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PubMed2026

CAR-T Cell Therapy: Manufacturing Platforms and Clinical Consequences.

Chimeric antigen receptor (CAR) T-cell therapy has transformed hematological cancer care, yet variability in efficacy, durability, and safety cannot be explained solely by antigen selection or patient factors. We propose that manufacturing platforms are active biological determinants of outcome. Viral vectors, used in all licensed products, provide stable genomic integration and durable expression but are limited by cost, cargo capacity, and centralized production. Nonviral strategies, including transposons, CRISPR knock-ins, and messenger RNA delivery, enable faster, less-expensive manufacturing with larger payloads, while introducing distinct safety and persistence profiles. This review presents a three-layer mechanistic framework that reframes manufacturing as biology: integration biology determines genomic risk and transgene stability; clonal fitness shapes persistence, dominance, and exhaustion; and epigenomic imprinting, influenced by gene transfer method, cytokines, and culture stress, preconfigures functional trajectories. Clinical observations link platform choice to immune recovery, where prolonged B-cell aplasia and delayed T-cell reconstitution contribute to infection-related nonrelapse mortality, and hematopoietic reserve at apheresis emerges as a practical predictor. Finally, manufacturing is positioned as the key to democratizing cell therapy. Decentralized, nonviral production aligned with regulatory standards may enable equitable access and transition CAR-T therapy from innovation to sustainable global care.

Humans↗

PubMed2026

DNM1L depletion leads to accelerated heteroplasmy shifting of m.10191C allele through ATG7-dependent pathways.

Nucleotide composition bias in mitochondrial DNA (mtDNA) makes the heavy strand prone to form a DNA secondary structure called a guanine quadruplex (G4). This secondary structure has been shown to inhibit polymerase processivity in vitro. We previously identified pathogenic mtDNA variants that lead to increased G4-forming propensity, including a T to C mutation at m.10191 (m.10191 T > C) that causes Leigh syndrome. Cells treated with G4 binding agent (G4BA) berberine show a reduction in m.10191C pathogenic heteroplasmy levels. To help better understand the underlying mechanism behind berberine-induced heteroplasmy shift, we examined the relationship between mitochondrial fission and berberine-mediated shift. Here we show that knockdown of the fission factor DNM1L leads to an accelerated heteroplasmy shift towards the healthy mtDNA allele, lowering m.10191C by 10% in 3 weeks, compared to the 5 weeks required for berberine alone. The specific mechanism involves ATG7, as knockdown of ATG7 is able to partially delay this accelerated heteroplasmy shift. Taken together, we show that DNM1L knockdown is able to accelerate berberine-induced m.10191C heteroplasmy shifting through an autophagy-related mechanism.

Humans↗

PubMed2026

Thermal analysis techniques for microplastic mass quantification: Methodological challenges and standardization needs.

Microplastics (MPs, 1 μm-5 mm) and nanoplastics (NPs, <1 μm) are ubiquitous contaminants requiring standardized quantification methods. This systematic review evaluates thermal analysis techniques for mass-based MP detection, including pyrolysis-gas chromatography-mass spectrometry (Py-GC-MS), thermogravimetry-MS (TGA-MS), thermal extraction desorption-GC-MS (TED-GC-MS), and differential scanning calorimetry (DSC). Database searches (Web of Science, from inception to December 1, 2025) following PRISMA guidelines identified studies across seven environmental matrices (water, soil/sediment, atmosphere, biota, human tissues). We identify critical standardization gaps: inconsistent marker ion selection, unvalidated conversion factors for tire and road wear particles (TRWPs), and the absence of certified reference materials for complex matrices. Py-GC-MS demonstrates versatility but suffers from lipid interference in biological samples; TED-GC-MS offers superior sensitivity (sample capacity ∼200× Py-GC-MS) but lacks real-time chromatographic monitoring. To advance data comparability, we propose: (i) harmonized ion selection hierarchies based on specificity-sensitivity balance, (ii) matrix-specific TRWP quantification protocols, and (iii) inter-laboratory validation using environmental reference materials. This review provides a methodological roadmap for standardizing thermal analysis in MP research.

Humans↗

PubMed2026

Messaging Strategies for Tobacco Prevention and Cessation Among People with Depression: A Scoping Review.

