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PubMed2026

Space to grieve and grow: A systematic review of psychosocial interventions for people newly diagnosed with multiple sclerosis.

OBJECTIVE: This systematic review synthesized evidence from intervention studies published over the past 25 years that aimed to improve coping and psychosocial well-being among individuals early in the multiple sclerosis (MS) disease course. The goal was to evaluate intervention characteristics, theoretical foundations, and psychosocial outcomes, and to identify gaps for future research. METHODS: Following PRISMA guidelines, a comprehensive search was conducted across PubMed, CINAHL, PsycINFO, and Web of Science (2000-2025). Eligible studies included quantitative or mixed-methods interventions that addressed coping or psychosocial well-being among adults newly diagnosed with MS. Data extraction and quality assessment were completed independently by multiple reviewers using the Joanna Briggs Institute Critical Appraisal Tools. RESULTS: Seven studies (n = 345) met inclusion criteria, representing cognitive-behavioral therapy, mindfulness, acceptance-based, and nurse- or peer-delivered interventions. The interval between diagnosis and intervention enrollment ranged from 14 days to >4 years, suggesting different phases of adjustment. All interventions produced significant short-term improvements in at least one psychosocial domain (e.g., anxiety, depression, stress, coping, or illness acceptance). However, sustained effects beyond 6-12 months were inconsistent. Common mechanisms across interventions included enhancing self-efficacy, stress management, and adaptive coping. CONCLUSIONS: The available evidence suggests that brief psychosocial interventions for adults in the early years after MS diagnosis are feasible and may provide short-term benefits for selected psychosocial outcomes. However, the evidence base remains limited, heterogeneous, and preliminary. Future studies should more clearly define diagnosis timing, use adequately powered designs and longer follow-up, and examine mechanisms of change.

Humans↗

PubMed2026

Variants in the interferon regulatory factor 5 gene confer genetic risk for systemic lupus erythematosus in a Han Chinese population.

BACKGROUND: Interferon regulatory factor 5 (IRF5), integral to interferon signaling pathways, has been identified as a susceptibility locus for systemic lupus erythematosus (SLE). Nevertheless, the relationship between IRF5 variants and SLE risk within the Han Chinese demographic remains inadequately characterized. MATERIALS AND METHODS: Genotyping of two functional single nucleotide variants (SNVs) in IRF5 was conducted in 167 individuals with SLE and 246 healthy controls utilizing sequence-specific primer polymerase chain reaction (PCR-SSP). Chi-square and Fisher's exact tests were employed to assess associations. RESULTS: The rs10954213 variant demonstrated a significant association with SLE susceptibility under the recessive model (GG vs. AG+AA, OR = 2.20, 95% CI: 1.30-3.75, p = 0.003, adjusted p [pc] = 0.030) and homozygous model (GG vs. AA, OR = 2.43, 95% CI: 1.36-4.42, p = 0.003, pc = 0.032). Similarly, the rs2004640 variant was associated with an increased risk of SLE across allelic (T vs. G, OR = 1.66, 95% CI: 1.22-2.26, p = 0.001, pc = 0.011), dominant (TG+TT vs. GG, OR = 1.77, 95% CI: 1.19-2.63, p = 0.005, pc = 0.047), and homozygous models (TT vs. GG, OR = 3.72, 95% CI: 1.58-8.78, p = 0.002, pc = 0.016). Haplotype analysis identified protective haplotype HT1 (A/G, OR = 0.54, 95% CI: 0.41-0.73, p < 0.001) and risk haplotype HT4 (G/T, OR = 2.51, 95% CI: 1.42-4.42, p = 0.001). CONCLUSIONS: These findings indicate that IRF5 gene variants substantially modulate susceptibility to SLE in the Han Chinese population. They hold potential as biomarkers for evaluating SLE risk and offer valuable perspectives into disease pathogenesis.

Adult↗

PubMed2026

Protective association of the ELMO1 rs741301 variant against diabetes mellitus and diabetic nephropathy: a systematic meta-analysis of case-control studies.

