Month: September 2022

Categories : CancerTags :

Killer T Cells Grab and Twist Cancer Cells Like Expert Warriors

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Killer T cells about to destroy cancer cell
Killer T cells about to destroy cancer cell (centre). Credit: NIH

While killer T cells have long been known to kill cancer cells with a cytotoxic weapon, new research has shown that they deliver the lethal strikes like expert warriors, grabbing and pulling the cancer cell’s membrane to more easily penetrate it like a dagger penetrating armour. The findings are detailed in a paper published in Developmental Cell.

Killer T cells are armed with lytic granules containing two key components for immune attack: a perforin proteins stabs a hole in the cell membrane, and the lethal granzymes which kill the cell.

T cells cosy up to targeted diseased cells in a close junction called the ‘cytotoxic immunological synapse’.

A research team at UNSW Sydney has found that mechanical forces generated by T cells influence how effectively perforin can punch through tumour cell membranes. The researchers describe the cell interactions and the integration of forces at both the front and rear of the cell.

The researchers detected physical forces within T cells that propel lytic granules toward the immunological synapse where their payloads are released. These forces also enable T cells to grab onto regions of the cancer cell membrane where the membranes of both immune and target cells are pulled and manipulated.

“It was very exciting to discover that, in addition to its mechanical tension and biochemical configuration, the shape of the target cell membrane plays an important role in T cell mediated cancer cell killing,” said Dr Daryan Kempe at UNSW Medicine & Health who co-led the research.

By stretching and bending the membranes of tumour cells in a certain direction, T cells made it easier for perforin to punch through, but only if the membranes were bent in the right direction.

Bias towards outwardly curved cell membranes

Using human melanoma cell lines, the researchers demonstrated that perforin preferentially perforated outwardly curved tumour cell membranes, rather than inwardly curved ones – which may help the T cells avoid being harmed by their own attack.

“As the granules arrive, their contents will be emptied at this region of the membrane that is very highly curved. That there was a bias between positively curved and negatively curved membranes was completely unexpected,” said senior Associate Professor Maté Biro at UNSW Medicine & Health.

Source: University of New South Wales

Categories : CancerTags :

Specific Drug Sequence for Metastatic Breast Cancer Lowers Costs

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Photo by Andrea Piacquadio on Unsplash

Giving standard chemotherapy drugs in a specific sequence for certain types of metastatic breast cancer can cut costs while preserving quality of life, according to a study in the Journal of Clinical Oncology.

The study, led by researchers from UNC Lineberger Comprehensive Cancer Center and UNC Gillings School of Global Public Health, developed three different computer models to predict how a hypothetical set of 10 000 patients with specific types of metastatic breast cancer would respond to different sequences and types of chemotherapy. For this study, the patient’s cancer was either endocrine resistant or was triple-negative breast cancer.

Many chemotherapy choices are available to treat metastatic breast cancer. While oncologists may prefer certain drugs to use early in treatment, the best order in which to give the drugs is unclear. The researchers consulted oncologists and experts in the field to choose which chemotherapy drugs were preferred choices to include in the study.

Mimicking clinical practice, and based upon existing data, the researchers then assumed that if a person started treatment with one drug, they would change to a second-choice treatment after their cancer stopped responding to the first drug, or if the side effects weren’t tolerable. The purpose of the study was to test whether putting the drugs in one sequence compared to another could keep the patient on treatment for similar times while decreasing their side effect and/or cost burden.

“The cost of cancer drugs in the US has rapidly increased, even for generics. As a society, we urgently need more strategies to reduce cancer drug costs without compromising outcomes, and our analysis provides quantifiable evidence to help providers choose lower priced, but equally effective sequences of drugs,” said Stephanie B. Wheeler, PhD, MPH, professor of health policy & management at UNC Gillings and associate director of community outreach and engagement at UNC Lineberger and corresponding author of the article. “More spending on cancer care does not necessarily confer greater health benefits.”

The costs calculated in this study were inclusive of medical and nonmedical costs borne by patients, including lost productivity. In this simulation, after two years, nearly all women would have completed the first three sets of treatment, but the cancer would cause the death of about one-third of the women. Productivity days lost due to sickness were similar across chemotherapy sequences, so most of the cost difference was due to drug savings. In the simulation, patients were placed in three groups, depending on what treatments they had already received for earlier episodes of breast cancer.