INTRODUCTION: Depression is strongly associated with higher tobacco use and lower quit rate; few communication campaigns have been designed with these mental health factors in mind. This scoping review compiles existing research on tobacco prevention and cessation messaging involving people with depression to identify gaps and opportunities for future message development. METHODS: Sources included PubMed, PsycINFO, Scopus, Academic Search Premier, and ProQuest Central (November - December 2024). The 55 studies included examined tobacco prevention or cessation messages and measured depression, depressive symptoms, or mental health as a primary outcome or analytic covariate. Study characteristics, target population, delivery format, message content, theoretical frameworks, outcomes, and gaps were extracted. RESULTS: RCTs made up half (51%) of the included studies, and most (78%) were conducted in the U.S. Nearly half (46%) required participants to have a mental health condition. Interventions most often used interactive (65.5%) or text-based (47.3%) communication and focused on tobacco cessation (89%) rather than vaping (9%). Common outcomes included feasibility or acceptability (37.7%) and point prevalence abstinence (37.7%). Mental health-specific messages showed mixed effectiveness. CONCLUSIONS: Despite progress in integrating mental health into tobacco messaging, targeted interventions for people with depression remain limited. Few studies tested long-term outcomes or used biochemical verification; many relied on untargeted generalized messaging.

Journal Article↗

PubMed2026

Targeted Nanoparticle Delivery CRISPR/Cas9: overcoming biological barriers, enhancing stability, and improving therapeutic precision.

Clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) has emerged as a promising gene-editing platform for genetic disorders; however, its in vivo application remains limited by low delivery efficiency and biological barriers. Many CRISPR payloads fail to reach target sites due to extracellular degradation, immune clearance, and intracellular trafficking limitations. This review examines the interplay between biological barriers and nanoparticle engineering strategies for CRISPR/Cas9 delivery. A barrier-oriented engineering approach is proposed as a central framework, encompassing ligand-based surface modification for enhanced targeting and uptake, improved circulation stability via PEGylation and biomimetic coatings, and optimized payload release through endosomal escape strategies. Stimulus-responsive nanoparticle systems further enable spatiotemporal control over payload release. Nuclear targeting strategies, including optimization of nuclear localization signals (NLS) and exploitation of endogenous trafficking pathways, are highlighted as key factors for improving genome-level editing efficiency. Despite these advances, major challenges-including limited intracellular delivery efficiency, insufficient targeting precision, and safety concerns-continue to hinder clinical translation. Future directions highlight artificial intelligence-driven nanoparticle design, personalized delivery systems, and next-generation CRISPR platforms. Overall, an integrated, barrier-oriented engineering strategy is essential for advancing CRISPR/Cas9 delivery toward clinical applications, ultimately advancing global good health and well-being.

CRISPR/Cas9↗

PubMed2026

Sarcomas: Research on Ultrarare Subtypes Gains Ground.

Rare cancers account for almost one fourth of all cancers. Sarcomas belong to the group of cancerous diseases with an incidence of less than 6 cases per 100,000 inhabitants. Over the past decade, activities were launched worldwide to elucidate the peculiarities of many of the more than 100 sarcoma subtypes described in the World Health Organization handbook. The major contributor to exact diagnosis is molecular pathology. The subgroup of ultrarare sarcomas (URS) poses a significant problem as each URS type has its own morphology, biology, natural history, and prognosis. In 2020, 35 international sarcoma centers agreed to standards of evaluating URS. The threshold was set to an incidence of less than 1 case per 1,000,000 inhabitants, and 77 URS subtypes were defined. Also quality criteria for centers to be selected for retrieving data to registries were consented. This issue of Cancer Epidemiology, Biomarkers & Prevention contains the first article to validate these principles of URS using the data from a nationwide cancer database. The authors from Taiwan also pointed out limitations of the approach. Combination with the national death database allowed to calculate overall survival (OS) and identified age as a significant factor for OS per URS type. These new data might foster future research on diagnosis and treatment of URS. See related article by Lee et al., p. 1654.

Humans↗

PubMed2026

The Neurological Impact of Metabolic and Bariatric Surgery: A Systematic Review of Post-Operative Neuropathic and Non-Neuropathic Complications.

