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Category: biotech/medical – Page 259

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.

Navigating Postacute Care Options for Patients After Hospital Discharge: A Review

Approximately 25% to 40% of hospitalized adults are discharged to receive postacute care either at home through home health or in skilled nursing facilities, inpatient rehabilitation facilities, or long-term acute care hospitals.

This Narrative Review considers postacute care settings to assist hospital-based clinicians in effectively collaborating with patients, caregivers, and interdisciplinary care teams to facilitate transitions to high-quality postacute care.

Clinicians often care for patients who cannot return to their previous level of support in the community due to new functional impairments or complex posthospital care needs. After hospital discharge, these patients may require postacute care (PAC)—broadly defined as medical and rehabilitative services intended to help individuals recuperate and rehabilitate. PAC can be provided at home through home health (HH) or in skilled nursing facilities (SNFs), inpatient rehabilitation facilities (IRFs), and long-term acute care hospitals (LTACHs). A key criterion for PAC eligibility is the need for skilled nursing and/or rehabilitative services as determined by the treating physician.1-3 Payers require that these health services be reasonable and necessary for the treatment of a specific illness or injury, and that given their complexity (eg, wound care, intravenous infusion), they be provided only by a health professional. Yet, clinicians often play a passive role in PAC planning; many report a lack of knowledge around PAC capabilities, quality, and constraints.4-6

The epidemiology of PAC in the US is best understood for Traditional Medicare (or fee-for-service). Among hospitalized Medicare beneficiaries, approximately 40% were discharged to PAC in 2023: 18% to HH, 17% to SNF, 5% to IRFs, and 1% to LTACHs,7 accounting for approximately $60 billion of Medicare spending annually.7 Up to three-quarters of regional differences in Medicare spending are attributable to PAC, suggesting that discharge decisions are often driven by local practice norms rather than patient need. This underscores the need to improve and standardize PAC best practices.8,9

Hospital-based physicians, nurse practitioners, and physician assistants play an important role in PAC discharge planning due to their in-depth understanding of a patient’s complex medical needs. A better understanding of the qualifications and services provided can help clinicians engage in a more helpful role in the PAC discharge planning process. This Narrative Review provides an overview of PAC settings with the goal of helping clinicians collaborate most effectively with patients, caregivers, and interdisciplinary care teams to promote transition to high-quality PAC. We present a general summary of the most common types of PAC, followed by a comparison of the supporting evidence for each PAC setting. Descriptions of elements of PAC are based on the benefits covered by Traditional Medicare, which generally inform other payers’ coverage policies. Lastly, we review best practices for clinicians to actively discuss PAC options with patients, helping to orchestrate transitions of care to PAC for eligible individuals.

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