Outcomes in the three groups were:

  • For people who had not previously received the common chemotherapy drug categories, including a taxane (e.g., paclitaxel) or an anthracycline (e.g., capecitabine), treatment with paclitaxel then capecitabine followed by doxorubicin corresponded to the highest expected gains in quality of life and lowest costs.
  • For people who had previously received a taxane and an anthracycline drug, treatment with carboplatin, followed by capecitabine, followed by eribulin, corresponded to the highest expected gains in quality of life and lowest costs.
  • For people who had previously received a taxane but not an anthracycline, treatment sequences beginning with capecitabine or doxorubicin, followed by eribulin, were most cost-effective.

“The drugs we studied are already recommended and reimbursed for the treatment of metastatic breast cancer, but the optimal sequencing of them has been unclear, which has led to considerable variation in physician preference and practice. Our study suggests that treatment sequencing approaches that minimise costs early may improve the value of care,” Wheeler said. “The implications of this study are fairly straightforward for medical oncologists and those developing value-based clinical pathways to implement in practice now.”

Associate professor Katherine E. Reeder-Hayes, one of the study’s authors, said the treatment choices for metastatic breast cancer are constantly changing, and new options for targeted therapy have emerged even since this study was conducted. “Many oncologists and patients find that there aren’t any more targeted therapies that fit the cancer’s molecular profiles, so they are left with the choice of a number of chemotherapy drugs that may feel pretty similar or have an unclear balance of pros and cons.

“In that scenario, I hope our study will help expand the framework that we use to make these decisions from one where we just think about the biologic action of the drug to one where we also consider the bigger picture of what the treatment experience is like for the patient, including their financial burden, investment of time, and side effects,” Reeder-Hayes added. “The most potent drug isn’t always the next best choice depending on what the patient values and wants to accomplish with their treatment.”

Source: UNC Lineberger Comprehensive Cancer Center

Categories : Respiratory DiseasesTags :

Asthma from Smoke Exposure Can Pass Down the Generations

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Cigarette smoking
Source: Sabine R on Unsplash

Children are more likely to develop asthma if their father was exposed to secondhand smoke when he was a child, according to a study published today in the European Respiratory Journal. The researchers also found that the children have an even higher asthma risk if their father was exposed to secondhand smoke and then also became a smoker.

The researchers say their findings highlight how smoking can cause intergenerational harm, impacting even grandchildren.

The research drew on on data from the Tasmanian Longitudinal Health Study (TAHS). TAHS began in 1968 and is one of the world’s largest and longest ongoing respiratory studies.

For this study, researchers looked at 1689 children who grew up in Tasmania, and their fathers and their paternal grandparents. They compared data on whether the children had developed asthma by age 7 with data on whether the fathers grew up with parents who smoked when they were under age 15. They also included data on whether the fathers were current or former smokers.

First author Mr Jiacheng Liu said, “We found that the risk of non-allergic asthma in children increases by 59% if their fathers were exposed to secondhand smoke in childhood, compared to children whose fathers were not exposed. The risk was even higher, at 72%, if the fathers were exposed to secondhand smoke and went on to smoke themselves.”

Researcher Dr Dinh Bui said, “Our findings show how the damage caused by smoking can have an impact not only on smokers, but also their children and grandchildren. For men who were exposed to secondhand smoke as children, our study suggests that they can still lower the risk they pass on to their own children, if they avoid smoking.”

Senior author Professor Shyamali Dharmage said, “We can’t be certain of how this damage is passed on through generations, but we think it may be to do with epigenetic changes. This is where factors in our environment, such as tobacco smoke, interact with our genes to modify their expression. These changes can be inherited but may be partially reversible for each generation.

“It’s possible that tobacco smoke is creating epigenetic changes in the cells that will go on to produce sperm when boys grow up. These changes can then be passed on to their children.”

The researchers will now investigate if the increased risk of asthma persists into adult life and whether fathers who were exposed to secondhand smoke as children pass on any increase in allergies or other lung diseases to their children.

Source: University of Melbourne

Categories : CancerTags :

A New Analytical Technique for Dense Breast Tissue Mammograms

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Source: National Cancer Institute

Researchers have developed a two-pronged approach to imaging breast density in mice, resulted in better detection of changes in breast tissue, including spotting early signs of cancer. If applied in humans, the technology may also help with prognosis of disease as density can be linked to specific patterns of mammary gland growth, including signs of cancer development. The findings appeared in the American Journal of Pathology.

