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The proliferation and sustained detection of novel psychoactive benzodiazepines in forensic and clinical toxicology, combined with their potential for adverse events, poses an enduring threat to public health and safety with complex characteristics and challenges unique from other subclasses of novel psychoactive substances (NPS). This study aimed to systematically review the published effects, observations, and toxicological data from postmortem and human performance studies (including clinical, driving under the influence of drugs (DUID), and drug-facilitated crimes (DFC)) involving NPS benzodiazepines from 2021 to 2025. The challenges this class of compounds present to clinicians, toxicologists, and medical professionals were also addressed, including both analytical and interpretative challenges. Literature reviews were performed in PubMed, Google Scholar, Google Search, toxicology journals, and conference abstract proceedings using search terms such as "NPS benzodiazepines," "designer benzodiazepines," and compound specific searches; authoritative websites such as NPS Discovery, National Forensic Laboratory Information System, and the European Union Drug Agency were also consulted. A total of 259 NPS benzodiazepine-related studies were identified including 29 postmortem, 15 DUID, 27 clinical, and 5 DFC studies detailed in this review. NPS benzodiazepines were widely pervasive in both postmortem and human performance cases with overlapping toxic and recreational concentrations; often involving polysubstance use with other central nervous system depressants and stimulants. Unique clinical presentations, observed effects, and autopsy findings were also reported for NPS benzodiazepines. This review provides an updated, consolidated resource to support toxicologists and clinicians in interpretation, emerging risk assessment, and evolving challenges associated with NPS benzodiazepines across postmortem and human performance settings.
In Malaysia, aviation accidents fall under the jurisdiction of the Air Accident Investigation Bureau (AAIB) and are subject to statutory investigation. The primary aim of these investigations is to reconstruct crash events, determine root causes, and recommend safety improvements, including modifications to aircraft design, to enhance survivability and prevent future incidents. Aviation pathology plays a crucial role in this process by confirming victim identities, establishing causes of death, contributing to crash sequence reconstruction, and ensuring a comprehensive analysis of human factors. This review examines key aspects of aviation pathology, including injury mechanisms and patterns, the forensic autopsy approach for aviation fatalities, and the correlation between injury findings and crash dynamics. Understanding these elements is essential for improving aviation safety and refining investigative methodologies.
Multiple interconnected parameters contribute to bone strength. The assessment of bone strength and fragility, which are crucial measures of bone health, is essential not only in the clinical setting for diagnosis but also in forensic medicine, where it aids in identifying the underlying cause of various bone traumas. This study aimed to examine the correlation between the bone strength parameters cortical thickness index (CTI), cortical bone thickness (CBT), endocortical area (ECA), and endocortical volume (ECV), and age, body mass index (BMI), and volumetric bone mineral density (vBMD) in a female autopsy-population. Measurements were performed on the left femur and derived from 103 post-mortem computed tomography (PMCT) images of females aged 24-95 years. Linear regression analysis showed a significant correlation between age and all the bone parameters, except for ECA. When BMI was accounted for, there was still a significant correlation between age and CTI, vBMD, CBT, and ECV. Individuals in the underweight and normal weight categories demonstrated lower CTI and CBT values than those classified as obese. A significant correlation was observed between vBMD and the four bone parameters CTI, CBT, ECV and ECA. This study highlights the importance of considering various bone strength parameters and their relationship with age, BMI, and vBMD in assessing bone strength.
In forensic practice, the reconstruction of criminal behavior and charge determination are often entrusted solely to law enforcement, with forensic medicine playing a marginal, confirmatory role. Nonetheless, accurate injury analysis remains fundamental and, in specific contexts, may be decisive. The authors present a case that underscores the crucial role of interdisciplinary forensic collaboration - particularly between forensic pathologist and ballistics expert - in the reconstruction of the event dynamics and in supporting judicial decision-making aimed at the accurate charge determination of the event. On the shutter of a bookstore a ticking object wrapped in white cloth was discovered. A bomb disposal technician intervened to neutralize the device. During the operation, the device exploded, causing the amputation of the left hand, loss of the right eye and bilateral thigh lacerations with retained foreign bodies. The technician claimed the explosion occurred spontaneously. Based on this, charges included mass murder, considering the alleged explosive power. A multidisciplinary forensic analysis integrating crime scene investigation, injury pattern review, radiological imaging and explosive residue testing was conducted. A detailed injury analysis and technical assessment of the device disproved this version, redefining the victim's position at the time of detonation and substantially reducing the inferred explosive capacity. This led to the reclassification of some criminal charges.
