vulnerable to bursting. Our study found that blood vessels are capable of adapting after an aneurysm forms. They can restructure their collagen fibers in multiple directions instead of just one, making it better able to handle the new loads without rupturing.

“The first restructuring phase involves putting down a layer collagen fibres in two directions to deal with the new load, and the second phase involves re-orienting existing layers to adjust to these two directions, explained Chao Sang, who was a primary investigator on this research as part of his doctoral dissertation.

“The long-term restructuring is akin to a scar forming after a cut has healed, while this first phase that we observed can be thought of as having a role similar to clotting immediately after the cut–the body’s first response to protect itself,” added Robertson, who has a secondary appointment in the Swanson School’s Department of Bioengineering. “Now that we know about this first phase, we can begin to investigate how to promote it in patients with aneurysms, and how factors like age and preexisting conditions affect this ability and may place a patient at higher risk for aneurysm rupture

Source: News-Medical.Net

Journal information: Sang, C., et al. (2020) Adaptive Remodeling in the Elastase-Induced Rabbit Aneurysms. Experimental Mechanics. doi.org/10.1007/s11340-020-00671-9.

Categories : Cancer Diet and NutritionTags :

Breast Cancer in Mice Inhibited by Restricted Feeding Times

On By ModernMedia

Restricting calorie intake to an eight-hour window coinciding with physical activity reduced breast cancer risk in female mouse models.

Researchers from University of California San Diego School of Medicine, Moores Cancer Center and Veterans Affairs San Diego Healthcare System (VASDSH) found that the restricted feeding times, which are kind of circadian rhythm-linked intermittent fasting, enhanced metabolic health and tumour circadian rhythms in female mice with obesity-driven postmenopausal breast cancer. Breast cancer is the second most common cancer in US women, after skin cancer.

“Previous research has shown that obesity increases the risk of a variety of cancers by negatively affecting how the body reacts to insulin levels and changing circadian rhythms,” explained senior author Nicholas Webster, PhD. professor at UC San Diego School of Medicine and senior research career scientist at VASDSH. “We were able to increase insulin sensitivity, reduce hyperinsulinemia, restore circadian rhythms and reduce tumor growth by simply modifying when and for how long mice had access to food.”

Female mouse models mimicking postmenopausal hormone conditions were used to investigate if time-restricted feeding of obese mice affected the tumour growth and development, and reduced metastasis to the lungs. The mice were split into three groups, one with constant access to food, one with access for eight hours at night when they have the greatest activity, and the last was fed an unrestricted low-fat diet.

Obesity and menopause disrupt the circadian rhythm, with increased risk of insulin resistance and thereby chronic diseases such as cancer. A number of cancers are known to be associated with insulin resistance, such as breast cancer and pancreatic cancer. High insulin levels in obese mice drive tumour growth. Artificially increasing insulin levels has been shown to accelerate tumour growth whilst lowering them is similar to the effect of limiting eating.
Manasi Das, PhD, postdoctoral fellow in the Webster lab and first author, said: “Time-restricted eating has a positive effect on metabolic health and does not trigger the hunger and irritability that is associated with long-term fasting or calorie restriction. Through its beneficial metabolic effects, time-restricted eating may also provide an inexpensive, easy to adopt, but effective strategy to prevent and inhibit breast cancer without requiring a change in diet or physical activity.”

Webster believes that time-restricting eating warrants further investigations as it may present a way to reduce breast cancer risk, or that of cancer in general.

“The increase in risk of breast cancer is particularly high in women who are overweight and have been through menopause. For this reason, doctors may advise women to adopt weight loss strategies to prevent tumor growth,” said Das. “Our data suggests that a person may benefit from simply timing their meals differently to prevent breast cancer rather than changing what they eat.”

Source: Medical Xpress

Journal information: Manasi Das et al. Time-restricted feeding normalizes hyperinsulinemia to inhibit breast cancer in obese postmenopausal mouse models, Nature Communications (2021). DOI: 10.1038/s41467-020-20743-7

Categories : COVIDTags :

EU to Restrict AstraZeneca Exports to Tackle Vaccine Shortage

On By ModernMedia

In response to AstraZeneca’s COVID vaccine production and delays, the European Union has warned that it will tighten exports of the company’s vaccine to countries outside its borders.

EU Health Commissioner Stella Kyriakides warned it would “take any action required to protect its citizens”, adding that she had requested detailed delivery schedules and a meeting next week with the company. She added that “in the future, all companies producing vaccines against Covid-19 in the EU will have to provide early notification whenever they want to export vaccines to third countries”.

