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PubMed2026

Effect of a digitally augmented general health promotion intervention on abstinence from health-risk behaviors among emergency department discharge patients: A randomized controlled trial.

BACKGROUND: Noncommunicable diseases (NCDs) are the leading global cause of death and are driven by modifiable behaviors, such as tobacco use, harmful alcohol consumption, unhealthy diet, and physical inactivity. Recognizing that emergency department (ED) visits represent a unique opportunity to promote behavior change, this trial evaluated a digitally augmented, theory based general health promotion approach, combining a brief telephone-based intervention with mobile instant messaging support, to help discharged ED patients abstain from health risk behaviors. METHODS AND FINDINGS: This assessor-blinded randomized controlled trial was conducted in a major public hospital ED in Hong Kong. Adults (18-65 years) triaged as semi-urgent or non-urgent and with ≥1 health-risk behavior and smartphone access were randomized to receive a digitally augmented, theory‑based general health‑promotion intervention consisting of a brief telephone‑based AWARD‑model intervention (Ask, Warn, Advise, Refer, and Do-it-again) followed by weekly WhatsApp or WeChat messages for 6 months, or to a control group receiving brief telephone advice only. The primary outcome was self-report abstinence from ≥1 health-risk behavior at 6 months; secondary outcomes included the proportion of participants who achieved self-reported abstinence from ≥1 health-risk behavior at 12 months and reduction in the number of behaviors at 6 and 12 months. Of the 2,134 screened patients, 572 were enrolled (286 per group). At 6 months, 30.1% of the intervention participants versus 19.9% of the controls achieved self-reported abstinence (RR = 1.51; 95% CI, 1.13-2.02; P = 0.006). The intervention also significantly increased the likelihood of fewer risky behaviors at 6 (RR = 1.54; P = 0.01) and 12 (RR = 1.48; P = 0.02) months. Physical inactivity showed the greatest improvement at 6 months (31.7% versus 16.2%; P < 0.001). The effects attenuated after cessation of booster messaging. Limitations include reliance on self-reported outcomes, the single-center study design, and loss to follow-up, which may have affected the generalizability of the results. CONCLUSIONS: A digitally augmented, theory-based general health promotion strategy delivered at ED discharge through brief telephone intervention and mobile instant messaging support demonstrated short-term benefits in promoting self-reported abstinence and reducing health-risk behaviors at 6 months. However, the absence of a sustained effect at 12 months suggests that extended support or maintenance strategies may be required to maintain these improvements over time. Multicenter trials with longer follow-up are warranted to evaluate long-term effectiveness. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov (Registration No: NCT06077565).

Humans↗

PubMed2026

Relationships between cannabis and cocaine use in a randomized trial of combined buprenorphine and naltrexone for DSM-IV cocaine dependence.

BACKGROUND: Cannabis is the most commonly used drug in the United States, and among people who use cannabis, polysubstance use is common and understudied. We aimed to examine the association of tetrahydrocannabinol (THC) positive urine drug screen (+UDS) with the odds of submitting a cocaine + UDS during cocaine use disorder treatment. METHODS: We conducted a secondary data analysis of a previously reported double-blind, placebo-controlled clinical trial, CTN0048. Participants meeting criteria for opioid abuse/dependence were assigned to receive extended-release naltrexone and one of three conditions of buprenorphine (placebo, 4 mg/day, 16 mg/day) for 8 weeks. Generalized estimating equations (GEE) were used to analyze urine samples (Liu et al., 2018) collected over time, examining the association between THC + UDS and cocaine + UDS during treatment. RESULTS: Participants (n = 301) averaged 46 (SD = 8.64) years of age, were majority male (78.41 %), non-Hispanic (89.70 %), and African American (66.45 %). GEE results indicated that patients who submitted THC + UDS had significantly higher odds of submitting cocaine + UDS compared to participants who submitted THC-negative UDS across the 25 time points examined (OR = 1.47, 95 % CI = 1.21-1.79, p = 0.00). Time (OR = 0.9998, 95 % CI: 0.9997, 0.9999, p = 0.018) and the covariate of sex assigned at birth (OR = 1.77, 95 % CI = 1.13-2.77, p = 0.013) were also significant in the model, indicating very small decreases in the odds of submitting a cocaine + UDS over time for all patients and 77 % higher odds of submitting cocaine + UDS for females. CONCLUSION: THC + UDS was associated with increased odds of submitting a cocaine + UDS during treatment. Further investigation is needed to discern whether decreasing THC use will result in reduced cocaine use; however, these results suggest that it may be beneficial to counsel patients on cannabis use cessation both before and during treatment for cocaine use, as it is related to cocaine use treatment outcomes. TRIAL REGISTRATION: Secondary data analysis of ClinicalTrials.gov, TRN: NCT01402492 ("A randomized study to test the safety and effectiveness of buprenorphine in the presence of naltrexone for the treatment of cocaine dependence"; National Drug Abuse Treatment Clinical Trials Network (CTN) clinical trial: CTN0048), Registration date: 27 July 2011.