Non-communicable diseases are a growing public health challenge, shaped not only by biological predispositions but also by geo-demographic, socioeconomic, psychological, and lifestyle factors. A comprehensive understanding of these determinants is essential for developing targeted public health strategies. This study aimed to examine the multifactorial determinants of individual health status by analyzing geo-demographic, socio-economic, behavioral, psychological, and lifestyle variables. Data were collected from 4,010 participants (age: 37.2 ± 15.4 years; 59.5% female) across 10 Mediterranean and neighboring countries using the multinational MEDIET4ALL e-survey. Health status was categorized as healthy, at-risk, or with diseases. Multinomial logistic regression, Quade's Rank ANCOVA and series of multiple regression models were conducted. Collectively, around 25% of respondents declared to be at-risk of or with known disease. BMI emerged as the strongest negative predictor of health status (β = -0.145), with both obesity and underweight significantly increasing the odds of being at risk (OR = 1.8 and 5.2, respectively) and having diseases (OR = 2.2 and 11.9, respectively). Other significant negative predictors included psychological distress (notably anxiety, β = -0.091), insomnia (β = -0.084), alcohol consumption (β = -0.053), and prolonged sitting time (β = -0.037). Conversely, life satisfaction was the strongest significant protective factor (β = 0.066), followed by higher education, better sleep quality, and adherence to the Mediterranean Diet and lifestyle (β = 0.034 to 0.050). Socio-economic disparities, including employment status (β = -0.045) and living environment (β = -0.031), also significantly influenced health outcomes with rural environment and employed individual showing lower odd ratios of being at-risk and/or having diseases (p < 0.001). Furthermore, individuals residing in Mediterranean regions, females, married or cohabiting individuals, and non-smokers exhibited significantly lower odds of being at-risk or having diseases (p < 0.05). While gender remained a significant predictor in the final refined comprehensive regression model (β = -0.049), marital status lost significance, suggesting that its protective effect may be mediated by psychological well-being and health-related behaviors. These findings highlight the complex interplay of lifestyle, mental health, and socio-environmental factors in determining health outcomes, while emphasizing the urgent need for multi-level public health interventions, including policies promoting physical activity, healthy eating, mental well-being, and equitable healthcare access. Future research should employ longitudinal designs to establish causal relationships and guides preventive strategies.
Disseminated tuberculosis, specifically tuberculous pericarditis, represents a diagnostically challenging yet critical contributor to unexpected death in forensic practice, particularly among young migrants from endemic regions who lack access to healthcare. Forensic histopathology is often the first and only means to identify this reportable disease. Without a systematic forensic autopsy including histology, this death would have been certified as "undetermined". The present case emphasizes the necessity of improved TB screening initiatives for high-risk populations such as recent immigrants from endemic nations. We present the case of a 24-year-old male immigrant of Black ethnicity who was referred for forensic autopsy after an unexpected death. The individual was pronounced dead upon arrival at the hospital. No previous clinical history or antemortem medical data were available. External examination revealed a slim, cachectic physique with a slumped posture. Autopsy examination showed granulomatous pericarditis and extensive purulent lung abnormalities, with no signs of trauma or toxication. Histopathological analysis of the pericardium showed multinucleated giant cells, lymphocytes, epithelioid cells, and central necrosis, all of which are indicative of tuberculous pericarditis. Additionally, lung tissue examination revealed disseminated tuberculous involvement with granulomatous inflammation. The cause of death was determined to be disseminated tuberculosis, which resulted in respiratory and circulatory collapse, despite the absence of documented premortem symptoms or medical history. This case highlights the indispensable role of systematic autopsy and histopathological examination in identifying undiagnosed tuberculosis in medicolegal investigations, especially in high-risk populations. Forensic pathology enhances mortality data quality, enables contact tracing to prevent transmission, and informs targeted screening programs to strengthen TB control.
