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PubMed2026

Metatranscriptomic analysis of viral sequences associated with Culex nigripalpus at an Alabama aquaculture site.

Mosquitoes associated with aquaculture habitats can harbor diverse viruses, yet the viromes of many locally abundant species remain poorly characterized. At an aquaculture-associated site in Auburn, Alabama, we surveyed mosquito populations and found Culex nigripalpus to be the dominant species collected. To characterize viruses associated with this mosquito, we performed RNA-seq on pooled female Cx. nigripalpus and compared complementary bioinformatic workflows for viral detection and genome recovery. One workflow removed host-associated reads by mapping to the closest available mosquito reference genome prior to assembly, whereas a second workflow used fully de novo assembly and viral database annotation. Additional protein-level filtering, cross-workflow comparison, and comparison of Trinity and rnaSPAdes assemblies were used to prioritize well-supported viral candidates. Across the original analyses, 16 submitted accessions corresponding to 12 collapsed virus/name groups were recovered, including Merida virus, Hubei mosquito virus 5, Zhejiang mosquito virus, Hubei virga-like virus 3, Rinkaby virus, Elemess virus, Qingnian mosquito virus, Serbia narna-like virus 2, XiangYun narna-levi-like virus 8, Ecclesville picorna-like virus, and baculovirus-like fragments. Several candidates were supported across multiple workflows, while others were recovered only under specific analytical conditions, indicating that candidate recovery was influenced by assembly and filtering choices. Selected viral contigs were independently supported by RT-PCR amplification. Overall, these results provide a first characterization of viral sequences associated with Cx. nigripalpus from an Alabama aquaculture-associated site and show that comparison across assembly and filtering strategies helped prioritize the most consistently supported viral candidates.

Animals↗
PubMed2026

Ifebemtinib plus garsorasib in previously treated metastatic colorectal cancer with KRASG12C mutation: a multicentre, randomised, phase 1b/2 trial.

