Day: May 30, 2024

Categories : DermatologyTags :

Linked Biological Pathways Drive Skin Inflammation

On By ModernMedia
Picture by Macrovector on Freepik

A certain biological pathway involving interleukin-17 drives the inflammation seen in the skin disease psoriasis, according to a new study published in the journal Immunity. The work could lead to improved therapies for all inflammatory skin diseases, including atopic and allergic dermatitis and a type of boil called hidradenitis suppurativa, say the study authors.

Led by researchers at NYU Langone Health, the new study found that the interleukin-17 (IL-17) pathway, whose activity is blocked by existing anti-inflammatory drugs, activates a protein called hypoxia inducible factor 1-alpha (HIF-1-alpha) in psoriasis. Researchers say that IL-17 has long been known to be active in inflammation, but the role of HIF-1-alpha has until now been unclear.

The research team also found that HIF-1-alpha let inflamed skin cells more actively break down sugar for energy, supporting their metabolism and leading to the production of a waste product called lactate. When consumed by inflammatory T cells, lactate triggered production of IL-17, fuelling even more inflammation.

The findings show that in human skin tissue samples from psoriatic patients, measures of gene activity around IL-17 and HIF-1-alpha were similar, suggesting that these factors are interconnected. Experiments in mice treated to develop psoriasis found that subsequent treatment with an experimental drug that blocks the action of HIF-1-alpha, called BAY-87-2243, resolved inflammatory skin lesions.

Further, skin samples from 10 patients successfully treated with anti-inflammatory drug etanercept showed diminished activity for both IL-17 and HIF-1-alpha, suggesting to researchers that when IL-17 is blocked, so is HIF-1-alpha.

“Our study results broadly show that activation of HIF-1-alpha is at the crux of metabolic dysfunction observed in psoriasis and that its action is triggered by IL-17, another key inflammatory-signaling molecule,” said corresponding study author Shruti Naik, PhD, associate professor at NYU Grossman School of Medicine.

Further experiments were performed on skin samples from five patients with psoriasis whose healthy and inflamed skin was separately treated with either BAY-87-2243 or an existing combination of topical drugs (calcipotriene and betamethasone dipropionate). Researchers then compared differences in inflammatory gene activity as a measure of impact and found that the HIF-1-alpha inhibitor had a greater effect than existing topical drugs. Specifically, skin samples that responded to HIF-1-alpha therapy had 2,698 genes that were expressed differently, while standard-of-care-treated samples had 147 differently expressed genes.

Genetic analysis of skin samples from another 24 psoriatic patients treated with the IL-17A-blocking drug secukinumab showed only decreased, not heightened, gene activity connected to HIF-1-alpha when compared to HIF-1-alpha gene activity in nine healthy patients with no psoriatic disease. Researchers say this indicates HIF-1-alpha’s blocked action was codependent on blockage of IL-17.

Additional experiments in mice showed that blocking glucose uptake in the skin slowed psoriatic disease growth by limiting glucose metabolism, or glycolysis. Both the number of immune T cells tied to inflammation and the cell levels of IL-17 also decreased. The researchers found further that levels of lactate, the main byproduct of glycolysis, in psoriatic skin cell cultures dropped once exposed to the glycolysis-inhibiting drug 2-DG.

Directly targeting lactate production in psoriatic mice using a topical skin cream containing lactate dehydrogenase, which breaks down lactate, also slowed disease progression in the skin, with reduced numbers of inflammatory gamma-delta T cells and reduced IL-17 activity. Gamma-delta T cells were shown to take up lactate and use it to produce IL-17.

“Evidence of HIF-1-alpha’s depressed action, or downregulation, could also serve as a biomarker, or molecular sign, that other anti-inflammatory therapies are working,” said study co-senior investigator Jose U. Scher, MD, professor at NYU Grossman School of Medicine.

Scher, who also serves as director of NYU Langone’s Psoriatic Arthritis Center and the Judith and Stewart Colton Center for Autoimmunity, says the team plans to develop experimental drugs that can block HIF-1-alpha and lactate action in the skin “to end the underlying vicious cycle of IL-17-driven inflammation in skin disease. Our research fundamentally expands the scope of feasible therapeutic options.”