Humans↗

PubMed2026

Emerging Principles in Spatial Functional Genomics.

Spatial transcriptomic and proteomic atlases have enabled mapping of gene programs within intact tissues, but these measurements remain largely descriptive and do not define the mechanisms controlling tissue biology. Pooled CRISPR screening provides scalable causal interrogation of gene function but remains largely confined to dissociated systems that lack spatial context. In vivo spatial functional genomics (SFG) bridges these approaches by integrating genetic perturbations with in situ transcriptomic and proteomic readouts to measure gene function within intact tissue ecosystems. By preserving spatial organization, SFG enables interpretation of perturbations through effects on cell-cell interactions, diffusible signals, multicellular niches, and tissue architecture. Here, we outline key design axes of SFG: perturbation strategy, barcoding strategy, and phenotypic readout. We discuss computational challenges, including spatial autocorrelation, neighborhood dependence, and context-aware null modeling, and highlight how SFG reveals non-cell-autonomous, architecture-dependent mechanisms of gene function, advancing toward predictive models of tissue organization and gene function.

Genomics↗

PubMed2026

Insights into the regulation of the HOTAIR proximal promoter.

HOTAIR (HOX transcript antisense RNA) is a HOXC-cluster long intervening non-coding RNA (lincRNA) whose cancer relevance is tightly coupled to how its transcription is wired into hormone, hypoxia, inflammatory, and developmental signaling. HOTAIR is known to associate with cancer cell proliferation, motility, tumor invasion, and metastasis. The present mini-review focuses on the regulatory architecture and mechanistic complexity of HOTAIR transcriptional regulation, with emphasis on three organizing principles. First, we consider the impact of promoter choice between a canonical proximal promoter (P1), which supports the 2.2-2.4 kb transcript, and an alternative upstream promoter/TSS (P2), which contributes to context-dependent transcription initiation. Second, we examine the long-distance enhancer-promoter communication between HOTAIR distal enhancer and P1/P2. Third, we summarize the recent epigenetic and epi-transcriptomic mechanisms involved in HOTAIR transcript initiation and elongation. A combination of these events determines isoform-specific transcription to govern cell-type-, context-, and cancer specific modulation of HOTAIR expression that promotes tumor formation and cancer progression. Finally, the review proposes how large-scale RNA datasets, long-read sequencing, and isoform-specific studies can refine our understanding of this versatile lincRNA's regulation.

Humans↗

PubMed2026

Machine learning-ready genomic biomarkers: ATF3 polymorphisms predict postoperative analgesic demand through AI-compatible phenotyping.