BACKGROUND: Ifebemtinib is a potent oral focal adhesion kinase inhibitor. Preclinical evidence supports combining ifebemtinib with the KRASG12C inhibitor garsorasib. This study aimed to evaluate this combination in KRASG12C-mutated solid tumours. METHODS: This multicentre, phase 1b/2 study had a phase 1b component to establish the recommended phase 2 dose and a phase 2 multitumour expansion component. In phase 1b, the safety and tolerability of ifebemtinib combined with garsorasib was assessed using a 3 + 3 design in KRASG12C-mutated solid tumours. No dose-limiting toxic effects were observed, and the recommended phase 2 dose was established as ifebemtinib 100 mg orally once daily plus garsorasib 600 mg orally twice daily. Here, we report the results of the cohort of previously treated KRASG12C-mutated metastatic colorectal cancer from phase 2 expansion. Eligible patients (aged ≥18 years) who had histologically confirmed locally advanced or metastatic colorectal cancer harbouring the KRASG12C mutation, an Eastern Cooperative Oncology Group performance-status score of 0 or 1, and had disease progression after previous irinotecan-based or oxaliplatin-based combination therapy, were recruited from seven of nine participating tertiary hospitals in China. On the basis of the recommended phase 2 dose, phase 2 comprised a single-arm study to evaluate the safety and efficacy of ifebemtinib combined with garsorasib and an open-label, randomised study in which patients were randomly assigned (1:1) to receive ifebemtinib plus garsorasib or garsorasib alone, by use of centralised computer-generated block randomisation with no stratification. Investigators were masked to the block size. The primary efficacy endpoint of phase 2 was investigator-assessed objective response rate (Response Evaluation Criteria in Solid Tumours, version 1.1), assessed in the safety analysis set in the single-arm study and in all randomly assigned patients (intention-to-treat population) in the randomised study. At least six objective responses (safety analysis set) were required in the single-arm study to proceed to the randomised study. This study is registered with ClinicalTrials.gov, NCT06166836 and NCT05379946, and is active but not recruiting. FINDINGS: Between April 7, 2023 and Dec 13, 2024, 51 patients were enrolled in phase 2 (15 in the single-arm study and 36 in the randomised study). In the single-arm study, the median age was 53 years (IQR 39 to 63), nine (60%) patients were female, six (40%) were male, and all were Asian. In the randomised study, the median age was 51 years (IQR 42 to 59) in the combination group and 63 years (IQR 54 to 66) in the monotherapy group, 24 (67%) were female, 12 (33%) were male, and all patients were Asian. In the single-arm part, the confirmed objective response rate was 46·7% (95% CI 21·3 to 73·4). Seven patients had partial responses, triggering progression to the randomised study. In the randomised study, the confirmed objective response rate was 38·9% (95% CI 17·3 to 64·3) with the combination therapy versus 16·7% (95% CI 3·6 to 41·4) with garsorasib alone (between-group difference 22·2%, 95% CI -7·7 to 49·1; one-sided p=0·068). In the single-arm study, grade 3 treatment-related adverse events occurred in four (27%) of 15 patients, and in the randomised study, grade 3 treatment-related adverse events occurred in six (33%) of 18 patients in the combination group and five (28%) of 18 in the garsorasib group. Grade 3 treatment-related adverse events occurring in at least two patients were diarrhoea (six [18%]), proteinuria (two [6%]), and intestinal obstruction (two [6%]) in patients treated with combination therapy (combined), and increased alanine aminotransferase and γ-glutamyltransferase (two [11%] each) in patients treated with garsorasib alone. Serious adverse events occurred in ten (30%) patients in the combination group and in four (22%) patients in the monotherapy group. One patient in the garsorasib monotherapy group died due to the underlying malignancy within 30 days after completing study treatment, which was reported as a serious adverse event. The death was assessed by the investigators as not related to garsorasib. No grade 4 treatment-related adverse events or treatment-related deaths were reported across all cohorts. INTERPRETATION: The combination of ifebemtinib and garsorasib showed promising anticancer activity and manageable safety profile in previously treated patients with KRASG12C-mutated metastatic colorectal cancer. Although the improvement in response rate did not reach statistical significance in the randomised study, these findings support further evaluation of ifebemtinib plus garsorasib in this population. FUNDING: InxMed, InventisBio, National Natural Science Foundation of China, the Jian Bing Ling Yan + X Research and Development Program of Zhejiang Province, and the Zhejiang Province Medical and Health Science and Technology Plan Project.

Humans↗
PubMed2026

Hierarchical modeling of tumor subtypes in cell lines using large-scale genomic datasets.

Cancer cell lines (CLs) are widely used to study tumor biology and drug response, yet their translational relevance is often limited by inaccurate subtype annotations. Existing CL-tumor matching approaches are frequently constrained by flat classification schemes, weak subtype definitions, and the exclusion of normal tissue references, leading to potential confounding of tumor-specific and tissue-of-origin signals. To address these limitations, a hierarchical classification (HC) framework is presented in which CLs are aligned with patient tumors across biological resolutions, from organ to molecular subtype. Gene expression profiles from 802 CLs, 5,612 tumors from The Cancer Genome Atlas (TCGA) , and 8,939 non-cancerous tissues were integrated to separate oncogenic signals from tissue-specific signals. Node-specific features were selected using maximum relevance minimum redundancy, and balanced accuracies of 89% in cross-validation and 75%, and 80% on external datasets were achieved. Through the framework, 43 CLs were reassigned, and clinically relevant underrepresented subtypes were identified.

cancer cell lines↗
PubMed2026

Exercise-associated epigenetic remodeling and TCR repertoire dynamics in Lynch syndrome carriers.

