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JVC-001 is a new live attenuated measles–mumps–rubella vaccine (measles AIK-C, mumps RIT4385, and rubella Takahashi strains). Two phase 3 studies were conducted, one to verify the non-inferior immunogenicity of JVC-001 versus the approved mumps and measles–rubella vaccines (J301 study) and another to compare the immunogenicity and safety of different titers (J302 study). Both studies were multicenter, randomized, observer-blinded, phase 3 studies. J301 compared the immunogenicity elicited with a single dose of JVC-001 or control vaccines (measles–rubella vaccine + mumps vaccine [Hoshino strain]). J302 was a titer-confirmation study of a single dose of a low- or high-titer formulation of JVC-001. Both studies enrolled healthy Japanese children (aged 1 year) and had a primary efficacy endpoint of seropositive rate on Day 43. Overall, 861 participants completed J301 (JVC-001, n = 429; control, n = 432) and 100 participants completed J302 (low-titer, n = 48; high-titer, n = 52). For measles and rubella virus antibody titer, non-inferiority of JVC-001 was demonstrated: seropositive rates were ≥ 99.5 %. For mumps virus genotype D antibody titer, seropositive rates were 80.6 % (95 % confidence interval 76.5 % to 84.4 %) with JVC-001 and 88.1 % (84.6 % to 91.0 %) with control vaccination. Thus, non-inferiority for mumps virus genotype D antibody titer was not confirmed. Seropositive rates were similar in the low- and high-titer groups. There were no events leading to discontinuation, or cases of aseptic meningitis in either study. Although the non-inferiority of JVC-001 to currently approved vaccines was not demonstrated for the mumps component, clinical significance and consistent efficacy were indicated. Vaccine titer did not affect immunogenicity. JVC-001 is expected to have a lower risk of aseptic meningitis to currently approved vaccines and raised no new safety signals emerged. •JVC-001 is a new MMR vaccine (measles: AIK-C, mumps: RIT4385, rubella: Takahashi).•Comparative clinical trial of JVC-001 was conducted using MR and mumps vaccines.•Non-inferiority of immunogenicity was not demonstrated only against mumps virus.•However, clinical significance and consistent efficacy were indicated for JVC-001.•Different virus doses of JVC-001 did not affect immunogenicity and safety profile.

Rice internodes must have the proper shape to support high-yielding panicles. The shape of internodes is controlled by various factors involved in their formation, such as developmental patterns, cell division, cell elongation, and cell wall biosynthesis. To understand the regulation of internode development, we screened dwarf mutants to identify those with a phenotype of ectopic deposits of phenolic components in parenchyma cell walls of internodes. We named these mutants ectopic deposition of phenolic components1 (edp1). Two alleles were identified, edp1-1 and edp1-2. Furthermore, these mutants showed disordered cell files in internode parenchyma. These abnormal phenotypes were very similar to that of a previously reported dwarf50 (d50) mutant. Genetic analyses of edp1 mutants revealed that the edp1 loci are distinct from d50. Our results indicate that analyses of edp1 mutants as well as the d50 mutant will be useful for understanding the molecular mechanisms behind ectopic deposition of cell wall phenolic components in internode parenchyma cells and the regulation of internode development.

To improve current cancer immunotherapies, strategies to modulate various immunosuppressive cells including myeloid derived suppressor cells (MDSC) which were shown to be negative factors in immune‐checkpoint blockade therapy, need to be developed. In the present study, we evaluated the role of the local renin‐angiotensin system (RAS) in the tumor immune‐microenvironment using murine models bearing tumor cell lines in which RAS was not involved in their proliferation and angiogenetic ability. Giving angiotensin II receptor blockers (ARB) to C57BL/6 mice bearing murine colon cancer cell line MC38 resulted in significant enhancement of tumor antigen gp70 specific T cells. ARB administration did not change the numbers of CD11b+ myeloid cells in tumors, but significantly reduced their T‐cell inhibitory ability along with decreased production of various immunosuppressive factors including interleukin (IL)‐6, IL‐10, vascular endothelial growth factor (VEGF), and arginase by CD11b+ cells in tumors. ARB also decreased expression of immunosuppressive factors such as chemokine ligand 12 and nitric oxide synthase 2 in cancer‐associated fibroblasts (CAF). Last, combination of ARB and anti‐programmed death‐ligand 1 (PD‐L1) antibodies resulted in significant augmentation of anti‐tumor effects in a CD8+ T cell‐dependent way. These results showed that RAS is involved in the generation of an immunosuppressive tumor microenvironment caused by myeloid cells and fibroblasts, other than the previously shown proliferative and angiogenetic properties of cancer cells and macrophages, and that ARB can transform the immunosuppressive properties of MDSC and CAF and could be used in combination with PD‐1/PD‐L1 immune‐checkpoint blockade therapy. Local renin–angiotensin system is involved in generation of immunosuppressive tumor microenvironment caused by myeloid cells and fibroblasts. Angiotensin receptor blockers can transform the immunosuppressive properties of myeloid derived suppressor cells and cancer‐associated fibroblasts and could be used in combination with PD‐1/PD‐L1 immune checkpoint blockade therapy.

The bioactive lysophospholipid mediator sphingosine-1-phosphate (S1P) promotes the egress of newly formed T cells from the thymus and the release of immature B cells from the bone marrow. It has remained unclear, however, where and how S1P is released. Here, we show that in mice, the S1P transporter spinster homolog 2 (Spns2) is responsible for the egress of mature T cells and immature B cells from the thymus and bone marrow, respectively. Global Spns2-KO mice exhibited marked accumulation of mature T cells in thymi and decreased numbers of peripheral T cells in blood and secondary lymphoid organs. Mature recirculating B cells were reduced in frequency in the bone marrow as well as in blood and secondary lymphoid organs. Bone marrow reconstitution studies revealed that Spns2 was not involved in S1P release from blood cells and suggested a role for Spns2 in other cells. Consistent with these data, endothelia-specific deletion of Spns2 resulted in defects of lymphocyte egress similar to those observed in the global Spns2-KO mice. These data suggest that Spns2 functions in ECs to establish the S1P gradient required for T and B cells to egress from their respective primary lymphoid organs. Furthermore, Spns2 could be a therapeutic target for a broad array of inflammatory and autoimmune diseases.

