Cellular decision-making relies on the integration of multiple extracellular cues into coordinated functional responses. Synthetic biology provides tools to rewire this process by engineering receptors that convert defined inputs into programmable outputs. Here, we describe a synthetic receptor-based architecture that enables monocytic-like cells to sense an immune-regulatory ligand and conditionally activate a phagocytic program. We engineered a synthetic Notch-based receptor (SNIPR) that detects programmed death-ligand 1 (PD-L1), a broadly expressed immune-regulatory ligand. Upon PD-L1 engagement, the circuit triggers programmable outputs, including expression of a fluorescent reporter or CV1-Fc, as model effector that interferes with CD47-mediated inhibition of phagocytosis. We show that circuit activation scales with PD-L1 levels, partially attenuates PD-1/PD-L1 signaling, and that conditional CV1-Fc expression enhances engulfment of SKOV-3 ovarian cancer cells by THP-1-derived macrophages in vitro. Collectively, this work reframes PD-L1 from an end-point therapeutic target to a programmable input signal for synthetic circuit activation and establishes a modular framework for ligand-responsive control of engineered macrophage behaviour.
Systematic Review OBJECTIVES: The objective of this study was to investigate female participation in spinal cord injury (SCI) motor rehabilitation randomized controlled trials (RCTs) which included the overall proportion of female participants and how this proportion changed with time post-injury (TPI), study quality and the intervention investigated. Systematic searches were conducted in MEDLINE, Embase, PsycInfo and CINAHL databases inclusive to December 31, 2024. Study eligibility included RCTs or RCT crossovers published in English and investigated an intervention for motor rehabilitation on adult participants with traumatic and/or non-traumatic SCI. Data from the RCTs was extracted and summarized using online Excel, with statistical analyses conducted in RStudio. Overall, 252 RCTs met the inclusion criteria and were included in the dataset. Of these, 237 RCTs reported the sex of participants. The overall proportion of female participants was 22.4%, with no significant changes between 2000 and 2024. No significant differences were found between the proportion of female participants and TPI. High quality studies had significantly higher female participation compared to low quality studies (p = 0.008). Significantly higher female participation was found in RCTs investigating technology-based interventions (p < 0.001), with no significant differences found in pharmacological or non-technology-based interventions. The underrepresentation of female participants in studies of SCI motor rehabilitation limits the generalizability of research results and potentially hinders the availability of rehabilitation strategies for female individuals. Understanding what challenges may be preventing higher enrollment and implementing recruitment strategies may aid in increasing the number of female participants in SCI rehabilitation RCTs.
There is an urgent need to overcome the limitations associated with limited autologous bone availability, allogeneic bone rejection, and the insufficient bioactivity of traditional materials for bone-defect repair. In this study, skin secretions from Andrias davidianus (SSAD) were compounded with methacrylated gelatin (GelMA) to develop a novel bioink and construct bone-regeneration scaffolds loaded with osteoblasts via extrusion-based 3D bioprinting. The optimized GelMA/SSAD bioink (50% v/v SSAD, 6% w/v GelMA) demonstrated excellent printability characterized by shear-thinning behavior and high-resolution structure formation and significantly enhanced mechanical strength. In vitro studies demonstrated that the scaffolds were not only biocompatible but also effective in promoting osteoblast proliferation, differentiation, and mineralization, as evidenced by significantly increased ALP activity and the upregulated expression of key osteogenic genes (RUNX2 and OCN). In a rat cranial bone defect model, the new bone volume fraction of the GelMA/SSAD scaffolds (12.54%) was markedly higher than that of the pure GelMA control group (9.82%) eight weeks after implantation. Multimodal analyses revealed that the scaffold synergistically accelerated bone regeneration by promoting TRAP-positive osteoclast activity and increasing type III collagen deposition. Overall, this SSAD-based bioink combines excellent printability, biocompatibility, and strong osteogenic activity, thereby providing a promising strategy for functional bone repair.
