Tokai University

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.

In this nationwide retrospective study, we sought to evaluate the oncologic and functional outcomes and safety of transoral surgery (TOS) for hypopharyngeal and laryngeal squamous cell carcinomas in Japan and to clarify the appropriate indications for various TOS modalities. Data were obtained from the Head and Neck Cancer Registry of Japan. Patients who underwent transoral or endoscopic resection between 2011 and 2016 were selected. Detailed clinical information was collected from 55 institutions using web-based case report forms. Surgical modalities analyzed included endoscopic mucosal resection (EMR), endoscopic submucosal dissection (ESD), endoscopic laryngopharyngeal surgery (ELPS), transoral laser microsurgery (TLM), and transoral videolaryngoscopic surgery (TOVS). In total, 1825 patients were included (hypopharyngeal cancer, 62.5 %; laryngeal cancer, 37.5 %). Most cases (77.5 %) were T1 or lower, and 90.8 % were Stage II or earlier. TLM is predominantly used for glottic cancers, ELPS/ESD for superficial hypopharyngeal lesions, and TOVS for more advanced tumors, reflecting distinct indications for each modality. The 5-year disease-specific survival (DSS), recurrence-free survival (RFS), and overall survival (OS) were 97.1 %, 84.3 %, and 85.4 %, respectively. The laryngeal preservation rate was 98.2 %. Tracheostomy was performed in 5.0 % of cases, mainly for airway protection; major complications, including pneumonia (2.4 %), hemorrhage (1.1 %), fistula formation (0.4 %), and vocal cord fixation (2.6 %), occurred in <3 % of patients. Postoperative functional outcomes were favorable, with persistent dysphagia (Functional Outcome Swallowing Scale stage ≥ 3) in 1.6 % and tube feeding dependence in 1.8 %. Non-robot-assisted TOS demonstrated excellent oncologic control and functional preservation of the larynx with low complication rates in early-stage hypopharyngeal and laryngeal cancers. Each surgical modality has distinct indications depending on the tumor site, depth of invasion, and institutional expertise. These findings support the use of TOS as a safe and effective treatment option for selected patients. Further procedural standardization and data accumulation are required to refine the indications and facilitate their broader adoption in clinical practice.

As populations age worldwide, breast cancer mortality among older patients continues to rise despite therapeutic advances. This study investigates differences in treatment patterns and outcomes between older and younger patients with metastatic breast cancer. We analyzed clinical data from the Advanced Breast Cancer Database (ABCD) maintained by the Japanese Breast Cancer Research Group. The dataset included patients registered between June 1, 2020, and October 31, 2023, encompassing clinicopathologic information, treatment details, breast cancer specific survival (BCSS), and overall survival (OS). A total of 1629 patients were included. The frequency of chemotherapy and genomic testing decreased with age, yet patients in their 70s demonstrated treatment durations and survival outcomes comparable to those of younger patients. In contrast, patients aged ≥ 80years exhibited shorter duration of second-line therapy (adjusted HR:0.65, 95% CI: 0.43-1.04) and poorer OS (adjusted HR:0.62, 95% CI: 0.37-1.04) and BCSS (adjusted HR:0.66, 95% CI: 0.38-1.14), despite most deaths being attributable to breast cancer rather than non-cancer-related causes. This multicenter retrospective study demonstrates that patients in their 70s can achieve comparable benefits from systemic therapy to younger individuals, emphasizing the importance of not withholding treatment based solely on chronological age. Conversely, the limited effectiveness of later-line therapies in patients aged ≥ 80 highlights the need for individualized treatment strategies that balance efficacy, quality of life, and comorbidities through comprehensive geriatric assessment and shared decision-making.

