Tag: 12/7/23

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An Existing Cancer Drug Could Have a New Target: Cancer Cells’ ‘Fountain of Youth’

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A team of scientists has found that ponatinib, an existing cancer drug could be repurposed to target a subset of cancers that currently lack targeted treatment options and is often associated with poor outcomes. Their findings are published in Nature Communications.

Cancerous cells have a ‘fountain of youth’ by continually lengthening telomeres, but some use a different mechanism called the alternative lengthening of telomeres (ALT). This subset makes up 15% of all cancers and is especially prevalent in aggressive tumours such as osteosarcoma and glioblastoma. The team, led by Nanyang Technological University, Singapore (NTU Singapore), showed that ponatinib, a cancer drug approved by the US Food and Drug Administration, blocks key steps in the ALT mechanism that leads it to fail.

The scientists found that ponatinib helped to shrink bone tumours (a type of ALT cancer) without causing weight loss, a common side effect associated with cancer drugs. In mice with tumours treated with ponatinib, they found a reduction in a biomarker for ALT cancer as compared to untreated mice.

The researchers say that the findings move them a step closer to developing a targeted therapeutic option for ALT cancers, which lack clinically approved targeted treatments to date.

Dr Maya Jeitany and a team of researchers from the NTU School of Biological Sciences, together with collaborators are seeking to address this unmet need.

Dr Jeitany, study lead and senior research fellow at NTU’s School of Biological Sciences, said: “A prominent feature of cancer is its ability to evade cell death and acquire indefinite replication – to stay immortal, in other words – which it can do through the alternative lengthening of telomeres (ALT) mechanism. While a sizeable portion of cancer cells depend on this mechanism, there is no clinically approved targeted therapy available.

“Through our study, we identified a novel signalling pathway in the ALT mechanism and showed that the FDA-approved drug ponatinib inhibits this pathway and holds exceptional promise in stopping the growth of ALT cancer cells. Our findings may provide a new direction for the treatment of ALT cancers by repurposing an FDA-approved drug for these types of tumours.”

Commenting as an independent expert, Assistant Professor Valerie Yang, medical oncologist with the Department of Lymphoma and Sarcoma at the National Cancer Centre Singapore, said: “Sarcomas and glioblastomas are both highly complex cancers that are more prevalent in young people and currently have limited treatment options. The identification of a drug that is FDA-approved which can be repurposed to target ALT, an Achilles heel in these cancers, is very exciting.”

To date, there is no clinically approved targeted treatment for ALT cancers. Furthermore, many ALT cancers, such as osteosarcoma and glioblastoma, show resistance to chemotherapy, highlighting the need for a more targeted form of treatment.

Drug affects telomeres in ALT cancer cells

Through high-throughput drug screening and subsequent testing of shortlisted compounds, the scientists discovered that ponatinib, a drug approved by the FDA for a type of bone marrow cancer, can kill ALT cancer cells effectively.

When osteosarcoma and liposarcoma cells were treated with ponatinib, the scientists found that the drug led to DNA damage, dysfunctional telomeres, and triggered senescence. Importantly, the synthesis of telomeres in the cells also dropped after 18 to 20 hours of treatment with the drug.

Pre-clinical studies conducted on mice that had received transplants of human bone cancer cells further validated the potential of ponatinib. The drug reduced the tumour sizes without affecting the mice’s body weight, a common side effect associated with cancer treatments.

In mice with tumours treated with ponatinib, there was also a reduction in a biomarker for ALT cancer as compared to untreated mice – an indicator that the drug was effective in inhibiting ALT cancer growth.

The scientists ran further tests to identify ponatinib’s mode of action on telomeres in ALT cancer cells and identified a signalling pathway (a series of chemical reactions in which a group of molecules in a cell work together to control a cell function) that could be responsible for the drug’s effect on ALT.

The researchers are now studying further how ponatinib affects telomeres to understand in more detail the signalling pathway they have identified. They are also assessing potential ponatinib-based combinatorial drug treatments for ALT cancers.

Source: Nanyang Technological University

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A Natural Repair Process for Damaged Auditory Hair Cells

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Photo by Dylann Hendricks on Unsplash

Auditory researchers have discovered how hair cells can repair themselves after being damaged, an important insight could benefit efforts to develop new and better ways to treat and prevent hearing loss. Their findings are published in the free online journal eLife.

Found in the inner ear, hair cells derive their name from the hair-like structures that cover them and serve as mechanical antennas for sound detection. The prevailing belief is that when auditory hair cells are killed, they are gone for good. But this new research from University of Virginia School of Medicine shows that these delicate cells have the ability to repair themselves from damage caused by loud noises or other forms of stress.

“For many years, auditory research has placed considerable emphasis on the regeneration of sensory hair cells. Although these efforts continue, it is equally important to enhance our comprehension of the intrinsic mechanisms that govern the repair and maintenance of these cells. By gaining a deeper understanding of these inherent repair processes, we can uncover strategies to fortify them effectively. One such approach in the future might involve the utilisation of drugs that stimulate repair programs,” said researcher Jung-Bum Shin, PhD, of UVA’s Department of Neuroscience. “In essence, when replacement of hair cells proves challenging, the focus shifts towards repairing them instead. This dual strategy of regeneration and repair holds strong potential in advancing treatments for hearing loss and associated conditions.”

