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Category: biotech/medical – Page 19

Present state and future of screening for atrial fibrillation: a state-of-the-art review

AFib AF

Atrial fibrillation (AF) is the most common arrhythmia and is a leading cause of stroke and heart failure yet often remains undiagnosed. Screening has been proposed to identify asymptomatic AF and initiate preventive treatment, but evidence for reduction in hard clinical endpoints such as stroke and heart failure remains inconclusive. In this state-of-the-art review, we critically examine major AF screening trials across opportunistic, systematic and consumer-driven strategies, focusing on design features, population selection, monitoring strategies and outcomes. Variability in trial design, particularly in randomisation timing, participation rates and intensity of monitoring, significantly affects both AF detection and clinical outcomes. Systematic screening shows promise, but many trials were underpowered for hard outcomes.

Understanding the Role of Gut Microbial Enzyme in CMD

Studies of the putative functional relationships between the gut microbiota and host cardiometabolic diseases (CMDs), including atherosclerosis, diabetes, and metabolic dysfunction-associated steatohepatitis (MASH), have garnered unprecedented attention in recent years.1,2 Although causality has not yet been unequivocally established, interventions targeting the gut microbiota, such as antibiotics and fecal microbiota transplantation, have been demonstrated to improve health.3 Although such interventions show unique clinical value in specific scenarios such as recurrent Clostridioides difficile infection,4 they typically show interindividual variability in efficacy and raise safety concerns, altogether underscoring the need for safer, more precise, and targeted strategies.5 A deeper understanding of the molecular mechanisms by which gut microbiota exert their functions in health and disease will be crucial to such goals.

Enzymes are intracellular proteins that perform defined biological processes, and enzyme-targeting drugs constitute a significant proportion of current therapeutics.6 In recent years, growing evidence has indicated that gut microbial enzymes are key mediators of microbiota-derived functions.7 Such enzymes contribute to CMDs pathogenesis primarily through 3 mechanisms: generating bioactive metabolites that influence intestinal barrier integrity, inflammation, and other essential physiological processes; regulating the homeostasis of critical host metabolites, such as ceramides and cholesterol; and metabolizing xenobiotics derived from diet and drugs, thereby modulating nutrient absorption and drug efficacy.

Given the complexity of the functions of gut microbiota, it is arguably overly simplistic to categorize them as symbionts that are probiotic or pathogenic. Rather, by identifying and characterizing key microbial enzymes, we will be able to precisely modulate gut microbiota functions in health and disease. When a clear enzymatic cause is identified, therapies targeting microbial enzymes capitalize on a function-driven mechanism. This allows for precision that is independent of taxonomy and avoids off-target consequences stemming from compositional heterogeneity of the functional microbes across individuals. The operational feasibility and druggability of these therapies are further supported by mature enzyme-based therapy development paradigms. Ultimately, enzyme-targeted interventions are expected to work alongside conventional whole-microbiota or strain-level approaches, thereby enriching the toolkit for developing gut microbiome-based therapeutics.

Why lungs age unevenly: Vulnerable cells may guide new therapies

Aging is associated with increased risk for nearly every lung disease, including acute conditions like pneumonia and chronic diseases like chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, and lung cancer. Now, one of the most comprehensive analyses of human lung aging has found that not all cells age equally.

The study, published in Nature Communications, has found that certain types of lung cells are especially vulnerable to aging. The findings could inform treatments that target the defective cells, say the researchers.

“This data allows us to start thinking about lung aging not as a passive state that we have to accept, but as something that we may be able to modify with therapies and interventions,” says senior author Naftali Kaminski, MD, Boehringer Ingelheim Pharmaceuticals, Inc. Professor of Medicine (Pulmonary) at Yale School of Medicine and chief of pulmonary, critical care and sleep medicine at Yale.

Why simulating an entire cell cycle took years, multiple GPUs and six days per run

By simulating the life cycle of a minimal bacterial cell—from DNA replication to protein translation to metabolism and cell division—scientists have opened a new frontier of computer vision into the essential processes of life. The researchers, led by chemistry professor Zan Luthey-Schulten at the University of Illinois Urbana-Champaign, present their findings in the journal Cell.

The team simulated a living cell at nanoscale resolution and recapitulated how every molecule within that cell behaved over the course of a full cell cycle. The work took many years: vast computer resources, large experimental datasets, a suite of experimental and computational techniques and an understanding of the roles, behaviors and physical interactions of thousands of molecular players.

The researchers had to account for every gene, protein, RNA molecule and chemical reaction occurring within the cell to recreate the timing of cellular events. For example, their model had to accurately reflect the processes that allow the cell to double in size prior to cell division.

