Tokyo Medical University

To examine the characteristics of major depressive episodes (MDEs) with underlying anxious distress (ANXD), specifically whether these characteristics are influenced by the presence of Benazzi's depressive mixed state (DMX) or are unique to ANXD. Sociodemographic and clinical characteristics of patients with or without ANXD and of patients with ANXD with or without Benazzi's DMX were retrospectively examined in 160 patients with MDEs. Overall, 45.6% of patients met the criteria for ANXD. The mean Quick Inventory of Depressive Symptomatology Self-Report (QIDS-SR) total score and frequencies of Benazzi's DMX, psychotic features, and psychiatric adverse events associated with antidepressants were significantly higher in patients with ANXD than in those without ANXD. Benazzi's DMX and male sex were independently associated with ANXD (odds ratio, 95% confidence interval: 4.95 [2.45-10.04], p < 0.001 and 2.11 [1.04-4.27], p < 0.038, respectively), regardless of depressive symptom severity or bipolar disorder diagnosis. In patients with ANXD with Benazzi's DMX, the rate of bipolar disorder diagnosis, QIDS-SR suicidal ideation score, and number of MDEs were significantly higher. The frequency of psychiatric adverse events associated with antidepressants and sociodemographic disadvantages in education and marital status were also numerically higher compared with patients with ANXD only. Although ANXD itself is not a defining feature of bipolarity, its coexistence with Benazzi's DMX suggests an underlying bipolar disorder. Furthermore, high suicidality, high frequency of psychiatric adverse events associated with antidepressants, and sociodemographic disadvantages may be influenced by Benazzi's DMX. Further studies are required to validate these findings.

Moyamoya disease (MMD) has a strong genetic basis, with the rare RNF213 p.Arg4810Lys variant (rs112735431) representing a major risk factor, while the broader genetic architecture and disease-relevant vascular cell types remain incompletely understood. We conducted a genome-wide association study in Japanese individuals (n=47 656; 401 MMD cases and 47 255 controls). Population-level features at MMD risk loci were examined by regional allele frequency and haplotype analyses. We performed single-nucleus RNA-seq of superficial temporal arteries from patients with MMD (n=3). Cell type-specific enrichment of genome-wide association study signals was assessed using the Single-Cell Disease Relevance Score. Endothelial signatures were validated by integration with publicly available single-cell data sets from controls (n=5) and immunohistochemistry for candidate markers (n=1). Beyond rs112735431, we identified a genome-wide significant signal in the HDAC9-TWIST1 region (rs12530920; P=3.3×10-14; odds ratio, 1.77). Conditional analysis on rs112735431 revealed a protective RNF213 missense variant, p.Asp1331Gly (rs8074015; P=3.7×10-9; odds ratio, 0.53), whose minor allele was mutually exclusive with rs112735431-A on haplotypes. Population analysis revealed geographic variation and extended haplotype structure of the rs112735431-A allele in Japan. Single-nucleus RNA-seq identified a mesenchymal-like endothelial cell (MEC) population with selective FN1 expression. Genome-wide association study-prioritized disease genes were strongly enriched in MECs. MECs showed mesenchymal pathway activation with a regulatory program distinct from canonical endothelial states. The proportion of MECs was markedly increased in MMD (72% versus 28% in controls), and fibronectin 1 (FN1) expression in endothelial regions was confirmed by immunohistochemistry. Our findings identify a protective RNF213 p.Asp1331Gly variant (rs8074015) that is mutually exclusive with the known rs112735431-A allele. Genetic risk converges on an MEC state markedly expanded in MMD.