Repairing the damaged cells

In order to sense sound, hair cells are naturally fragile, but they also must withstand the continuous mechanical stress inherent in their jobs.

Prolonged exposure to loud noise harms hair cells in a variety of ways, and one of those is by damaging the cores of the “hairs” themselves. These hair-like structures are known as stereocilia, and Shin’s new research shows a process they use to repair themselves.

The hair cells do this by deploying a protein called XIRP2, which has the ability to sense damage to the cores, which are made of a substance called actin. Shin and his team found that XIRP2 first senses damage, then migrates to the damage site and repairs the cores by filling in new actin.

“We are especially excited to have identified a novel mechanism by which XIRP2 can sense damage-associated distortions of the actin backbone,” Shin said. “This is of relevance not only for hair cell research, but the broader cell biology discipline.”

The pioneering work has netted a grant to fund additional research into how the cores are repaired. By understanding this, scientists will be better positioned to develop new ways to battle hearing loss – even the kind that comes from aging, the researchers say.

“Age-related hearing loss affects at least a third of all older adults,” Shin said. “Understanding and harnessing internal mechanisms by which hair cells counteract wear and tear will be crucial in identifying ways to prevent age-related hearing loss. Furthermore, this knowledge holds potential implications for associated conditions such as Alzheimer’s disease and other dementia conditions.”

Source: University of Virginia Health System

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Mouse Study Highlights Potential Therapeutic for Metabolic Syndrome

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Photo by Diana Polekhina on Unsplash

Mopping up free radicals with antioxidants was a major health fad in the 1970s. In an effort to supposedly blunt the effects of aging and stave off chronic disease, people took huge amounts of antioxidants in the form of minerals and vitamins. Not only was this ineffective, it sometimes caused harm because untargeted antioxidants also compromised beneficial cellular signalling pathways. As theories of mitochondrial causes of disease fell out of favour, this health fad disappeared along with bell bottoms and disco.

Now, research recently published in Free Radical Biology and Medicine suggests a new way of dealing with free radicals: rather than mop them up, take a pill that selectively keeps them from being produced in the first place. Building on this work, collaborative research between the Buck and Calico Labs shows that specifically inhibiting free radical production at a particular mitochondrial site prevents and treats metabolic syndrome in mice, by preventing and reversing insulin resistance.

“We think that mitochondrial radical production drives many chronic diseases of aging, and that blocking the production of free radicals is a viable disease-treating and anti-aging intervention,” said Martin Brand, PhD, Buck Professor Emeritus and senior investigator of the study. “We’ve found a way to selectively keep problematic free radicals in check without compromising normal energy production in the mitochondria. These compounds act like a cork in a wine bottle. They plug a specific site so that it doesn’t produce free radicals, without hindering the mitochondria’s critical function of energy metabolism. We look forward to continuing this groundbreaking area of research.”

The orally bioavailable compound that has been developed, S1QEL1.719 (a new “S1QEL” – Suppressor of site IQ Electron Leak), was given both prophylactically and therapeutically to mice fed a high-fat diet that causes metabolic syndrome. Treatment decreased fat accumulation, strongly protected against decreased glucose tolerance and prevented or reversed the increase in fasting insulin levels by protecting against the development of insulin resistance.

Acting on mitochondrial complex I highlights potential interventions for other conditions

S1QEL1s act on site IQin mitochondrial complex I. (The mitochondrial electron transport chain consists of four protein complexes integrated into the inner mitochondrial membrane. Together they carry out a multi-step process, oxidative phosphorylation, through which cells derive 90% of their energy.)

First author and Buck staff scientist Mark Watson, Ph.D., says current literature strongly implicates complex I in a number of different diseases, from metabolic syndrome to Alzheimer’s, fatty liver disease, and noise-induced hearing loss, as well as the underlying aging process itself.

“S1QELs don’t sequester oxidants or radicals. Rather, they specifically inhibit radical production at the IQ site on complex I without interfering with other sites,” Watson said. “So the normal redox signaling that we require in our cells will continue. S1QELs just modulate that one site. They are very clean, very specific, and do not disrupt mitochondrial functioning like inhibitors of mitochondria do.”

Brand says the data shows that free radical production from complex I is an essential driver of insulin resistance and metabolic syndrome, a major disease of poor lifestyle choices and of aging. He says this feature is a strong reason to revisit the mitochondrial theory of aging. “These compounds fine-tune mitochondrial production of free radicals,” he said. “And it’s really interesting; just inhibiting this specific site improves the whole redox environment and prevents metabolic disease, and that is amazing.”

Source: Buck Institute for Research on Aging

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Would it be Ethical to Entrust Human Patients to Robotic Nurses?

