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Zolbetuximab is a chimeric monoclonal antibody that targets claudin‐18.2, a candidate biomarker in patients with advanced gastric/gastroesophageal cancer. This nonrandomized phase 1 study (NCT03528629) enrolled previously treated Japanese patients with claudin‐18.2–positive locally advanced/metastatic gastric/gastroesophageal cancer in two parts: Safety (Arms A and B, n = 3 each) and Expansion (n = 12). Patients received intravenous zolbetuximab 800 mg/m2 on cycle 1, day 1 followed by 600 mg/m2 every 3 weeks (Q3W; Safety Part Arm A and Expansion) or 1000 mg/m2 Q3W (Safety Part Arm B). For the Safety Part, the primary endpoint was safety (i.e., dose‐limiting toxicities [DLTs]) and a secondary endpoint was objective response rate (ORR) by investigator. For the Expansion Part, the primary endpoint was ORR by investigator and secondary endpoints included ORR by central review and safety. Additional secondary endpoints for both the Safety and Expansion Parts were disease control rate (DCR), overall survival (OS), progression‐free survival (PFS), duration of response, pharmacokinetics, and immunogenicity. In 18 patients, no DLTs (Safety Part) or drug‐related treatment‐emergent adverse events (TEAEs) grade ≥3 were observed. Most TEAEs were gastrointestinal. In 17 patients with measurable lesions, best overall response was stable disease (64.7%) or progressive disease (35.3%). The DCR was 64.7% (95% confidence interval 38.3–85.8). In Arm A and Expansion combined (n = 15), median OS was 4.4 months (2.6–11.4) and median PFS was 2.6 months (0.9–2.8). In Arm B (n = 3), median OS was 6.4 months (2.9–6.8) and median PFS was 1.7 months (1.2–2.1). Zolbetuximab exhibited no new safety signals with limited single‐agent activity in Japanese patients. Here we show for the first time that zolbetuximab treatment does not lead to any new safety signals specifically in Japanese patients with advanced G/GEJ cancer; most (94.4%) patients experienced zolbetuximab‐related gastrointestinal adverse events, which were not severe (grade 1–2) and did not lead to study discontinuation or death. Zolbetuximab monotherapy exhibited limited anticancer efficacy in this study. The promising efficacy profile of zolbetuximab when combined with chemotherapy observed in phase 2 trials and the tolerable safety profile observed in this study suggest that zolbetuximab in combination with chemotherapy may be a suitable treatment specifically for Japanese patients with advanced G/GEJ cancer.

The growth and metastasis of malignant tumors is largely dependent on angiogenesis. Angiogenic factors produced by tumor cells are known to promote tumor angiogenesis. The aim of this study was to investigate which angiogenic factor is the most important in the progression of neuroblastoma (NB). The relative expression levels of vascular endothelial growth factor-A (VEGF-A), VEGF-C, basic fibroblast growth factor (bFGF), and platelet-derived endothelial growth factor (PD-ECGF/TP) were studied in 28 NB tumor specimens by real-time quantitative reverse transcriptase/polymerase chain reaction (RT-PCR). The relationships between the expression of these four angiogenic factors and stage, patient age, primary site, MYCN copy number, and lymph node metastasis were analyzed. High VEGF-A expression was correlated with stage 4 disease (blood-borne metastasis). No relationship between VEGF-A expression and age, primary site, MYCN copy number, or lymph node metastasis was found. The expression of VEGF-C, bFGF, or PD-ECGF/TP showed no correlation with stage, age, primary site, MYCN copy number, or lymph node metastasis. Our findings suggest that VEGF-A, but not VEGF-C, bFGF, or PD-ECGF/TP, may be associated with progression of NB. VEGF-A could be a target for antiangiogenic therapy for disseminated NB.

Nonribosomal peptide synthetases (NRPSs) assemble structurally diverse bioactive natural products through selective communication between adenylation (A) and carrier protein (CP) domains. Although rational rewiring of these protein–protein interactions could enable customized NRPS design, this remains challenging due to the dynamic nature of protein interfaces. Here we show that structure-guided interface reprogramming enables productive non-cognate A– CP pairings across enterobactin, vibriobactin, pyochelin, and vicenistatin biosynthetic systems. Engineered interactions between the A domains EntE, VibE, or PchD and the non-cognate CPs VinL or EntB were validated by biochemical, kinetic, and structural analyses. Reconstituted pathways containing engineered VibE, EntB, and EntF restored enterobactin production and increased yield to 2.2-fold that of the native EntE–EntB–EntF system. Interface-engineered PchD also enhanced production of a non-native salicylic acid–norspermidine conjugate. An X-ray structure and molecular dynamics simulations of an engineered non-cognate A–CP complex reveal recognition principles for programmable NRPS interface design.