PURPOSE: To determine whether ATF3 polymorphisms can serve as genetic biomarkers for machine learning-based precision analgesia by establishing a genotype-phenotype association suitable for predictive modeling of postoperative opioid requirements. METHODS: In a prospective cohort of 167 adults undergoing abdominal surgery, ATF3 SNPs rs3122721 and rs3125293 were genotyped. A structured dataset architecture was developed to represent genetic profiles as input features for supervised learning models, enabling translational analysis of genotype‑dependent opioid consumption over 72 h. RESULTS: Patients with homozygous genotypes of the ATF3 SNPs had significantly higher opioid requirements than non‑carriers, despite reporting similar subjective pain scores. This consistent genotype‑dependent pattern provided a clinically relevant phenotype suitable for integration into predictive algorithms. CONCLUSION: ATF3 genotyping offers a promising biomarker for computationally informed precision analgesia. By linking genomic variability to clinically meaningful outcomes within a structured clinical and genomic framework, this approach supports the future development of risk-stratified clinical decision-support systems to optimize postoperative pain management.Trial registration ChiCTR1900021991, registered 30 April 2019. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at https://doi.org/10.1007/s13755-026-00480-9.

ATF3↗

PubMed2026

Effects of faba bean-based crisping culture on phenotypic characteristics, muscle quality, and serum metabolome in Nile tilapia: Screening biomarkers to assess the degree of crisping.

Feeding Nile tilapia (Oreochromis niloticus) a faba bean-based crisping diet enhances muscle hardness (crispness) and overall flesh quality. However, the underlying mechanisms and reliable biomarkers remain insufficiently defined. This study integrated phenotypic traits, muscle texture, collagen content, serum antioxidant enzyme activities (SOD, CAT, and GSH-Px), MDA levels, and serum metabolomics to understand the determinants of muscle crisping. Fish were assigned to a crisping diet or a control group for 90 days. Individuals in the crisping group were implanted with passive integrated transponder (PIT) tags to enable correlation analyses among phenotypic traits (body weight/length/frame changes), serum indicators (NAM, FAD, and GSH-Px) and muscle hardness. Compared with controls, the crisping diet significantly increased muscle hardness, gumminess, and chewiness, accompanied by elevated collagen content. Antioxidant profiles were altered, with higher activities of serum SOD and CAT, together with elevated MDA levels and reduced GSH-Px activity (P < 0.05). Metabolomic analysis identified 830 differential metabolites (682 upregulated and 148 downregulated), predominantly comprising carboxylic acids and derivatives, glycerophospholipids, and benzene derivatives. Enrichment analysis indicated significant involvement in general metabolic pathways, ATP-binding cassette (ABC) transporters, amino acid biosynthesis, and glycine, serine, and threonine metabolism (P < 0.05). Notably, acetylpyruvate was upregulated in glutathione metabolism, nicotinate and nicotinamide metabolism, and galactose metabolism; pantothenic acid was upregulated in glycine, serine, and threonine metabolism; whereas δ-tocotrienol was downregulated. Correlation analysis revealed weak negative associations between muscle hardness and phenotypic traits (body weight/length/frame changes D5-7, D5-10, D7-8) (P < 0.05). In contrast, serum NAM and FAD were weakly positively correlated with muscle hardness, whereas GSH-Px showed a weak negative correlation (P < 0.05). Collectively, these findings suggest that body weight, body length, frame measurements (D5-7, D5-10, and D7-8), and serum NAM, FAD, and GSH-Px are associated with the degree of muscle crispness in Nile tilapia fed a faba bean-based crisping diet and may serve as candidate biomarkers under these culture conditions.

Animals↗

PubMed2026

Proteomic analysis of cisplatin-induced spermatogenesis defects in mice.

