Day: August 21, 2025

Categories : CancerTags :

Existing Drug Class May Help Patients with Immunotherapy-resistant Melanoma

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3D structure of a melanoma cell derived by ion abrasion scanning electron microscopy. Credit: Sriram Subramaniam/ National Cancer Institute

Increased activity in a specific biological pathway may explain why many patients with a deadly form of skin cancer do not respond to the latest cancer treatments, a new study shows.

Publishing in the journal Cancer Research, the study featured data generated from experiments with human tissues and cells from patients with advanced melanoma that were implanted into mice. Results uncovered therapeutic targets that could limit melanoma growth in patients whose cancer failed to respond to initial treatment with immune checkpoint inhibitors.

Led by researchers at NYU Langone Health and its Perlmutter Cancer Center, the study focused on a subgroup of melanoma patients with mutations in the neurofibromin 1 (NF1) gene. NF1 mutations are just one type among several mutations, including those in the BRAF, NRAS, and PARP genes, that are linked to many cases of cancer, particularly melanoma. As many as 27% of melanoma patients are estimated to have NF1 mutations.

While immunotherapy, which stimulates the immune system to attack cancer cells as it would an invading virus, has proved to be a successful treatment, it does not work well for more than half of NF1-mutant melanoma patients.

“There is a pressing need for new drug therapies for melanoma patients with neurofibromin 1 mutations that do not respond to the latest immunotherapy, and for which there are no subsequent effective treatment options,” said study lead investigator Milad Ibrahim, PhD. Ibrahim is a postdoctoral fellow in the Dr Iman Osman Laboratory in the Ronald O. Perelman Department of Dermatology at the NYU Grossman School of Medicine.

To investigate why these patients were treatment resistant, investigators examined tumour cells from 30 melanoma patients who did not respond to immunotherapy. NF1 mutations were found in 40% of these melanoma samples. The samples came from NYU Langone’s extensive repository from more than 6000 melanoma patients.

Molecular testing showed that the signalling pathway built around a protein called epidermal growth factor receptor (EGFR) was more active in NF1 mutant melanoma cells than in cells with other melanoma-gene mutations. Increased EGFR activity has long been linked to abnormal cell growth in tumours and shorter survival with various cancers. The researchers also found that NF1 mutant melanoma cells depended on increased EGFR activity for survival, regardless of the presence of other mutations.

Because EGFR-inhibiting drugs are already used to treat some head and neck cancers, as well as colorectal and lung cancers, researchers then tested two drugs in the class, cetuximab and afatinib, in both NF1 mutant cell cultures and cancer cell lines without NF1 mutations. After transplanting both tumour cell types into mice and treating them with these drugs, results showed that both EGFR inhibitors were effective against cells and transplanted tumours with NF1 mutations, and they had no effect on melanomas without NF1 mutations.

“Our study results reveal a unique vulnerability in melanoma patients with neurofibromin 1 mutations, that an overexpression of the epidermal growth factor receptor pathway is essential for their survival and growth,” said the study’s senior investigator, Professor Iman Osman, MD.

“While further tests are needed, our results support a novel approach of deploying EGFR inhibitors either alone or in combination with other immunotherapies for treatment of melanoma patients whose tumours harbour NF1 mutation,” said the study’s co-senior investigator, Associate Professor Markus Schober, PhD.

However, Schober says this requires further testing in a clinical trial, which the research team plans to develop. He adds that if trial findings prove successful, the team’s research could provide a lifeline for many of these melanoma patients.

Source: NYU Langone Health

Categories : Substance Use Surgeries & ProceduresTags :

Alcohol Withdrawal Syndrome is a Hidden Surgery Risk

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Credit: Pixabay CC0

Alcohol withdrawal syndrome (AWS) is a potentially life-threatening condition that may complicate patients’ recovery after surgery.

Previous studies have estimated that up to 50% of hospitalised patients with AUD will develop some degree of AWS. Up to 7% of these patients may progress to severe withdrawal, including delirium tremens (DT) that can range in severity from irritability and confusion to tremors, nausea, vomiting and seizures.

A new study by surgeons at The Ohio State University Wexner Medical Center and The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC – James) looked at a national sample of 3 million adult surgical patients between 2016-2019.

Of those patients, 16 504 (0.5%) were diagnosed with AWS, including 6591 (0.2%) with DT. 

“We found that alcohol withdrawal syndrome is linked with poorer surgical outcomes, extended hospitalisations and increased costs. These findings underscore the need for standardised perioperative screening and targeted management strategies to reduce these risks,” said study lead author Timothy Pawlik, MD, PhD, professor and chair of Ohio State’s Department of Surgery.