Methamphetamine use during pregnancy is an increasing public health concern with potentially severe consequences for fetal development and survival. This study aimed to evaluate the sociodemographic, autopsy, histopathological, and toxicological findings of fetal deaths with toxicologically confirmed postmortem methamphetamine detection. This retrospective autopsy-based descriptive study included 28 fetal death cases referred from multiple regions across Türkiye and evaluated by the First Specialization Board of the Council of Forensic Medicine between 2020 and 2024. Cases were selected on the basis of methamphetamine detection in postmortem fetal blood together with forensic assessment of methamphetamine exposure/toxicity as a primary or contributory factor in death. Macroscopic autopsy findings were integrated with histopathological and toxicological analyses. The mean gestational age was 29.11 ± 5.44 weeks, and 53.6% of cases were female. The mean maternal age was 29.85 ± 4.58 years; 78.6% of mothers were primigravida, and 78.6% lacked regular prenatal care. In 60.7% of cases, fetal expulsion or discovery occurred in the home setting. Small for gestational age was identified in 57.1% of cases. Histopathological findings included placental infarction (10.7%), chorioamnionitis (17.9%), funisitis (3.6%), and perinatal pneumonia (14.3%). Median postmortem fetal blood methamphetamine and amphetamine concentrations were 0.126 mg/L (IQR: 0.057-0.406) and 0.020 mg/L (IQR: 0.008-0.044), respectively. Fetal deaths with toxicologically confirmed postmortem methamphetamine detection highlight the serious clinical and medicolegal consequences of substance use during pregnancy. The high frequency of inadequate prenatal care and home-based fetal expulsion or discovery underscores important gaps in the early identification and referral of vulnerable pregnant women and supports the need for coordinated obstetric, psychiatric/addiction, forensic, and social support pathways.
The Mediterranean lifestyle is increasingly recognized as a multidimensional determinant of health. However, cross-country comparisons using harmonized instruments remain limited. This study aimed to provide a comprehensive country-by-country comparison of Mediterranean lifestyle adherence and associated psychosocial and lifestyle correlates across 10 Mediterranean and neighboring countries participating in the MEDIET4ALL project. Cross-sectional data were collected from 4,010 participants (age: 37.2 ± 15.4 years; 59.5% female) using the multinational MEDIET4ALL e-survey. Mediterranean lifestyle adherence was assessed using the MedLife Index and its three domains. Psychosocial status, sleep characteristics, physical activity, sedentary behaviour, social participation, and technology use were evaluated using validated instruments. Significant cross-country differences were observed in global MedLife adherence and across all domains (p < 0.001, η 2 = 0.07-0.11), as well as in the distribution of adherence categories across countries (χ 2 = 113.936, p < 0.001). Spain consistently showed higher MedLife scores than several countries (z = 3.42-8.12, adjusted p < 0.001-0.02) and tended to display higher proportions of participants in the high-adherence category, whereas lower adherence was observed in multiple non-Mediterranean and North African contexts. Psychological distress differed significantly between countries (p < 0.001), with several contexts showing elevated depression, anxiety, or stress levels (z ≈ 3.57-14.29, adjusted p < 0.001-0.05). Life satisfaction and social participation also varied substantially (194.86, p < 0.001), with some European countries reporting lower social participation compared with Mediterranean and neighboring contexts (z = 3.79-9.31, adjusted p < 0.001-0.05). Sleep parameters and insomnia severity differed markedly across countries (H = 66.64-198.63, p < 0.001), with less favourable sleep profiles observed in several contexts (z ≈ 3.28-12.82, adjusted p < 0.001-0.05). Physical activity and sedentary behaviour showed pronounced variability (p < 0.001), with Jordan reporting the lowest physical activity levels and Tunisia lower sedentary time. Mediterranean lifestyle adherence and its psychosocial and behavioural correlates vary substantially across countries, reflecting distinct constellations of sociocultural, socioeconomic, and lifestyle factors rather than dietary patterns alone. These findings highlight the importance of multidimensional, context-sensitive approaches to Mediterranean lifestyle promotion and provide a descriptive framework to inform tailored public-health strategies and future longitudinal and intervention research.