“Having a means to accurately assess mammary gland density in mice, just as is done clinically for women using mammograms, is an important research advance,” said Priscilla A. Furth, MD, professor of oncology and medicine at Georgetown Lombardi Comprehensive Cancer Center, and corresponding author of the study. “This method has the benefit of being applicable across all ages of mice and mammary gland shapes, unlike some methods used in earlier studies.”

While working as an undergraduate in Furth’s lab, Brendan Rooney developed an innovative analytic computer program (C’20), which allowed for sorting of mammary gland tissue to one of two imaging assessments. At first, Rooney looked at younger mouse glands and found that a program that removed background ‘noise’ in those images helped boost detection of abnormalities in what are typically rounder, more lobular tissues. But as aging occurs and the chances of developing cancer increase, lobules diminish and ridges become more apparent, just as falling autumn leaves expose tree branches. The mammary ridges represent ducts that carry milk and other fluids. When the de-noising technique was applied to the images from the older mice, it was found to be less reliable in detecting ridges. Therefore Rooney and the team turned to a different imaging program, which has primarily been used to detect blood vessel changes in the eye’s retina.

“The idea for the analytic program came from routine visual observations of tissue samples and the challenges inherent in observing differences in breast tissue with just a microscope. We found that visual human observations are important but having another read on abnormalities from optimal imaging programs added validity and rigor to our assessments,” says Rooney, the lead author of the study. “Not only does our program result in a high degree of diagnostic accuracy, it is freely available and easy to use.”

Now that the broad strokes of the research have been laid down and proof-of-principle has been established, Rooney has started medical school with a possible eye toward specializing in oncology. Both Furth and Rooney believe that future studies will need to refine and streamline their research approach in mice, including better density measurements that could enable sorting of samples into higher and lower probabilities of cancer.

Source: Georgetown University Medical Center

Categories : COVIDTags :

More Evidence Linking Blood Clotting and COVID Severity

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Source: CC0

New research shows that the Omicron variants cause significantly lower levels of blood clotting, thereby providing further evidence for the link between the severity of the disease and the prevalence of persistent micro blood clots in individuals with acute and Long COVID.

Prof Resia Pretorius, a researcher in the Department of Physiological Sciences at Stellenbosch University (SU), South Africa, first made this connection late in 2020 when she detected small amyloid-like blood clots in the plasma of individuals suffering from COVID. Amyloids are a type of protein associated with various inflammatory diseases. As part of a long-term collaboration with Prof Douglas Kell from the University of Liverpool, they showed that these micro clots contained pro-inflammatory molecules. The results of both studies were published in the journal Cardiovascular Diabetology, in 2020 and 2021.  

These insoluble micro clots inhibit or may temporarily block blood flow to capillaries and hence impair oxygen transfer to tissues. At present, they believe that this oxygen impairment in various parts of the body can account for most of the symptoms of Long COVID, such as constant fatigue, shortness of breath, brain fog, joint and muscle pain.

Prof Resia Pretorius

Prof Pretorius said the persistent prevalence of micro clots may have significant clinical value: “Our findings suggest that hypercoagulation and vascular damage are key role players causing the wide range of symptoms we see in patients with Long COVID. There is a golden thread running through pathologies noted in post-viral syndromes such as Long COVID.”

More recently, Prof Pretorius and Prof Kell worked with a team of clinicians in South Africa and the United States, to ascertain whether the difference in the degree of clotting between different viral strains of the SARS-CoV-2 virus provides a plausible explanation for the relatively low severity of the Omicron variants during acute COVID infection.

While the earlier variants caused severe disease and critically ill patients, the heavily mutated Omicron variants have been shown to have milder symptoms, most commonly a runny nose, rhinitis headaches, fatigue (from mild to severe), sneezing and a sore throat.

For the purposes of the study, they revisited data and blood samples from stored blood samples from ten patients with COVID due to the Beta and Delta variants between October 2020 and September 2021 before the patients received treatment.

The team also collected blood from patients infected with the Omicron variants. In all ten samples it was found that the Omicron samples presented with a significantly lower total amount of microclots compared to earlier Beta and Delta variants.  