The study findings were published in the Journal of American College of Surgeons.

Patients with AWS were generally younger, male and more likely to have Medicaid, according to Pawlik, who holds the Urban Meyer III and Shelley Meyer Chair for Cancer Research at The Ohio State University College of Medicine.

AWS raises the risk of postoperative complications, especially respiratory failure and sepsis. The study found that patients with AWS had longer hospital stays (median 11 vs 6 days) and higher costs ($44 300 vs $28 800). 

AWS was associated with a $10 030 higher adjusted hospitalisation cost per patient undergoing surgical care, contributing to an overall excess cost of $165.6 million, said study first author Azza Sarfraz, MBBS, a surgical oncology fellow at Ohio State. 

“The lack of standard screening delays early detection and intervention,” Pawlik said. “Developing strategies for early identification, inpatient withdrawal management, and perioperative risk stratification may improve surgical outcomes, lower healthcare costs, and enhance patient care.” 

Source: Ohio State University Wexner Medical Center

Categories : Implants and Prostheses OphthalmologyTags :

Oxford Researchers Develop Uniquely Shaped Microstent to Combat Glaucoma

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A schematic of the eye’s anterior segment, demonstrating the anatomical placement of the microstent. The stent diverts aqueous humour from the anterior chamber to the suprachoroidal space through the flexible tube, creating a subconjunctival bleb supported by the expanding element. Credit: Yunlan Zhang, Zhong You, Jared Ching.

A team of researchers at the University of Oxford have unveiled a pioneering ‘microstent’ which could revolutionise treatment for glaucoma, a common but debilitating condition. The study has been published in The Innovation, Cell Press.

Glaucoma is a leading cause of vision loss, second only to cataracts. Globally, 7.7 million people were blind or visually impaired due to glaucoma in 2020. The condition can cause irreversible damage to the optic nerve, due to increased pressure within the eyeball. Current treatment options – principally surgery to create openings in the eye or insert tubes to drain fluid – are highly invasive, carry risk of complications, and have limited durability.

‘Our deployable microstent represents a significant advancement in glaucoma treatment,’ said lead author Dr Yunlan Zhang (University of Oxford at the time of the study/University of Texas). ‘Current surgical implants for this type of glaucoma have been shown to have limited long-term effectiveness, being susceptible to failure due to fibrosis (scarring) in the eye.’ 

The new microstent features a unique structural shape that allows it to expand once in the eye. At 200µm, less than a quarter of a millimetre, the stent’s tiny diameter enables it to fit within the needle of a standard hypodermic syringe, for minimally-invasive insertion. Once in place and expanded, the microstent spans the fluid-filled space between the white of the eye and the membrane that covers it.

By supporting this space, the stent reduces the excessive fluid buildup and resulting intraocular pressure in the eye which is responsible for the most common type of glaucoma, primary open-angle glaucoma. Initial trials carried out in rabbits found that the microstents lowered eye pressure in less than a month with minimal inflammation and scarring. Furthermore, the microstent achieved a greater reduction of eye pressure than a standard tubular implant.

This development has the potential to transform the landscape of glaucoma therapy. By offering an enhanced solution in the minimally invasive glaucoma surgery field that combines mechanical innovation with biocompatibility, we hope to improve patient outcomes and quality of life.

Senior co-author Dr Jared Ching (Department of Engineering Science, University of Oxford).

Senior co-author, Professor Zhong You (Department of Engineering Science, University of Oxford) said: ‘Our microstent is made from a durable and super-flexible nickel-titanium alloy called nitinol, renowned for its proven long-term safety for ocular use. Its unique material and structural properties help prevent subsequent movement, improve durability, and ensure long-term efficacy.’

The research team used advanced modelling techniques to guide the microstent’s design and ensure compatibility with the anatomy of the eye. The device’s superelastic properties enable it to accommodate how the eye changes and stretches over time without permanent deformation, enhancing its durability and functionality.

Over half a million people in the UK have glaucoma – 2% of everyone over the age of 40 – and it is one of the most common causes of blindness worldwide. The introduction of this microstent could mark a pivotal step in enhancing treatment efficacy and accessibility.

The study ‘A Novel Deployable Microstent for the Treatment of Glaucoma has been published in The Innovation, Cell Press.

Source: Oxford University

Categories : HIV PaediatricsTags :

Gene Therapy Shot at Birth May Shield Children from HIV for Years

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Colourised transmission electron micrograph of an HIV-1 virus particle (yellow/gold) budding from the plasma membrane of an infected H9 T cell (purple/green).

