医学最新文献

Background: Integrating brain multimodal features (e.g. structural, functional, and cerebrospinal fluid metabolomic data) offers a promising approach to elucidate the neural mechanisms underlying erectile dysfunction (ED).

Methods: Using two-sample Mendelian randomization, we assessed causal effects of 83 whole-brain morphological, 191 resting-state fMRI, and 338 cerebrospinal fluid metabolite phenotypes on ED. A p-value < 0.05 indicated statistical significance.

Results: Reduced volumes in the left and right accumbens and enlarged volumes in the left pars opercularis and right putamen were associated with increased ED risk. Increased connectivity between occipital/precuneus and superior frontal gyrus (default/executive networks) elevated ED risk, while connectivity between postcentral/precentral and subcortical regions (motor/subcortical-cerebellum networks) reduced risk. Several metabolites were identified: elevated 4-Methylcatechol sulfate, adenine, gulonate, pyroglutamine, and thioproline increased ED risk, while higher cortisone, malate, phosphate, and X-21733 decreased risk.

Conclusion: We identified four morphological, two functional connectivity, and nine metabolic causal relationships with ED, enhancing understanding and suggesting novel therapeutic targets.

Gut microbial O-demethylation has been reported for plant-derived dietary compounds containing O-methylated aromatic(s). However, the significance of gut microbial O-demethylation in drug metabolism and disposition remains unexplored. This study examined 64 clinically used oral drugs containing one or more methoxylated aromatics for gut microbial O-demethylation using high-resolution mass spectrometry (HRMS). For 35 of the tested drugs, including the anticancer agent etoposide, we detected metabolites corresponding to O-demethylation (i.e., a mass difference of -14 and its multiples) when individual drugs were incubated with mouse cecal contents. We confirmed that the O-demethylated metabolite (M1) of the model drug etoposide is etoposide catechol using HRMS and proton nuclear magnetic resonance spectroscopy. By testing an in-house collection of 56 gut bacteria individually, we identified seven previously unknown gut bacterial species that exhibit etoposide O-demethylating activity. Etoposide anticancer therapy has been associated with an increased risk of acute myeloid leukemia. We demonstrated that M1 is more genotoxic to myeloid cells when it is orally administered to mice, whereas M1 is less cytotoxic against MCF-7 and HeLa cancer cells than the parent etoposide, suggesting that the gut microbiota may contribute to the secondary genotoxicity of etoposide via O-demethylation. Comparative pharmacokinetic analysis of orally administered etoposide in control and antibiotic-treated mice showed that systemic exposure to etoposide increased 1.9-fold, while M1 exposure decreased 3.7-fold in antibiotic-treated mice, suggesting that gut microbial O-demethylation is a significant determinant of etoposide metabolism and disposition. Collectively, our study reveals the prevalence of gut bacteria with O-demethylation activity, illustrates the contribution of gut microbial O-demethylation to altering drug efficacy and toxicity with the model drug etoposide, and provides a knowledge basis for in-depth characterization of other drugs identified as being susceptible to gut microbial O-demethylation.

Immune checkpoint regulators, such as the V-domain Ig suppressor of T cell activation (VISTA), play a critical role in shaping the tumor microenvironment (TME) and facilitating immune evasion. In ovarian cancer, VISTA exhibits more abundant and consistent expression than other immune checkpoints, including Programmed Death-Ligand 1 (PD-L1). This study examined the role of platelets in the regulation of VISTA in ovarian cancer using both in vitro and in vivo models. Our findings demonstrate that platelets upregulate VISTA expression in both myeloid and tumor cells, thereby promoting an immunosuppressive TME. Elevated VISTA levels were associated with higher platelet counts and poorer clinical outcomes. These results highlight that platelet-mediated VISTA upregulation is a potential therapeutic target for improving antitumor immune responses in ovarian cancer.