Naik points out that while many available therapies for psoriasis, including steroids and immunosuppressive drugs, reduce inflammation and symptoms, they do not cure the disease. She said further experiments are needed to refine which experimental drug works best, with respect to HIA-1-alpha inhibition, before clinical trials could start.

Source: NYU Langone Health / NYU Grossman School of Medicine

Categories : Diseases, Syndromes and ConditionsTags :

New Approach to Epstein-Barr Virus and Resulting Disease

On By ModernMedia
An electron micrograph showing three Epstein-Barr virus (EBV) particles colourised red-orange. Credit: NIAID

The Epstein-Barr virus can cause a spectrum of diseases, including a range of cancers. Emerging data now show that inhibition of a specific metabolic pathway in infected cells can diminish latent infection and therefore the risk of downstream disease, as reported by researchers from the University of Basel and the University Hospital Basel in the journal Science.

Exactly 60 years ago, pathologist Anthony Epstein and virologist Yvonne Barr announced the discovery of a virus that has carried their names ever since. The Epstein-Barr virus (EBV) made scientific history as the first virus proven to cause cancer in humans. Epstein and Barr isolated the pathogen, which is part of the herpesvirus family, from tumour tissue and demonstrated its cancer-causing potential in subsequent experiments.

Most people are carriers of EBV: 90% of the adult population are infected with the virus, usually experiencing no symptoms and no resulting illness. Around 50% become infected before the age of five, but many people don’t catch it until adolescence. Acute infection with the virus can cause glandular fever – also known as “kissing disease” – and can put infected individuals out of action for several months. In addition to its cancerogenic properties, the pathogen is also suspected to be involved in the development of autoimmune diseases such as multiple sclerosis.

As yet, no drug or approved vaccination can specifically thwart EBV within the body. Now, a research group from the University of Basel and the University Hospital Basel has reported a promising starting point for putting the brakes on EBV. Their results have been published in the journal Science.

EBV hijacks the metabolism of infected cells

Researchers led by Professor Christoph Hess have deciphered how the immune cells infected with EBV – the so-called B cells – are reprogrammed. Known as “transformation,” this process is necessary for the infection to become chronic and cause subsequent diseases such as cancer. Specifically, the team discovered that the virus triggers the infected cell to ramp up the production of an enzyme known as IDO1. This ultimately leads to greater energy production by the power plants of infected cells: the mitochondria. In turn, this additional energy is needed for the increased metabolism and the rapid proliferation of B cells reprogrammed by EBV in this way.

Clinically, the researchers focused on a group of patients who had developed EBV-triggered blood cancer following organ transplantation. To prevent a transplanted organ from being rejected, it is necessary to weaken the immune system using medications. This, in turn, makes it easier for EBV to gain the upper hand and cause blood cancer, referred to as post-transplant lymphoma.

In the paper, which has now been published, the researchers were able to show that EBV upregulates the enzyme IDO1 already months before post-transplant lymphoma is diagnosed. This finding may help to develop biomarkers for the disease.

Second chance for a failed drug

“Previously, IDO1 inhibitors have been developed in the hope that they could help to treat established cancer – which has unfortunately turned out not to be the case. In other words, there are already clinically tested inhibitors against this enzyme,” explains Christoph Hess. Accordingly, this class of drugs might now receive a second chance in applications aimed at dampening EBV infection and thereby tackling EBV-associated diseases. Indeed, in experiments with mice, IDO1 inhibition with these drugs reduced the transformation of B cells and therefore the viral load and the development of lymphoma.

“In transplant patients, it’s standard practice to use drugs against various viruses. Until now, there’s been nothing specific for preventing or treating Epstein-Barr virus associated disease,” says Hess.

Source: University of Basel

Categories : Healthcare Politics and RegulationsTags :

BAT Calls for Progressive Regulation to Achieve a Smoke-free South Africa

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Photo by Sara Kurfess on Unsplash
  • As the globe recognises both World Vape Day and World No Tobacco Day this month, BAT calls for regulatory framework that encourages adult smokers to switch to smokeless alternatives.
  • South Africa’s adult smoking prevalence is growing; studies suggest switching exclusively to reduced risk¹ alternatives could significantly reduce smoking related disease associated with smoking.
  • BAT advocates for regulatory principles focused on adult-only access, product quality, and enforcement, while investing in smokeless products.