Metabolic and bariatric surgery achieves durable weight loss and meaningful improvement in obesity-related comorbidities yet carries a risk of neurological complications that remains under-recognised in routine clinical practice. This systematic review, registered with PROSPERO (CRD42024591611) and conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 guidelines, searched MEDLINE, Embase, Emcare, CINAHL and Cochrane databases through September 2023 to evaluate the incidence, spectrum, timing, pathophysiology and management of post-operative neurological complications. Twelve studies comprising over 5000 patients were included. Reported incidence ranged from 1.4% to 16%, with peripheral neuropathy the most frequent manifestation. Mononeuropathies, particularly carpal tunnel syndrome, were prominent in several cohorts, while central complications including Wernicke encephalopathy occurred less commonly but with considerably greater severity. Thiamine deficiency was the predominant aetiological factor. Onset varied from days to several years postoperatively, with early presentations typically compression-related and later ones nutritionally mediated. Outcomes were generally favourable with early intervention, though severe or delayed cases were associated with persistent neurological deficits and occasional mortality. Neurological complications after bariatric surgery are heterogeneous and largely preventable, and structured post-operative follow-up with consistent adherence to nutritional supplementation remains central to reducing long-term harm.

Humans↗

PubMed2026

Ultra-high-field 7T MRI reveals neural abnormalities of attention networks in relation to cognitive impairment in hypertension.

Hypertension is a significant risk factor for cognitive impairment (CI), yet the corresponding neural network abnormalities remain underexplored. In this study, we examined the associations among global and domain-specific cognitive dysfunction, neuroimaging measures, and blood pressure in a subgroup of hypertensive patients with CI (N = 41) from a randomized controlled trial who underwent ultra-high-field 7 T MRI. Structural atrophy related to CI was localized to regions overlapping the attention networks. Both whole-brain and within-network dysfunction of the attention networks were associated with worse global cognitive performance. Notably, hyperconnectivity within key attention network hubs, including the right anterior insula and posterior intraparietal sulcus, was associated with declined processing speed in hypertensive patients, mediating the association between pulse pressure and processing speed. These findings provide new insights into the neural pathophysiology of hypertension-related CI and suggest potential network-based targets for intervention.

Magnetic Resonance Imaging↗

PubMed2026

A Multi-omics Regulated Cell Death Framework Defines Immune Phenotypes and Guides Precision Therapy in Colorectal Cancer.

Colorectal cancer (CRC) is molecularly and immunologically heterogeneous, contributing to variable treatment response. Because regulated cell death (RCD) intersects with tumor metabolism, immune regulation, and therapeutic susceptibility, we built an RCD-centered framework for CRC stratification. Multi-cohort transcriptomic data were used to infer RCD subtypes with non-negative matrix factorization (NMF) and non-negative least squares (NNLS). Genomic, bulk RNA-seq, single-cell RNA-seq, and spatial transcriptomic datasets were integrated to characterize subtype-associated biology. Machine-learning models were developed for immunotherapy response and survival-risk estimation. Candidate compounds were screened by GDSC2-based drug-sensitivity modeling and molecular docking, and FSTL3 was functionally assessed in vitro. The framework separated CRC samples into two RCD-related phenotypes resembling immune-hot and immune-cold states. RCD1 showed immune activation and higher mutational burden, whereas RCD2 showed immune-suppressed features, intratumoral heterogeneity, and aggressive biology. RCD-associated signatures showed potential for predicting immunotherapy response and survival risk. Dasatinib was prioritized for immune-cold, high-risk tumors, with preliminary evidence supporting its activity in CRC cells, while functional assays suggested a role for FSTL3 in growth, invasion, epithelial-mesenchymal transition, and apoptosis regulation. These findings suggest that RCD-based multi-omics analysis may refine CRC stratification and help generate therapeutic hypotheses.

Colorectal cancer↗

PubMed2026

Longitudinal Neurocognitive Changes for Patients With Hematologic Malignancies Undergoing Hematopoietic Stem Cell Transplantation: A Systematic Review With Structured Narrative Synthesis.