Klebsiella pneumoniae is a leading cause of healthcare-associated infections worldwide, yet its population structure and transmission dynamics remain largely uncharacterized in New Zealand hospitals. We conducted a 15-month prospective genomic surveillance pilot at Wellington Regional Hospital, embedding Oxford Nanopore MinION sequencing directly within the diagnostic laboratory. Clinical and screening isolates (n=157) underwent on-site sequencing and genotyping. Following quality control, 121 (77%) high-quality genomes (118 complete assemblies) were analysed for diversity, antimicrobial resistance (AMR), virulence loci and plasmid content and assessed for evidence of in-hospital transmission. The cohort covered many ages (0 to 95 years), with nearly half of the patients aged ≥65 years. The local K. pneumoniae population was highly diverse, comprising 75 distinct sequence types (STs), of which 68% were single-isolate STs. Although a few lineages recurred intermittently (e.g. ST253 and ST17), no clone showed evidence of patient-patient transmission. Plasmid reconstructions showed backbones dominated by F-type, Col, and mosaic multi-replicon elements. Acquired AMR genes were plasmid-borne in 35/118 complete genomes. Chromosomes mostly carried intrinsic determinants typical of K. pneumoniae: bla SHV (intrinsic ampicillin resistance) and fosA and oqxAB (which may raise minimum inhibitory concentrations but, in their intrinsic forms, do not exceed clinical breakpoints). Few isolates carried markers of K. pneumoniae virulence plasmids (iuc/iro siderophores and rmpA/rmpA2; Kleborate virulence score ≥3), and none showed convergence of virulence and acquired AMR. This study shows that prospective, hospital-based nanopore sequencing is feasible in routine diagnostic settings and can deliver high-resolution genomic intelligence for infection prevention and control. In this setting, K. pneumoniae isolates arose from a genotypically heterogeneous background without evidence of patient-patient transmission. This pilot establishes a genomic baseline for K. pneumoniae in a major New Zealand hospital and supports a trigger-based framework for early detection of high-risk clones before they become established.
Accurate classification of postmortem decomposition stages is a critical step in estimating the postmortem interval (PMI) and tracing the initial decomposition environment. Research on the decomposition staging methodological system is gradually shifting from empirical observation to the establishment of systems based on multidimensional quantitative indicators. This paper focuses on two key pathways, "macroscopic morphological evolution" and "microscopic molecular succession", and systema-tically reviews the evolutionary patterns and applicability of the decomposition staging system in three typical environmental media: surface exposure, burial, and aquatic systems. It also summarizes research progress in constructing stage classification models utilizing microbiome and metabolomic features. Furthermore, it highlights the integrated application of decomposition characteristic quantification techniques, multi-omics data integration, and machine learning algorithms in decomposition analysis systems. It analyzes the prospects and challenges of applying these approaches to build a standardized and practical decomposition staging system, aiming to provide theoretical support for establishing a decomposition staging system with high accuracy and strong adaptability to different environments. 准确划分尸体腐败阶段有利于死亡时间推断与初始腐败环境的溯源。尸体腐败阶段分期方法体系的研究正逐步从经验判断转向基于多维量化指标的建立。本文聚焦于“宏观形态演变”与“微观分子演替”两条路径，系统综述地表暴露、埋葬与水体三类典型环境介质中尸体腐败分期体系的演化规律与适用特征，梳理总结利用微生物组学与代谢组学特征构建分期判别模型的研究进展，重点探讨腐败特征量化技术、多组学数据整合以及机器学习算法在腐败分析体系中的融合应用，并分析其在构建标准化、可实战化腐败分期体系中的应用前景与挑战，以期为建立精度高、环境适应性强的尸体腐败分期体系提供理论支撑。.
To assess whether thoracic and abdominal skin lesions predict CT-detected intrathoracic and intra-abdominal injuries in adults with blunt torso trauma. This single-center retrospective study included 1523 adults (June 2014-June 2024) with blunt thoracic and/or abdominal trauma who underwent both chest CT and contrast-enhanced abdominal CT. Skin lesions and their anatomical locations were extracted from forensic examination forms. Outcomes were any pathological finding on chest CT and abdominal CT. Associations were evaluated using logistic regression, and discrimination was assessed using ROC curves (AUC). Median age was 42 (IQR 27-59) years, and 69.7% were male. Traffic accidents were the most common mechanism (45.9%). Chest CT pathology was present in 24.8% and abdominal CT pathology in 10.6%. Any thoracic skin lesion was associated with higher odds of chest CT pathology (52.6% vs 19.7%; OR 4.52, 95% CI 3.38-6.04; AUC 0.615). Any abdominal skin lesion was associated with higher odds of abdominal CT pathology (33.9% vs 7.6%; OR 6.22, 95% CI 4.28-9.06; AUC 0.639). Region-specific lesion models showed limited discrimination (AUC ∼0.50-0.55). Skin lesions are strongly associated with CT-detected intrathoracic and intra-abdominal injuries in blunt torso trauma, but their standalone discriminative performance is limited; they should be interpreted as supportive risk markers rather than definitive screening criteria.