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Photo by Alex Knight on Unsplash

Advancements in AI have resulted in typically human characteristics like creativity, communication, critical thinking, and learning being replicated by machines for complex tasks like driving vehicles and creating art. With further development, these human-like attributes may develop enough to one day make it possible for robots and AI to be entrusted with nursing, a very ‘human’ practice. But… would it be ethical to entrust the care of humans to machines?

In a step toward answering this question, Japanese researchers recently explored the ethics of such a situation in the journal Nursing Ethics.

The study was conducted by Associate Professor Tomohide Ibuki from Tokyo University of Science, in collaboration with medical ethics researcher Dr Eisuke Nakazawa from The University of Tokyo and nursing researcher Dr Ai Ibuki from Kyoritsu Women’s University.

“This study in applied ethics examines whether robotics, human engineering, and human intelligence technologies can and should replace humans in nursing tasks,” says Dr Ibuki.

Nurses show empathy and establish meaningful connections with their patients, a human touch which is essential in fostering a sense of understanding, trust, and emotional support. The researchers examined whether the current advancements in robotics and AI can implement these human qualities by replicating the ethical concepts attributed to human nurses, including advocacy, accountability, cooperation, and caring.

Advocacy in nursing involves speaking on behalf of patients to ensure that they receive the best possible medical care. This encompasses safeguarding patients from medical errors, providing treatment information, acknowledging the preferences of a patient, and acting as mediators between the hospital and the patient. In this regard, the researchers noted that while AI can inform patients about medical errors and present treatment options, they questioned its ability to truly understand and empathise with patients’ values and to effectively navigate human relationships as mediators.

The researchers also expressed concerns about holding robots accountable for their actions. They suggested the development of explainable AI, which would provide insights into the decision-making process of AI systems, improving accountability.

The study further highlights that nurses are required to collaborate effectively with their colleagues and other healthcare professionals to ensure the best possible care for patients. As humans rely on visual cues to build trust and establish relationships, unfamiliarity with robots might lead to suboptimal interactions. Recognising this issue, the researchers emphasised the importance of conducting further investigations to determine the appropriate appearance of robots for facilitating efficient cooperation with human medical staff.

Lastly, while robots and AI have the potential to understand a patient’s emotions and provide appropriate care, the patient must also be willing to accept robots as care providers.

Having considered the above four ethical concepts in nursing, the researchers acknowledge that while robots may not fully replace human nurses anytime soon, they do not dismiss the possibility. While robots and AI can potentially reduce the shortage of nurses and improve treatment outcomes for patients, their deployment requires careful weighing of the ethical implications and impact on nursing practice.

“While the present analysis does not preclude the possibility of implementing the ethical concepts of nursing in robots and AI in the future, it points out that there are several ethical questions. Further research could not only help solve them but also lead to new discoveries in ethics,” concludes Dr Ibuki.

Source: Tokyo University of Science

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Faecal Microbiota Transplants Could Boost Melanoma Immunotherapy

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

In a world-first clinical trial published in the journal Nature Medicine, a multi-centre study has found faecal microbiota transplants (FMT) from healthy donors are safe and show promise in improving response to immunotherapy in patients with advanced melanoma.

While immunotherapy drugs can significantly improve survival outcomes in those with melanoma, they are only effective in 40–50% of patients. Preliminary research has suggested that the human microbiome may play a role in whether or not a patient responds.

“In this study, we aimed to improve melanoma patients’ response to immunotherapy by improving the health of their microbiome through faecal transplants,” says Dr John Lenehan, Medical Oncologist at London Health Sciences Centre’s (LHSC).

A faecal transplant involves collecting stool from a healthy donor, screening and preparing it in a lab, and transplanting it to the patient. The goal is to transplant the donor’s microbiome so that healthy bacteria will prosper in the patient’s gut.

“The connection between the microbiome, the immune system and cancer treatment is a growing field in science,” explains Dr Saman Maleki, senior investigator on the study. “This study aimed to harness microbes to improve outcomes for patients with melanoma.”

The phase I trial included 20 melanoma patients recruited from LHSC, CHUM and Jewish General Hospital. Patients were administered approximately 40 faecal transplant capsules orally during a single session, one week before they started immunotherapy treatment.

The trial found that combining faecal transplants with immunotherapy is safe for patients. The study also found 65% of patients who retained the donors’ microbiome had a clinical response to the combination treatment. Five patients experienced adverse events sometimes associated with immunotherapy and had their treatment discontinued.

“We have reached a plateau in treating melanoma with immunotherapy, but the microbiome has the potential to be a paradigm shift,” says oncologist Dr Bertrand Routy.

The study is unique due to its administration of faecal transplants (from healthy donors) in capsule form to cancer patients – a technique pioneered in London by Dr Michael Silverman.

“Our group has been doing faecal transplants for 20 years, initially finding success treating C. difficile infections. This has enabled us to refine our methods and provide an exceptionally high rate of the donor microbes surviving in the recipient’s gut with just a single dose,” says Dr Silverman. “Our data suggests at least some of the success we are seeing in melanoma patients is related to the efficacy of the capsules.”

The team has already started a larger phase II trial involving centres in Ontario and Quebec.

Source: Lawson Health Research Institute