Lynch syndrome (LS) carriers are at elevated cancer risk. Emerging evidence suggests that exercise may serve as a non-pharmacologic preventive strategy, yet the epigenetic and immunological mechanisms underlying its protective effects in this population remain unclear. Here, we perform integrative multi-omics profiling of DNA methylation, gene expression, and the T cell receptor (TCR) repertoire in LS carriers undergoing a 52-week aerobic cycling intervention. We identify compartment-specific DNA methylation changes, including innate immune activation in cfDNA and oncogenic pathway repression in tissue. Integrative transcriptomic analysis highlights ISL1 as a key exercise-repressed, epigenetically regulated gene, and identifies FLCN as a colorectal cancer (CRC)-associated methylation target. TCR analysis reveals an exercise-associated increase in systemic repertoire diversity and tissue-specific clonal convergence, thus suggesting antigen-driven recruitment. Collectively, these findings uncover epigenetic and immune remodeling as potential mechanisms of exercise-mediated protection in LS.

Lynch syndrome↗
PubMed2026

Emerging techniques of CRISPR/Cas system in antiviral therapy and diagnostics: Applications, limitations, and translational perspectives.

The CRISPR/Cas (clustered regularly interspaced short palindromic repeats) system is a versatile technology for developing antiviral medicines and editing viral genomes in both diagnostics and vaccine synthesis. Emerging insights into class 2 effectors, such as Cas9, Cas12, and Cas13, which target viral DNA and RNA, have revolutionized vaccines against viruses such as HIV, HPV, HBV, and EBV. Innovative diagnostic techniques such as SHERLOCK, DETECTR, and FELUDA have demonstrated system's diversity and accuracy in detecting the virus markers, supporting clinical decision-making, indicating adaptability and precision of CRISPR. This review critically evaluates CRISPR's role in RNA editing, emphasizing its importance for functional genomics and development of recombinant vaccines. Translational challenges are critically discussed, including off-target effects, delivery limitations, and ethical issues, for which unique approaches such as high-fidelity Cas variants, non-viral delivery systems, and bioethical frameworks are evaluated to address these limitations. This review also covers other social implications, such as accessibility and biosecurity risks, associated with CRISPR technologies Collectively, these advances underscore the transformative potential of CRISPR technologies in shaping next-generation antiviral diagnostics and therapeutics.

CRISPR-Cas Systems↗
PubMed2026

Mapping Wastewater Pathogens and Their Associated Environmental and Public Health Risk Factors: A Systematic Review and Meta-Analysis.

BACKGROUND: Wastewater-based epidemiology (WBE) has emerged as a critical tool for public health surveillance, yet its application across diverse pathogens and geographical settings remains inconsistent. This systematic review synthesizes global evidence on wastewater surveillance to identify associated risk factors. METHODS: Following PRISMA 2020 guidelines (PROSPERO: CRD420261297382), a systematic search was conducted across PubMed, Scopus, Google Scholar, and Web of Science for studies published between 2000 and 2025. RESULTS: Thirty-nine peer-reviewed studies were included. The evidence base is geographically skewed toward the European Region (48.7%) and the Americas (23.1%), with significant underrepresentation in LMICs. Viruses were the primary biological target (89.7%), followed by bacteria (7.7%) and parasites (2.6%). A proportion meta-analysis of 31 eligible studies demonstrated a pooled wastewater pathogen detection prevalence of 62% (95% CI: 47.5-74.6%), with the European Region yielding the highest regional estimate (73%) and the African Region the lowest (8.3%). Conventional PCR and sequencing methods showed higher pooled detection rates (92.4% and 90.1%, respectively) than RT-qPCR (47.9%). CONCLUSION: WBE provides a robust early-warning system indicating a need for broader pathogen diversity, incorporating bacterial and parasitic surveillance and expansion into rural and resource-limited regions.

Contamination↗
PubMed2026

Dengue and chikungunya vaccines past, present and future: implications for travelers.