OBJECTIVES: Neurocognitive changes in hematological malignancies (HM) and as a sequela of hematopoietic stem cell transplantation (HSCT) remain under-recognized. These changes may substantially affect patients' quality of life. Therefore, this review systematically evaluated longitudinal neurocognitive changes in patients with HM undergoing HSCT. METHODS: Following PRISMA guidelines, PubMed, Scopus, and CINAHL were searched on October 30, 2025. Longitudinal studies assessing neurocognitive changes in patients with HM undergoing HSCT, with or without healthy controls, were included. Risk of bias was assessed using an adapted National Institutes of Health quality assessment tool for before-after studies. Effect sizes with 95% confidence intervals were calculated to quantify changes in neurocognitive performance. RESULTS: Nine of 2012 studies met the inclusion criteria, with overall moderate study quality. Improvements may occur post-HSCT; however, allogeneic HSCT and myeloablative conditioning were main risk factors identified for persistent cognitive decline. In line with white matter damage, executive function and attention/processing speed impairments likely represent core deficits, which may affect other cognitive impairments. Post-HSCT changes depend on task characteristics, cognitive load, and conditioning intensity. CONCLUSIONS: Future research should emphasize regular neurocognitive assessment to guide cognitive rehabilitation, implement pre-transplant cognitive rehabilitation strategies to mitigate post-HSCT cognitive decline, and enhance treatment outcomes.

Humans↗

PubMed2026

Behind the Curtain of Care. Nurses' Experiences Providing Care to Consumers With Alcohol and Other Drug Issues: A Qualitative Scoping Review.

AIM: To scope and synthesise qualitative literature relating to nurses' experiences of providing care to consumers with alcohol and other drug issues and explore how meaning is constructed in practice. DESIGN: Scoping review. METHODS: A scoping review was conducted following Arksey and O'Malley's framework. Findings were analysed using thematic analysis. DATA SOURCES: Systematic searches were conducted between September and November 2025 across Medline, Emcare, CINAHL and Google Scholar, using controlled vocabulary and keywords relevant to nurses' experiences of providing care to consumers with alcohol and other drug issues. RESULTS: Twenty-four studies from 12 countries were included. Seven themes were identified: emotional aspects of care, education, training and skills in practice, the spectrum of stigma, ethical issues in professional practice, navigating pain management, limited support, and how meaning is constructed in practice. CONCLUSION: Nurses' experiences of providing care to consumers with alcohol and other drug issues are shaped by multiple intersecting factors influencing care delivery and professional practice. Further research is needed to examine how workplace culture, language and interpersonal interactions influence healthcare experiences, and inform education, service development and support needs. REPORTING METHOD: Reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) checklist. PATIENT OR PUBLIC CONTRIBUTION: No patient or public contribution.

alcohol and other drugs↗

PubMed2026

Retention strategies and participant retention rates among prospective longitudinal pregnancy cohorts: a systematic mapping review.

Prospective longitudinal pregnancy cohorts can answer questions about fetal and early life exposures and later health outcomes; however, there are challenges to retaining participants in longitudinal studies, particularly over life transitions like the birth of a child. Optimal methods for retaining participants in longitudinal research are unclear. A systematic mapping review was conducted to identify prospective cohort studies and randomized controlled trials that enrolled pregnant participants and their infants. Data on retention rates and 17 retention strategies was extracted. A random effects meta-analysis generated pooled annual retention rates inversely weighted to the number of baseline participants. Spearman rank coefficients were used to assess correlation between strategy use and retention. A random-effects meta-regression was used to determine if select retention strategies were associated with participant retention. We identified 130 studies, involving 472 022 pregnancies. A downward trend in pooled mean retention rates were observed. Studies utilized an average of 6.8 (SD 3.9) retention strategies. Statistically significant associations were not observed between strategy use and retention rates at follow-up (p > 0.05). Prospective studies of pregnant people and their infants used multiple retention strategies. Participant retention rates declined over time, suggesting that additional factors may influence study participation in the postpartum period.

Humans↗

PubMed2026

Toxicological effects of propyl 4-hydroxybenzoate on gallstone pathogenesis: An integrated mendelian randomization, network toxicology, and experimental study.