In a recent webinar on the topic, Dr Mark Walsh, an emergency medicine physician at the Saint Joseph Regional Medical Center in the United States of America, said the foundational work of Profs Pretorius and Kell has helped them to explain the clotting complications of COVID-induced coagulopathies (CAC) of patients with acute COVID. He is also one of the co-authors on the article.

“We could not understand why patients with CAC would clot and bleed at the same time. We now have the pathophysiological foundation for a point-of-care bedside medicine approach, based on the foundations of excellent research,” he said.

Early in the pandemic, Dr Walsh and his team of emergency physicians in the USA, developed a protocol to provide safe anticoagulation treatment to severely ill COVID patients. The team was guided by thromboelastography, a point-of-care protocol to monitor bleeding and clotting.

According to Prof Kell, more importantly, the findings are consistent with the view that these insoluble micro clots are not a side-effect of COVID-19, but a part of how the disease develops. However, he warned, we do not yet know how this will impact or relate to other post-viral syndromes such as Long-COVID, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), post-Zika or post-Dengue diseases.

The paper, titled “Relative hypercoagulopathy of the SARS-CoV-2, Beta and Delta variants when compared with the less severe Omicron variants is related to TEG parameters, the extent of fibrin amyloid microclots, and the severity of clinical illness” is in press in the journal Seminars in Thrombosis and Hemostasis, and a preprint is available at https://www.researchsquare.com/article/rs-1970823/v1

The webinar, “COVID-induced Coagulopathy (CAC): The clot thickens…or not?” is presented by Dr Mark Walsh, Prof Resia Pretorius and Prof Douglas Kell, and moderated by Dr Asad Khan. It is available at https://youtu.be/yyf7xunWydM

Categories : CancerTags :

A Practice-changing Treatment for Refractory Metastatic Colon Cancer

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Colon cancer cells
Colon cancer cells. Source: National Cancer Institute on Unsplash

In a phase III clinical trial, fruquintinib achieved improved overall survival (OS) in refractory metastatic colon cancer (mCRC) compared to best supportive care (BSC) alone, according to a randomised trial reported at the European Society for Medical Oncology (ESMO) annual congress.

BSC plus fruquintinib improved median OS to 7.4 months compared to 4.8 months with BSC plus placebo.

Patients with mCRC have few treatment options and a poor prognosis. Regorafenib is currently the only tyrosine kinase inhibitor (TKI) with an indication for mCRC.

The heavily treated patient population had received a median of five prior therapies, including regorafenib in about half of cases, N. Arvind Dasari, MD, of the University of Texas MD Anderson Cancer Center in Houston, presenting the results.

“These results are both clinically and statistically significant and consistent across all prespecified subgroups,” said Dr Dasari. “Fruquintinib was also well tolerated and consistent with a prior established safety profile. Overall, these results are consistent with [a prior trial conducted in China] and support a new practice-changing global oral treatment option for patients with metastatic colorectal cancer, enriching the treatment continuum for these patients.”

Dr Dasari noted that the VEGF pathway is a key mediator of angiogenesis, and fruquintinib is a selective and potent inhibitor of VEGF receptors 1, 2, and 3. In the phase III FRESCO trial conducted in China, fruquintinib resulted in statistically significant improvement in OS and progression-free survival (PFS), and received an approved indication for mCRC in fourth line and beyond.

Dr Dasari reported findings from the FRESCO-2 trial, which was designed to evaluate fruquintinib in a more diverse, multiregional patient population. Investigators enrolled patients with mCRC and a treatment history that included chemotherapy, anti-VEGF therapy, and anti-EGFR therapy. Patients with progression or intolerance to TAS-102, and regorafenib were eligible, as well as patients previously treated with an immune checkpoint inhibitor or a BRAF inhibitor.

Patients randomised 2:1 to BSC plus either fruquintinib or placebo. Treatment continued until disease progression or development of unacceptable toxicity.

The primary endpoint was OS, and the principal statistical assumption was that the control arm would have a median OS of 5.0 months, which would be improved to 6.8 months with fruquintinib.

The trial had 691 patients with a median follow-up of 11.2 months. Almost all of the patients had prior exposure to a VEGF inhibitor, about 40% had received an EGFR inhibitor, about 60% had received TAS-102 or regorafenib, and about 40% had received both. Dr Dasari said the patient population resembled the patients that clinicians see in clinical practice.

The primary analysis showed a 2.6-month improvement in median OS with fruquintinib, which translated into a survival hazard of 0.662.