NdWFamide is an Aplysia cardioexcitatory tri-peptide containing D-tryptophan. To investigate the roles of this peptide, we examined the immunohistochemical distribution of NdWFamide-positive neurons in Aplysia tissues. All the ganglia of the central nervous system (CNS) contained NdWFamide-positive neurons. In particular, two left upper quadrant cells in the abdominal ganglion, and the anterior cells in the pleural ganglion showed extensive positive signals. NdWFamide-positive processes were observed in peripheral tissues, such as those of the cardio-vascular system, digestive tract, and sex-accessory organs, and in the connectives or neuropils in the CNS. NdWFamide-positive neurons were abundant in peripheral plexuses, such as the stomatogastric ring. To examine the NdWFamide contents of tissues, we fractionated peptidic extracts from the respective tissues by reversed-phase high-pressure liquid chromatography and then assayed the fractions by competitive enzyme-linked immunosorbent assay. A fraction corresponding to the retention time of synthetic NdWFamide contained the most immunoreactivity, indicating that the tissues contained NdWFamide. The prevalence of the NdWFamide content was roughly in the order: abdominal ganglion >heart >gill >blood vessels >digestive tract. In most of the tissues containing NdWFamide-positive nerves, NdWFamide modulated the motile activities of the tissues. Thus, NdWFamide seems to be a versatile neurotransmitter/modulator of Aplysia and probably regulates the physiological activities of this animal.

Lenvatinib is an approved first-line therapy for unresectable hepatocellular carcinoma (HCC), but the effect of dose modification on its efficacy is unclear. We analyzed the relationship between the relative dose intensity during the initial 4 weeks of therapy [4W-relative dose intensity (RDI)] and the efficacy of lenvatinib therapy in the real-world setting. A total of 48 consecutive patients with unresectable HCC who received lenvatinib therapy for more than 4 weeks were included. The 4W-RDI was calculated as the cumulative dose in the initial 4 weeks divided by the weight-based standard dose, and we evaluated its association with overall survival (OS) and best response by modified Response Evaluation Criteria in Solid Tumor (mRECIST). The baseline factors predicting high 4W-RDI were analyzed further. The median durations of follow-up and of therapy among the 48 participants were 7.6 and 6.6 months, respectively. The median OS was not reached. Drug interruption and/or dose reduction were necessary in 30 patients (62.5%) and the median 4W-RDI was 70% (range 22%-100%). Patients with 4W-RDI ≥70% had longer OS [hazard ratio (HR) 0.28, 95% confidential interval (CI):0.09-0.90, p = 0.03], and longer duration of lenvatinib therapy (HR 0.39, 95%CI:0.16-0.92, p = 0.03). Patients with 4W-RDI ≥70% showed higher disease control rate compared to those with 4W-RDI <70% (91.7% vs. 54.2%, p = 0.008). A baseline albumin level >3.4g/dL or ALBI score less than -2.171 were significantly associated with achieving 4W-RDI ≥70%. In conclusion, 4W-RDI of lenvatinib therapy is associated with favorable radiological response and longer OS.

Previous studies have revealed that reading fiction is associated with dispositional empathy and theory-of-mind abilities. Earlier studies established a correlation between fiction reading habits and the two measures of social cognition: trait fantasy (i.e., the tendency to transpose oneself into fictitious characters) and performance on the Reading the Mind in the Eyes Test (RMET; a test of the ability to identify others’ mental states based on their eyes). Recently, experimental studies have shown that brief exposure to fiction enhances RMET performance. Nevertheless, these studies have been conducted only in Western countries, and few published studies have investigated these relationships in Asian countries. This research aims to address this gap. Study 1, which involved 338 Japanese undergraduates, conceptually replicated the previously reported correlations between fiction reading and fantasy and RMET scores (after statistically controlling for the effect of outliers). However, Study 2, which involved 304 Japanese undergraduates, failed to replicate the causal relationship. Participants read an excerpt either from literary fiction or from nonfiction, or engaged in a calculation task, before completing the RMET. Brief exposure to literary fiction did not increase the RMET score. In sum, this study replicated the associations of fiction reading with fantasy and RMET scores in Japan, but failed to replicate the causal relationship.