CONTEXT: Diabetes mellitus (DM), an endocrine disorder, is characterised by persistently elevated blood glucose levels due to inadequate insulin production. Diabetic nephropathy (DN), is a critical complication associated with DM, often leading to end-stage renal failure and increased mortality. OBJECTIVE: This meta-analysis aimed to evaluate the association between the ELMO1 rs741301 polymorphism and susceptibility to DN among individuals with diabetes. METHOD: A systematic literature search was conducted for studies published between 2014 and 2024 using Embase, Google Scholar, and PubMed. Eligible case-control studies investigating the association between ELMO1 rs741301 and DN among individuals with DM were selected according to predefined inclusion criteria. Nine case-control studies comprising 880 individuals with DM and 1008 individuals with DN were included in the meta-analysis. RESULTS: The pooled analysis demonstrated a significant protective association between the ELMO1 rs741301 polymorphism and DN under the allelic model (OR = 0.77, 95% CI: 0.67-0.88), recessive model (OR = 0.74, 95% CI: 0.61-0.90), and dominant model (OR = 0.68, 95% CI: 0.53-0.88). In contrast, no statistically significant association was observed under the over-dominant model. CONCLUSION: The findings suggest that the ELMO1 rs741301 polymorphism may be associated with a reduced susceptibility to DN among individuals with DM. These findings provide evidence for a potential genetic contribution of ELMO1 to DN susceptibility and may help improve understanding of the genetic factors underlying diabetic complications. Further well-designed studies in diverse populations are warranted to validate this association.

Humans↗

PubMed2026

Genetic evidence for a causal relationship between melatonin metabolism and depression.

To investigate the causal relevance of melatonin metabolism, which provides the biological basis for circulating melatonin levels, to specific depression symptom subtypes, we performed a targeted systematic review of melatonin metabolism pathways in the human brain and liver. Using two-sample Mendelian randomization (MR), we assessed the causal effects of metabolism pathways and/or individual genes on major depressive disorder (MDD) and nine symptom subtypes derived from Patient Health Questionnaire-9 (PHQ-9). Instrumental variables (IVs) were expression quantitative trait loci (eQTL) for eight individual genes, one synthesis route, and three degradation routes. Results were assessed using Bayesian colocalization and phenome-wide association analyses. At the pathway-level, the genetically proxied synthesis-route signal was associated with PHQ-9 Assessment 5 (PHQ9A5, OR: 0.89, 95% CI: 0.85-0.93), but sensitivity analyses suggested this association was primarily driven by TPH1 and may reflect serotonin-related biology. In contrast, higher brain melatonin degradation raised the risk of both PHQ9A1 (OR: 1.03, 95% CI: 1.02-1.04) and PHQ9A7 (OR: 1.03, 95% CI: 1.02-1.03). Within degradation, up-regulation of the kynurenine sub-pathway increased the odds of PHQ9A3 (OR: 1.05, 95% CI: 1.02-1.07), PHQ9A4 (OR = 1.04, 95% CI: 1.02-1.06) and PHQ9A7 (OR: 1.05, 95% CI: 1.02-1.07). Gene-level analyses were largely concordant, except for SULT1A1, whose higher expression was genetically protective for PHQ9A3 but risk-increased for PHQ9A1 and PHQ9A4. Overall, these results demonstrate that melatonin metabolism exerts symptom-specific and pathway-specific causal effects on depression. A stratified view of melatonin's role may help optimize the application of exogenous melatonin supplementation.

Melatonin↗

PubMed2026

Pervasive hybridization and introgression in Diervilleae (Caprifoliaceae).