PURPOSE OF REVIEW: Novel vaccines for dengue and chikungunya viruses offer new prevention options against two globally important arboviral diseases. This review summarizes recent developments in vaccine licensure, implementation, real-world experience and research priorities, with emphasis on implications for both endemic populations and travelers. RECENT FINDINGS: Of the three live-attenuated dengue vaccines licensed to date, TAK-003 is authorized in >40 countries and Butantan-DV in Brazil, while manufacturing of CYD-TDV is discontinued. Long-term and postmarketing data continue to refine understanding of serotype-specific protection, waning immunity, and rare adverse events.For chikungunya, two single-dose vaccines are licensed-a live-attenuated vaccine (VLA1553) and virus-like particle vaccine (PXVX0317). Uptake is guided by emerging safety and effectiveness data, with each platform offering potential advantages in different settings.Further data on long-term protection, safety, effectiveness, use in vulnerable populations and integration into outbreak management and immunization systems is anticipated. SUMMARY: Dengue and chikungunya vaccines are increasingly being used in immunization programs and pretravel consultations. Further real-world data are needed-particularly for seronegative dengue vaccine recipients and older, immunocompromised or medically at-risk adults. Research priorities include developing single-dose, nonlive dengue vaccines suitable for high-risk groups, understanding long-term chikungunya vaccine performance, and exploring broader flaviviral or pan-arboviral platforms.

Humans↗
PubMed2026

Targeting TP53 in triple-negative breast cancer: Molecular pathogenesis, therapeutic implications, and emerging pharmacological strategies.

Triple-negative breast cancer (TNBC) remains a highly aggressive and therapeutically challenging subtype, defined by the absence of oestrogen, progesterone, and HER2 expression. Tumour Protein 53 (TP53) mutations represent the most frequent genetic alteration, occurring in over 80% of cases and driving tumour initiation, progression, and therapeutic resistance. Mutant p53 proteins not only lose canonical tumour-suppressive functions but also often acquire gain-of-function (GOF) oncogenic properties that promote metastasis, genomic instability, and resistance to mechanisms like ferroptosis. This review examines the biological role of TP53 in TNBC pathogenesis and evaluates emerging pharmacological strategies aimed at targeting these vulnerabilities. Key approaches include the pharmacological reactivation of mutant p53 using small molecules such as APR-246, COTI-2, and the mutation-specific reactivator rezatapopt (PC14586), which has shown significant clinical tumour reduction in Y220C-mutant patients. Other strategies involve targeted protein degradation, the exploitation of synthetic lethal interactions (e.g., Chk1 or Aurora kinase B inhibition), and the use of natural products like cryptolepine or piperine derivatives. Recent clinical evidence further highlights the potential of combining epigenetic agents like decitabine with chemotherapy in TP53-mutant populations. Integrating TP53 mutation status into biomarker-driven treatment paradigms is a pivotal step toward achieving precision oncology and improving clinical outcomes for patients with TNBC.

Precision oncology↗
PubMed2026

Hydroxyl Radical Inactivation of Vesicle-Cloaked and Free Murine Norovirus: Linking Biomolecular Oxidation to Lifecycle Disruption and Infectivity Loss.

Hydroxyl radicals (•OH) play a central role in inactivating human viruses during advanced oxidation processes for water and wastewater treatment, solar disinfection, and natural attenuation in sunlit aquatic environments. Human norovirus, a leading cause of gastroenteritis, is efficiently transmitted through water and exhibits strong environmental persistence. The recent discovery of vesicle-cloaked virus clusters (viral vesicles) further challenges water treatment and reuse, particularly for norovirus elimination. We investigated •OH inactivation kinetics and mechanisms of murine norovirus 1 (MNV-1), a human norovirus surrogate, in free-virus and vesicle-cloaked forms. •OH rapidly inactivated both MNV-1 vesicles and free MNV-1 with second rate constants of ∼1010 M-1 s-1; however, the vesicle membrane provided a 2.24-fold protective effect to cloaked MNV-1, resulting in slower inactivation kinetics than those of free MNV-1. •OH oxidized viral capsid proteins and genomes together with vesicle proteins and lipids, resulting in impaired CD300lf receptor and cell-based binding, disrupted genome replication, and diminished viral assembly. Despite these biochemical and functional impairments, most vesicle structures remained largely intact following •OH exposure. This study establishes a quantitative framework linking biomolecular damage to viral infectivity loss through functional impairment and lifecycle disruption, providing mechanistic insights into advance water disinfection strategies and public health protection.