Streptococcus pneumoniae commonly colonizes the nasopharynx asymptomatically, but certain conditions trigger its transition to invasive disease. The mechanisms driving this expansion are not fully understood. We used a murine model of pneumococcal nasopharyngeal colonization followed by respiratory syncytial virus (RSV) infection to investigate bacterial expansion. We measured bacterial loads in nasal and bronchoalveolar lavage fluids and analyzed growth arrest-specific protein 6 (Gas6) expression. The effect of the Axl receptor inhibitor BGB324 (bemcentinib) on RSV-mediated growth was assessed, and macrophage phenotypes were analyzed in vivo and in vitro. RSV infection increased bacterial loads and upregulated Gas6 expression in the nasal cavity. Inhibition of the Axl receptor with BGB324 effectively attenuated RSV-mediated pneumococcal growth. Furthermore, RSV infection decreased M1-like macrophage markers in the nasal cavity. In vitro assays confirmed that Gas6 suppresses M1 polarization, fostering an environment conducive to bacterial proliferation. Our findings reveal that the RSV-induced Gas6/Axl axis facilitates pneumococcal overgrowth by modulating macrophage function. Targeting this axis or modulating macrophage polarization may offer novel therapeutic strategies for preventing severe pneumococcal infections exacerbated by RSV.

Bacterial extracellular vesicles (EVs) are emerging mediators of host-microbe communication; however, their role in human disease remains unclear. Here, we identify two bacterial small tRNAs (tsRNAs) enriched in gut commensal Klebsiella pneumoniae-derived EVs (KpEVs) that are markedly elevated in the serum of patients with hepatocellular carcinoma (HCC). These tsRNAs suppress the production of nitric oxide (NO) by macrophages, a critical antitumor molecule. Notably, KpEVs reach the liver more efficiently than bacterial cells, thus facilitating bacterial translocation from the gut by inducing distinctive immunosuppressive macrophages. Mechanistically, KpEVs drive an M2-like macrophage phenotype, enhance phagocytosis, and inhibit both NO production and caspase-1-dependent pyroptosis during infection. The results show that KpEVs shape a liver microenvironment promoting gut-liver bacterial translocation, which may also influence HCC progression. Our study uncovers a previously unrecognized strategy by which K. pneumoniae exploits EVs to modulate host immunity of distant organs, highlighting tsRNAs as potential biomarkers and therapeutic targets.

Protein phosphorylation is a central post-translational modification regulating cellular signaling, frequently dysregulated in cancer. Mass spectrometry (MS)-based phosphoproteomics has emerged as a powerful approach to systematically profile phosphorylation events, thereby revealing aberrant kinase activity and therapeutic vulnerabilities that are not captured by genomic or transcriptomic analyses. Recent advances across the workflow-including optimized sample preparation and phosphopeptide enrichment, isotope- or label-free quantitative strategies, high-resolution mass spectrometry platforms, specialized algorithms for site identification and quantification, and integrative informatics analyses-have enabled the detection of tens of thousands of phosphorylation sites even from small clinical specimens. These developments have facilitated the characterization of signaling pathways across diverse cancer types, leading to the identification of targetable kinases and informing therapeutic strategies. In this review, we highlight studies that employed phosphoproteomic analyses of clinical specimens or patient-derived cancer cells to delineate signaling characteristics and to propose and validate therapeutic targets. Collectively, MS-based phosphoproteomics is poised to become a cornerstone of precision oncology. By enabling comprehensive and quantitative mapping of phosphorylation events, this technology allows mechanistic dissection of cancer signaling pathways and uncovers therapeutic vulnerabilities that may be exploited with targeted agents.

Gene therapy has emerged as a promising therapeutic strategy in oncology by targeting the molecular mechanisms that drive malignant transformation. Among gene-based approaches, oncolytic viruses (OVs) are distinctive in their ability to selectively replicate within tumor cells, induce direct oncolysis, and simultaneously stimulate systemic antitumor immunity by exploiting defects in cancer cell antiviral responses. Recent studies have identified Coxsackievirus A11 (CVA11) as a highly potent immunostimulatory OV. CVA11 demonstrates strong tumor-selective replication, robust cytolytic activity, and marked induction of antitumor immune responses. Notably, CVA11 has been shown to induce complete tumor regression in human non-small cell lung cancer models. In addition, CVA11 enhances chemosensitivity in oxaliplatin-resistant colorectal cancer and may have broader applicability in treatment-refractory malignancies, including pancreatic cancer. This review summarizes current gene therapy strategies for malignant tumors with a particular focus on the biological properties and therapeutic potential of CVA11. We discuss its mechanisms of tumor selectivity, immune activation, and potential integration with chemotherapy and gene-based cancer vaccines. Collectively, these findings position CVA11 as a promising next-generation oncolytic virus for cancer gene therapy and immunotherapy.