BACKGROUND: Cisplatin is a crucial chemotherapeutic agent used for treating various cancers; however, its excessive use can cause irreversible damage to the reproductive system, and the protein expression profile of cisplatin-induced testicular injury remains unclear. METHODS: Male C57BL/6 mice were treated with cisplatin at various doses, and testes were collected for histological, immunofluorescence, and proteomic analyses. Germ cell loss and apoptosis were assessed using H&E staining, TUNEL assays, and immunofluorescence for LIN28A, SYCP3, MVH, and CDK1. Label-free quantitative proteomics identified differentially expressed proteins, which were analyzed for functional enrichment and protein-protein interactions. RESULTS: We observed that cisplatin treatment led to smaller testes, reduced sperm count, and a significant decrease in the number of spermatocytes and spermatids in mice. Label-free quantitative proteomic analysis revealed that cisplatin significantly reduced the expression of cyclin-dependent kinase 1 (CDK1), a key spermatogenesis regulator, in the testes. Reduction in CDK1 expression is correlated with spermatogenic arrest, particularly in spermatocytes. CONCLUSION: These findings highlight the critical role of CDK1 in cisplatin-induced spermatogenic dysfunction and provide new insights into fertility preservation strategies for patients with cancer undergoing chemotherapy.

Animals↗

PubMed2026

Adjuvant CDK4/6 inhibitors in early-stage breast cancer: Clinical evidence and considerations for risk stratification and treatment selection.

Hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer is the most common biologic subtype and carries a persistent risk of recurrence, particularly in patients with high-risk, early-stage disease. Cyclin-dependent kinase 4 and 6 inhibitors, initially established as a standard component of first-line therapy in the metastatic setting based on improvements in progression-free and overall survival, have since been evaluated in the adjuvant setting. While adjuvant palbociclib did not improve invasive disease-free survival, the monarchE and NATALEE trials demonstrated that abemaciclib and ribociclib, respectively, reduce recurrence risk in patients with high-risk, early-stage disease, with emerging overall survival data further supporting their use. However, the absolute magnitude of benefit varies substantially with baseline risk, and treatment-related toxicity and adherence challenges must be considered, as approximately 20% to 25% of patients discontinue therapy before completion. The integration of these agents into clinical practice also intersects with ongoing efforts to deescalate axillary surgery, as treatment eligibility has been largely defined by anatomic staging, particularly nodal status. Available data suggest that the incremental impact of axillary surgery on identifying candidates for cyclin-dependent kinase 4 and 6 inhibition is modest, especially among the favorable-risk populations now eligible for surgical deescalation. As the field evolves, advances in molecular risk stratification, genomic profiling, and dynamic biomarkers are poised to shift treatment selection from anatomic staging toward biologically driven approaches. Multidisciplinary decision-making that integrates tumor biology, anticipated absolute benefit, toxicity, patient preferences, and surgical considerations will be essential to ensure individualized care.

Humans↗

PubMed2026

Orchard netting impacts on biodiversity leading to cascading effects at the ecosystem level.

Agriculture must ensure food production without further compromising the ecosystem functions upon which it depends. Agricultural practices should therefore avoid harming farmland biodiversity, especially of taxa that supply the key ecosystem services (e.g. pollination, pest control and nutrient uptake) that ultimately support crop production. Orchards are among the largest permanent plantations worldwide and are increasingly characterised by the spread of plastic nets used to protect fruits/nuts from either abiotic (anti-hail, anti-rain, shade nets) or biotic (exclusion nets) hazards. Despite having received little attention to date, these nets may impact natural communities, acting both as physical barriers and as drivers of habitat changes to which biota must respond. Species-level responses to netting depend on the organism's ability to enter the netted environment and successfully exploit available resources. Net-mediated ecological filtering and plastic behavioural responses may alter species interactions, leading to cascading ecological impacts that may create species-poorer 'netted communities' with simplified ecological networks. Such changes may erode biological control potential, other ecosystem functions, and overall system stability. We conducted a systematic review on the effects of protection nets on biota, and reported novel empirical evidence on anti-hail nets' impacts on communities of orchard-dwelling birds, flower-visiting insects, and rodents. In total, we identified 48 studies from the literature, however this literature was strongly biased towards apple orchards, western countries, and pest taxa. Net deployment was highly effective in deterring target pest species, in some cases regardless of their original function, as even weather-protection nets limited pest populations. Side effects on non-target taxa were also often reported, such as decreases in pollinators and natural enemies, and/or increases in secondary pests or microbial diseases. However, most assessments largely disregarded non-pest taxa and the broader ecological consequences of netting. The few studies that addressed the effects of nets at the guild/community level, including our empirical study, confirmed that orchard netting resulted in species-poor assemblages, with possible ecosystem-level consequences. We propose that future assessments should pay more attention to the indirect effects of netting on non-target taxa, and on the supply of crop-supporting ecosystem services mediated by wild species occurring in agroecosystems. Due to the trade-offs between these services and net-mediated crop protection, integrated alternatives should be tested to improve the environmental sustainability of food production and biodiversity conservation in farmed landscapes.