Diervilleae (Caprifoliaceae) is a horticulturally important lineage with striking floral diversity and a long history of interspecific crossing, suggesting reticulate evolution. We integrated nuclear SNPs and whole plastome data to reconstruct a phylogenomic backbone for the tribe and to identify hybrids, cultivated accessions, and introgression among lineages. Nuclear and plastid phylogenies consistently recover Weigela and Diervilla as reciprocally monophyletic and resolve four major lineages within Weigela, providing a reproducible framework for revising sectional limits and species boundaries. Cultivated accessions form a well supported clade sister to W. florida and show predominantly W. florida ancestry while retaining contributions from multiple wild lineages, consistent with recurrent crossing, backcrossing, and selection. Analyses of wild populations reveal recurrent hybrids and enable plausible parental combinations to be inferred. Tests across the genome further indicate strong evidence for historical introgression across Diervilleae, with the strongest signals involving W. middendorffiana, W. maximowiczii, and Diervilla. Fossil evidence, divergence time estimation, and paleodistribution modelling together suggest range expansion during the Miocene and Pliocene followed by climate driven contraction, providing a spatiotemporal context for episodic contact, introgression, and the East Asia-North America disjunction.

Hybridization, Genetic↗

PubMed2025

Diagnostic and clinical utility of exome sequencing and chromosomal microarray in children with GDD/iD: a meta-analysis.

BACKGROUND: Global developmental delay/intellectual disability (GDD/ID) is among the most common neurodevelopmental disorders, with up to half of cases are attributed to genetic factors. Chromosome microarray (CMA) has traditionally been the primary genetic test for idiopathic GDD/ID. However, whole exome sequencing (WES) and whole genome sequencing (WGS) have recently emerged, substantially increasing diagnostic yields in these populations. METHODS: We conducted a comprehensive literature search of PubMed, Scopus, EMBASE, and the Cochrane Library from inception to April 29, 2025. Studies reporting the diagnostic utility of these tests in children with GDD/ID were included and analyzed. RESULTS: A total of 102 studies, comprising 55,752 children, were reviewed. The pooled diagnostic yield of WES was 0.37 (95% CI: 0.33-0.41; I2 = 93%), significantly higher than that of CMA at 0.19 (95% CI: 0.16-0.21; I2 = 95%). Subgroup analyses showed that WES yielded significantly higher diagnostic rates than CMA in both same-sample comparisons (OR = 2.27, 95% CI: 1.08-4.78) and different-sample comparisons (OR = 1.65, 95% CI: 1.15-2.37). Only one study evaluated WGS, reporting a diagnostic yield of 0.27. Meta-regression revealed a significant association between CMA diagnostic yield and the proportion of male participants (p < 0.01), but not with WES. No significant difference in diagnostic utility was observed between isolated GDD/ID and GDD/ID with comorbidities. CONCLUSION: In children with unexplained GDD/ID, WES demonstrates superior diagnostic and clinical utility compared to CMA. Incorporating WES as a first-line investigation in the diagnostic evaluation of GDD/ID may be warranted.

Humans↗

PubMed2026

Genomic and One Health insights into Vibrio parahaemolyticus from environmental, seafood and clinical sources.

Vibrio parahaemolyticus is a leading cause of seafood-borne gastroenteritis worldwide, with climate warming facilitating its spread to high-latitude areas. In this study, we analyzed 212 genomes of environmental and seafood-associated isolates collected from seven cities in Zhejiang Province, China (2019-2024), alongside 228 clinical genomes from public databases. The 212 isolates were assigned to 172 sequence types (STs), with ST490 being the most frequent (5/212, 2.36%). Forty-four serotypes were identified, dominated by OL3:KUT (12.68%). High ST and serotype diversity were observed across different sample types and sources, with median pairwise single nucleotide polymorphisms (SNPs) ranging from 57,431 to 58,378, indicating comparable genetic diversity across groups. All isolates carried tlh and T3SS1 but lacked tdh and T3SS2. Resistance rates against ampicillin and cefazolin were 54.72% (116/212) and 44.34% (94/212), respectively, with multidrug resistance (MDR) detected in nine isolates, predominantly from seafood (7/9). A total of 63 distinct antimicrobial resistance genes (ARGs) spanning seven classes were identified. Isolates from aquaculture farms and wet markets exhibited greater resistance category diversity and higher ARG carriage than those from coastal or riverine sites. In contrast, the 228 clinical isolates harbored only 25 ARGs across two classes, with a significantly lower proportion of isolates carrying multiple ARG classes (0.44% vs. 6.13%, P < 0.001). Human isolates formed tighter phylogenetic clusters, although a minority were closely related to environmental/foodborne strains. Overall, our findings demonstrate the genetic diversity and resistance potential of V. parahaemolyticus across environmental, seafood, and clinical sources, highlighting the importance of the One Health approach to comprehensive public health risk assessment.