Treatment with fruquintinib more than doubled the median PFS, from 1.8 months with placebo to 3.7 months, a 68% reduction in the hazard ratio. Seven patients in the fruquintinib arm had objective responses versus none in the placebo arm. The clinical benefit rate (response plus stable disease) was 55.5% with fruquintinib and 16.1% with placebo.

Grade ≥3 treatment-related adverse events occurred in 36.0% of the treatment arm and 11.3% of the placebo arm.

FRESCO-2 was not designed as a head-to-head comparison with regorafenib and was instead designed to validate fruquintinib for mCRC, said ESMO invited discussant Filippo Pietrantonio, MD, of the National Cancer Institute in Milan, Italy. The primary endpoint would have been noninferiority or equivalence. Even so, the trial set a high bar, as almost half the patients were 65 or older, had received multiple prior lines of therapy, and there were limitations on the proportion of patients with prior regorafenib treatment.

“Despite the challenges, FRESCO-2 is a positive trial, so fruquintinib may be a new standard-of-care option in patients with refractory metastatic colorectal cancer,” said Dr Pietrantonio. “This agent significantly prolonged overall survival and progression-free survival independently from prior treatment.”

“Sustained inhibition of angiogenesis is still important in later treatment lines, and fruquintinib provided an additional incremental gain of survival,” he added. “Real world and phase IV data are necessary to further assess the safety of fruquintinib, especially in underrepresented populations, and quality-of-life data are necessary as well.”

Source: MedPage Today

Categories : Injury & Trauma PaediatricsTags :

Behavioural Problems in Kids after Traumatic Brain Injuries

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Boy hanging from tree
Photo by Annie Spratt on Pexels

Kids who experience a traumatic brain injury (TBI), even a mild one, have more emotional and behavioural problems than kids who do not, according to a study published in NeuroImage.

“These hits to the head are hard to study because much of it depends on recall of an injury since the impacts do not all require a visit to a doctor,” said study first author Daniel Lopez, a PhD candidate at Del Monte Institute for Neuroscience. “But being able to analyse longitudinal data from a large cohort and ask important questions like this gives us valuable information into how a TBI, even a mild one, impacts a developing brain.”

Researchers used MRI and behavioural data collected from thousands of children who participated in the Adolescence Brain Cognitive Development (ABCD) Study. They revealed children with a mild TBI experienced a 15-percent increased risk of an emotional or behavioural problem. The risk was the highest in children around ten years old. Researchers found that children who had a significant hit to the head but did not meet diagnostic criteria for a mild TBI also had an increased risk of these behavioural and emotional problems.

The University of Rochester Medical Center is one of 21 research sites collecting data for the National Institutes of Health ABCD Study. Since 2017, 340 children have been part of the 10-year study that is following 11 750 children through early adulthood. It looks at how biological development, behaviours, and experiences impact brain maturation and other aspects of their lives, including academic achievement, social development, and overall health.

Researchers hope future ABCD Study data will better reveal the impact these head hits have on mental health and psychiatric problems. “We know some of the brain regions associated with increased risk of mental health problems are impacted during a TBI,” said Ed Freedman, PhD, associate professor of Neuroscience and co-principal investigator of the ABCD Study at the University of Rochester. Freedman also led this study. “With more time and data, we hope to gain a better understanding of the long-term impact of even a mild TBI.”

Source: University of Rochester Medical Center

Categories : COVIDTags :

Increased Alzheimer’s Disease Risk Seen after COVID Infection

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Plaques and neurons. Source: NIAH

In a study published in the Journal of Alzheimer’s Disease, researchers report that people 65 and older who were infected with COVID show a substantially higher risk, up to 80% higher than without infection, of developing Alzheimer’s disease within a year, according to a study of more than 6 million patients 65 and older. The researchers found that the highest risk was observed in women at least 85 years old.

The findings showed that the risk for developing Alzheimer’s disease in older people nearly doubled (0.35% to 0.68%) over a one-year period following infection with COVID. The researchers say it is unclear whether COVID triggers new development of Alzheimer’s disease or accelerates its emergence.

“The factors that play into the development of Alzheimer’s disease have been poorly understood, but two pieces considered important are prior infections, especially viral infections, and inflammation,” said study co-author Professor Pamela Davis at the Case Western Reserve School of Medicine.