Biodiversity↗

PubMed2026

Clinical performance evaluation of single-shade versus multi-shade composite resins in non-carious cervical lesions: a 36-month randomized clinical trial.

BACKGROUND: Composite resins are widely used as the material of choice for definitive restorations due to their ability to integrate functional and aesthetic aspects in dental rehabilitation. Recently, one-shade composite resins have been introduced to simplify the clinical workflow. OBJECTIVES: This study aimed to compare the clinical performance of a "chameleon effect" composite resin with that of a multi-shade composite resin in non-carious cervical lesions after 36 months of follow-up. METHODS: This study was a randomized, controlled, double-blind clinical trial with an equivalence design using a split-mouth approach. The sample consisted of 60 patients presenting at least two non-carious cervical lesions, totaling 120 restorations. Restorations were performed using two materials from the same commercial brand: Vittra Unique (one-shade group) and Vittra APS (multi-shade group). The clinical performance of the restorations was longitudinally evaluated according to the FDI criteria. Survival analysis was performed using Kaplan-Meier curves and the log-rank test, while other clinical parameters were compared using the chi-square test (α = 0.05). RESULTS: At baseline, no statistically significant differences were observed between the groups regarding the evaluated biological, functional, and aesthetic parameters (p > 0.05). Both materials demonstrated clinically acceptable performance according to the FDI criteria, with no significant differences between them. CONCLUSIONS: After 36 months, no significant differences were observed between the one-shade and the multi-shade composite resins in the restoration of non-carious cervical lesions. CLINICAL SIGNIFICANCE: This 36-month randomized clinical trial demonstrates that single-shade composite resins achieve structural durability and aesthetic integration equivalent to traditional multi-shade layering when restoring non-carious cervical lesions. This evidence validates a simplified, single-shade restorative workflow, significantly reducing chairside time and operator-dependent variables without compromising the clinical longevity.

Humans↗

PubMed2026

Modelling the effects of biological intervention in a dynamical gene network.

Cellular response to environmental and internal signals can be modeled by dynamical gene regulatory networks (GRN). In the literature, three main classes of gene network models can be distinguished: (1) non-quantitative (or data-based) models which do not describe the probability distribution of gene expressions; (2) quantitative models which fully describe the probability distribution of all genes co-expression; and (3) mechanistic models which allow for a causal interpretation of gene interactions. We propose two rigorous frameworks to model gene alteration in a dynamical GRN, depending on whether the network model is quantitative or mechanistic. We explain how these models can be used for design of experiment, or, if additional alteration data are available, for validation purposes or to improve the parameter estimation of the original model. We apply these methods to the Gaussian graphical model, which is quantitative but non-mechanistic, and to mechanistic models of Bayesian networks and penalized linear regression.

Gene Regulatory Networks↗

PubMed2026

Comparative evaluation of molecular technologies for the identification of prevalent non-tuberculous mycobacteria in pulmonary infections: a systematic review and meta-analysis.