The vaccine, developed by Oxford University and the British-Swedish company AstraZeneca, is still yet to be approved in the EU but should receive it by the end of January, with distribution set to start on the 15th of February. The EU has been suffering from a number of vaccination programme setbacks, including a previous announcement last week from Pfizer that its own deliveries were being delayed in order to upgrade manufacturing capabilities at a plant in Belgium, provoking ire amongst EU politicians. Italy’s PM has resigned over handling of the pandemic.

The EU had signed a deal in August to secure 300 million doses from AstraZeneca, with an option for another 100 million. Last week, AstraZeneca had announced a slowdown in delivery due to “reduced yields at a manufacturing site within our European supply chain”. The problem is thought to be from a manufacturing plant also in Belgium, which is run by an AstraZeneca partner firm. The exact size of the shortfall is not known but some believe it to be a drop of 31 million doses, or 60% of those meant to be delivered by the end of the quarter.

Where this leaves low and middle-income countries counting on the Oxford/AstraZeneca vaccines is unclear, but it certainly will add to mounting tension between countries seeking vaccines for their populations amidst the spread of more contagious COVID variants. President Cyril Ramaphosa warned in an address to the World Economic Forum that vaccine nationalism was a growing concern and threat to global recovery. The African Union’s vaccine task team has thus far managed to secure only 270 million doses.

Source: BBC News

Categories : AgeingTags :

For Older IBD Patients, Vedolizumab is a Safer Option

On By ModernMedia

Vedolizumab appeared to be safer than tumour necrosis factor (TNF) inhibitors in older adults with inflammatory bowel disease (IBD), according to the results of a large retrospective study.

Vedolizumab is a fully humanised monoclonal antibody which targets α4β7 integrin, and prevents leukocyte movement from the blood into inflamed gut tissue.

At the virtual Crohn’s and Colitis Congress, Bharati Kochar, MD, of Massachusetts General Hospital in Boston, presented data showing that all-cause hospitalisation during the 12 months after initiating biologic treatment was lower in new users of vedolizumab than in those starting TNF inhibitors, with a hazard ratio of 0.81 (95% CI 0.68-0.96)

“The American population is rapidly aging, and the number of Americans 65 and older in 2060 will be more than double what it was in 2014,” Dr Kochar said. “The combination of increasing IBD incidence, improvements in disease treatment-related knowledge, and decreasing IBD mortality is resulting in a high prevalence of older adults with IBD,” she added.

It is estimated that a quarter of Americans over 65 have IBD, yet are less likely to receive adequate immunosuppression. Over 65s are underrepresented in IBD clinical trials, creating a lack of understanding over what medications work or not in this age group.

To answer this question, Dr Kochar and her team analysed a 20% sample of Medicare claims database. Patients were included if they were diagnosed with Crohn’s disease or ulcerative colitis and if they initiated treatment with vedolizumab, infliximab, adalimumab, golimumab, or certolizumab from 2014 to 2018 after being on Medicare for 12 months while not receiving any of those medications.

There were 488 new users of vedolizumab and 2213 initiators of TNF inhibitors in the analysis group, with an average age of 71. More than half were women and most were white, 44% had ulcerative colitis and over half of patients had Carlson Comorbidity Index scores of 2 or higher.

There was otherwise no significant difference between vedolizumab and TNF for IBD-related hospitalisation (HR 0.77, 95% Ci 0.53-1.12), IBD-related surgery: (HR 0.78, 95% CI 0.49-1.22), or new steroid prescription within 60 days of starting the biologic (HR 1.01, 95% CI 0.86-1.18).

In the 6-month period prior to biologic initiation, nearly one-third had a prescription for budesonide, 58% had a prescription for a systemic corticosteroid, and nearly one-third were being prescribed immunomodulators.

“In conclusion, I think it’s important to use your clinical judgment to treat the patient in front of you, and these data should simply help contextualise risk for older IBD patients newly initiating vedolizumab or TNF inhibitors,” said Dr Kochar.

“There is a vast need for additional large and robust comparative effectiveness and safety studies for older adults with IBD, with the rapid proliferation of new IBD medications,” she concluded.

Source: MedPage Today

Presentation information: Kochar B, et al “Comparative effectiveness and safety of vedolizumab and anti-tumor necrosis factor agents in older adults with inflammatory bowel diseases in Medicare administrative claims database” CCC 2021

Categories : COVID Immune SystemTags :

NSAIDs Suppress Antibodies in COVID Infections

On By ModernMedia

A new study has found that non-steroidal anti-inflammatory drugs (NSAIDs) suppress antibody counts as well as inflammatory levels in mice infected with the SARS-CoV-2 virus.