Stem Cell Treatments For Parkinson’s And Heart Failure Approved in World First

Japan has approved ground-breaking stem-cell treatments for Parkinson’s and severe heart failure, one of the manufacturers and media reports said Friday, with the therapies expected to reach patients within months.

Pharmaceutical company Sumitomo Pharma said it received the green light for the manufacture and sale of Amchepry, its Parkinson’s disease treatment that transplants stem cells into a patient’s brain.

Japan’s health ministry also gave the go-ahead to ReHeart, heart muscle sheets developed by medical startup Cuorips that can help form new blood vessels and restore heart function, media reports said.

Cancer drug reduces early Alzheimer’s-like brain hyperconnectivity in lab tests

Neuroscientists at King’s College London have pinpointed a mechanism behind the increased neural connectivity observed in the very early stages of Alzheimer’s disease. Published in Translational Psychiatry, the study also demonstrated that a cancer medication has the potential to reduce this hyperconnectivity.

The research showed that low levels of the protein amyloid-beta could induce hyperconnectivity and this pattern closely resembled changes seen in the brains of people with mild cognitive impairment (MCI). Amyloid-beta is thought to be instrumental in Alzheimer’s disease, where it creates plaques—or sticky clumps of amyloid-beta proteins—around the neurons.

These new findings suggest that low levels of amyloid-beta alone are enough to trigger early, disease-relevant changes in how brain cells connect.

Mitochondrial complex-derived ROS induces lysosomal dysfunction and impairs autophagic flux in human cells carrying the APOE4 allele

The APOE4 allele is the strongest genetic risk factor for sporadic Alzheimer’s disease (sAD), yet its cell-autonomous effects remain poorly understood. While young, asymptomatic APOE4 carriers exhibit abnormal brain metabolism, the mechanistic link between mitochondrial dysfunction and lysosomal-autophagic failure remains unclear. In this study, we conducted a comprehensive analysis of primary human fibroblasts from APOE3 controls, APOE4, and sAD donors to assess mitochondrial bioenergetics, oxidative stress, autophagy, and lysosomal function. APOE4 fibroblasts displayed increased mitochondrial content-associated markers (PGC1α, mtDNA) accompanied by reduced respiratory capacity, elevated proton leak, and excessive mitochondrial ROS. In parallel, APOE4 fibroblasts showed impaired autophagic flux and reduced LC3-TOMM20 colocalization, indicating defective mitophagy. Lysosomal proteolytic activity, assessed using DQ-BSA, was significantly reduced and remained unresponsive under to starvation, in contrast to the partial recovery observed in sAD cells. Pharmacological targeting of mitochondrial ROS with site-specific inhibitors revealed that complex III-derived ROS is the predominant driver of redox stress in APOE4 fibroblasts, while complex I contributes primarily in sAD. Notably, selective inhibition of complex III-derived ROS with S3QEL restored lysosomal degradation, autophagic flux, and mitochondrial respiration in APOE4 cells. Together, these findings demonstrate that mitochondrial oxidative stress disrupts the mitochondria-lysosome axis in an APOE4-specific manner, revealing early and mechanistically distinct vulnerabilities that may precede neurodegeneration. Our results challenge the notion that APOE4 merely amplifies AD pathology and instead identity site-specific redox signaling as a promising target for allele-informed interventions.

Keywords: APOE4; Autophagy; Human fibroblasts; Lysosome; Mitochondria; Mitochondrial complex III; S3QEL.

Copyright © 2024. Published by Elsevier B.V.

Preventing breast cancer resistance to CDK4/6 inhibitors using genomic findings

Researchers at Memorial Sloan Kettering Cancer Center (MSK) have made an important discovery about how genetic mutations in breast cancer patients can interact and drive resistance to certain drugs called CDK4/6 inhibitors. This finding, published in Nature, suggests a new strategy for predicting and preventing resistance to specific therapies based on the tumor’s genetic profile.

“This represents a major advance in understanding and predicting cancer behavior in response to treatment,” says physician-scientist Pedram Razavi, MD, Ph.D., who led the study with physician-scientist Sarat Chandarlapaty, MD, Ph.D. The study’s first author was Anton Safonov, MD, a physician-scientist in the MSK Breast Translational Program.

“To our knowledge, this is the first example showing that a complete genomic analysis of breast cancer, including both inherited and tumor-specific alterations, can predict the precise biological mechanism of resistance before therapy even begins,” Dr. Razavi adds.

CDK4/6 Inhibitor Resistance in Hormone Receptor-Positive Metastatic Breast Cancer: Translational Research, Clinical Trials, and Future Directions

The emergence of CDK4/6 inhibitors, such as palbociclib, ribociclib, and abemaciclib, has revolutionized the treatment landscape for hormone receptor-positive breast cancer.

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