“Since infection with SARS-CoV2 has been associated with central nervous system abnormalities including inflammation, we wanted to test whether, even in the short term, COVID could lead to increased diagnoses,” she said.

The research team analysed health records of 6.2 million adults 65 and older in the US who received medical treatment between February 2020 and May 2021 and had no prior diagnosis of Alzheimer’s disease.

They then divided this population two groups: one composed of people who contracted COVID during that period, and another with people who had no documented cases of COVID. More than 400 000 people were enrolled in the COVID study group, while 5.8 million were in the non-infected group.

“If this increase in new diagnoses of Alzheimer’s disease is sustained, the wave of patients with a disease currently without a cure will be substantial, and could further strain our long-term care resources,” Prof Davis said. “Alzheimer’s disease is a serious and challenging disease, and we thought we had turned some of the tide on it by reducing general risk factors such as hypertension, heart disease, obesity and a sedentary lifestyle. Now, so many people in the U.S. have had COVID and the long-term consequences of COVID are still emerging. It is important to continue to monitor the impact of this disease on future disability.”

Professor Rong Xu, the study’s corresponding author, said the team plans to continue studying the effects of COVID-19 on Alzheimer’s disease and other neurodegenerative disorders — especially which subpopulations may be more vulnerable — and the potential to repurpose FDA-approved drugs to treat COVID’s long-term effects.

Previous COVID-related studies led by CWRU have found that people with dementia are twice as likely to contract COVID; those with substance abuse disorder orders are more likely to contract COVID; and that 5% of people who took Paxlovid for treatment of COVID symptoms experienced rebound infections within a month.

Source: Case Western Reserve University

Categories : Environmental EffectsTags :

Humans Create Their own Pollution-cleaning Zone

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Source: Paul Wong on Unsplash

People typically spend 90% of their lives indoors or in vehicles, exposed to a multitude of chemicals from various sources, from vehicle exhausts to fumes from cooking and cleaning. The human body is also a potent emitter of chemicals from its own breath and skin. One of nature’s cleaners for these chemicals is hydroxyl (OH) radicals, primarily formed when UV radiation in sunlight interacts with ozone and water vapour. However, glass windows filter out UV radiation, lowering the indoor concentration of OH radicals.

Indoors, on the other hand, the air is of course far less affected by direct sunlight and rain. Since UV rays are largely filtered out by glass windows it has been generally assumed that the concentration of OH radicals is substantially lower indoors than outdoors and that ozone, leaking in from outdoors, is the major oxidant of indoor airborne chemical pollutants.

OH radicals are formed from ozone and skin oils

However, now it has been discovered that high levels of OH radicals can be generated indoors, simply due to the presence of people and ozone. This has been shown by a team led by the Max Planck Institute for Chemistry in cooperation with researchers from the USA and Denmark.

“The discovery that we humans are not only a source of reactive chemicals, but we are also able to transform these chemicals ourselves was very surprising to us,” said Nora Zannoni, first author of the study, now at the Institute of Atmospheric Sciences and Climate in Bologna, Italy. “The strength and shape of the oxidation field are determined by how much ozone is present, where it infiltrates, and how the ventilation of the indoor space is configured,” adds the scientist from Jonathan Williams’ team. The levels the scientists found were even comparable to outside daytime OH concentrations levels.

The oxidation field is generated by the reaction of ozone with oils and fats on the skin, especially the unsaturated triterpene squalene, which constitutes about 10% of the skin lipids that protect the skin and keep it supple. The reaction releases a host of gas phase chemicals with double bonds that further react with ozone to generate OH radicals. These squalene degradation products were characterised and quantified, with the total OH reactivity determined in parallel enabling the OH levels to be quantified empirically.

The experiments were conducted at the Technical University of Denmark (DTU) in Copenhagen. Four test subjects stayed in a special climate-controlled chamber under standardized conditions. Ozone was added to the chamber air inflow in a quantity that was not harmful to humans but representative of higher indoor levels. The team determined the OH values before and during the volunteers’ stay both with and without ozone present.

In order to understand how the human-generated OH field looked like in space and time during the experiments, results from a detailed multiphase chemical kinetic model from the University of California, Irvine were combined with a computational fluid dynamics model from Pennsylvania State University, both based in the USA. After validating the models against the experimental results, the modeling team examined how the human-generated OH field varied under different conditions of ventilation and ozone, beyond those tested in the laboratory. From the results, it was clear that the OH radicals were present, abundant, and forming strong spatial gradients.