International humanitarian organizations providing surgical care in conflict-affected settings have an ethical obligation to adopt practices that promote sustainable surgical services. Our objective was to evaluate the prevalence of sustainable surgical practices and policies implemented by humanitarian organizations in conflict-afflicted settings, as well as to document instances where surgical services were disrupted or discontinued due to the outbreak of conflict. A review of primary literature was conducted using Medline. Articles were included if they described sustainable surgical practices or policies in conflict-affected settings. Sustainability was defined according to a previously published modified Delphi consensus framework, which outlined key pillars of sustainability in global surgery partnerships. A grey literature review was also performed to identify sustainable policies published by international humanitarian organizations on their online platforms. Of 1,057 articles screened, 29 articles met inclusion criteria, describing 54 surgical programs implemented by 17 international humanitarian organizations -most commonly Médecins Sans Frontières (n = 27) and International Committee of the Red Cross (n = 5). These programs were implemented in 36 conflicts between 1946 and 2023, most commonly in Sub-Saharan Africa (n = 20), the Middle East (n = 11), and Southeast Asia (n = 9). The following six sustainability pillars were explicitly described: context-relevant education (94.4%), multidisciplinary involvement (74.1%), outcome measurement (72.2%), stakeholder engagement (66.7%), handover to local stakeholders (18.5%), and multisource funding (13.0%). Escalating violence led to permanent closure of 13.0% of programs and led to service interruptions in 9.3%. The mean duration of programs was 9.5 ± 9.7 years. Publicly available policies were identified for six organizations (35.3%), and all but one organization captured every aforementioned pillar of sustainability. International humanitarian organizations have increasingly adopted sustainable practices and policies when delivering surgical care in conflict-affected settings-most notably in the area of context-relevant training. We encourage global actors to continue prioritizing this domain, especially in fragile states where service cessation or interruptions can occur at any time, necessitating sustainable surgical care delivered by trained local physicians. This review highlights exemplary practices documented in the literature and offers insights into how global surgery partners can build on existing efforts.
Acute exacerbations of chronic rhinosinusitis (AECRS) are increasingly recognized as a distinct clinical entity that significantly impacts quality of life. Despite its clinical relevance, data on its prevalence, clinical characteristics, and underlying bacteriology remain limited. This study investigated the clinical features of AECRS and characterized the bacterial profile of middle meatus cultures during exacerbation episodes. Furthermore, characteristics of AECRS were compared across chronic rhinosinusitis (CRS) phenotypes. Retrospective cohort study. Single tertiary care referral center, King Saud University Medical City (KSUMC). Medical records from patients with established AECRS with positive middle meatus cultures from 2015 to 2025 were extracted. Data included demographics, CRS phenotype, comorbidities, prior treatments, microbiological findings, and clinical outcomes. Bacterial etiology and clinical characteristics of AECRS across phenotypes, including chronic rhinosinusitis with nasal polyposis, chronic rhinosinusitis without nasal polyposis, and allergic fungal rhinosinusitis. 104. The study enrolled 104 patients (mean age 39.9 years); 49 (47.1%) had asthma and 21 (20.2%) had aspirin-exacerbated respiratory disease. Endoscopic pus was present in 71 (68.3%), and 77 (74%) had prior sinus surgery. The most common isolates were methicillin-sensitive Staphylococcus aureus 35 (33%), methicillin-resistant Staphylococcus aureus 26 (25%), and Pseudomonas species 24 (23.1%). Oral antibiotics were administered in 75 (72.1%) of AECRS episodes, while oral steroids were used in 27 (26%). Clinical improvement following antibiotic therapy was documented in 64 (85.3%) cases. High resistance was observed for ampicillin, penicillin, and oxacillin. AECRS presents considerable heterogeneity in both clinical presentation and microbiology. Therefore, culture-directed therapy is recommended due to variable antibiotic resistance patterns. Asthma was strongly associated with treatment failure. These findings emphasize the importance of individualized management strategies in AECRS. Retrospective design, and single tertiary care center.
Adverse social conditions across the life course influence brain aging and dementia, yet their compounded impact on clinical phenotypes remains underexplored, particularly in Latin America, where social inequality and dementia burden are high. We studied 3941 individuals from six Latin American countries, including cognitively unimpaired controls (CU), Alzheimer's disease (AD), and frontotemporal lobar degeneration (FTLD). A life-course questionnaire captured eight domains of social vulnerability, used to derive a social vulnerability index and latent vulnerability profiles. Brain health was characterized across 37 cognitive, functional, mental health, and dementia severity indicators. Higher vulnerability was mostly associated with executive and memory deficits in CU, cognitive and functional impairment in AD, and social cognition and neuropsychiatric symptoms in FTLD. Multidimensional brain health was affected across groups. Compounded social vulnerability is a key determinant of clinical expression in aging and dementia, underscoring the need for life-course-informed and equity-oriented dementia models.