Vibrio parahaemolyticus↗

PubMed2026

Targeted sequencing reveals a distinct genetic alteration landscape in oral multiple primary squamous cell carcinomas.

OBJECTIVE: Oral multiple primary cancers (MPCs) are associated with poor clinical outcomes, yet their genomic characteristics remain insufficiently understood. DESIGN: Fifty-four formalin-fixed paraffin-embedded (FFPE) tumor samples from 30 patients with oral MPCs were analyzed using high-depth targeted sequencing of a customized 14-gene panel derived from prior whole-exome sequencing data. Detected alterations were analyzed after removal of synonymous mutations. RESULTS: Non-silent genomic alterations were identified in 59.3% (32/54) of samples, involving 19 patients. A total of 70 variant loci across 13 genes were detected. AKAP13 was the most frequently mutated gene at both the sample (22.2%, 12/54), with recurrent mutations observed across multiple patients. In contrast, TP53 mutations occurred at a substantially lower frequency (11.1%, 6/54). Marked inter- and intra-patient mutational heterogeneity was observed. CONCLUSIONS: FFPE-based targeted sequencing enabled an initial characterization of genomic alterations in oral MPCs. Recurrent alterations in AKAP13, GLI2, JMJD1C, and DNAH8, together with the relatively low frequency of TP53 alterations, identify candidate genomic features for further investigation and provide a basis for future studies of the molecular basis of oral MPCs.

Humans↗

PubMed2026

Optimized AAV5-RPGR ORF15 Gene Therapy Rescues Photoreceptor Structure and Function in X-Linked Retinitis Pigmentosa Mouse Model.

PURPOSE: To develop and evaluate an rAAV5-based gene therapy vector expressing an optimized human RPGR ORF15 transgene (rAAV5-RPGR) for the treatment of X-linked retinitis pigmentosa caused by RPGR mutations, addressing the challenges of cloning the unstable wild-type ORF15 sequence. DESIGN: This was a prospective experimental study. SUBJECTS: This was an animal study. METHODS: An optimized RPGR ORF15 sequence was designed to eliminate problematic secondary structures and cryptic splice sites. In vitro expression was validated in HEK 293T and photoreceptor-like 661 W cells. A complete Rpgr knockout mouse model (Rpgr-knockout [KO]) was generated and characterized phenotypically. Therapeutic efficacy was assessed in Rpgr-KO mice via subretinal injection of rAAV5-RPGR at low (1 × 10⁹ vg/eye), medium (3 × 10⁹ vg/eye), or high (1 × 10¹⁰ vg/eye) doses. Structural and functional outcomes were evaluated at 12- and 14-month postinjection. Short-term safety was assessed in rabbits 1 month after subretinal injection. MAIN OUTCOME MEASURES: Level of RPGR protein expression and Protein isoform profile (elimination of truncated isoforms), Cellular localization of transgene expression and Dose-dependence of expression, outer nuclear layer thickness, and electroretinography parameters. RESULTS: (1) The optimized vector increased RPGR protein expression 3.3-fold in vitro compared to wild-type and eliminated truncated isoforms. (2) Subretinal delivery of rAAV5-RPGR in mice demonstrated dose-dependent transgene expression localized correctly to photoreceptor inner segments. (3) In Rpgr-KO mice, high-dose treatment significantly preserved outer nuclear layer thickness at the injection site (42% greater than controls at 14 months, P < .01) and central retina (P < .05), reduced aberrant rhodopsin mislocalization (P < .01), and partially restored retinal function. ERG showed significantly improved scotopic a-wave (≥100 vs <90 µV in controls at 10 cd·s/m²) and photopic b-wave amplitudes (49-66 vs 31-46 µV at 30 cd·s/m²) in treated mice. (4) No vector-related toxicity was observed in rabbits. CONCLUSIONS: rAAV5-RPGR mediated efficiently, targeted expression of optimized RPGR-ORF15, significantly preserved photoreceptor structure and function in a severe X-linked retinitis pigmentosa mouse model, and demonstrated a favorable safety profile. This study provides preclinical proof-of-concept for RPGR-targeted gene replacement therapy.