NSAIDs inhibit the enzymes cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2), which are needed for prostaglandin generation – lipid molecules involved in homeostasis and inflammation. The study used ibuprofen and meloxicam in mice infected with SARS-CoV-2. The researchers aimed to observe: viral infection through modified expression of angiotensin-converting enzyme 2 (ACE2), the cell entry receptor for SARS-CoV-2, effects on viral replication and modulated response of the immune system. However, they did not observe altered viral infection or replication.

“NSAIDs are arguably the most commonly used anti-inflammatory medications,” said principal investigator Craig B Wilen, Assistant Professor of Laboratory Medicine and Immunology, Yale University School of Medicine.

As well as taking NSAIDs for chronic conditions, eg arthritis, people take them “for shorter periods of time during infections, and [during] acute inflammation as experienced with COVID-19, and for side effects from vaccination, such as soreness, fever, and malaise,” Dr Wilen explained.

“Our work suggests that the NSAID meloxicam dampens the immune response to SARS-CoV-2 infection. Taking NSAIDs during COVID-19 could be harmful or beneficial, depending on the timing of administration,” said Dr Wilen. Dexamethasone, a potent anti-inflammatory but not an NSAID, is detrimental when administered at early stages of COVID but beneficial at later stages. NSAIDs may similarly be detrimental at the early stage because they counteract beneficial inflammation.

An antibody reduction by NSAIDs might not be harmful, but it could also reduce the immune system’s ability to mount a defence early on, or even reduce the length or magnitude of immunity or vaccination protection, Dr Wilen said. Antipyretics such as paracetamol have also been observed to blunt immune system response to vaccination.  

According to Dr Wilen, the original motivation from the study “was a twitter thread, suggesting NSAIDs should not be used during COVID-19. This seemed suspicious to us, so we wanted to investigate.”

Dr Wilen and his team believed there would be no effect of NSAIDs on viral infection, which turned out to be correct. However, they also thought there would be no effect on antibody response.

“In fact, we initially didn’t even carefully look at the antibody response, because we didn’t expect it to be altered by NSAIDs. This turned out to be wrong,” commented Dr Wilen.

Source: Medical Xpress

Journal information: Jennifer S. Chen et al. Non-steroidal anti-inflammatory drugs dampen the cytokine and antibody response to SARS-CoV-2 infection, Journal of Virology (2021). DOI: 10.1128/JVI.00014-21

Categories : Expert Opinion Medical IndustryTags :

Like 60s Cars, Brand Drugs Have no Price Competition

On By ModernMedia

Brand name drugs, like American cars in the 1960s, are subject to broadly rising prices with little evidence of competing on cost.

Before the oil embargo by Arab countries in 1973 allowed competition from more affordable, fuel efficient cars that we take for granted today, the Big Three car manufacturers, Ford, Chrysler and General Motors, would annually announce price increases at about the same time. Any adjustment by one manufacturer, for example, in size, was quickly matched by competitors.New research analysed the prices for five classes of drugs, and found them to be increasing in lock-step from 2015 to 2020. These classes are direct-acting oral anticoagulants (DOACs), P2Y12 inhibitors, glucagon-like peptide-1 (GLP-1) agonists, dipeptidyl dipeptidase-4 (DPP-4) inhibitors, and sodium-glucose transport protein-2 (SGLT-2) inhibitors.

The study had limitations due to not taking into account measures such as rebates, which would affect the price for the patient. However, even if these were taken into consideration, the researchers believe the overall prices would still increase and have to be borne by some patients who would not benefit from certain rebates. “Rebates, list prices, and net prices have been growing for brand-name medications, and rebate growth has been shown to positively correlate with list price growth, thereby impacting costs faced by patients paying a percentage of (or the full) list price,” the researchers noted. “Therefore, the lock-step price increases of brand-name medications, without evidence of price competition, raise concerns and would be expected to adversely affect patient adherence to medications and thus clinical outcomes.”

Unlike the oil crisis which broke open the automobile market to foreign competitors, the solution with “Big Pharma” is less clear. The researchers recommend policies which would limit such lock-step price increases, reduced patent exclusivity periods, and quicker introduction of generic equivalents.

Source: MedPage Today

Journal information: Liu P, et al “Trends in Within-Class Changes in US Average Wholesale Prices for Brand-Name Medications for Common Conditions From 2015 to 2020” JAMA Netw Open 2021; DOI: 10.1001/jamanetworkopen.2020.35064.

Categories : Uncategorized

Exercise can Block Muscle Wasting from Chronic Inflammation

On By ModernMedia

In yet another discovery pointing to the benefits of physical activity, human muscle has been shown to stave off the destructive effects of chronic inflammation through exercise.