Menke-Hennekam syndrome (MKHK) is a rare autosomal dominant disorder caused by mutations in the CREBBP and EP300 genes. The absence of established diagnostic criteria and non-specific clinical manifestations complicate timely diagnosis and management. This report presents a case of MKHK in which early diagnosis and intervention were achieved through the application of rapid whole-genome sequencing (rWGS), a tool that offers superior speed and genomic coverage compared to whole-exome sequencing (WES). This case report describes a male Han Chinese neonate who presented at birth (0 days) with intrauterine growth restriction, respiratory distress, and feeding difficulties. During follow-up, he developed hearing loss and demonstrated global developmental delay. Clinical examination revealed craniofacial dysmorphism. Trio rWGS was performed in the neonatal period, with results returned within 72 h of sample submission at 23 days of age. Trio rWGS identified a de novo missense variant in the CREBBP gene (c.5570A > C, p.His1857Pro). Sanger sequencing confirmed its absence in both parents, and the variant was classified as likely pathogenic despite no prior documented cases. Based on integrated genetic and clinical findings, a neonatal diagnosis of MKHK-ID4 was established. Following this diagnosis, early targeted interventions were initiated, including hearing aid fitting, enrollment in a comprehensive rehabilitation program, and planning for necessary surgical corrections. Significant developmental improvement was observed at the 15-month follow-up assessment. In this case, rWGS facilitated a neonatal diagnosis of MKHK-ID4 and enabled early multidisciplinary intervention during a critical neurodevelopmental window. This experience suggests that such an approach may contribute to improved developmental outcomes in this rare disorder, though further studies are required to confirm its broader applicability and long-term benefits.
Urinary stone disease (USD, or urolithiasis) is common and poses a substantial healthcare and economic burden on the working-age population. This study aimed to provide epidemiological insights into the prevalence, incidence, trends, and risk factors of USD among the Chinese population. We conducted a prospective cohort study involving 966,481 participants from the CHinese Electronic health Records Research during 2009-2022 in Yinzhou, China (CHERRY). Temporal trends were estimated using annual percentage changes (APC) via Joinpoint regression analyses. Stratified Cox proportional hazards regression and propensity score analyses were employed to evaluate potential risk factors, population attribution factor (PAF) and number needed to prevent (NNTP). From 2014/2015 to 2021, there was an annualized increase in USD incidence by 5.3-6.8% (P < 0.05). Identified risk factors for USD included tobacco smoking, alcohol drinking, high body mass index, diabetes, hyperlipidemia, hypertension, and cardiovasculardisease while regular exercising served as a protective factor of USD. The PAF ranged from 1.3% for non-drinking behavior to 22.5% for regular exercising (weekly). Correspondingly, the NNTP ranged from 182 for non-smoking behavior to 21 for weekly exercising. USD is a common disease affecting approximately 1 in 10 Chinese, with the incidence rate increasing by 5-6% annually over the past 6-7 years. Lifestyle factors and metabolic syndromes are potential risk factors for the development of USD.
The primary objective of this study was to explore the existence and identify predictors of incongruent perceptions of pain, fatigue, and sleep disturbance, and to examine their associations with negative mood, intimate relationship, and quality of life in colorectal cancer patient- caregiver dyads. 271 colorectal cancer dyads completed questionnaires designed to assess a range of outcomes, including patient symptoms (pain, fatigue, sleep disturbance), negative mood, intimate relationship, and quality of life. Pearson's correlation, multiple linear regression analysis and structural equation modeling were used to analyze the data. There were significant disparities in incongruent perceptions of sleep disturbance between patients and caregivers (t=-3.241, p < 0.001). For incongruent sleep disturbance, regression analysis showed patient education level (B=-1.014, p = 0.001) and caregiver education level (B=-1.140, p < 0.001) demonstrated significant negative associations. Longer patient diagnosis duration (B=-1.876, p = 0.010) was negatively associated. Caregiver religious affiliation (B=-1.611, p = 0.027) and marital status (B= -3.097, p = 0.001) showed negative associations. Patient gender (B= 1.361, p = 0.037) and caregiver gender (B = 1.803, p = 0.004) exhibited positive associations. Dyadic relationship type (B = 1.568, p = 0.043) was positively associated. The analysis revealed that incongruent perceptions of sleep disturbance exhibited a significant correlation with the quality of life and negative mood of both individuals within colorectal cancer patient-caregiver dyads. The model fit estimates were as follows: χ2/df = 1.570, GFI = 0.967, CFI = 0.957, IFI = 0.922, RMSEA = 0.036, SRMR = 0.053. Pathway analysis demonstrated that incongruent perceptions of sleep disturbance exerted a significantly direct effect on the quality of life of both individuals in colorectal cancer patient-caregiver dyads, albeit in opposite directions (B=-0.238, p < 0.001; B = 0.358, p < 0.001, respectively). Furthermore, the analysis revealed an actor-partner mediating effect of incongruent perceptions of sleep disturbance, negative mood, intimate relationship, and quality of life. The findings of the present study indicated that incongruent perceptions of sleep disturbance were associated with negative mood, low intimate relationship satisfaction, and low quality of life. The individual attributes of patients (gender, educational level and time since diagnosis) and caregivers (gender, educational level, religious beliefs and marital status), as well as dyadic factors such as relationship, could predict patient-caregiver concordance on assessing patients' symptoms. It is recommended that healthcare providers should reinforce patient-caregiver dyadic symptom education to reduce incongruent perceptions of sleep disturbance in colorectal cancer dyads with a view to enhancing their quality of life. More sleep management and substantial emotional support should be provided by family caregivers and healthcare providers.