Animals↗

PubMed2026

Pharmacogenomic and drug interactions risk in cardio-oncology: A precision medicine perspective for India.

Cardio-oncology patients may face complex treatment regimens due to the concurrent existence of cancer and cardiovascular disease, leading to a considerable polypharmacy burden. This significantly increases the prospect of drug-drug interactions (DDIs) and gene-drug interactions. The majority of these interactions arise from comparable pharmacokinetic and pharmacological pathways associated with drug transporters and cytochrome P450 enzymes. The significance of pharmacogenomics in tailored treatment strategies are emphasised by the fact that genetic variability enhances individual differences in drug response, safety, and efficacy. This narrative review focus on the effects of key genetic polymorphisms (e.g., DPYD, CYP2C19, and CYP2C9) on the metabolism and efficacy of commonly prescribed anticancer and cardiovascular medications such as fluoropyrimidines, clopidogrel, and warfarin. In addition it explore the role of pharmacogenomic variants on drug-drug interactions within the field of cardio-oncology. The study ultimately emphasizes the necessity of precision medicine in India to address the genetic diversity and underrepresentation in global genomic databases. The absence of pharmacogenomic testing, infrastructural deficiencies, financial constraints, and insufficient clinical integration hinder the widespread use of this technology in India. The Genome India Project and other national initiatives establish the foundation for pharmacogenomic-guided therapy. Utilizing genetic data, together with artificial intelligence-based predictive tools, for clinical decision-making may enhance medication safety and yield optimal outcomes in Indian cardio-oncology patients.

Humans↗

PubMed2026

Diagnostic value of blood p-tau subtypes in Alzheimer's disease progression and pathology: systematic review and meta-analysis.

BACKGROUND: Alzheimer's disease (AD) is the most common neurodegenerative disease and the most likely to lead to dementia. With the availability of the latest therapies, the need for Alzheimer's disease diagnosis is now gradually increasing. Whereas blood phosphorylated-tau (p-tau) has demonstrated excellent performance in the prediction and diagnosis of disease progression and Aβ positivity in AD, there are differences between different p-tau subtypes. Therefore, a pooled analysis of different blood p-tau subtypes is of more important clinical value. METHOD: Relevant literature was screened by complete search in four databases, Pubmed, Embase, Cochrane Library and Scopus. Relevant data and AUC and their confidence intervals of the included literature were extracted and analyzed by classification according to p-tau subtypes. Quality assessment was performed using the QUADAS-2 tool. RESULT: Our results reveal that p-tau217 performs better in the diagnostic performance in most stages of AD, which is consistent with the guidelines. However, our results concluded that p-tau217 has poorer diagnostic performance in the stages of cognitive unimpaired or less cognitively impaired, especially in the Aβ positivity diagnosis of SCD and CU. Head-to-head meta-analyses formally confirmed that p-tau217 significantly outperforms p-tau181 across AD dementia, Aβ positivity, tau positivity, and biological staging (all P < 0.05), whereas no significant difference was observed between p-tau231 and p-tau181. CONCLUSION: By integrating single-arm pooled AUC estimates with formal head-to-head statistical comparisons, our study provides evidence-based support for plasma p-tau217 as the subtype with the most robust diagnostic performance across AD pathology and biological staging. Head-to-head analyses formally confirmed that p-tau217 significantly outperforms p-tau181 in Aβ positivity, Tau positivity, and biological staging.

Humans↗

PubMed2026

Investigating telomere length and hTERT-MNS16A VNTR polymorphism in Bipolar disorder: Insights into clinical features.