BAT, a leading tobacco and nicotine products company, publicly re-affirmed its position that no underage person should use nicotine products. As such, the Company has called for a regulatory framework in South Africa that encourages adult smokers to switch to smokeless alternatives and that facilitates the robust prevention of underage access.

The smoking prevalence among adults in South Africa is 27.4%², which seems to be growing. This is partly attributable to the rampant sale of illicit cigarettes across the country, which BAT South Africa’s internal estimates put at around 70% of the market. More than 9.7 million² people in South Africa continue to smoke, despite the serious risks. According to population modelling studies³, a significant reduction in smoking related disease could be achieved if smokers switched exclusively to reduced risk¹ alternatives.

Dr Edward Makgotlho, Area Head of Scientific Affairs for BAT Sub-Saharan Africa, said:

“We believe that underage consumers should never use nicotine, and the role of regulation in helping to ensure this is vital. As well as mandating appropriate age limits, age verification solutions need to be introduced at points of sale, and the importance of enforcing regulation cannot, and should not, be forgotten.”

BAT has set out four principles that should be applied in South Africa for effective and impactful regulation relating to smokeless tobacco and nicotine products:

1.      Consumer access to relevant products: Regulations in all countries where cigarettes are sold should also allow a wide range of smokeless alternatives, to ensure that consumers can access these alternatives and make informed choices about switching, based on the best available scientific evidence.

2.      Adult-only consumers: The use and sale of smokeless tobacco and nicotine products by and to underage consumers should be prohibited by law.

3.      Product quality and safety: Robust and properly enforced quality and safety standards should be at the heart of regulation, to protect consumers.

4.      Robust enforcement: Regulation should provide enforcement authorities with the necessary powers to apply penalties and sanctions to those who fail to comply with regulations, particularly those who supply non-compliant products and provide product to those who are underage.

Countries that have implemented regulation that recognises the harm reduction potential of smokeless products and support their use for adult smokers have experience a rapid decline in smoking. The United Kingdom, United States and Japan are all reporting their lowest smoking rates on record, while Sweden is on track to declare itself smoke-free this year – 16 years ahead of the European Union’s 2040 target.

“The migration of smokers to these alternatives is crucial both for countries looking to reduce their smoking rates and for global public health more broadly. Whether or not governments are able to take advantage of these products and maximise their harm reduction potential depends as much on the implementation of progressive, risk-proportionate regulation as it does on changes in consumer behaviour,” said Dr Makgotlho.

BAT’s global purpose is to create A Better Tomorrow™ by Building a Smokeless World. This commitment is demonstrated in various ways, including the Company’s investment of more than R6.9 billion a year in the development of smokeless tobacco and nicotine products, which are sold in 75+ markets globally, including South Africa.

References:

1.       Based on the weight of evidence and assuming a complete switch from cigarette smoking. These products are not risk-free and are addictive.

2.       BATSA market research as at 2024, conducted by an external market research house.

3.       Camacho OM & Ebajemito J, et al. 2021. Evidence from the Scientific Assessment of Electronic Cigarettes’ Role in Tobacco Harm Reduction. Contributions to Tobacco & Nicotine Research, 30(2): 63-108. Available: https://doi.org/10.2478/cttr-2021-0007

Levy DT & Gartner C, et al. 2023. The Australia Smoking and Vaping Model: the Potential Impact of Increasing Access to Nicotine Vaping Products. Journal of Nicotine & Tobacco Research, 25(3): 486-497. Available: https://doi.org/10.1093/ntr/ntac210

Yach D & Human D, et al. 2023. Integrating Harm Reduction into Tobacco Control. SmokeFreeSweden.org. Available: https://smokefreesweden.org/lives-saved.pdf

Categories : UncategorizedTags :

Enhancing Checkpoint Inhibitor Therapy by Striking at the Right Time

On By ModernMedia
Photo by Malvestida on Unsplash

A multidisciplinary research team at the University of California, Irvine has revealed that the circadian clock can be leveraged to enhance the efficacy of checkpoint inhibitor cancer therapy. Checkpoint inhibitors block different proteins from binding to tumour cells, allowing the immune system’s T cells to kill the tumour.