This study aimed to present a method for measuring the mechanical strength and electrical chargeretention properties of fibers containing nano-sized oxide particles, which have become widely usedin recent years, and to clarify the fundamental physical properties of these fibers. There have beenfew studies measuring the mechanical and electrical properties of composite fibers containing nanosizedoxide particles. Polyester fibers containing SiO2 and ZrO2 nanoparticles were fabricated usingindustrial techniques to clarify the effect of particle introduction on strength. Furthermore, theelectrostatic charge properties of fibers containing these particles, which act as insulators, weremeasured, revealing that mechanical strength and electrical charge retention properties are mutuallyexclusive parameters. Increasing the nanoparticle content decreased mechanical strength, butprolonged the charge half-life and improved electrostatic retention. Furthermore, it was shown thatthis phenomenon can be represented using an equivalent circuit model of a resistor and a capacitor.

Covalent inhibitors for nucleophilic residues, particularly cysteine (Cys) and selenocysteine (Sec), have resurfaced as precision therapies for modifying disease-associated enzymes. The main advantage of covalent inhibition is its ability to form a stable covalent bond with a particular residue near the binding site. Permanent alteration of Cys and Sec residues by covalent inhibitors is possible since the sulfur and selenium atoms have high chemical reactivities and intrinsic variations in the redox behaviors, which enable the rational design of covalent inhibitors targeting the Cys/Sec residues. Moreover, recent breakthroughs covering a wide range of warheads (reactive moieties of covalent inhibitors), from traditional thiol-selective motifs (e.g., acrylamides) to emerging selenol-selective analogs (e.g., Ebselen D, diacyl furoxan derivatives, etc.), exhibit the potent inhibition against kinases and redox-regulating enzymes having a thiol/selenol group in the active sites. Although we have comprehensively encountered numerous promising therapeutic potentials and preclinical data of Cys/Sec-targeted covalent inhibitors, there is still a room of challenges in attaining the precise Cys-/Sec-selectivity, reducing the warhead toxicity, and improving the in vivo stability. This mini-review combines recent insights and developments of thiol- and selenol-selective warheads within the midst of the intersection of chemical biology and medicinal chemistry. We also discuss future directions of the relevant research with the goal of improved safety and effectiveness. Schematic representation of covalent inhibition: A small-molecule warhead with a guiding system form a covalent bond to the thiol (SH) or selenol (SeH) reactive site of a kinase or redox-regulating enzyme.

Triple junctions between fundamental tectonic units are where different compositions and magmatic processes interact. We investigated the intersection of a spreading center with an island arc within the Philippine Sea Plate, i.e. an arc-ridge-arc triple junction, using a combination of submersible sampling and shipboard geophysics. We use Ar Ar dating, elemental concentrations and Sr-Nd-Pb radiogenic isotope ratios to constrain the structure, age and origin of magmatism as spreading interacted with the arc. Between 33 and 31 Ma the tip of the West Philippine Basin spreading center was in the back-arc west of the Kyushu-Palau arc. Spreading volcanism had mantle-like Ce/Pb and Th/Ce indicating a lack of slab flux. Radiogenic isotopes form a trajectory towards low 143 Nd/ 144 Nd and high 20x Pb/ 204 Pb, but extend to Δ 208 Pb/ 204 Pb > 85 which corresponds to an EM-2-like mantle component rather than pelagic sediment input from the slab. The final stage of spreading-related activity occurred between 31 and 28.5 Ma when the spreading axis rotated from NW-SE to E -W and propagated eastwards into the arc. It resulted in magmatism contemporaneous with the adjacent frontal arc. This final magmatism extended the radiogenic isotopic trajectories observed in the earlier spreading towards less radiogenic Pb and higher 143 Nd/ 144 Nd, i.e. towards MORB from the EM-2 component. However, during the final stage magmatism La/Sm, Nb/Zr increased while Pb and Sr isotopes became progressively more radiogenic, demonstrating a progressive decrease in the degree of partial melting and preferential tapping of the EM-2 component. This change in melt generation and composition appears a common process at the end of spreading. • Magmatism at arc-ridge-arc triple junction in the Philippine Sea Plate was studied. • CBF Rift spreading center intersected KPR arc, caused overlapping MORB magmatism. • Interaction between a volcanic arc and a spreading centre caused excess magmatism. • Spreading center at wanning stage preferentially consumes more enriched mantle.