Norovirus↗
PubMed2026

Molecular Determinants and Therapeutic Targeting of Stop Codon Readthrough in Eukaryotic Translation.

Accurate translation termination is essential for proteome integrity and in eukaryotes is primarily governed by the release factors eRF1 and eRF3, which ensure precise recognition of stop codons and efficient release of nascent polypeptides. However, proteome integrity is challenged by mutations that generate premature termination codons (PTCs), leading to truncated, nonfunctional proteins and degradation of the aberrant transcript via nonsense-mediated mRNA decay (NMD). Collectively, these events account for ∼1800 human genetic diseases. Translational readthrough, the process by which near-cognate tRNAs decode stop codons and allow ribosomes to continue elongation beyond the stop codon, represents a possibility to suppress PTCs and restore full-length protein synthesis. Initially discovered in viruses as a mechanism to expand coding capacity, readthrough is now recognized as a regulated feature of eukaryotic gene expression influenced by both cis-acting sequence elements and trans-acting factors. Recent evidence highlights the remarkable context dependence of readthrough, revealing variation across transcripts, tissues, and developmental stages. In this review, we examine the molecular determinants that define stop codon recognition and readthrough efficiency, with particular emphasis on nucleotide context. We further discuss the mechanisms and binding sites of small molecules that promote PTC readthrough, and summarize the clinical development landscape of readthrough-inducing compounds for the treatment of diseases caused by nonsense mutations.

Humans↗
PubMed2026

Epigenetics and In Silico Transcriptome Analysis of Pediatric Acute Myeloid Leukemia.

Pediatric acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy that accounts for about 15%-20% of childhood leukemias. Despite therapeutic advances, relapses remain common, and survival for high-risk patients is below 60%. Unlike adult AML, pediatric AML displays distinct genetic mutations, including FLT3-ITD, NPM1, KMT2A rearrangements, and core-binding factors (CBF) fusions, as well as extensive epigenetic dysregulation. Aberrant DNA methylation, histone modifications, and altered non-coding RNA expressions disrupt hematopoietic differentiation and activate oncogenic transcriptional networks. Recent advances in silico transcriptomic analysis have transformed the study of pediatric AML by integrating gene expression and epigenetic data to identify molecular drivers and regulatory networks. Computational RNA-seq pipelines and pathway analyses have highlighted key epigenetic regulators, including DNMT3A, TET2, and HDACs, as potential therapeutic targets. Multi-omics approaches combining transcriptomic, methylomic, and chromatin accessibility data are increasingly used to define biomarkers for diagnosis, prognosis, and therapeutic response. This review provides a comprehensive overview of the molecular and epigenetic landscape of pediatric AML, emphasizing the power of in silico transcriptome analysis to uncover disease mechanisms, refine patient stratification, and guide the development of precision-based epigenetic therapies aimed at improving long-term outcomes in children with AML.

Humans↗
PubMed2026

Oxygen-controlled gamma-irradiation and annealing enable terminal processing of collagen-based biomaterials.