Antibody‒drug conjugates (ADCs) have taken on a significant role in precision oncology. These molecules, referred to as 'biological missiles', can deliver cytotoxic drugs directly to cancer cells. Traditional ADCs rely on endocytosis and intracellular release of payloads, but this approach becomes complicated due to issues like antigen loss, tumor heterogeneity, and impaired endocytosis, leading to therapeutic resistance. To address these challenges, noninternalizing ADCs have been developed, utilizing extracellular payload release methods. These structures employ advanced linker technologies to ensure stability in vivo and selective activation in the tumor microenvironment, achieving effective cytotoxic diffusion among tumor cells through the 'bystander effect'. This review discusses the evolution from early linker designs to complex methods based on tumor-specific conditions or external triggers. It also examines the categories of noninternalizing ADC linkers and the latest developments in clinical research, exploring prospects for enhancing the efficacy and safety of ADCs in oncology applications.

Asthma represents a classic respiratory disorder marked by chronic inflammation in the airways. This study aims to demonstrate the mechanism of bronchial epithelial cell-derived extracellular vesicles (BEC-EVs) carrying miR-27b-3p in airway inflammation in asthmatic mice, providing potential therapeutic targets for asthma. BECs and their EVs were isolated from mice and characterized. Asthmatic mouse models were established using ovalbumin and neutrophils were isolated. Histopathological changes and collagen deposition in lung tissues were observed. The levels of proinflammatory factors in the BALF and neutrophils were measured by ELISA. dsDNA levels in BALF or neutrophils were quantified using a dsDNA kit. Expression of cy3-labeled miR-27b-3p in neutrophils was detected. The levels of miR-27b-3p, ZMAT3, FGF1, Cit-H3, and MPO in lung tissues and cells were detected by RT-qPCR and Western blot. The binding relationships between miR-27b-3p and ZMAT3 and between ZMAT3 and FGF1 were verified. Combined experiments were used to validate the molecular mechanism by which BEC-EVs promote NET formation and regulate airway inflammation in asthmatic mice via the miR-27b-3p/ZMAT3/FGF1 axis. After BEC-EVs treatment, peribronchial inflammatory cell infiltration and collagen deposition were aggravated, and Cit-H3, MPO, and dsDNA were increased in OVA-induced mice, indicating exacerbated airway inflammation and promoted NET formation. BEC-EVs delivered miR-27b-3p to neutrophils and upregulated miR-27b-3p expression, which inhibited ZMAT3 to promote FGF1 expression. ZMAT3 overexpression or FGF1 knockdown partially reversed the BEC-EVs-induced NET formation. BEC-EVs promote NET formation and further aggravate airway inflammation in OVA-induced asthmatic mice by delivering miR-27b-3p to neutrophils, inhibiting ZMAT3, and promoting FGF1 expression.

Vancomycin-resistant Enterococcus (VRE) is a leading cause of multidrug-resistant infections in hospitalized patients, yet no reproducible microbiota therapies exist to selectively displace it. Here we harness intra-species competition within Enterococcus to suppress VRE colonization. Through in vitro screening and mouse colonization models, we identified a single antibiotic-susceptible strain, E. faecalis X98, that significantly reduced VRE burden both in vitro and in mouse experiments, whereas multi-strain consortia failed due to competitive interference among consortium members. In parallel, we subjected the vancomycin-sensitive strain E. faecalis OG1RF to phage selection, which produced a prophage-integrated derivative with convergent glycosyltransferase mutations that secreted a VRE-killing factor, conferring enhanced antagonism even without exogenous phage. These findings reveal ecological and evolutionary principles for selecting strains as targeted microbial therapeutics. Exploiting intra-species antagonism and phage-driven evolution provides a practical framework for developing microbiota-based interventions that minimize collateral damage to the microbiome while addressing antibiotic-resistant pathogens.

Background: Being playful and having the capability to play are considered fundamental aspects of being human and are closely linked to well-being in adulthood. Despite the health-promoting potential, being playful has, to our knowledge, not been explored in Scandinavian contexts in relation to older persons with functional impairments, such as those living in nursing homes.

Objective: This study, therefore, aims to explore older persons' lived experiences of being playful in nursing homes, to gain an in-depth understanding of the phenomenon and to contribute knowledge that may support person-centred care and well-being.

