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Abstract Background Cisplatin (CDDP)-induced nephrotoxicity is the most important complication of CDDP treatment. 5-Hydroxytryptamine type 3 receptor antagonists (5-HT3RAs) are widely used to prevent chemotherapy-induced nausea and vomiting (CINV). However, in patients with the triple antiemetic (neurokinin-1 receptor antagonist, 5-HT3RA, and dexamethasone) therapy, the advantage of palonosetron in comparison with other 5-HT3RAs on CDDP-induced nephrotoxicity and CINV remains unclear. In the present study, we investigated the effect of palonosetron on CDDP-induced nephrotoxicity and CINV in patients with the triple antiemetic therapy by a retrospective cohort study and a pharmacovigilance analysis. Methods We retrospectively analyzed the effect of 5-HT3RAs on the development of nephrotoxicity and CINV in 110 patients who received CDDP, fluorouracil, and triple antiemetic therapy for the treatment of esophageal cancer. Moreover, the effect of 5-HT3RAs on CDDP-induced nephrotoxicity was validated in patients with the triple antiemetic therapy using the Japanese Adverse Drug Event Report (JADER) database. Results In a retrospective study, the incidence of nephrotoxicity (≥ grade 1) in patients receiving palonosetron (18%) was significantly lower than that in patients receiving ramosetron (another 5-HT3RA) (36%, p = 0.044). Moreover, severe nephrotoxicity ≥ grade 3 was observed in one patient treated with ramosetron, whereas hematological toxicity was comparable between the two groups (p = 0.553). Furthermore, the incidence rate of CINV within 120 h following CDDP administration in patients treated with palonosetron (18%) was significantly lower than that in patients receiving ramosetron (39%, p = 0.026). JADER database analyses revealed that the reporting odds ratio of palonosetron for CDDP-induced acute kidney injury was 0.282 (95% confidence interval: 0.169–0.472). Conclusions The findings of the present study suggested a greater potential of palonosetron against CDDP-induced nephrotoxicity and CINV than other 5-HT3RAs in patients with the triple antiemetic therapy.

Physiological functions of juvenile hormone (JH) and molting hormone have been demonstrated in insects. JH, molting hormone and their mimics (insect growth regulators, IGRs) show endocrine-disrupting effects not only on target pest insects but also on other arthropod species such as crustaceans. However, little is known about the endocrine-disrupting effects of IGRs on benthic crustaceans. In this study, laboratory experiments were conducted to investigate effects of representative innate JH in crustaceans (methyl farnesoate, MF) and molting hormone (20-hydroxyecdysone, 20E, active form of ecdysteroid) on larval stages of the kuruma prawn Marsupenaeus japonicus, which is a decapod crustacean living in warm seawater. Larval development of kuruma prawn progresses in the order of nauplius, zoea, mysis, and then post-larvae with molting and metamorphosis, but it is unknown whether both MF and 20E have crucial roles in metamorphosis and molting of this species. Treatments of either MF or 20E on shrimp larvae were attempted at each developmental stage and those effects were validated. In terms of EC50 values between mortality and metamorphosis, there were apparent differences in the transition from nauplius to zoea (MF: 7.67 and 0.12 μM; 20E: 3.84 and 0.06 μM in survival and metamorphic rates, respectively). In contrast, EC50 values in MF and 20E treatments showed high consistency in the transitions between zoea to mysis (EC50 values for survival; MF: 1.25 and 20E: 0.22 μM), and mysis to post-larvae (EC50 values for survival; MF: 0.65 and 20E: 0.46 μM). These data suggest that nauplius has strong resistance against exposure to MF and 20E. Moreover, both chemicals induced high mortality triggered by the disruption of molting associated with metamorphosis. To our knowledge, this is the first experimental evidence that investigates in vivo physiological functions of MF and 20E in the larval stages of kuruma prawn, shedding light on not only ecotoxicological impacts of IGRs released into nature, but also endocrine mechanisms underlying larval development with metamorphosis in benthic decapod crustaceans.

The development of effective treatments against cancers is urgently needed, and the accumulation of CD8+ T cells within tumors is especially important for cancer prognosis. Although their mechanisms are still largely unknown, growing evidence has indicated that innate immune cells have important effects on cancer progression through the production of various cytokines. Here, we found that basic leucine zipper transcription factor ATF-like 2 (Batf2) has an antitumor effect. An s.c. inoculated tumor model produced fewer IL-12 p40+ macrophages and activated CD8+ T cells within the tumors of Batf2-/- mice compared with WT mice. In vitro studies also revealed that the IL-12 p40 expression was significantly lower in Batf2-/- macrophages following their stimulation by toll-like receptor ligands, such as R848. Additionally, we found that BATF2 interacts with p50/p65 and promotes IL-12 p40 expression. In conclusion, Batf2 has an antitumor effect through the up-regulation of IL-12 p40 in tumor-associated macrophages, which eventually induces CD8+ T-cell activation and accumulation within the tumor. [ABSTRACT FROM AUTHOR]

Interleukin 34 (IL-34) constitutes a cytokine that shares a common receptor, colony-stimulating factor-1 receptor (CSF- 1R), with CSF-1. We recently identified a novel type of monocytic cell termed follicular dendritic cell-induced monocytic cells (FDMCs), whose differentiation depended on CSF-1R signaling through the IL-34 produced from a follicular dendritic cell line, FL-Y. Here, we report the functional mechanisms of the IL-34-mediated CSF-1R signaling underlying FDMC differentiation. CRIPSR/Cas9-mediated knockout of the Il34 gene confirmed that the ability of FL-Y cells to induceFDMCscompletely depends on the IL-34 expressed by FL-Y cells. Transwell culture experiments revealed that FDMC differentiation requires a signal from a membrane-anchored form of IL-34 on the FL-Y cell surface, but not from a secreted form, in a direct interaction between FDMC precursor cells and FL-Y cells. Furthermore, flow cytometric analysis using an anti-IL-34 antibody indicated that IL-34 was also expressed on the FL-Y cell surface. Thus, we explored proteins interacting with IL-34 in FL-Y cells. Mass spectrometry analysis and pulldown assay identified that IL-34 was associated with the molecular chaperone 78-kDa glucoseregulated protein (GRP78) in the plasma membrane fraction of FL-Y cells. Consistent with this finding, GRP78-heterozygous FL-Y cells expressed a lower level of IL-34 protein on their cell surface and exhibited a reduced competency to induce FDMC differentiation compared with the original FL-Y cells. These results indicated a novel GRP78-dependent localization and specific function of IL-34 in FL-Y cells related to monocytic cell differentiation. [ABSTRACT FROM AUTHOR]