BACKGROUND: The increasing prevalence of non-tuberculous mycobacteria pulmonary disease (NTM PD) is a burden to public health. Successful management of NTM PD critically depends on accurate species identification and reliable drug susceptibility testing to guide appropriate antibiotic therapy. Emerging molecular technologies offer rapid diagnostic solutions compared to conventional methods, but their performance varies. This study aims to provide a comprehensive evaluation of current molecular techniques for NTM identification and to present a global antibiotic resistance profile. METHODS: A systematic literature search was conducted in PubMed and Web of Science for studies published between 2005 and 2024. Studies applying molecular methods for NTM identification and resistance detection in humans were included. Data on study characteristics, diagnostic methods, sample types, sample sizes, identification sensitivity, and drug susceptibility results were extracted. Meta-analysis was performed using R with the meta4diag package. The quality of included studies was assessed using the QUADAS-2 tool. RESULTS: The analysis included 49 studies on NTM identification and 33 studies on antibiotic resistance. For species identification, all evaluated molecular technologies (MALDI-TOF MS, PCR-based methods, Sequencing, DNA chip, and DNA strip) demonstrated high pooled sensitivities (>0.92). Subgroup analysis revealed that sample type significantly affected performance for MALDI-TOF MS. Preliminary analysis of antibiotic resistance rates revealed varying patterns. For slowly growing mycobacteria, a significantly high Ethambutol resistance rate was observed in M. avium (69.20%). Among rapidly growing mycobacteria, resistance to Imipenem was notable (54.22%), and Clarithromycin resistance varied significantly within the Mycobacterium abscessus complex. CONCLUSION: Emerging molecular technologies have revolutionized the methodology for NTM identification with excellent performance. However, their performance can be influenced by sample type, particularly for MALDI-TOF MS. The alarming and heterogeneous antibiotic resistance patterns also highlight the critical need for rapid and accurate species identification and drug susceptibility testing to inform effective therapeutic strategies. Key messagesMolecular technologies demonstrate high accuracy for NTM identification.Antibiotic resistance is a serious concern with variations among NTM species and subspecies.Rapid and accurate species identification and drug susceptibility testing are crucial for guiding effective clinical management of NTM PD.

Humans↗

PubMed2026

LC-IMS-MS profiling of avocado acetogenins reveals tissue-dependent distribution and cultivar-specific metabolic signatures.

This study presents a comprehensive characterisation of acetogenin-related metabolites in avocado using an LC-IMS-MS workflow. A total of 26 metabolites were semi-quantified across peel, pulp and seed tissues from three cultivars (Hass, Bacon and Fuerte). The integration of ion mobility spectrometry enabled the generation of the first experimental database of collision cross section (CCS) values for avocado acetogenins, improving confidence in metabolite annotation. Results revealed a pronounced tissue-dependent distribution, with seeds and pulp as the primary reservoir of several acetogenins, whereas the peel consistently exhibited lower concentrations. In contrast, acetogenin levels remained largely stable throughout ripening. Clear cultivar-dependent differences were observed, with Hass displaying a distinct metabolic profile compared to Bacon and Fuerte. Multivariate analysis confirmed these findings, showing tissue-dependent cultivar differentiation. This study provides new insights into avocado chemical diversity and highlights the potential of avocado by-products as consistent and promising sources of bioactive acetogenins.

Persea↗

PubMed2026

Corneal Epithelial Alterations Associated With Cyclin-Dependent Kinase 4/6 Inhibitor Therapy in Hormone Receptor-Positive Breast Cancer.