A new study in Nature shows that delivering a single injection of gene therapy at birth may offer years-long protection against HIV, taking advantage of a critical window in early life that could reshape the fight against paediatric infections in high-risk regions.

This study is among the first to show that the first weeks of life, when the immune system is naturally more tolerant, may be the optimal window for delivering gene therapies that would otherwise be rejected at older ages.

“Nearly 300 children are infected with HIV each day,” said first author Amir Ardeshir, associate professor of microbiology and immunology at the Tulane National Primate Research Center, who conducted the study alongside fellow researchers at the California National Primate Research Center. “This approach could help protect newborns in high-risk areas during the most vulnerable period of their lives.” 

“This is a one-and-done treatment that fits the critical time when these mothers with HIV in resource-limited areas are most likely to see a doctor.”

Amir Ardeshir

In the study, nonhuman primates received a gene therapy that programs cells to continuously produce HIV-fighting antibodies. Timing proved critical to the one-time treatment offering long-term protection.

Those that received the treatment within their first month of life were protected from infection for at least three years with no need for a booster, potentially signifying coverage into adolescence in humans. In contrast, those treated at 8–12 weeks showed a more developed, less tolerant immune system that did not accept the treatment as effectively.

“This is a one-and-done treatment that fits the critical time when these mothers with HIV in resource-limited areas are most likely to see a doctor,” Ardeshir said. “As long as the treatment is delivered close to birth, the baby’s immune system will accept it and believe it’s part of itself.”

More than 100 000 children acquire HIV annually, primarily through mother-to-child transmission after birth from breastfeeding. Antiretroviral treatments have shown success in suppressing the virus and limiting transmission. However, adherence to treatment and access to doctors both decline after childbirth, particularly in areas with limited access to healthcare.

To deliver the treatment, researchers used an adeno-associated virus (AAV), a harmless virus that can act as a cargo truck to deliver genetic code to cells. The virus was sent to muscle cells, unique in their longevity, and delivered instructions to produce broadly neutralising antibodies, or bNAbs, which are capable of neutralising multiple strains of HIV.

This approach solved a longstanding problem with bNAbs. Previous studies found them effective at fighting HIV, but they required repeated infusions, which are costly and pose logistical challenges in low-resource settings.

“Instead, we turn these muscle cells – which are long-lived – into micro factories that just keep producing these antibodies,” Ardeshir said.

Newborns showed greater tolerance and expressed high levels of bNAbs, which successfully prevented infection, while older infants and juveniles were more likely to have produced anti-drug antibodies that shut down the treatment.

Researchers also found that exposing fetuses to the antibodies before birth helped older infants accept the gene therapy later, avoiding the immune rejection that often occurs with age.

Still, Ardeshir said a one-time injection at birth offered a more cost-effective and feasible real-world solution, while putting less burden on the mother for a follow-up visit.

Questions remain as to how the results translate to human infants and children, who may be less susceptible to AAV-delivered treatments. The study also used one strain of simian–human immunodeficiency virus, which doesn’t reflect the variety of HIV strains.

If successful, however, this treatment could dramatically reduce mother-to-child HIV transmission rates in high-risk regions such as sub-Saharan Africa, where 90% of paediatric HIV cases can be found. It may also be adapted to protect against other infectious diseases like malaria, which disproportionately affects young children in low-income countries.

“Nothing like this was possible to achieve even 10 years ago,” Ardeshir said. “This was a huge result, and now we have all the ingredients to take on HIV.”

Source: Tulane University

Categories : Immune SystemTags :

Unusual Allies: Vagus Nerve Cells Emerge as Defenders Against Flu Damage

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Study finds sensory cells that detect tissue damage, irritants also rein in harmful immune responses to protect the lungs

Clusters of mouse vagus nerve sensory cells reveal the presence of TRPV1, a molecular sensor that detects irritants, heat, and inflammation. A new HMS study reveals nerve cells with this sensor play a central role in taming inflammation and tissue damage in the lung during flu infection. Image: Chiu Lab.

A group of nerve cells known for their role in detecting chemical irritation, tissue damage, heat, and pressure now emerge as critical defenders against the worst ravages of the flu caused by an overactive immune response, according to new research by scientists at Harvard Medical School and the Harvard T.H. Chan School of Public Health.

The cells, called TRPV1 vagal nociceptors, live in the vagus nerve, which sends signals from internal organs – including the heart, lungs, and gut – to the brain to help regulate heart rate, breathing, digestion, and other functions. In the lungs, these cells trigger the protective cough reflex that forces the airways to expel foreign particles, mucus, and other irritants.