Proton pump inhibitors (PPIs) are among the most frequently prescribed medications. However, they are often used inappropriately and may cause adverse effects in long-term use. This study aimed to explore internists' beliefs, attitudes and behaviors regarding deprescribing PPIs in Türkiye, by using the Theoretical Domains Framework (TDF). This qualitative study was conducted at a university hospital in Türkiye. Data were collected through face-to-face, in-depth interviews conducted in March-April 2023. The participants were selected through convenience sampling from among the residents and specialists working in the internal medicine department. A semi-structured interview guide, including two vignettes, was used. The data were evaluated using thematic analysis in Atlas.ti program. A total of 12 participants (10 residents and two specialists) participated in the study. Internists' behaviors related to deprescribing were mapped to 12 TDF domains including barriers (environmental context and resources, reinforcement, social influences, optimism/pessimism and emotions, social/professional role and identity, and knowledge and skills, beliefs about consequences) and enablers (intention and goals, memory, attention, and decision-making processes, beliefs about consequences). Despite the challenges posed by a fragmented healthcare system, heavy workload, poor coordination among providers, and patients' strong expectations of PPIs as "rescue" drugs, the participants still expressed an intention to deprescribe. This study highlights the need for systemic changes to improve deprescribing practices for PPIs in Türkiye. To promote deprescribing, appropriate behavior change techniques and implementation strategies should be identified and evaluated to ensure integrated care, evidence-based guidelines, and patient-centered practice. Not Applicable.
Small differences between females and males in cognitive abilities have been consistently reported, but the factors underlying these sex differences remain unclear. Social and cultural factors are thought to play a key role, but studies on this topic have been inconclusive. Examination of genetic factors may shed some light on the mechanisms underlying cognitive sex differences. Using data from the Philadelphia Neurodevelopmental Cohort, a large, general population sample of individuals aged 8 to 21 years old (N = 4,694), we tested for sex differences in the genetic factors (i.e., Gene × Sex interactions) underlying cognitive ability. Participants completed the Penn Computerized Neurocognitive Battery, which consists of 14 tests designed to capture accuracy and speed in five domains: 1) executive function (abstraction and mental flexibility, attention, working memory), 2) episodic memory (verbal, facial, spatial), 3) complex cognition (verbal reasoning, nonverbal reasoning, spatial processing), 4) social cognition (emotion identification, emotion differentiation, age differentiation), and 5) speed (motor, sensorimotor). Composite domain scores were derived using confirmatory factor analysis, and general accuracy (g) and speed (gs) using principal component analysis. Small sex differences were observed on most cognitive measures (standardized mean difference (SMD) = 0.061-0.182). Males showed significantly higher genetic variance and lower environmental variance in executive (female σ2g = 0.301 v. male σ2g = 0.598, p = 0.001, female σ2e = 0.243 v. male σ2e = 0.024, p = 0.007), and complex (female σ2g = 0.291 v. male σ2g = 0.610, p = 0.001, female σ2e = 0.259 v. male σ2e = 0.023, p = 0.006) accuracy. Females showed significantly higher genetic and lower environmental variance on complex (female σ2g = 0.575 v. male σ2g = 0.135, p = 0.009, female σ2e = 0.222 v. male σ2e = 0.641, p = 0.012) and social (female σ2g = 0.589 v. male σ2g = 0.129, p = 0.009, female σ2e = 0.236 v. male σ2e = 0.672, p = 0.012) speed. Genetic correlations between females and males were not significantly different from 1 on any cognitive measure. Altogether, our results suggest that while the same genetic factors influence cognition in females and males, the magnitude of effect of these genetic factors differs. We observed small differences between females and males on most cognitive measures, as well as sex differences in heritability on some measures. Future studies are needed to delineate how environmental, genetic, and other biological factors jointly influence cognition. Small differences in cognition between females and males have been consistently reported across abilities, cultures, and decades. However, the factors underlying these cognitive sex differences