Misinterpretation of insect-related postmortem artifacts as traumatic injuries remains a critical diagnostic challenge in forensic pathology, particularly in enclosed indoor environments. We report a case involving a deceased adult male found indoors with multiple superficial perioral and facial lesions initially suspected to be perimortem trauma. However, based on photographic evaluation by a forensic entomologist, the lesions were identified as likely caused by postmortem activity of Monomorium pharaonis (pharaoh ants), a synanthropic species commonly found in human dwellings. Numerous ant eggs and larvae were subsequently discovered in the folds of the decedent's clothing, and the lesion morphology was consistent with postmortem necrophagy rather than true antemortem injury. This case represents the first formally documented instance in South Korea in which pharaoh ant-induced artifacts led to the avoidance of an erroneous forensic interpretation of violence. The findings highlight the importance of considering insect activity in the differential diagnosis of soft tissue lesions and demonstrate how inconspicuous insect activity can mimic violence-related injuries. Integration of entomological expertise-particularly early in scene evaluation-is essential to prevent unnecessary autopsies and medicolegal errors.
Nitazenes constitute a structurally diverse class of non-fentanyl synthetic opioids that have rapidly emerged in the European illicit drug market since 2019. Bridging analytical, seized drug epidemiology, and interpretative gaps would support meaningful interpretation of nitazene-related deaths. This study presents a fit-for-purpose LC-MS/MS method for the quantitation of six nitazenes, etazene, isotonitazene, N-pyrrolidino isotonitazene, metonitazene, N-pyrrolidino metonitazene, and protonitazene in postmortem blood. The method was applied to analyze 57 nitazene-positive autopsy cases received between December 2020 and December 2024 by the Swedish National Board of Forensic Medicine. During this period, metonitazene (n = 38) and protonitazene (n = 10) were the most encountered nitazenes, with femoral blood concentrations in mono-intoxicated cases ranging from 0.3 to 34 ng/g and 1.7 to 4.9 ng/g respectively. Complementary in vitro MOR activation studies using AequoScreen® assays demonstrated that these nitazenes possess potencies (0.17-6.0 nM) and efficacies comparable to, or exceeding, those of fentanyl. The predominance of metonitazene prompted further investigation into its metabolism and stability profile, where analysis of authentic postmortem cases indicated the presence of three possible metabolites (N-desethyl, acetamido, 5-amino metonitazene) alongside other amino-containing degradation products. Further studies elucidating true metabolites from postmortem or storage-related breakdown products would support interpretation of nitazene exposure in casework. These findings provide an overview of nitazenes in Swedish forensic casework and address a critical gap in region-specific data, underscoring the need for sustained analytical vigilance and proactive toxicovigilance strategies to ensure timely detection and accurate interpretation of nitazene-related mortalities in an evolving drug landscape.
Forensic entomotoxicology, which was first mentioned in a publication in 1994, focuses on the detection of drugs and toxins in necrophagous insects to provide valuable information in a variety of areas. This discipline faces fundamental limitations as its findings are often not easily transferable to practical contexts, thereby necessitating a case-specific approach for effective application. To overcome these challenges, a systematic review of scientific literature available on 31 December 2024 was conducted in order to summarise strengths and weaknesses of forensic entomotoxicology in accordance with the PRISMA guidelines. After 81 relevant sources were selected, four main lines of research in entomotoxicology were identified: 1) effects of exogenous substances on larvae and, consequently, how the estimated minPMI (minimum Post-Mortem Interval) should be adjusted, 2) identification of cause of death, 3) study of the impact of exogenous substances on the environment using larval masses and 4) possible methods for analysing larvae to identify the substances they contain. Overall, findings are heterogeneous and sometimes contradictory, indicating that exogenous substances can influence larval development and be detected in entomological samples, but in ways that are strongly species-, substance- and context-dependent and not yet robust enough for straightforward extrapolation to casework. By critically synthesising these issues, this review clarifies the main strengths and recurring limitations of forensic entomotoxicology and indicates when its use may be informative, when it should be interpreted with caution, and which methodological issues need to be addressed in future research.