“Lots of processes are taking place throughout the human body during exercise, and it is difficult to tease apart which systems and cells are doing what inside an active person,” said Nenad Bursac, professor of biomedical engineering at Duke. “Our engineered muscle platform is modular, meaning we can mix and match various types of cells and tissue components if we want to. But in this case, we discovered that the muscle cells were capable of taking anti-inflammatory actions all on their own.”

Inflammation can be beneficial, such as a low-level response which clears out debris and helps regeneration, or it can be detrimental, such as the lethal COVID cytokine storms. Chronic inflammation as in arthritis or sarcopenia can be damaging as it takes away the ability of muscle to contract, resulting in weakening.

One inflammatory molecule in particular, interferon gamma, has been shown to be associated in many different types of muscular wasting. Interferon gamma is primarily produced by T lymphocytes and natural killer (NK) cells.

“We know that chronic inflammatory diseases induce muscle atrophy, but we wanted to see if the same thing would happen to our engineered human muscles grown in a Petri dish,” said Zhaowei Chen, a postdoctoral researcher in Bursac’s laboratory and first author of the paper. “Not only did we confirm that interferon gamma primarily works through a specific signaling pathway, we showed that exercising muscle cells can directly counter this pro-inflammatory signaling independent of the presence of other cell types or tissues.”

To determine if interferon gamma was the true culprit, Berac and Chen grew contractile human muscle tissue in vitro, then flooded it with interferon gamma over seven days. As predicted, the muscle shrank and lost strength,

They then applied interferon gamma again, but this time electrically stimulating the muscle to contract. They expected the simulated exercise to result in some muscle regrowth as seen in their previous studies, but to their surprise, the muscle suffered almost no effect from the chronic inflammation.They demonstrated that exercise blocked a particular molecular pathway as used in a pair of drugs to treat rheumatoid arthritis, tofacitinib and baricitinib, which produce the same anti-inflammatory effect.

“When exercising, the muscle cells themselves were directly opposing the pro-inflammatory signal induced by interferon gamma, which we did not expect to happen,” Bursac said. “These results show just how valuable lab-grown human muscles might be in discovering new mechanisms of disease and potential treatments. There are notions out there that optimal levels and regimes of exercise could fight chronic inflammation while not overstressing the cells. Maybe with our engineered muscle, we can help find out if such notions are true,” Bursac concluded.

Source: Medical Xpress

Journal information: Z. Chen el al., “Exercise mimetics and JAK inhibition attenuate IFN-γ-induced wasting in engineered human skeletal muscle,” Science Advances (2020). advances.sciencemag.org/lookup … .1126/sciadv.abd9502

Categories : COVID Immune SystemTags :

New “Double Antibodies” can Treat COVID Variants

On By ModernMedia

A new generation of “double antibodies” has been developed which can protect against all SARS-CoV-2 variants, as well as inhibiting mutations against the antibodies.

These “bispecific”  antibodies were created by the Institute for Research in Biomedicine (IRB; Bellinzona, Switzerland), which is affiliated to the Università della Svizzera italiana (USI).

While traditional antibody-based immunisation is able to offer protection against SARS-CoV-2, there is still a need to protect against variants which may achieve “vaccine escape”, as well as inhibiting mutations which give rise to resistance, as with antibiotic resistance in bacteria.

The researchers overcame these difficulties by splicing together a pair of antibodies to make a “bispecific” antibody that simultaneously targets two viral sites. The bispecific antibody treatment has proved effective in mouse models, which maintained body weight when infected with SARS-CoV-2, compared to infected controls, which lost 20-30% body weight before humane euthanisation. The paper is available on the bioRxiv preprint server.

Study author Luca Varani of USI explained: “We exploited our knowledge of the molecular structure and biochemical traits of the virus to fuse together two human antibodies, obtaining a single bispecific molecule simultaneously attacking the virus in two independent sites critical for infectivity. Supercomputing simulations allowed us to refine and validate the bispecific antibody design, which was later produced and tested in the laboratory. Although the virus can mutate and escape from the attack of a single first-generation antibody, we have shown that it cannot do so against the double action of the bispecific.

“A single injection of the bispecific antibody provides instantaneous protection against the disease in pre-clinical trials. The antibody effectively reduces viral burden in the lungs and mitigates inflammation typical of COVID-19”, said Daniel Ruzek from the Czech Academy of Sciences who led the antibody pre-clinical testing.

The effectiveness of the bispecific antibodies holds promise for human clinical trials, with the prospect of being both an effective prevention and treatment of COVID.

Source: News-Medical.Net

Journal information: Gasparo, R D., et al. (2020) Bispecific antibody prevents SARS-CoV-2 escape and protects mice from disease. bioRxiv.doi.org/10.1101/2021.01.22.427567.