remain unclear. Social and cultural factors are thought to play a key role, but there has been less examination of potential genetic factors. We tested for sex differences in the genetic factors underlying a range of cognitive abilities in a large, general population sample of individuals aged 8 to 21 years old. Small sex differences were observed across most cognitive domains, with female advantages in memory and social cognition, and male advantages in executive and complex cognition. Moreover, differences between females and males in the magnitude of genetic factors underlying cognition were observed for executive, complex, and social cognition, suggesting that some cognitive sex differences are partly driven by sex differences in underlying genetic factors. Most research on the underlying causes of sex differences in cognitive abilities has focused on social and cultural factors, but our findings highlight the importance of considering genetic factors, as well as how these genetic factors act jointly with social and cultural factors to impact cognition. Given the impact of cognition on social, emotional, and health outcomes, further work is needed to delineate the interplay between environmental and genetic factors that underlie cognitive sex differences.
Sustaining evidence-based HIV prevention interventions remains a challenge, particularly among at-risk youth in Africa. The 4 Youth by Youth (4YBY) sustainment study is a hybrid type 2 cluster randomized controlled trial that evaluates the sustainability and cost-effectiveness of a crowdsourced approach to sustaining a package of evidence-based HIV prevention services. The study will be conducted across 40 community sites, supported by 18 community-based organizations (CBOs) providing HIV prevention services in Nigeria. Given their longstanding engagement with young people, CBOs serve as key partners in assessing long-term sustainability strategies for the 4YBY intervention, which has proven effective in increasing HIV prevention service uptake among youth. This protocol describes a cluster randomized controlled trial that will be conducted across 40 sites, all randomized into two arms. Half of the sites (20) will be assigned to receive the standard 4YBY intervention (4YBY-S), while the other 20 sites will receive the standard 4YBY intervention plus an enhanced sustainability strategy (4YBY-S + 4YBY-E). While the 4YBY-S group will continue implementing core intervention activities, the 4YBY-E group will receive additional sustainability-focused support. The Enhanced Sustainability Strategy in the 4YBY-E arm consists of four key components. First, "People" involves identifying and training sustainability teams within CBOs to champion intervention longevity. Second, "Learning", where bi-weekly collaborative sessions will be established to foster knowledge-sharing and problem-solving among stakeholders. Third, "Adaptation Monitoring" will focus on continuously tracking and modifying intervention strategies to better align with local needs. Finally, "Nurturing Coaches" includes dedicated coaches who will provide technical assistance, conduct audits, and offer feedback to strengthen sustainability efforts. Evaluation will be guided by Youth Participatory Action Research (YPAR), the PEN-3 Cultural Model, Proctor's Implementation Outcomes Framework, and the Consolidated Framework for Implementation Research (CFIR). The study hypothesizes that sites receiving the enhanced sustainability strategy (4YBY-S + 4YBY-E) will exhibit greater sustainability of core intervention components, defined as the continued delivery, adaptation, and integration of the intervention within community-based organizations-compared to sites receiving only the standard 4YBY intervention (4YBY-S). Additionally, the 4YBY-S + 4YBY-E arm is expected to achieve a higher uptake of HIV prevention services at 24 months, reflecting both the intervention's effectiveness and its long-term viability within community settings. This protocol represents one of the first cluster randomized controlled trials evaluating intervention sustainment strategies for a youth-led, evidence-based HIV prevention program in Africa. Findings will advance implementation science by establishing a threshold for sustainable strategies and identifying the key factors that support the long-term integration and continuation of HIV prevention services for at-risk youth. The results critically impact scaling up community-led interventions and shaping policy frameworks to strengthen the global HIV response. The protocol was registered with clinicaltrials.gov under registration NCT07072481.