Muscle atrophy, characterized by progressive loss of muscle mass and function, is driven by muscle-specific E3 ligases MAFbx and MuRF1. While transcriptional regulation of E3 ligases is documented, the mechanism of their regulation by the ubiquitin-proteasome system remains unclear. This study aims to identify a deubiquitinase (DUB) regulating these E3 ligases and reveal the mechanisms underlying the mitigation of muscle atrophy through inhibition of the discovered DUB. Differentiated C2C12 myotubes were screened using siRNAs to identify DUB genes that can regulate muscle atrophy. Muscle fibre cross-sectional area (CSA), grip strength and gene expression (MAFbx, MyoD, etc.) were evaluated in muscle atrophy-induced mouse model. Human translational relevance was analysed using GTEx skeletal muscle data. We identified that OTU DUBs family genes are increased (log2 FC > 1, p < 0.05) in DEX-induced muscle atrophy. Pharmacological (ubiquitin isopeptidase inhibitor I, G5) and genetic inhibition of YOD1 alleviated DEX- and denervation-induced muscle atrophy by MAFbx destabilization. The UBX domain of YOD1 was found to interact with the LZ domain of MAFbx, and YOD1 stabilized the MAFbx protein by removing polyubiquitin chains at lysine 48 in MAFbx. In in vivo mouse models, G5 treatment effectively ameliorated DEX- or NTX-induced muscle atrophy. Specifically, G5 increased grip strength by 37.64% (DEX, p < 0.0001) and 36.37% (NTX, p < 0.01), while muscle fibre size was improved by 35.85% (DEX, p < 0.01) and 30.76% (NTX, p < 0.0001). These improvements were accompanied by the restoration of MyoD and eIF3-f expression. Consistently, GTEx-based analysis revealed that high YOD1 expression in human skeletal muscles is significantly associated with an increased proportion of smaller fibres (< 2000 μm2), correlating with enriched proteostasis (NES = 1.51)-related and muscle development (NES = -1.44)-related transcriptional signatures. Our study indicates that YOD1 inhibition destabilizes MAFbx protein levels, leading to protection against DEX- and denervation-induced muscle atrophy. Integration of human GTEx data further supports the translational relevance of YOD1 as a regulator of muscle fibre homeostasis. This study provides new insights into the post-translational regulation of muscle-specific E3 ligases and presents evidence showing that targeting YOD1 is a promising therapeutic approach for the prevention and treatment of muscle atrophy.
Ulcerative colitis (UC) is characterized by complex spatiotemporal heterogeneity, which poses significant challenges for effective treatment. Herein, we constructed DS-HDLTQs, a core-shell nanodelivery platform with dynamic dual-targeting capabilities. This platform utilizes hyaluronic acid (HA) and D-mannose (D-Man) to target acute inflammation and promote repair. It also features a dopamine-alginate (DA-SA, or DS) shell to achieve pH-responsive release specifically at colonic lesions. In animal experiments, DS-HDLTQs achieved 83.3% mucosal healing in just 7 days, significantly outperforming single-targeting systems. The DA-SA protective layer ensures pH-responsive release in the colon with an efficiency of up to 92.7%. Such therapeutic enhancement is driven by three synergistic mechanisms: molecular functional synergy (restoring antioxidants), spatiotemporal targeting-pathological process synergy (accelerating barrier reconstruction), and immune-epithelial repair synergy (promoting macrophage polarization and epithelial regeneration). DS-HDLTQs demonstrated a 12.7-fold increase in drug concentration at the lesion site. This design resolves the core contradiction between dynamic pathology and oral delivery efficiency, providing a new paradigm for UC treatment and potential applications in other inflammatory diseases.
Cholangiocarcinoma (CCA) comprises a heterogeneous group of biliary malignant tumors with poor prognosis and limited therapeutic options. Recent studies have highlighted the role of the immune system in the development and progression of intrahepatic CCA (iCCA). In this study, we investigated the role of the scavenger receptor MARCO in iCCA. Employing transcriptomic, spatial proteomic and histological analyses of human samples, MARCO was found on a specific subtype of tumor-associated macrophages linked to immunosuppression and extracellular matrix remodeling within the tumor microenvironment. High MARCO expression in human iCCA tumors correlated with worse overall survival, T cell dysfunction and increased collagen deposition. In line with this, MARCO expression was associated with a TH2-skewed immune response and was increased in macrophages exposed to IL-4 and IL-13. Marco-/- mice were protected against iCCA development, exhibiting reduced tumor burden, fewer innate immune cells related to TH2 responses and attenuated fibrosis. Moreover, Marco-/- mice exhibited lower levels of immunosuppressive markers on macrophages and cytotoxic T cells, resulting in improved overall survival and reduced lung metastases in an orthotopic tumor model. The use of an anti-MARCO antibody further reduced tumor volume in wild-type mice. This study identifies MARCO as a key regulator of immunosuppression, fibrosis and tumor progression in iCCA, and supports its potential as a novel therapeutic target for macrophage-directed immunotherapy.