BACKGROUND: Gallstone disease is a prevalent digestive disorder with substantial global socioeconomic burden. Propyl 4-hydroxybenzoate (PP), a widely used paraben preservative, exhibits potential metabolic and hepatic toxicity, yet its role in gallstone pathogenesis remains unclear. This study aimed to explore the causal association between PP exposure and gallstone formation and the underlying mechanism. METHODS: Two-sample Mendelian randomization (MR) was performed using genome-wide association study (GWAS) data. Network toxicology, molecular docking, and molecular dynamics simulation were applied to screen for core targets. In vivo experiments, transcriptome sequencing, Western blot (WB), and ELISA were conducted for mechanistic validation. RESULTS: MR confirmed a causal link between circulating PP levels and an elevated risk of gallstones (P < 0.05), with AKT1 identified as the key target. In mice, PP aggravated gallstone formation by activating the AKT1-NF-κB-CXCL1 pathway, enhancing hepatic inflammation and neutrophil extracellular traps (NETs) formation; these effects were reversed by AKT inhibition. CONCLUSION: PP promotes gallstone formation via the AKT1-NF-κB-CXCL1-NETs axis. Our findings highlight PP as an environmental risk factor for gallstones, providing novel insights into their prevention and targeted therapy.

Animals↗

PubMed2026

A Letter Matters: ADRB2 rs1042713 c.46A Modulates Anti-osteogenic Effect of Epinephrine in Human Mesenchymal Stem Cells.

Osteoporosis (OP) is a systemic bone disease affecting millions worldwide, characterized by long-term asymptomatic development that manifests in low-energy fractures. Due to their high stability, genetic markers represent a promising strategy for early diagnostics. The ADRB2 rs1042713 polymorphism is one such marker, considered as a potential predictor for OP. Although the anti-osteogenic role of the β2-adrenergic receptor is well-established, debate continues on which allele (G or A) of this polymorphism drives bone deterioration. In this study, we examined the influence of the ADRB2 rs1042713 G/G and A/A variants on osteogenic differentiation in patient-derived mesenchymal stem cells (MSCs) under treatment with the endogenous agonist epinephrine. We show that epinephrine (whose levels are often elevated in comorbid conditions) drastically impairs osteogenic differentiation, specifically at the matrix mineralization stage in MSCs A/A. Epinephrine fails to activate the canonical β2-adrenergic receptor pathway and promotes receptor perinuclear and nuclear localization in MSCs A/A. Crucially, metformin, a common anti-diabetic drug, rescues this anti-osteogenic effect. These results open new perspectives for early diagnostics by identifying epinephrine sensitivity as a critical factor, while also suggesting a potential therapeutic strategy to counteract epinephrine detrimental effect in individuals carrying the ADRB2 rs1042713 A-allele.

Humans↗

PubMed2026

A systematic review of human avoidance learning: Cognition, computation, and methods.

Avoidance behaviour is fundamental for survival but can become maladaptive in clinical conditions. A large body of literature has accumulated on the dynamics of human avoidance learning. However, current theories and overviews do not provide an exhaustive account of this evidence. In this systematic review, we identify N = 116 studies on human avoidance learning. We analyse these studies with the goal of distilling robust empirical phenomena as a basis for theory-building, and examine their diagnostic value in differentiating between competing theories. We find that the evidence is difficult to reconcile with foundational two-factor and classical safety-signal accounts, and most strongly supports expectancy- and inference-based views, in which avoidance responses are selected with respect to represented consequences. At the same time, no current framework provides a complete account of the evidence: several findings point to an additional role for operant valuation, Pavlovian influences, and contextual or latent-state control over the expression of avoidance. Methodologically, we observe that the problem setting in the most common experimental paradigms is radically simpler than real-world avoidance and therefore unlikely to expose the limits of inferential or reflective mechanisms. Consequently, we argue that paradigms with greater computational demands and more realistic action affordances are required to identify the mechanisms underlying avoidance learning. Collectively, these insights provide a foundation for theoretical refinement, computational modelling, and methodological innovation, with implications for advancing interventions targeting maladaptive avoidance.

Humans↗

PubMed2026

Targeting Gasdermins for Therapeutic Interventions in Central Nervous System Injury.