Endometriosis progression is driven by oxidative stress and excessive angiogenesis within an inflammatory microenvironment. To overcome these challenges, we designed ROS/pH dual-responsive Alpelisib-loaded nanoparticles (Alp@TAT-AT7-NPs) functionalized with an anti-NRP1 peptide for targeted therapy. The nanoparticles exhibited superior stability, responsive drug release, and selective internalization by NRP1-overexpressing endothelial cells. In vitro results showed efficient inhibition of NRP1 and downstream PI3K/AKT signaling, along with decreased reactive oxygen species (ROS) and enhanced antioxidant enzyme activities. In an endometriosis rat model, treatment with Alp@TAT-AT7-NPs significantly reduced ectopic lesion burden and angiogenic markers (VEGF, CD34), while suppressing systemic inflammation and oxidative injury indicators such as IL-6, TNF-α, and MDA. Fluorescence imaging confirmed preferential accumulation of nanoparticles in CD31⁺ vascular regions. Mechanistic studies demonstrated that modulation of the Sema3A-NRP1-PI3K/AKT signaling axis restored redox homeostasis and inhibited pathological angiogenesis. These findings identify Alp@TAT-AT7-NPs as a synergistic nanoplatform that integrates microenvironment responsiveness with NRP1-targeted intervention, providing a promising therapeutic strategy for endometriosis.
Staphylococcus hyicus is recognized as one of causative agents of porcine exudative epidermitis in piglets. However, research on clinical pathogenic S. hyicus remains limited. In this study, multidrug-resistant S. hyicus was isolated from a large-scale pig farm with cases of fatal exudative epidermitis in piglets. By characterizing the phenotypes and genotypes of S. hyicus isolates, we provide insights for clinical management of exudative epidermitis. Two 21-day-old piglets with clinical signs underwent necropsy and histopathological examination. 48 samples from lactating sows and suckling piglets were collected for pathogen identification. Antimicrobial and disinfectant susceptibility of the isolates was determined using broth microdilution, as well as whole-genome sequencing (WGS) was used to identify antimicrobial resistance genes. Moreover, comparative genomic analysis with public genomes in the Genbank database was performed. The virulence of mecA-carrying S. hyicus was evaluated using the Galleria mellonella infection model. Exudative epidermitis was first observed in 3-day-old piglets. Through necropsy, pathogen isolation, and other diagnostic approaches, S. hyicus was preliminarily identified as the primary causative agent of this episode, and 23 S. hyicus were isolated from samples. Antimicrobial susceptibility testing indicated most of isolated S. hyicus were susceptible to doxycycline, vancomycin and linezolid, while resistant to florfenicol, erythromycin, spectinomycin, amoxicillin, ceftiofur, enrofloxacin that are commonly used for pigs. Twelve resistance genes were identified by WGS, including aadD, ant(6)-Ia, aph(2'')-Ia, blaZ, erm(B), erm(C), fexA, lnu(B), lsa(E), mecA, tet(L), and tet(M). Compared with 39 GenBank genomes, mecA-carrying S. hyicus in our study carried more resistance genes and exhC islands closely related to previous Chinese strains. Based on our findings, we implemented a targeted treatment protocol that brought the outbreak under control and reduced piglet mortality to below 5%. This study successfully isolated pathogenic mecA-carrying S. hyicus responsible for high mortality in piglets, characterized its drug resistance phenotypes and genotypes, offering valuable insights for the prevention and control of this pathogen in piglets.