“Our modeling team is the first and currently the only group that can integrate chemical processes between the skin and indoor air, from molecular scales to room scales,” said Manabu Shiraiwa, a professor at UC Irvine who led the modeling part of the new work. “The model makes sense of the measurements — why OH is generated from the reaction with the skin.”

Shiraiwa added that there remain unanswered questions, like the way humidity levels impact the reactions the team traced. “I think this study opens up a new avenue for indoor air research,” he said.

Adapt test methods for furniture and building materials

“We need to rethink indoor chemistry in occupied spaces because the oxidation field we create will transform many of the chemicals in our immediate vicinity. OH can oxidise many more species than ozone, creating a multitude of products directly in our breathing zone with as yet unknown health impacts. This oxidation field will also impact the chemical signals we emit and receive,” said project leader Jonathan Williams, “and possibly help explain the recent finding that our sense of smell is generally more sensitive to molecules that react faster with OH.”

The new finding also has implications for our health: Currently, chemical emissions of many materials and furnishings are being tested in isolation before they are approved for sale. However, it would be advisable to also conduct tests in the presence of people and ozone, says atmospheric chemist Williams. This is because oxidation processes can lead to the generation of respiratory irritants such as 4-oxopentanal (4-OPA) and other OH radical-generated oxygenated species, and small particles in the immediate vicinity of the respiratory tract. These can have adverse effects, especially in children and the infirm.

Source: Max Planck Institute for Chemistry

Categories : PaediatricsTags :

Anti-diarrhoeal Drug Loperamide Could Treat Autism Symptoms

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Bottle of pills
Source: Pixabay CC0

At present, there are no effective treatments for the core symptoms of autism spectrum disorder (ASD), which included difficulties with socialising and communicating. Using a computer analysis, researchers have discovered that a common anti-diarrhoeal drug may have potential in treating the social difficulties associated with ASD. Their findings are reported in the journal Frontiers in Pharmacology.

By looking at how different drugs affected ASD-related proteins in a computer model, they identified potential candidates to treat it. The most promising candidate was a commonly used antidiarrhoeal drug called loperamide was , and the researchers have an interesting hypothesis about how it may work to treat ASD symptoms, some of the most common of which involve difficulties with social interaction and communication.

“There are no medications currently approved for the treatment of social communication deficits, the main symptom in ASD,” said Dr Elise Koch of the University of Oslo, lead author on the study. “However, most adults and about half of children and adolescents with ASD are treated with antipsychotic drugs, which have serious side effects or lack efficacy in ASD.”

Repurposing drugs as new treatments

In an effort to find a new way to treat ASD, the researchers turned to drug repurposing, which involves exploring existing drugs as potential treatments for a different condition. The approach has plenty of benefits, as there is often extensive knowledge about existing drugs in terms of their safety, side-effects and the biological molecules that they interact with in the body.

To identify new treatments for ASD, the researchers used a computer-based protein interaction network. Such networks encompass proteins and the complex interactions between them. It is important to account for this complexity when studying biological systems, as affecting one protein can often have knock-on effects elsewhere.

The researchers constructed a protein interaction network that included proteins associated with ASD. By investigating existing drugs and their interaction with proteins in the network, the team identified several candidates that counteract biological process underlying ASD.

The most promising drug is called loperamide, which is commonly used for diarrhea. While it might seem strange that an anti-diarrhoeal drug could treat core ASD symptoms, the researchers have developed a hypothesis about how it may work.

From an upset gastrointestinal system to ASD

Loperamide binds to and activates a protein called the μ-opioid receptor, which is normally affected by opioid drugs, such as morphine. Along with the effects that you would normally expect from an opioid drug, such as pain relief, the μ-opioid receptor also affects social behavior.

In previous studies, genetically engineered mice that lack the μ-opioid receptor demonstrated social deficits similar to those seen in ASD. Interestingly, drugs that activate the μ-opioid receptor helped to restore social behaviors.        

These results in mice highlight the tantalising possibility that loperamide, or other drugs that target the μ-opioid receptor, may represent a new way to treat the social symptoms present in ASD, but further work is required to test this hypothesis. In any case, the current study demonstrates the power of assuming that old drugs may indeed learn new tricks.

Source: Frontiers Blog