IMPORTANCE: Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors are standard therapy for hormone receptor-positive (HR+), HER2-negative breast cancer. By blocking the G1/S cell-cycle transition, these agents may impair renewal of the corneal epithelium. No controlled study has systematically evaluated corneal epithelial changes in patients receiving CDK4/6 inhibitors. OBJECTIVE: To determine whether CDK4/6 inhibitor-based therapy is associated with cornealepithelial alterations independent of aromatase inhibitor exposure and tear film dysfunction. DESIGN, SETTING, AND PARTICIPANTS: Retrospective comparative cross-sectional study at a tertiary ophthalmology center. A total of 132 women were enrolled: 45 receiving a CDK4/6 inhibitor plus an aromatase inhibitor (CDKAI group), 44 receiving aromatase inhibitor monotherapy (AI group), and 43 age-matched postmenopausal controls without systemic oncologic therapy. EXPOSURES: CDK4/6 inhibitor (ribociclib, palbociclib, or abemaciclib) combined with an aromatase inhibitor; aromatase inhibitor alone; or no systemic oncologic therapy. MAIN OUTCOMES AND MEASURES: Prevalence and severity of punctate epitheliopathy and vortex keratopathy, assessed by a masked ophthalmologist. Secondary outcomes included Schirmer I test, tear film break-up time, and Ocular Surface Disease Index (OSDI). RESULTS: PE was present in 44.4% of eyes in the CDKAI group vs 4.7% in the AI group and 2.3% in controls (χ² = 34.31; P < .001). All moderate (13.3%) and severe/complicated (8.9%) PE cases occurred exclusively in the CDKAI group. Vortex keratopathy was observed in 13.3% of CDKAI patients and in none of the other groups (P = .025). Schirmer values, tear film break-up time, and OSDI scores did not differ among groups (all P > .05). Within the CDKAI group, PE was not associated with treatment duration (P = .963) or tear film parameters. CONCLUSIONS AND RELEVANCE: In this comparative study, CDK4/6 inhibitor-based therapy was associated with significantly higher prevalence and severity of PE and vortex keratopathy, independent of aromatase inhibitor exposure and in the absence of measurable tear film dysfunction. These findings suggest a direct cytostatic effect on the corneal epithelium. Symptom scores were low, although OSDI interpretation was limited by incomplete responses. Proactive corneal surface evaluation with fluorescein staining may be warranted during CDK4/6 inhibitor treatment.

Humans↗

PubMed2026

Targeting Both Oncogenic Signaling and Dependence Receptor Function is Required to Fully Suppress MET Exon 14 Skipping-Driven tumorigenesis.

Receptor tyrosine kinases (RTKs) classically function as oncogenic drivers that promote survival and proliferation upon ligand binding. A subset of RTKs can also function as dependence receptors, inducing apoptosis in the absence of their ligands. Genetic alterations that enhance RTK signaling are well characterized in cancer and can be targeted with kinase inhibitors, which show limited efficacy in some clinical settings. Elucidation of whether oncogenic mutations can promote tumorigenesis by directly abolishing the pro-apoptotic activity of dependence receptors could help improve strategies to target RTKs. Here, we identified MET exon 14 skipping (METex14Del) as a paradigmatic example of an oncogenic alteration that drives tumorigenesis through genetic inactivation of the dependence receptor function of an RTK. METex14Del removed both the caspase cleavage site and adjacent CBL-binding motif, preventing generation of the pro-apoptotic p40MET fragment while sustaining oncogenic MET signaling. Uncoupling regulatory functions of MET using genome editing showed that loss of apoptosis capacity is a critical determinant of METex14Del-driven tumorigenesis. Combined-but not individual-mutation of the caspase and CBL sites was sufficient to recapitulate resistance to apoptosis and tumor growth induced by METex14Del in HGF-humanized mouse models. Importantly, inducible re-expression of p40MET in METex14Del-expressing cells restored apoptotic sensitivity, decreased tumor formation in vivo, and resensitized tumors to capmatinib. Together, these findings redefine RTKs as receptors with dual oncogenic and tumor-suppressive functions and show that disruption of dependence receptor-mediated apoptosis is an oncogenic mechanism. These results provide a conceptual framework explaining why therapies targeting only RTK signaling may fail and support strategies restoring dependence receptor function to achieve durable tumor suppression.

Journal Article↗

PubMed2026

Electron shuttles facilitate methane-dependent arsenate reduction in paddy soils.