OBJECTIVE: To compare leukocyte telomere length (LTL; T/S ratio) and hTERT-MNS16A VNTR polymorphism between patients with bipolar disorder (BD) and healthy controls, and to examine their associations with clinical features in BD. METHODS: A total of 179 participants (100 BD patients, 79 healthy controls) were enrolled. Relative LTL was assessed by qPCR-based T/S ratio; hTERT-MNS16A VNTR genotyping by PCR and gel electrophoresis. Clinical variables including episode frequency, illness duration, age at onset, symptom severity scales, first episode polarity, and family history of mood disorder were evaluated. RESULTS: No significant differences were observed between BD patients and healthy controls in T/S ratio or hTERT-MNS16A VNTR genotype distributions (all p > 0.05). Within the BD group, S allele carriers (L/S or S/S) had significantly more depressive episodes than L/L homozygotes (1.45 ± 2.58 vs. 0.61 ± 1.52; p = .040). Significant inverse correlations were identified between T/S ratio and depressive episode count (ρ = -0.220, p = .028) and total mood episodes (ρ = -0.207, p = .039). Multivariable negative binomial regression revealed four independent predictors of depressive episode frequency: lower T/S ratio (p = 0.005), S allele carriage (L/S or S/S genotypes) (p = 0.001), first depressive episode polarity (p < 0.001), and family history of mood disorder (p = 0.035). CONCLUSION: Although LTL and hTERT-MNS16A VNTR genotype did not differ between BD patients and healthy controls, shorter telomere length and S allele carriage were independently associated with higher depressive episode frequency within the BD group, implicating telomere biology and hTERT genetic variation in the biological substrate of depressive illness burden.

Humans↗

PubMed2026

Synergistic transcriptional modules in Trichoderma asperellum enhance glutathione detoxification to counteract fungal pathogen toxins.

Trichoderma fungi are potent biocontrol agents. However, their defence mechanisms against pathogen-derived toxins remain poorly understood. We identified two synergistic transcription factor modules in T. asperellum that orchestrate the detoxification of cytotoxic secondary metabolites from the poplar blight pathogen Alternaria alternata. Overexpression of the central regulator TasMYB46 reduced disease lesion area by approximately 22% and was associated with decreased pathogen-induced reactive oxygen species (ROS) accumulation. Mechanistically, TasMYB46 directly activates the glutathione S-transferases TasGST61.1 and TasGST56.1 through distinct promoter binding sites (G-box/as-1/MBS), forming dedicated detoxification modules. Crucially, we identified urolithin C as the most abundant phytotoxin in A. alternata metabolites, which is efficiently detoxified through the TasMYB46-TasGST61.1 module. The transcription enhancer TasbHLH53.8 amplifies this system by binding to TasMYB46, boosting TasGST expression and enhancing glutathione-dependent detoxification capacity. This coordinated response elevates glutathione pools and antioxidant enzyme activities (GST/GPx), conferring increased oxidative stress resistance. This study reveals a novel defence mechanism in Trichoderma in which MYB-bHLH-GST modules enable biocontrol agents to neutralise pathogen-derived toxins. Given that Alternaria toxins threaten crops globally (tomatoes, potatoes, citrus), the discovered regulatory synergy represents a strategic advance in developing next-generation biocontrol solutions against toxin-producing plant pathogens.

Alternaria↗

PubMed2026

Prioritizing Parkinson's disease risk-associated mitochondrial candidate genes via multi-omics integrative analysis.