The study, published online today in the journal Nature Immunology, provides deeper insights into the intricate relationship among the circadian clock, immune regulation and tumour development and found that a therapeutic approach optimising time-of-day delivery based on an individual’s unique circadian patterns offers new avenues for prevention and treatment.

“Disruption of the internal biological pacemaker is an inherent aspect of modern society that may contribute to the rising incidence of many cancer types. We found that proper regulation of circadian rhythms is necessary to suppress inflammation and support peak immune function,” said corresponding author Selma Masri, UC Irvine associate professor of biological chemistry. “Understanding precisely how circadian disruption promotes disease progression could lead to behaviour modification to reduce cancer risk.”

Team members used an advanced single-cell RNA sequencing technique in a genetic model of colorectal cancer and identified clock-dependent changes controlling the number of myeloid-derived cells that suppress T cell activation. They discovered that disruption of the internal clock in the epithelial cells lining the intestine alters secretion of cytokine proteins, leading to heightened inflammation, increased numbers of immunosuppressive myeloid cells and cancer progression. These findings were leveraged to demonstrate that providing immunotherapy at the time of day when these immunosuppressive myeloid cells are most abundant significantly enhanced the efficacy of immune checkpoint blockades in solid tumours.

“As we enhance our understanding of the fundamental mechanism of circadian regulation of immunity, we will be able to harness the power of the body’s natural rhythms to fight cancer and develop more personalised and effective treatment strategies,” said lead author Bridget Fortin, a UC Irvine doctoral student in the Department of Biological Chemistry.

While this study represents a significant step forward in defining circadian control of anti-tumour immunity, the team believes future research should focus on exploring additional factors and cell types influencing time-of-day response to checkpoint inhibitor therapy.

Source: University of California – Irvine

Categories : NeurologyTags :

New Non-invasive Brain Stimulation may One Day Treat Addiction, Depression and OCD

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Source: CC0

Neurological disorders, such as addiction, depression, and obsessive-compulsive disorder (OCD), affect millions of people worldwide and are often characterised by complex pathologies involving multiple brain regions and circuits. These conditions are notoriously difficult to treat due to the intricate and poorly understood nature of brain functions and the challenge of delivering therapies to deep brain structures without invasive procedures.

In the rapidly evolving field of neuroscience, non-invasive brain stimulation enables the understanding and treating a myriad of neurological and psychiatric conditions, free of surgery or implants. Researchers, led by Friedhelm Hummel, who holds the Defitchech Chair of Clinical Neuroengineering at EPFL’s School of Life Sciences, and postdoc Pierre Vassiliadis, are pioneering a new approach in the field.

Their research, which is described in Nature Human Behaviour, makes use of transcranial Temporal Interference Electric Stimulation (tTIS). The approach specifically targets deep brain regions serving as control centres of several important cognitive functions and involved in different neurological and psychiatric pathologies.

“Invasive deep brain stimulation (DBS) has already successfully been applied to the deeply seated neural control centers in order to curb addiction and treat Parkinson, OCD or depression,” says Hummel. “The key difference with our approach is that it is non-invasive, meaning that we use low-level electrical stimulation on the scalp to target these regions.”

The innovative technique is based on the concept of temporal interference, initially explored in rodent models, and now successfully translated to human applications by the EPFL team. In this experiment, one pair of electrodes is set to a frequency of 2000Hz, while another is set to 2080Hz. Thanks to detailed computational models of the brain structure, the electrodes are specifically positioned on the scalp to ensure that their signals intersect in the target region.

It is at this juncture that the magic of interference occurs: the slight frequency disparity of 80Hz between the two currents becomes the effective stimulation frequency within the target zone. The brilliance of this method lies in its selectivity; the high base frequencies (eg, 2000Hz) do not stimulate neural activity directly, leaving the intervening brain tissue unaffected and focusing the effect solely on the targeted region.

