ABSTRACT Hepatocellular carcinoma (HCC) occurrence and progression are closely associated with hepatitis B virus (HBV) infection. Heat shock protein family A member 1B (HSPA1B), a key member of the heat shock protein 70 family, has attracted extensive attention in viral infection research, yet its specific function in HBV‐related HCC pathogenesis remains largely unknown. HSPA1B was identified as a cccDNA‐binding protein using the biotin‐avidin system, and its role in HBV infection and HCC progression was systematically investigated. In vivo experiments were performed using a mouse model established by tail vein injection of prcccDNA and pCMV‐KRAB‐Cre to evaluate the impact of HSPA1B on HBV transcription and replication. RNA sequencing was applied to HBV‐infected HepG2‐NTCP cells to analyze the differentially expressed genes regulated by HSPA1B, aiming to clarify the molecular mechanism underlying HSPA1B‐mediated promotion of HBV transcription and replication. Meanwhile, Western blot, RT‐qPCR, co‐immunoprecipitation and Transwell assays were used to explore the relationship between HSPA1B and HBV‐related HCC. We found that HSPA1B promoted HBV transcription and replication. Mechanistically, the increased expression of HSPA1B promoted HBV transcription and replication by downregulating SOX4 and enhancing the stability of the HBx protein. Further research indicated that HSPA1B can enhance the metastasis and invasion of HBx‐mediated HCC. Collectively, these results demonstrate a novel function of HSPA1B in regulating HBV transcription and HBV‐related HCC metastasis, indicating that HSPA1B may serve as a promising therapeutic target for HBV‐associated HCC.
ABSTRACT Tumors often exhibit immunosuppressive microenvironments (TMEs) and present as immunologically “cold.” Oncolytic viruses (OVs), particularly engineered vaccinia viruses (oncoVVs), are an encouraging therapy that directly lyses cancer cells and reprograms the TME. In this study, we evaluated the therapeutic potential of an oncolytic vaccinia virus expressing human C‐type lectin domain family 2 member A (oncoVV‐CLEC2A) in melanoma and ovarian cancer cells. OncoVV‐CLEC2A elevated reactive oxygen species (ROS) levels, suppressed Nrf2‐mediated antioxidant responses, and triggered autophagy. These changes promoted cytokine production (IL‐6, IFN‐α/β/γ, TNF‐α) via activation of AP‐1 and IRF3/7. In a B16‐F10 melanoma model, oncoVV‐CLEC2A increased serum levels of IFN‐γ, accompanied by augmented infiltration of CD8 + T cells and activation of NK cells. Taken together, oncoVV‐CLEC2A reshapes the TME by intensifying oxidative stress and autophagic activity, effectively turning “cold” tumors “hot.” Notably, the mutual reinforcement between ROS production and autophagy activation not only enhances viral replication but also triggers cytokine‐mediated immunity.