Central nervous system (CNS) injuries are the leading cause of permanent disability and premature death in adults worldwide, with their incidence continuing to rise amid social development. These injuries not only severely impair the quality of life but also impose a heavy burden on the global public health system. Current clinical interventions, such as decompression and thrombolysis, can alleviate primary injury but fail to effectively reverse the secondary neuroinflammatory damage. Traditional anti-inflammatory therapies, which cannot block the upstream source of the inflammatory cascade, have led to repeated failures in global clinical translation research over the past decades. Gasdermins were first characterized in studies of systemic inflammatory diseases. These proteins form transmembrane pores to drive the release of proinflammatory factors and inflammatory cell death, serving as key mediators of host innate immunity. Recent studies have revealed that gasdermins play critical roles in regulating the initiation and amplification of neuroinflammation following CNS injury. To clarify the therapeutic potential of gasdermins as targets for injury repair, this review systematically summarizes the structure and function of gasdermins, as well as their cell-specific activation and regulatory mechanisms. We further elaborate on their pathological roles in these injuries and the corresponding therapeutic strategies, aiming to provide a theoretical reference for basic research and clinical translation in this field.

Humans↗

PubMed2026

Bacterially produced dsRNA targeting SePGRP-LB reduces population fitness of Spodoptera exigua (Lepidoptera: Noctuidae) and increases its susceptibility to SeMNPV.

The beet armyworm, Spodoptera exigua (Hübner) (Lepidoptera: Noctuidae), is an important agricultural pest, and S. exigua multiple nucleopolyhedrovirus (SeMNPV) is a host-specific biological control agent. However, baculovirus efficacy can be limited by host antiviral responses. S. exigua peptidoglycan recognition protein LB (SePGRP-LB) has been identified as an antiviral immune factor, suggesting that its suppression may increase larval susceptibility to SeMNPV. In this study, bacterially produced double-stranded RNA targeting SePGRP-LB (bac-dsPGRP-LB) was orally delivered to larvae to induce RNA interference. Feeding bac-dsPGRP-LB reduced SePGRP-LB transcript levels by 24.0% to 65.7% over 7 d. SePGRP-LB knockdown prolonged fifth-instar larval development, reduced female pupal weight, shortened male adult longevity and the oviposition period, and decreased fecundity by approximately 51%. Life table analysis further showed significant reductions in the intrinsic rate of increase (r), finite rate of increase (λ), and net reproductive rate (R0) following bac-dsPGRP-LB treatment. During SeMNPV infection, co-feeding with bac-dsPGRP-LB significantly suppressed SePGRP-LB expression, increased the SeMNPV genomic load, and reduced larval survival compared with the SeMNPV + bac-dsGFP treatment. These findings identify SePGRP-LB as a promising RNAi target for simultaneously reducing S. exigua fitness and enhancing its susceptibility to SeMNPV under laboratory conditions.

SePGRP-LB↗

PubMed2026

Unconfined compressive strength prediction for the ordinary Portland cement-steel slag-silica fume ternary system based on response surface methodology.

This research was undertaken to address environmental concerns associated with industrial solid waste and to reduce cement consumption in geotechnical engineering. It specifically investigates the feasibility of using steel slag (SS) and silica fume (SF) as partial substitutes for ordinary Portland cement (OPC) in soil stabilization. The effects of SS, SF, OPC, and initial moisture content on the unconfined compressive strength (UCS) of stabilized soil were investigated through single-factor experiments and response surface methodology (RSM). The results show that SS and SF can synergistically enhance the strength of stabilized soil, although their interaction effect was not statistically significant within the investigated ranges. Compared with soil stabilized solely with OPC, the addition of 18 % SS and 10 % SF reduced OPC consumption by 3 % without compromising strength. Microstructural and compositional analyses further revealed that SS mainly supplied calcium- and silica-bearing components, while SF provided highly reactive silica and micro-filling effects, jointly promoting hydration reactions and improving the compactness of the stabilized soil matrix. As a result, more hydration products were formed in the OPC/SS/SF-stabilized soil than in the OPC-stabilized soil, which contributed to pore filling and strength enhancement. This study provides useful guidance for the sustainable utilization of industrial solid waste and the low-carbon development of soil stabilization materials.

Construction Materials↗