But the new research, published in Science Immunology and conducted in mice, shows that in the setting of flu, these cells do much more – they rein in the immune system and avert the smoldering inflammation that often occurs in the aftermath of a viral infection and can injure healthy tissue.

Each year, the flu sickens millions and kills between 290 000 and 650 000 people worldwide, according to the World Health Organization. While the immune system helps fight off the virus, an excessive inflammatory response can inflict tissue damage and worsen illness. The findings are especially relevant in the wake of the COVID-19 pandemic, which revealed how an aberrant immune response following viral infection can sometimes lead to serious organ damage and even organ failure.

“Our research shows that the infected lung is a battleground where nerves and immune cells engage in a delicate dance to safeguard our health,” said co-senior study author Isaac Chiu, professor of immunology in the Blavatnik Institute at HMS. “Understanding this powerful neuro-immune signaling axis will be increasingly important as we design better ways to prevent and treat immune-mediated damage in viral infections, which can sometimes be worse than the direct damage caused by the virus itself.”

The findings, he added, raise the possibility that vagus nerve function may be one variable that explains why some people with the flu go on to develop long-lasting and devastating immune-driven damage in their lungs while others recover once the initial infection is resolved.

“Flu infections are highly variable in severity and there is a need to understand why certain groups of people, such as the elderly, experience worse disease,” said study first author Nicole Almanzar, a doctoral student in the Chiu Lab. “Our study demonstrates that the nervous system is actively involved in regulating the response of the lungs to infection, offering a new perspective on viral infections that could help explain why particular factors increase risk of severe infections.”

The new study illuminates the complex interaction between body and brain and adds to a growing body of research showing that the nervous and immune systems engage in highly orchestrated crosstalk during infection to modulate body defenses.

Previous research led by Chiu has revealed the intricate interplay between the two systems in bacterial pneumonia, flesh-eating disease, meningitis, pain, and itch.

One of Chiu’s earlier studies found that during bacterial infections of the lung, the same set of vagal nerve neurons suppressed the immune defences. In the new study, however, the immune-taming function of these cells worked to shield the lung from excessive damage during viral infection.

“Context clearly matters,” Chiu said.

Disabling the neurons worsened flu damage in the lungs

In a set of experiments, researchers exposed a group of mice with genetically disabled or chemically silenced TRPV1 neurons to influenza A virus. Mice without these nerve cells fared notably worse than mice with functioning TRPV1 cells. Even though the overall amount of virus in the lungs was the same in both groups, mice lacking TRPV1 neurons suffered more severe lung pathology, higher levels of harmful inflammation, and lower survival rates. Interestingly, Almanzar noted, even though the overall viral load remained the same, the spread of the virus within the lobes of the lungs was more pronounced in mice without these protective neurons.

The researchers also found that the absence of TRPV1 neurons altered the lung’s immune landscape. The lungs of mice lacking these neurons had an overabundance of neutrophils and macrophages – two types of immune cells that, in excess, can worsen tissue damage. At the same time, interferon signalling – one of the body’s most important viral-defence pathways – was seriously impaired in these immune cells.

In another experiment, the researchers used an antibody to deplete inflammation-driving cells in flu-infected mice lacking TRPV1 neurons. These animals had notably better survival than untreated mice lacking these protective neurons. The observation further underscores how nerve cells help prevent harmful immune reactions that can sometimes be more dangerous than the virus itself.

The researchers noted that they do not yet know precisely how TRPV1 neurons restrain the march of inflammatory cells at the molecular level – a question they plan to explore in subsequent work.

“The vagus nerve is powerfully controlling inflammation, but how it does so remains a mystery to be solved,” Chiu said. “But we’re excited that it plays such a strong role in viral infections.”

Harnessing the immune brake for therapy

Moving forward, this insight opens the door to exciting new avenues for therapy. Instead of only targeting the flu virus or dampening immune activity, the research team said, future treatments could mimic the function of nerve cells to ensure the delicate balance between protective and damaging immune responses is not thrown off.

The idea is not that far-fetched, the researchers said, noting that the FDA recently approved a therapy for rheumatoid arthritis by vagus nerve stimulation.

“Imagine if you could harness this brake to control inflammation in the lungs and beyond,” Chiu said. “By stimulating related circuits where the vagus nerve shuts down immune cells, one could envision treating immune-mediated dysfunction of many kinds, including that caused by viral infections.”

Source: Harvard Medical School