Immune checkpoint inhibitors like pembrolizumab exhibit variable efficacy in metastatic gastric cancer (GC). This study aimed to identify molecular drivers of pembrolizumab response, explore mechanisms of immune checkpoint inhibitors (ICIs) efficacy, and develop a prognostic signature. Transcriptomic analysis of pembrolizumab-treated GC (TIGER database) identified 165 response-associated differentially expressed genes (DEGs). Functional annotation and single-cell RNA sequencing (scRNA-seq) data from the Gene Expression Omnibus (GEO) revealed that responder-upregulated genes (R-DEGs) were enriched in immune activation pathways and mainly localized to CD8 + T/NK cells. In contrast, non-responder-upregulated genes (D-DEGs) were linked to extracellular matrix (ECM) remodeling and mainly expressed in fibroblasts/endothelial cells. CellChat analysis demonstrated that key DEGs mediate immune-stromal crosstalk via MHC-I and collagen/laminin signaling. A prognostic signature (Lasso-StepCox[forward] Riskscore; LSR: APOD, APOH, BATF2, GJA1, MAGED1, SLC5A1, SLCO2A1, VWF, VCAN) was derived and validated in four independent GC cohorts from the GEO and Cancer Genome Atlas (TCGA) database. Multi-omics analyses showed that LSR-high tumors exhibited aggressive clinicopathological features, increased stromal components, reduced cytotoxic immune infiltration, diminished tumor mutational burden (TMB), and poorer prognosis. Immunohistochemistry (IHC) and spatial transcriptomics in GC showed that stromal VWF/VCAN expression correlates with reduced CD8⁺ T cell granzyme B expression, suggesting T cell dysfunction. High VWF expression in GC predicted poor survival, and a combined VWF/VCAN score showed enhanced prognostic stratification. This study highlights stromal-immune crosstalk as a driver of pembrolizumab resistance and provides a signature as a clinical tool for prognosis and personalized therapy in metastatic GC.
To examine the feasibility, learning effects, stability, and validity of mobile cognitive assessments (MCAs) among individuals with stroke. Longitudinal observational study utilizing frequent, brief, repeated, in vivo self-administered mobile assessments of cognitive functions. Everyday life settings. 20 participants with mild-to-moderate stroke (mean age: 55.5 years; 60% men; 45% Whites; 70% ischemic stroke). Not applicable. Over 14 days, participants used smartphones to complete a digital assessment protocol. The protocol included six ecological momentary assessment (EMA) surveys on self-reported health status, along with four mobile cognitive assessments (MCAs), each administered twice daily. MCAs included the Mobile Stroop Color Word Test (M-SCWT), Mobile Spatial Memory Test (M-SMT) Forward and Backward, Mobile Trail Making Test Parts A and B (M-TMT A & B), and Mobile Tower of Hanoi Test (M-THT). Thus, participants completed the entire 14-day protocol with up to 84 EMA surveys and 28 MCA tasks. Participants also completed a lab-based neuropsychological test battery during the initial lab visit. High adherence rates were observed (77% for M-TMT B to 85% for M-SCWT) during repeated administration of MCAs. Learning effects were observed in nearly all tests (p <0.024 to 0.001), except for the M-SMT Forward. Stability estimates across MCAs ranged from poor to moderate, with higher reliability for M-SCWT and lower stability for M-TMT A and M-THT. Agreement between MCAs and corresponding neuropsychological tests varied by domain, with stronger concordance for memory tasks and weaker agreement for inhibition and cognitive flexibility tasks. These findings are the first to demonstrate the feasibility and initial psychometric properties of smartphone-based assessments of cognitive function in individuals with stroke in daily life. MCAs may serve as a promising complement to traditional neuropsychological assessments, with further refinement needed to maximize their impact on rehabilitation research and practice. Not applicable; this study is not defined as a clinical trial.