Methods: This phenomenological study is grounded in a reflective lifeworld research approach. Lifeworld interviews were conducted with 15 older persons aged 68-100 years.

Results: The essential meaning of the phenomenon emerges as getting in touch with an inner dynamic life force that enables and enhances well-being. This meaning is further illuminated through four constituents: engaging in timeless inner wanderings, adapting to bodily change, opening towards belonging, and navigating in a state of dependency.

Conclusions: In older persons´ playful mode of being, the inner dynamic life force opens up to a profound sense of existential well-being. However, ageing, bodily changes, and institutional constraints shape how playfulness is expressed and manifested in the lifeworld, thereby influencing well-being and human dignity. Taken together, these findings point to the potential value of acknowledging playfulness in future research and care practice as a fundamental aspect of being human and a contributor to both well-being and human dignity.

Many complex models for antibody affinity prediction have been developed and successfully deployed. Recent results for T-cell receptor epitope prediction have shown, that even simple distance-based models can achieve a similar performance while requiring less parameters, being more easily interpretable and faster to compute. Encouraged by these results AbDist, a new distance-based model, was developed for antibody affinity prediction. It uses fragments around mutation sites to calculate distances between antibody sequences, demonstrating that a local environment alone suffices as an effective featurization. AbDist was used to perform classification and regression tasks on multiple disjunct public datasets. Its performance matches state-of-the-art machine-learning (ML) models. AbDist is interpretable, computationally efficient, and well suited for data-sparse, early-stage antibody engineering workflows, while sharing the limited out-of-distribution generalization common to current models. AbDist is available as an open-source, publicly accessible tool.

Purpose: Aboriginal and Torres Strait Islander children are custodians of the world's oldest living cultures yet experience systemic inequities that infringe upon their rights to health, education, safety, and cultural identity due to ongoing colonisation. Despite these persistent disparities, few studies have explored wellbeing from Aboriginal and Torres Strait Islander children's own perspectives and lived experiences. This study addresses this gap by privileging children's voices in a large-scale, culturally grounded qualitative investigation.

Method: This study represents the first phase of the What Matters 2Kids (WM2K) project, which aims to develop a culturally relevant wellbeing measure for Aboriginal and Torres Strait Islander children aged 5-11 years. Using an Indigenist methodology and culturally responsive Art and Yarning method, 219 Aboriginal and Torres Strait Islander children across 15 sites in urban, regional, and remote Australia participated in creative sessions to express what supports their wellbeing. Data was analysed using Reflexive Thematic Analysis and a Collaborative Yarning approach.

Results: Culture emerged as a foundational element underpinning and connecting all aspects of Aboriginal and Torres Strait Islander children's wellbeing. Within this cultural foundation, seven interconnected themes were identified: caring relationships, connection to Country and nature, feeling safe, hopes and dreams, strong mind and body, interests and activities, and strong identity. A culturally resonant visual analogy, the "Wellbeing Stones", was developed to conceptualise these findings.

Conclusions: This study provides critical insights into the holistic, relational, and culturally embedded nature of wellbeing for Aboriginal and Torres Strait Islander children, offering essential groundwork for developing culturally appropriate measurement tools and interventions with important implications for research, policy, and service provision.

Objective: To construct and interpret a machine learning model for predicting overall survival in nonsurgical prostate cancer with bone metastases (PCBM).

Methods: Data from 3,378 SEER database patients were utilized to develop machine learning survival models, with the best-performing model visually interpreted using SHAP.

Results: The Extra Survival Trees (EST) model performed best (validation AUC = 0.694, C-index = 0.643). SHAP analysis identified the Gleason score as the most critical survival factor, significantly outweighing clinical T stage. Visceral metastasis and advanced age also markedly increased mortality risk.

Conclusion: The EST model effectively assesses OS in nonsurgical PCBM. The Gleason score holds greater prognostic value than local anatomical staging in this cohort, suggesting clinicians should prioritize early, aggressive combination treatments for high-Gleason, high-burden patients.