Narcolepsy is a sleep disorder characterized by excessive daytime sleepiness, cataplexy, and rapid eye movement (REM) sleep abnormalities. A genome-wide association study (GWAS) identified a novel narcolepsy-related single nucleotide polymorphism (SNP), which is located adjacent to the carnitine palmitoyltransferase 1B (CPT1B) gene encoding an enzyme involved in β-oxidation of long-chain fatty acids. The mRNA expression levels of CPT1B were associated with this SNP. In addition, we recently reported that acylcarnitine levels were abnormally low in narcolepsy patients. To assess the efficacy of oral L-carnitine for the treatment of narcolepsy, we performed a clinical trial administering L-carnitine (510 mg/day) to patients with the disease. The study design was a randomized, double-blind, cross-over and placebo-controlled trial. Thirty narcolepsy patients were enrolled in our study. Two patients were withdrawn and 28 patients were included in the statistical analysis (15 males and 13 females, all with HLA-DQB1*06:02). L-carnitine treatment significantly improved the total time for dozing off during the daytime, calculated from the sleep logs, compared with that of placebo-treated periods. L-carnitine efficiently increased serum acylcarnitine levels, and reduced serum triglycerides concentration. Differences in the Japanese version of the Epworth Sleepiness Scale (ESS) and the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) vitality and mental health subscales did not reach statistical significance between L-carnitine and placebo. This study suggests that oral L-carnitine can be effective in reducing excessive daytime sleepiness in narcolepsy patients. University hospital Medical Information Network (UMIN) UMIN000003760.

Seismogenic plate‐boundary faults at accretionary margins (e.g., the Nankai margin, southwest Japan) may occur where the uppermost part of subducting oceanic crust, composed of basaltic rocks, is in contact with the overriding plate of a lithified accretionary prism. The plate‐boundary faults in ancient accretionary complexes typically record high‐velocity slip under fluid‐rich conditions. Although previous studies have emphasized the mechanical significance of fluids in terms of dynamic slip‐weakening, the source of fluid in seismogenic subduction zones remains poorly constrained. In this work, we focus on the hydrous smectite in the uppermost oceanic crust, an alteration product of intact basalt before arrival at the trench axis. A comparison between (1) new mineralogical data on basalt drillcore recovered by Integrated Ocean Drilling Program (IODP) Expedition 322 at site C0012, a reference site for subduction input to the Nankai Trough, and (2) mineralogical data on basalt within ancient oceanic crust embedded in a fossil accretionary complex of the Shimanto Belt, southwest Japan, suggests that progressive smectite–chlorite conversion would liberate bound fluids at a rate of 0.34 to 0.65 × 10−14 s−1 along the plate interface. This rate of fluid production appears to be more than an order of magnitude greater than that from other possible sources, including from overlying sediments via smectite–illite conversion and the expulsion of pore fluids, and may facilitate seismic slip along plate‐boundary faults. Key Points The uppermost oceanic basement is altered to form hydrous clay minerals Fluid is liberated via smectite to chlorite transition in seismogenic zone Fluid releasing rate from oceanic crust is higher than that from sediment

Although precapillary pulmonary hypertension is a rare but severe complication of patients with neurofibromatosis type 1 (NF1), its association with NF2 remains unknown. Herein, we report a case of a 44-year-old woman who was initially diagnosed with idiopathic pulmonary arterial hypertension and treated with pulmonary arterial hypertension-specific combination therapy. However, a careful assessment for a relevant family history of the disease and genetic testing reveal that this patient had a mutation in the NF2 gene. Using immunofluorescence and Western blotting, we demonstrated a decrease in endothelial NF2 protein in lungs from idiopathic pulmonary arterial hypertension patients compared to control lungs, suggesting a potential role of NF2 in pulmonary arterial hypertension development. To our knowledge, this is the first time that precapillary pulmonary hypertension has been described in a patient with NF2. The altered endothelial NF2 expression pattern in pulmonary arterial hypertension lungs should stimulate work to better understand how NF2 is contributing to the pulmonary vascular remodelling associated to these severe life-threatening conditions.

Background In this report, we describe the first successful case of transition from subcutaneous administration of treprostinil to selexipag in a patient with severe pulmonary arterial hypertension (PAH), by evaluating hemodynamic changes and exercise tolerance. Case presentation A 38-year-old female with idiopathic PAH (IPAH) had received initial triple combination therapy (macitentan PO, tadalafil PO, and treprostinil SC) and achieved excellent improvement in hemodynamics. Afterwards, due to the development of side effects from subcutaneous administration, we replaced treprostinil therapy with oral selexipag, resulting in stable hemodynamic parameters and exercise capacities. Conclusions We report the first case of successful replacement of treprostinil (20.1 ng/kg/min) with selexipag (1600 μg BID) as a component of triple combination therapy, which provides incentive to perform a larger, prospective exchange study.

There was no structured method for safely transition from parenteral prostanoids to oral medication. We enrolled 37 idiopathic/hereditary pulmonary arterial hypertension patients receiving triple combination therapy including parenteral prostanoids into structured transition program to oral selexipag. Four (10.8%) patients successfully transitioned under the protocol, and all of them presented long‐term safety.