ABSTRACT Children with lymphoreticular malignancies are highly vulnerable to respiratory viral infections (RVIs) because of disease‐ and chemotherapy‐related immunosuppression, yet data on their epidemiology, clinical spectrum, and outcomes from resource‐limited settings remain scarce. This study aimed to characterize the seasonal distribution, clinical presentation, and outcomes of RVIs other than SARS‐CoV‐2 in febrile children with lymphoreticular malignancies at a tertiary care centre in India. In this prospective, descriptive, cross‐sectional study (May 2023–November 2024), 33 children under 12 years of age with lymphoreticular malignancies were enrolled at a tertiary care centre in Delhi, India, contributing 70 febrile episodes with respiratory symptoms. All episodes were screened for SARS‐CoV‐2 by rapid antigen test at admission, independent of the viral PCR panel, and none tested positive. Nasopharyngeal swabs were analyzed by multiplex real‐time PCR (TRUPCR® Respiratory Viral Pathogen Panel Kit, 3B BlackBio, Bhopal, India; CFX96™, Bio‐Rad, Hercules, CA, USA) targeting 18 other respiratory viral pathogens. Respiratory viruses were detected in 34% of episodes (24/70). The most prevalent viruses identified were human coronavirus (HCoV α/β, 21%), human rhinovirus (HRV, 17%), human parainfluenza virus type 3 (HPIV‐3, 13%), influenza A (IAV,13%), and human adenovirus (HAdV, 13%). Co‐infections occurred in 13% of virus‐positive episodes, with HAdV being the predominant co‐pathogen. Upper respiratory tract infections (URTI) predominated (87%). Among virus‐positive episodes, breathlessness ( p = 0.005), URTI/LRTI classification ( p < 0.001), erythrocyte sedimentation rate (ESR; p < 0.001), and abnormal chest radiography ( p < 0.001) were significantly associated with viral status. Two patients (6%) died, both attributed to lower respiratory tract infection (LRTI) caused by human parainfluenza virus type 4 (HPIV‐4). The remaining 66% of episodes were PCR‐negative. No SARS‐CoV‐2 was detected in this cohort at any point during the study period. In approximately one‐third of febrile episodes of children with hematologic malignancies, a viral pathogen could be detected. Both fatalities in this cohort were associated with HPIV‐4‐related LRTI; although the numbers are small, this finding warrants clinical attention and continued epidemiological surveillance in this population. Multiplex PCR supports targeted management; prospective, multicentre stewardship studies are needed.
ABSTRACT Cervical cancer is the fourth most common malignancy in women worldwide. Biomarker‐assisted screening may improve diagnostic accuracy, but biomarkers predicting progression of low‐grade squamous intraepithelial lesions (LSIL) remain limited. We integrated single‐cell RNA sequencing and spatial transcriptomics to identify prognostic biomarkers associated with LSIL outcomes, followed by validation using improved in situ sequencing (IISS). Analysis of 341,978 single cells identified eight major cell populations and twelve epithelial subclusters, including a previously unrecognized subcluster, epi8. Although mainly derived from normal cervix, epi8 exhibited cancer‐associated features and shared molecular characteristics with the prognostic biomarkers FAM19A4 and miR124‐2 . In situ sequencing showed that epi8 localized adjacent to human papillomavirus‐infected basal cells, with stage‐dependent spatial changes during disease progression. Retrospective analysis further demonstrated that epi8‐associated markers stratified LSIL into progression, persistence, and regression groups, with CRYAB high /GAS5 high associated with progression and RPLP1 high /SNHG5 high associated with regression. We identified a previously unrecognized epithelial subcluster associated with early cervical carcinogenesis and demonstrated that its molecular markers enable risk stratification of LSIL, providing candidate biomarkers for precision triage in cervical cancer screening.
ABSTRACT Torque teno virus (TTV) is a recognized marker of immune competence, but its relevance in severe bacterial infections is unclear. We evaluated prevalence, viral load, and clinical relevance of TTV viremia in complicated Staphylococcus aureus infection (CSAI). In this ancillary analysis of two prospective pharmacokinetic cohort studies at a Swiss university hospital, stored plasma samples were tested for TTV DNA using TTV R‐GENE PCR, and cytokines were measured by multiplex immunoassay. Associations between TTV load, inflammatory biomarkers, and clinical outcomes (including 30‐day mortality) were assessed. Among 103 patients (median age 67.9 years; 85% with bloodstream infection), TTV viremia was detected in 76% at baseline with a median viral load of 2.85 log 10 copies/mL (IQR 1.87–3.56). Levels remained stable over 1 week despite declining inflammatory markers. Baseline TTV load was numerically higher in 30‐day non‐survivors (3.53 vs. 2.83 log 10 copies/mL; p = 0.054) and not associated with mortality after adjusting for age, sex, and SOFA score (OR 1.29 per log 10 increase; 95% CI 0.82–2.02; p = 0.268). TTV load was not associated with ICU admission, bacteremia duration, or length of stay. TTV viremia is common in CSAI but shows no significant association with inflammation or short‐term outcomes, suggesting limited value for risk stratification.