Gamma irradiation is a widely adopted method for terminal sterilization of medical devices; however, its application to collagen-based extracellular matrix (ECM) materials remains limited due to radiation-induced degradation of structural integrity and mechanical performance. Here, we present an engineered terminal-processing strategy that combines oxygen controlled gamma irradiation (25-30 kGy) with post-irradiation dry-heat annealing to preserve ECM functionality while achieving effective sterilization. By modulating oxygen availability during irradiation, this approach alters radical reaction pathways, suppresses oxygen-mediated oxidative degradation, and generates a metastable radical-containing intermediate, which is subsequently converted into a structurally stabilized collagen network through thermal annealing. As a result, the treated matrices preserved ECM integrity and recovered clinically relevant mechanical properties. Furthermore, the process achieved cumulative viral reductions exceeding 6 log10 across a representative panel including enveloped and non-enveloped DNA and RNA viruses, demonstrating compatibility with sterility assurance and viral safety requirements for biologically derived medical devices. Notably, preliminary observations indicate that mechanical integrity can be partially preserved even at elevated irradiation doses up to 50 kGy, suggesting potential applicability to sterilization validation frameworks requiring higher assurance levels. Overall, this work establishes a mechanistically grounded terminal-processing paradigm that enables control of radical fate, decouples sterilization efficacy from material degradation, and integrates sterilization, viral safety, and functional preservation into a unified and scalable framework for collagen-based biomaterials. This concept repositions gamma-irradiation from a purely degradative process to a controllable tool for tuning collagen structure and performance.

Gamma Rays↗
PubMed2026

Culture of infectious human norovirus isolated from live contaminated oysters.

Human noroviruses are a major cause of foodborne outbreaks worldwide. Filter-feeding shellfish, such as oysters, can bioaccumulate these viruses in their digestive tissue when grown in sewage-impacted coastal areas and are often implicated in norovirus foodborne outbreaks. Despite the high sensitivity of current molecular assays, these methods for norovirus detection in shellfish fail to distinguish between infectious and non-infectious particles. Assessing norovirus infectivity in shellfish remains a challenge due to the lack of suitable isolation methods that maintain capsid integrity. In this study, a protocol for isolating infectious norovirus from oyster tissues, based on chloroform-butanol elution and polyethylene glycol concentration (CB-PEG), was optimized for the recovery of human norovirus GI and GII. While CB-PEG method recovered various norovirus GI and GII genotypes, it was less efficient at the genomic level than a protocol based on proteinase K elution (adapted from ISO 15216) and showed genotype-dependent viral recovery rates. By optimizing the flocculation step, we improved the method's compatibility with human intestinal enteroid (HIE) cultures. Using this approach, we successfully quantified infectious norovirus GII.3 titers recovered from artificially-contaminated live oysters. Interestingly, infectious virus was better isolated following a freezing step of the digestive tissues, with titers ranging from 13 to 40 TCID50/mL for positive samples. In conclusion, this study established an optimized methodological approach for the relative quantification of infectious norovirus GII.3 in shellfish, paving the way for future research on viral persistence and inactivation strategies in this foodstuff.

Norovirus↗
PubMed2026

Mechanisms linking the gut microbiota to colorectal cancer development and progression.

Colorectal cancer remains a leading cause of global cancer mortality, with a concerning rise in early-onset cases driven by complex interactions between environmental exposures, lifestyle factors, and host genetics. Mounting evidence indicates that gut microbiota dysbiosis critically modulates this oncogenic process, acting as an active participant rather than a passive bystander. This review systematically synthesizes the dichotomous roles of the intestinal microbiome in colorectal tumorigenesis through the conceptual framework of the driver-passenger model. We discuss how early initiating driver bacteria, such as Polyketide synthase-positive Escherichia coli and enterotoxigenic Bacteroides fragilis, compromise mucosal barriers, induce chronic mucosal inflammation, and inflict direct genomic instability. As the local tumor microenvironment undergoes profound metabolic remodeling, opportunistic passenger pathogens, notably Fusobacterium nucleatum, become enriched, further promoting cellular proliferation and facilitating tumor immune evasion. Conversely, protective commensals, exemplified by Clostridium butyricum and Streptococcus thermophilus, exert robust tumor-suppressive effects through multifaceted mechanisms. These beneficial microbes actively antagonize malignant progression by redirecting tumor metabolic fluxes toward oxidative stress, orchestrating deep epigenetic reprogramming, and degrading core oncoproteins to reverse chemoresistance. Transitioning from fundamental mechanisms to clinical application, we evaluate a comprehensive spectrum of microbiota-targeted interventions, encompassing non-invasive diagnostic biomarkers, fecal microbiota transplantation, engineered bacteria, phage therapy, and postbiotics. Finally, we critically address the formidable translational challenges associated with microbial heterogeneity, long-term safety, and regulatory standardization, aiming to provide a balanced perspective on integrating microbiome-based strategies into next-generation precision oncology for colorectal cancer.