Methane-dependent arsenate reduction (M-AsR) occurs widely in paddy soils and can substantially enhance arsenic mobilization, posing potential ecological risks. However, the role of electron shuttles in this process remains poorly understood. In this study, we investigated the influence of anthraquinone-2,6-disulfonate (AQDS) on M-AsR in paddy soils. Fourteen-day incubation showed that 1 mmol/L AQDS facilitated 50.88 % of arsenate reduction and 31.31 % of methane oxidation. Quantitative polymerase chain reaction analysis revealed that AQDS significantly increased the abundance of functional genes associated with arsenate reduction (arrA, arsC) and anaerobic methane oxidation (mcrA) (P < 0.05). Microbial community analysis revealed that AQDS addition enriched Cloacibacterium, Sphingorhabdus, and Methylocystis, while decreasing the relative abundance of Methylobacter and Methylomonas. These findings indicate that electron shuttles facilitate M-AsR by modulating functional microbial populations, providing valuable insights into arsenic biogeochemistry and the coupled cycling of methane and arsenic in paddy soils.

Methane↗

PubMed2026

TNFα-dependent modulation of WT1-MMP9 regulatory axis links developmental and inflammatory pathways in glaucoma.

Glaucomas are heterogeneous optic neuropathies associated with extracellular matrix dysregulation, abnormal ocular morphogenesis, and inflammatory signaling. Targeted deep sequencing of 586 primary congenital glaucoma (PCG) cases and 1,757 controls identified rare pathogenic variants in multiple genes, including WT1 and MMP9. Notably, WT1 variants clustered within the nuclear export sequence. Further, functional analyses showed that combined wt1-pax6 suppression in zebrafish disrupted ocular morphogenesis, highlighting developmental interdependence. In human trabecular meshwork cells, WT1 acted as a transcriptional repressor of MMP9, while TNF-α signaling triggered nitric oxide-dependent nuclear export of WT1, resulting in delayed MMP9 upregulation. This effect was reversible by inhibiting nuclear export or nitric oxide synthase. A patient-derived mutation in the nuclear-export region of WT1, disrupted this regulatory switch, causing abnormal MMP9 expression. These findings position WT1 as an important regulator linking developmental and inflammatory mechanisms in glaucoma pathogenesis.

anterior segment dysgenesis↗

PubMed2026

Novel environmental contaminant 6PPD-quinone promotes malignant phenotypes in colorectal cancer cells and identifies candidate response-associated genes.

6PPD-quinone (6PPDQ), an oxidative transformation product of the widely used tire antioxidant 6PPD, is a ubiquitous environmental contaminant with bioaccumulation potential and widespread human exposure. Recent epidemiological evidence indicates a positive association between urinary 6PPDQ levels and colorectal cancer (CRC) risk; however, its biological effects on CRC-related phenotypes and associated molecular responses remain unclear. We integrated bioinformatics analysis, prognostic modeling, molecular docking and dynamics simulations, and in vitro experiments to investigate cellular and molecular responses to 6PPDQ in CRC models. Predicted 6PPDQ targets were intersected with CRC prognosis-related genes from The Cancer Genome Atlas, followed by functional enrichment and LASSO regression to construct a prognostic risk model, with 1-, 3-, and 5-year AUC values of 0.727, 0.754, and 0.778, respectively. Molecular docking and 100-ns molecular dynamics simulations suggested interactions between 6PPDQ and candidate proteins, including CPT2, SHC2, SRMS, and STK35. Functional assays showed that 6PPDQ exposure altered proliferation, wound-closure capacity, and invasion in Caco-2 and HCT116 cells across the nanomolar concentration range, with non-monotonic and cell-line-dependent responses. In contrast, NCM460 cells showed no increase in EdU incorporation at 10 or 100 nM, whereas reduced proliferation at higher concentrations was accompanied by increased LDH release. 6PPDQ also altered the expression of several prognosis-associated candidate genes. These findings identify cellular phenotypes and candidate molecular responses associated with 6PPDQ exposure under the tested in vitro conditions, but do not establish their causal roles or in vivo relevance. Further mechanistic and in vivo studies are required.

Humans↗