BACKGROUND: Mitochondrial dysfunction has been implicated in Parkinson's disease (PD), but the genetically regulated mitochondrial genes associated with PD risk remain incompletely defined. METHODS: We conducted a summary-data-based genetic epidemiology study integrating summary-based Mendelian randomization (SMR), Heterogeneity in dependent instruments (HEIDI) filtering, and Bayesian colocalization to prioritize mitochondrial-related molecular features associated with PD risk. Mitochondrial-related genes were defined using MitoCarta3.0. Genetically predicted gene expression and plasma protein abundance were evaluated using expression quantitative trait loci (eQTL) data from eQTLGen and GTEx v8, and protein quantitative trait loci (pQTL) data was assessed using International Parkinson's Disease Genomics Consortium (IPDGC) as the discovery genome-wide association study (GWAS) and FinnGen as the replication dataset. Prespecified QTL analyses were interpreted using FDR correction, HEIDI filtering, and colocalization support. DNA methylation QTL analysis, mitochondrial phenotype MR, and single-nucleus RNA-seq analysis were performed as complementary analyses. RESULTS: In the primary eQTL analysis, higher genetically predicted TTC19 expression was associated with lower PD risk (OR = 0.80, 95% CI: 0.74-0.87, PPH4 = 0.80), whereas higher MALSU1 expression was associated with increased PD risk (OR = 2.21, 95% CI: 1.59-3.06, PPH4 = 0.96). Both associations survived FDR correction, passed HEIDI filtering, and showed colocalization support. GTEx whole-blood data supported the direction of the TTC19 association. No mitochondrial protein reached significance after FDR correction and colocalization filtering in the primary pQTL analysis. Complementary methylation analysis highlighted cg06270993 as an exploratory regulatory signal for MALSU1. CONCLUSIONS: This MR-colocalization study prioritizes TTC19 and MALSU1 as genetically supported mitochondrial-related candidate genes associated with PD risk. Further validation is required to define their functional roles in PD pathogenesis.

Humans↗

PubMed2026

A hybrid effectiveness-implementation trial to integrate precision skin cancer risk feedback in federally qualified health centers.

BACKGROUND: Skin cancers are the most common type of cancer in the United States, occur in all segments of the population, and are preventable. Our previous research with primary care patients' demonstrated interest in and efficacy of a precision prevention intervention providing feedback on MC1R risk level (higher versus average) in combination with prevention education materials relative to a standard educational intervention. Our current study is a hybrid type 1 effectiveness-implementation trial deployed at six federally-qualified health centers. This paper presents the study protocol. METHODS: A community advisory panel will guide development of study materials and measures. Staff training at each clinic will be completed in-person. Patients will be approached and screened in-person. Those completing genetic testing and the baseline survey will be randomized to the precision versus standard intervention for each risk level with a target sample size of 286 for each combination. Primary outcomes of effectiveness, assessed at 6 and 12 months, include a tanning score (5 items assessing intentional and unintentional tanning), number of sunburns, conduct of a skin self-examination, and electronic health record documentation of clinician-patient communication about skin cancer prevention. Effectiveness comparisons will focus on the precision relative to the standard intervention among higher risk participants. Implementation data will be collected to identify barriers and facilitators. RESULTS: Effectiveness and implementation outcomes will be evaluated following study completion. CONCLUSIONS: Results will guide subsequent scale-up of the precision intervention, including modifications of the intervention as well as methods for implementation. CLINICAL TRIALS IDENTIFIER: NCT07222995.

Humans↗

PubMed2026

Clinical and genetic features of Ph-negative myeloproliferative neoplasms with dual-driver gene positivity.

OBJECTIVES: To investigate the clinical laboratory characteristics and gene mutation features of dual-driver gene positivity in patients with Philadelphia chromosome-negative myeloproliferative neoplasm (Ph-negative MPN). METHODS: We conducted a retrospective analysis of clinical data and genetic test results from 203 newly diagnosed patients with Ph-negative MPN. Of these, 194 had single-driver gene positivity and 9 had dual-driver gene positivity. High-throughput sequencing was used to detect mutations in JAK2, CALR, and MPL. Clinical characteristics and gene mutation profiles were compared between the two patient groups. RESULTS: The incidence of dual-driver gene positivity was 4.4% (9/203), with the most common combinations being JAK2 with CALR (4 patients) and JAK2 with MPL (4 patients). Compared with the single-driver group, the dual-driver group had a significantly higher risk of bleeding [4.1% (8/194) vs. 33.3% (3/9), P = 0.008] and a higher proportion of uncommon mutations [3.6% (7/194) vs. 33.3% (3/9), P = 0.006]. No statistically significant differences were observed between the two groups regarding age, thrombosis incidence, splenomegaly, or routine blood test indicators. During follow-up, 1 patient in the dual-driver group died from cerebrovascular disease. No leukaemia transformation or disease-related deaths occurred among the remaining patients. DISCUSSION: The increased bleeding risk in dual-driver patients may be related to a higher proportion of CALR mutations, elevated platelet counts, and higher variant allele frequencies, though these findings require validation in larger cohorts due to the small sample size. The higher prevalence of uncommon mutations suggests a more complex mutational landscape in this subgroup. CONCLUSION: Patients with Ph-negative MPN and dual-driver gene positivity may have a higher risk of bleeding and a more complex gene mutation profile.