The focus of this latest research is the human striatum, a key player in reward and reinforcement mechanisms. “We’re examining how reinforcement learning, essentially how we learn through rewards, can be influenced by targeting specific brain frequencies,” says Vassiliadis. By applying stimulation of the striatum at 80Hz, the team found they could disrupt its normal functioning, directly affecting the learning process.

The therapeutic potential of their work is immense, particularly for conditions like addiction, apathy and depression, where reward mechanisms play a crucial role. “In addiction, for example, people tend to over-approach rewards. Our method could help reduce this pathological overemphasis,” Vassiliadis, who is also a researcher at UCLouvain’s Institute of Neuroscience, points out.

Vassiliadis, lead author of the paper, a medical doctor with a joint PhD, describes tTIS as using two pairs of electrodes attached to the scalp to apply weak electrical fields inside the brain. “Up until now, we couldn’t specifically target these regions with non-invasive techniques, as the low-level electrical fields would stimulate all the regions between the skull and the deeper zones – rendering any treatments ineffective. This approach allows us to selectively stimulate deep brain regions that are important in neuropsychiatric disorders,” he explains.

Furthermore, the team is exploring how different stimulation patterns can not only disrupt but also potentially enhance brain functions. “This first step was to prove the hypothesis of 80Hz affecting the striatum, and we did it by disrupting it’s functioning. Our research also shows promise in improving motor behaviour and increasing striatum activity, particularly in older adults with reduced learning abilities,” Vassiliadis adds.

Hummel, a trained neurologist, sees this technology as the beginning of a new chapter in brain stimulation, offering personalised treatment with less invasive methods. “We’re looking at a non-invasive approach that allows us to experiment and personalise treatment for deep brain stimulation in the early stages,” he says. Another key advantage of tTIS is its minimal side effects. Most participants in their studies reported only mild sensations on the skin, making it a highly tolerable and patient-friendly approach.

Hummel and Vassiliadis are optimistic about the impact of their research. They envision a future where non-invasive neuromodulation therapies could be readily available in hospitals, offering a cost-effective and expansive treatment scope.

Original written by Michael David Mitchell. The original text of this story is licensed under Creative Commons CC BY-SA 4.0. Edited for style and length.

Source: Ecole Polytechnique Fédérale de Lausanne

Categories : Healthcare Politics and Regulations IT in HealthcareTags :

Earn CPD Points with EthiQal’s Webinar on Record Keeping

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On Wednesday 5 June at 18:00, EthiQal cordially invites you to attend their ethics webinar, “Documenting care: Effective record-keeping and requests for records”.

Hosted by Dr Hlombe Makuluma, Medicolegal Advisor at EthiQal, this webinar will be co-presented by two admitted attorneys, Mashooma Parker and Jessica Viljoen, who are both legal advisors within the claims team at EthiQal. The 90-minute session will cover compliance for record-keeping requirements as well as dealing with requests for patient records from patients and third parties.

Participants will gain valuable insights to ethically enhance their practice’s visibility and reach, fostering responsible and compliant advertising practices.

Mashooma Parker is a skilled Legal Advisor within the Claims & Legal team at EthiQal, specialising in medical malpractice. With a strong background in the legal field and a passion for assisting healthcare practitioners, Mashooma brings a wealth of expertise to navigate the complexities that arise with patients and third parties. Hosting the first topic, She will cover the requirements for healthcare practitioners to ensure quality record-keeping compliance with Booklet 9 of the HPCSA’s Ethical Guidelines.

Jessica Viljoen is an admitted attorney and legal advisor specialising in professional indemnity insurance for healthcare practitioners, and medical malpractice law. With her extensive experience within the medico-legal space, including her years of litigation experience, Jessica leverages her industry knowledge to provide legal advice and assistance to all specialties of medical practitioners throughout South Africa. She will present the second part of the talk, which will deal with Patient and Third-party requests for patient records and how to ensure compliance with the Promotion of Access to Information Act 2 of 2000.

The speakers will offer some useful tips from a medico-legal risk management perspective for health practitioners to be cognisant of, as well as to work through some practical examples to illustrate the importance of the topic.

At least one hour’s attendance on the Zoom Platform is required to earn CPD points, and for those unable to watch it live, a recording will be made available.

Click here to register now