Elimination of senescent cells (senolysis) was recently reported to improve normal and pathological changes associated with aging in mice . However, most senolytic agents inhibit antiapoptotic pathways , raising the possibility of off-target effects in normal tissues. Identification of alternative senolytic approaches is therefore warranted. Here we identify glycoprotein nonmetastatic melanoma protein B (GPNMB) as a molecular target for senolytic therapy. Analysis of transcriptome data from senescent vascular endothelial cells revealed that GPNMB was a molecule with a transmembrane domain that was enriched in senescent cells (seno-antigen). GPNMB expression was upregulated in vascular endothelial cells and/or leukocytes of patients and mice with atherosclerosis. Genetic ablation of Gpnmb-positive cells attenuated senescence in adipose tissue and improved systemic metabolic abnormalities in mice fed a high-fat diet, and reduced atherosclerotic burden in apolipoprotein E knockout mice on a high-fat diet. We then immunized mice against Gpnmb and found a reduction in Gpnmb-positive cells. Senolytic vaccination also improved normal and pathological phenotypes associated with aging, and extended the male lifespan of progeroid mice. Our results suggest that vaccination targeting seno-antigens could be a potential strategy for new senolytic therapies.

Imeglimin is a new anti-diabetic drug commercialized in Japan (Twymeeg®) and has been drawing much attention in diabetes research area as well as in clinical practice. In this study, we evaluated the effect of imeglimin on pancreatic β-cells. First, single-dose administration of imeglimin enhanced insulin secretion from β-cells and decreased blood glucose levels in type 2 diabetic db/db mice. In addition, single-dose administration of imeglimin significantly augmented insulin secretion in response to glucose from islets isolated from non-diabetic db/m mice. Second, during an oral glucose tolerance test 4-week chronic treatment with imeglimin enhanced insulin secretion and ameliorated glycemic control in diabetic db/db mice. Furthermore, the examination with electron microscope image showed that imeglimin exerted favorable effects on morphology in β-cell mitochondria and substantially increased the number of insulin granules in type 2 diabetic db/db and KK-Ay mice. Finally, imeglimin reduced the percentage of apoptotic β-cell death which was accompanied by reduced expression levels of various genes related to apoptosis and inflammation in β-cells. Taken together, imeglimin directly enhances insulin secretion in response to glucose from β-cells, increases the number of insulin granules, exerts favorable effects on morphology in β-cell mitochondria, and reduces apoptotic β-cell death in type 2 diabetic mice, which finally leads to amelioration of glycemic control.

Effects of combination therapy of dipeptidyl peptidase-4 (DPP-4) inhibitor and sodium-glucose co-transporter 2 (SGLT2) inhibitor on β-cells are still unclear, although combination agent of these two drugs has become common in clinical practice. Therefore, we aimed to elucidate the effects of DPP-4 inhibitor and/or SGLT2 inhibitor on β-cell mass and function and compared their effects between in an early and advanced phase of diabetes. We used 7-week-old db/db mice as an early phase and 16-week-old mice as an advanced phase and treated them for 2 weeks with oral administration of linagliptin, empagliflozin, linagliptin + empagliflozin (L + E group), and 0.5% carboxymethylcellulose (Cont group). Blood glucose levels in Empa and L + E group were significantly lower than Cont group after treatment. In addition, β-cell mass in L + E group was significantly larger than Cont group only in an early phase, accompanied by increased Ki67-positive β-cell ratio. In isolated islets, mRNA expression levels of insulin and its transcription factors were all significantly higher only in L + E group in an early phase. Furthermore, mRNA expression levels related to β-cell differentiation and proliferation were significantly increased only in L + E group in an early phase. In conclusion, combination of DPP-4 inhibitor and SGLT2 inhibitor exerts more beneficial effects on β-cell mass and function, especially in an early phase of diabetes rather than an advanced phase.