Polybromo 1 (PBRM1), encoding the BAF180 subunit of the polybromo-associated BAF (PBAF) chromatin-remodeling complex, is commonly lost or mutated across malignancies. Despite its prevalence, tailored therapeutics for PBRM1-defective cancers remain limited. PBRM1 loss is associated with elevated replication stress and DNA damage responses, implying dependence on compensatory repair pathways. Given the lack of genotype-matched drugs, exploiting DNA-repair dependencies may provide a precision option for PBRM1-deficient disease. We pursued a synthetic-lethality strategy in colorectal cancer to test whether clinically used PARP inhibitors selectively suppress PBRM1-deficient cells and to define the linked cell-cycle and stress-response mechanisms. We also compared PARP inhibition with broader chromatin-remodeler targeting. Isogenic PBRM1-/- HCT116 colorectal carcinoma cells were generated by CRISPR/Cas9 lentiviral editing using sgRNAs cloned into lenti-CRISPR-V2. Knockout was confirmed by Western blotting, Sanger sequencing, and RT-qPCR. A focused compound screen compared four agents PARP inhibitors olaparib and rucaparib, the multi-target chromatin remodeler inhibitor AU-24,118, and the SMARCA2/4-targeting degrader AU-1530 using dose-response CCK-8 viability assays and selectivity indices. We then validated our results by 12-day colony-formation assays. Mechanistic analyses measured drug-induced G2/M accumulation by propidium iodide staining and flow cytometry and quantified apoptosis by Annexin V/PI dual staining, with significance assessed by t-test or two-way ANOVA. PBRM1 loss confers selective hypersensitivity to PARP inhibitors, which intensify DNA-damage signaling, promote G2/M checkpoint arrest, trigger apoptosis, and induce stress-response genes such as CSRNP3. Although this effect appears context-dependent and was not observed uniformly across all PBRM1-/- models tested. These results support further evaluation of PBRM1 as a potential predictive biomarker in defined molecular contexts rather than as a universal marker of PARP inhibitor sensitivity.
Despite the higher lung cancer incidence among Black individuals, existing evidence on racial disparities in smoking-related lung cancer risk remains limited. This review aims to examine differences in smoking-related lung cancer risk between Black and White individuals. We conducted a systematic review and meta-analysis of U.S.-based observational studies from 1964 to June 2024. Eligible studies examined lung cancer incidence as the primary outcome and reported race-specific estimates for smoking-related risk. Meta-analysis was used to compare lung cancer risk across racial groups by smoking status (current/former/ever vs. never). Of 460 abstracts screened, 36 met inclusion criteria, and 11 articles were included in the meta-analysis. Individuals who currently smoke had greater odds of developing lung cancer compared to those who never smoked (OR = 15.52 (95% CI 13.98-17.23)). Similarly, individuals who formerly smoked had greater odds of developing lung cancer compared to those who never smoked (OR = 6.36 (95% CI 5.73-7.07)). In the weighted meta-analysis model, we did not demonstrate significant odds of incident lung cancer cases by race, irrespective of smoking status. Our findings did not provide statistical evidence of a difference in smoking-related lung cancer risk by race, though precision was limited, particularly for Black participants. Future research should evaluate pack-years and other risk factors to elucidate differences in smoking behaviors among high-risk populations.
Although mentoring remains a fundamental part of medical training, the traditional approach of a senior mentor guiding a junior trainee often fails to meet the diverse and evolving needs of learners in radiology. While peer and near-peer mentoring approaches have shown promise, they often lack a scalable, structured framework. We present a cascade mentoring model embedded within the radiology training environment, in which senior trainees mentor junior residents, who then supervise undergraduate learners. This model is aligned with the European Society of Radiology's (ESR) competency-based framework through the European training curriculum for radiology (ETC). It sets out the specific responsibilities of faculty members, early career radiologists, senior residents, junior residents and undergraduates. Mentorship activities include case discussions, clinical teaching, research collaboration and providing structured feedback. The cascade approach fosters skill acquisition, professional development and research engagement at every level. Senior residents can refine their expertise through teaching, junior residents can reinforce their foundational knowledge by guiding undergraduates, and undergraduates can gain structured, early exposure to radiology. Anticipated benefits include enhanced departmental integration, improved teaching skills among residents, greater undergraduate engagement and an optimised faculty workload. The Cascade Mentoring Model is an innovative, sustainable educational strategy that is aligned with the ETC. It empowers residents to become future educators and promotes radiology as a speciality. When implemented, overseen and evaluated deliberately, it has the potential to enhance radiology education programmes throughout Europe. Cascade mentoring can also help mitigate the shortage of radiologists by enhancing training capacity and retention of early-career radiologists. CRITICAL RELEVANCE STATEMENT: The cascade mentoring model provides a structured, scalable approach to radiology education aligned with the European training curriculum. By optimising faculty workload, strengthening residents' teaching skills and fostering early engagement, it supports high-quality training, workforce retention and sustainable radiology education across Europe. KEY POINTS: Traditional mentoring in radiology lacks scalability and responsiveness to learner diversity needs. Cascade mentoring structures near-peer teaching across undergraduate, resident and faculty levels. Model aligns with the ESR European training curriculum competency-based framework. Cascade mentoring enhances skills, teaching capacity, research engagement and professional development. Scalable approach supports workforce retention and sustainable radiology education in Europe.