Humans↗

PubMed2026

Unraveling the c-Myc-CASC19/HDAC1-NPM1 epigenetic axis: A novel regulatory circuitry and therapeutic target in gastric carcinogenesis.

Mounting evidence implicates long non-coding RNA cancer susceptibility candidate 19 (CASC19) in the pathogenesis of diverse malignancies. However, its functional role and molecular mechanisms in gastric cancer (GC) remain elusive. Herein, we identified a novel 717-bp transcript isoform of CASC19 in GC cells. This study aimed to delineate the biological functions and underlying mechanisms of this novel CASC19 transcript in GC pathogenesis. CASC19 was significantly upregulated in GC tissues and cell lines, correlating with adverse clinicopathological features and poor prognosis in GC patients. Functional investigations demonstrated that CASC19 overexpression potentiated GC cell proliferation, metastasis, and epithelial-mesenchymal transition, whereas CASC19 knockdown attenuated these malignant phenotypes and suppressed tumorigenesis in xenograft models. Mechanistically, CASC19 functioned as a molecular scaffold by recruiting histone deacetylase 1 (HDAC1) to the nucleophosmin 1 (NPM1) promoter. This recruitment sustained H3K27 deacetylation, thereby transcriptionally repressing NPM1 promoter activity and accelerating gastric carcinogenesis. Crucially, Depletion of HDAC1 or NPM1 partial rescued CASC19-mediated oncogenic effects. Intriguingly, the transcription factor c-Myc was found to transcriptionally activate CASC19 through direct binding to its promoter region. Collectively, our findings indicate that the c-Myc-CASC19/HDAC1-NPM1 axis acts as a potential prognostic biomarker candidate for GC and may represent a therapeutic vulnerability worthy of future investigation.

Humans↗

PubMed2026

Cis-regulatory variation in the MdCKX6 promoter is associated with allele-specific expression and fruit size in apple.

Fruit size is a key determinant of apple fruit quality and market value and is strongly influenced by phytohormone-regulated cell proliferation and expansion during early fruit development. Cytokinin oxidase/dehydrogenase (CKX) enzymes regulate cytokinin homeostasis by irreversibly degrading active cytokinins, but the contribution of natural variation in CKX genes to fruit size remains poorly understood. Here, we identified MdCKX6 as a candidate regulator of fruit growth in apple (Malus domestica). MdCKX6 exhibited pronounced allele-specific expression during fruit development in the cultivar 'Royal Gala'. Sequence analysis identified a promoter SNP associated with differential promoter activity and allele-specific expression. Genotyping of diverse apple cultivars and wild Malus accessions revealed a significant association between MdCKX6 promoter genotype and fruit size. Cultivars carrying low-expression alleles produced larger fruits, whereas high-expression alleles were associated with smaller fruits. To investigate gene function, MdCKX6 was overexpressed in tomato, resulting in reduced fruit size. Histological analyses of the transgenic tomato fruit revealed smaller pericarp cells. Transcriptome analysis of transgenic fruits revealed widespread changes in genes associated with cell-cycle regulation, cell wall modification, hormone-related processes, and transcriptional regulation. Together, these results identify MdCKX6 as a potential negative regulator of apple fruit growth and reveal an association between cis-regulatory variants, gene expression, and fruit size. This study provides new insights into the role of cytokinin metabolism in fruit development and highlights regulatory variation in MdCKX6 as a potential target for apple breeding.

Malus↗