Humans↗
PubMed2026

PPRC1 is a prognostic biomarker and key regulator of mitochondrial oxidative phosphorylation in multiple myeloma.

BACKGROUND: Multiple myeloma (MM) remains an incurable haematological malignancy, underscoring the need for novel prognostic biomarkers and therapeutic targets. This study aimed to investigate the clinical and biological significance of peroxisome proliferator-activated receptor gamma coactivator-related protein 1 (PPRC1) in MM. METHODS: Expression and clinical data were obtained from public databases and an independent local cohort. Kaplan-Meier and Cox regression analyses were performed to evaluate prognostic value. Differential expression analysis, pathway enrichment analysis and single-cell RNA-seq data analysis were used to explore biological functions. PPRC1 was silenced in MM cell lines using siRNA to assess its effects on cell survival and oxidative phosphorylation. RESULTS: PPRC1 was significantly upregulated in MM and was associated with advanced disease stage and poor overall survival. Multivariate Cox analysis identified PPRC1 as an independent prognostic factor. A nomogram incorporating PPRC1 and revised-ISS improved survival prediction. Functional analyses revealed that PPRC1 was positively correlated with oxidative phosphorylation and oncogenic signalling pathways. A potential connection between PPRC1 expression and immune cell infiltration was observed. PPRC1 knockdown inhibited cell proliferation, induced cell cycle arrest and apoptosis and impaired oxidative phosphorylation in MM. CONCLUSIONS: PPRC1 acts as a prognostic biomarker and metabolic regulator in MM by sustaining mitochondrial oxidative phosphorylation. These findings highlight PPRC1 as a potential therapeutic target in MM.

Humans↗
PubMed2026

In vitro evaluation of sacituzumab govitecan in non-small cell lung cancer with actionable genomic alterations.

PURPOSE: The TROP2-directed antibody-drug conjugate sacituzumab govitecan (SG) has shown substantial therapeutic benefit in several malignancies; however, preclinical evidence supporting its activity in non-small cell lung cancer (NSCLC) is rare. MATERIALS AND METHODS: We evaluated 16 NSCLC cell lines harboring actionable genomic alterations for TROP2 expression and treated them with SG or its unconjugated payload, SN-38, for 3 days to determine cytotoxic effects. Apoptosis and DNA damage signaling were assessed using flow cytometry and western blot. SG internalization and lysosomal trafficking were visualized by confocal microscopy. RESULTS: SG had greater cytotoxic potency than SN-38, across all NSCLC cell lines, independent of genomic subtype or TROP2 expression level. Cell lines that were sensitive to SN-38 showed enhanced vulnerability to SG (P < 0.0001). Higher SLFN11 expression, a recognized determinant of SN-38 responsiveness, correlated with lower SG IC50 values. Both SG and SN-38 triggered apoptotic and DNA damage responses within 6-48 h, with SG inducing stronger activation of these pathways than SN-38. SG was efficiently taken up in CUTO17 and SNU-3173 adenocarcinoma cells, with more than 60% of the conjugate internalized within 3 h and subsequently localized to lysosomes. CONCLUSION: Our study provides in vitro evidence supporting the potential activity of SG in NSCLC with actionable genomic alterations. The efficacy of SG closely paralleled intrinsic sensitivity to the SN-38 payload, suggesting that DNA-damage responses, rather than oncogenic drivers, predominantly contribute to SG activity.