Prostate cancer (PCa) is characterized by a unique metabolic dependency on the hyperactivated tricarboxylic acid (TCA) cycle, creating a distinct vulnerability to cuproptosis-a copper-dependent form of regulated cell death. However, metabolic plasticity allows tumor cells to evade single-pathway inhibition through compensatory glycolysis, limiting the efficacy of copper-based therapies. Therefore, there is an urgent need to develop integrated nanoplatforms capable of orchestrating a dual-pathway metabolic blockade to overcome this therapeutic resistance. Herein, we engineered a self-assembling copper-epigallocatechin gallate (EGCG) nanoreactor (Cu-EQ NP) designed to execute a synchronized dual-metabolic assault. The Cu-EQ NPs leverage the tumor microenvironment to release copper ions that trigger TCA-dependent cuproptosis, while the EGCG component simultaneously inhibits key glycolytic enzymes to prevent metabolic escape. Mechanistically, this lethality is self-amplified by EGCG-quinone-mediated depletion of glutathione (GSH) and the downregulation of the ATPase copper-transporting beta (ATP7B) efflux pump, leading to irreversible intracellular copper accumulation. Furthermore, we demonstrate that this metabolic collapse is highly immunogenic. In a syngeneic RM-1 mouse model, Cu-EQ NP-induced immunogenic cell death (ICD) released damage-associated molecular patterns (DAMPs) that successfully transformed the immunologically "cold" tumor microenvironment. This remodeling was characterized by enhanced dendritic cell maturation, M2-to-M1 macrophage repolarization, and robust infiltration of cytotoxic CD8 + T cells, resulting in potent tumor regression. The Cu-EQ nanoreactor represents a precision nanomedicine strategy that converts the specific metabolic vulnerabilities of PCa into a fatal weakness. By integrating dual-metabolic disruption with robust immune activation, this platform offers a promising therapeutic paradigm for overcoming resistance in advanced prostate cancer.
Cervical cancer (CC) treatment is limited by chemoresistance, inadequate drug accumulation, and the lack of real-time monitoring. Among the underlying mechanisms, heat shock protein 70 (HSP70) mediates resistance to both chemotherapy and photothermal therapy, making it a rational target for intervention. To address these issues, we developed a novel type of cyclic RGD (cRGD) encapsulated SN38 and IR820 loaded bismuth selenide theranostic nanoplatforms-Bi2Se3-cRGD@SN38/IR820 nanoparticles (Bi-A@SR NPs) based on a bismuth selenide (Bi2Se3) as core decorated with cRGD for tumor targeting, and co-loaded with SN38 and IR820. The RGD peptide contains a guanidino group from its arginine residue that can serve as a donor for nitric oxide (NO) generation, enabling the construct to provide both tumor-homing capability and on-demand NO release. The nanoplatform integrates computed tomography (CT) imaging and NIR fluorescence imaging (NIRF) to verify delivery and guide therapy. Upon 808 nm irradiation, photothermal and photodynamic effects generate hyperthermia and reactive oxygen species (ROS), which trigger on-site NO production from the RGD arginine moiety. This NO suppresses therapy-induced HSP70 upregulation, counteracting stress adaptation and enhancing chemo-phototherapy efficacy. By combining imaging-guided delivery, on-demand NO sensitization, and HSP70 inhibition, this nanotheranostic strategy offers a coordinated approach to improving treatment outcomes in CC.
We assessed the association between dolutegravir (DTG)-based antiretroviral therapy and kidney abnormalities among young people living with HIV in Kampala, Uganda. Cross-sectional albumin-creatinine ratio (ACR), proteinuria, and estimated glomerular filtration rate (eGFR) were measured. Among 483 participants, the mean serum creatinine was higher (0.68 vs. 0.59) and creatinine-based eGFR lower (118.8 vs. 113.9), among those on TDF/DTG. Cystatin C-based eGFR, prevalences of elevated ACR (9.6% vs. 13.0%), proteinuria (28.3% vs. 30.2%), and eGFR < 90 ml/min/1.73 m² (40.1% vs. 46.9%) were similar. Kidney abnormalities were not associated with regimen, supporting the need for longitudinal studies to clarify progression risk.