Actionable genomic alterations↗
PubMed2026

Nanopore-based epigenomic profiling reveals the absence of widespread CpG methylation in the African swine fever virus genome.

DNA methylation is a critical epigenetic mechanism implicated in regulating replication and transcription in DNA viruses. However, the epigenetic landscape of African swine fever virus (ASFV), a large double-stranded DNA virus infecting pigs, remains controversial. Here, we systematically profiled the DNA methylome of the first ASFV strain isolated in Hong Kong (HK_NT_202103) using Oxford Nanopore Technologies (ONT) R10.4.1 sequencing. We employed a paired design: native whole-genome sequencing (WGS) against a methylation-free whole-genome amplification (WGA) control. Using conservative thresholds, we found no evidence of 5-methylcytosine (5mC), especially typical CpG methylation, across the viral genome. Importantly, clear CpG methylation signals were successfully detected in the host genome from WGS data, confirming the functionality of the workflow to detect 5mC at CG sites. While widespread 5mC seems absent, a small number of putative N6-methyladenine (6mA) loci were identified. A specific 6mA candidate exhibited raw ionic current disruptions and gene-level intersection with another ASFV isolate (CAS19-01/2019), although it lacked single-base consensus across different methylation callers or between the two isolates. Although our biological findings are restricted to a single isolate under specific experimental conditions, this study introduces a novel, highly rigorous ONT framework for viral epigenomics research. Furthermore, the absence of ASFV CpG methylation indicates that host CpG-depletion remains a viable strategy for viral metagenomic enrichment. Ultimately, our work offers a critical methodological baseline for ASFV surveillance and highlights the necessity of targeted experimental validation for rare viral modifications.

African Swine Fever Virus↗
PubMed2026

The gut microbiota-obesity axis in the pathogenesis and prognosis of breast cancer.

BACKGROUND: Breast cancer (BC) remains a major global health concern, accounting for 11.7% of all cancer cases and ranking as the second leading cause of female cancer-related deaths worldwide. Increasing evidence highlights the interplay between&#xa0;gut microbiota (GM) dysbiosis and obesity-associated metabolic dysfunction in BC progression. This review aims to elucidate&#xa0;the role of GM in obese patients with BC. METHODS: A systematic literature search was conducted in PubMed and Web of Science databases for publications from July 2015 to January 2025. Search terms combined BC, GM, obesity, dysbiosis, immunity, and microbiome. Article selection prioritized studies investigating microbial alterations in BC patients, mechanistic links between obesity and cancer progression, and GM-targeted interventions. Both original studies and authoritative reviews were included, supplemented by manual reference screening. DISCUSSION: Obesity may trigger systemic inflammation, altered adipokine secretion, and disrupted steroid hormone metabolism via gut-derived &#x3b2;-glucuronidase activity, thereby exacerbating BC occurrence and recurrence. GM dysbiosis-driven metabolites such as branched-chain amino acids (BCAAs) and short-chain fatty acids (SCFAs) can activate oncogenic signaling pathways and immunosuppressive myeloid-derived suppressor cells (MDSCs), fostering tumor immune evasion. Conversely, dietary interventions, probiotics, and fecal microbiota transplantation (FMT) can alleviate dysbiosis, strengthen gut barriers, and restore anti-tumor immunity, improving chemotherapy response and reducing recurrence. However, challenges persist in deciphering BC subtype-related microbial signatures and optimizing microbiota-targeted therapies. CONCLUSION: Future longitudinal studies are needed to clarify causal relationships, validate microbial biomarkers, and translate preclinical findings into clinical applications. Addressing the gut-breast axis may offer transformative potential for precision oncology in obesity-driven BC.

Humans↗