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Abstract: Purpose: Mastermind-like domain containing 1 (MAMLD1) is a causative gene for the fetal development of male external genitalia. Almost 10% of patients with both severe and non-severe hypospadias exhibit mutations of MAMLD1. The aim of this work was to determine whether polymorphisms of MAMLD1 are a genetic risk factor for hypospadias. Material and methods: This study included 150 hypospadias with a range of severities and 150 controls. Direct sequencing of the MAMLD1 coding exons and their flanking splice sites was performed. In silico secondary and tertiary structure prediction and accessibility of changed amino acids were evaluated using JPred, Netsurf and PHYRE software. Functional studies of the transactivation of haplotypes on Hes3 promoter were performed in vitro using cDNAs of missense variants of MAMLD1. Results: The p.P286S polymorphism was identified in 17/150 patients and 12/150 controls (11.3% vs. 8.0%, p = 0.32). The p.N589S polymorphism was identified in 22/150 patients and 12/150 controls (14.6% vs. 8.0%, p = 0.068). The double polymorphism (S-S haplotype) was present in 16/150 patients and 6/150 controls (10.6% vs. 4.0%, p = 0.044, OR = 2.87, CI from 1.09 to 7.55). The association of polymorphisms consistently revealed a modification in the structure prediction or amino acid accessibility in all three in silico models. The P286S, N589S and P286S + N589S proteins did not exhibit reduced transactivating activity on Hes3 promoter. Conclusion: Polymorphisms of MAMLD1 gene are frequent in patients with hypospadias. Although no change in transactivation was noted on Hes3 promoter, the in silico studies and the significantly increased incidence of the S-S haplotype in hypospadiac patients raise the hypothesis of a particular susceptibility conferred by these variants. [Copyright &y& Elsevier]

Abstract: Expansion of the progenitor pool of oligodendrocytes (OLs) is a critical process for obtaining appropriate amounts of mature myelin-forming OLs in the developing and regenerating central nervous system. In vitro, fibroblast growth factor-2 (FGF2), together with platelet-derived growth factor (PDGF), is required to expand oligodendrocyte progenitor cells (OLPs) in an unlimited manner, maintaining them in the early progenitor stage. However, the intracellular mechanisms that prevent OLP maturation remain elusive. In order to investigate these mechanisms, we established a mouse OLP primary culture, which enabled us to undertake biochemical analyses. We found that the suppressive effects on maturation of early OLP to the late O4+ progenitor by PDGF+FGF2 treatment was abrogated by Mek inhibitor, while transfecting cells with a constitutively active Mek1 construct prevented OLP maturation, suggesting that the Mek-Erk pathway is implicated in the effects of the growth factor treatment. The activation of Mek-Erk pathway promoted proliferation of OLP suggesting that cell cycle progression has suppressive effects to the maturation of OLP. Furthermore, molecular screening using DNA microarrays revealed that Hes1, a negative regulator of bHLH transcription factors, is one of the downstream molecules induced by PDGF+FGF2 treatment. We confirmed that forced activation of Mek-Erk pathway is sufficient to induce Hes1 expression and that Hes1, in turn, exerts suppressive effects on the maturation of OL lineage by itself. Our observations thus indicate that Mek-Erk pathway plays pivotal role in preventing early OLP maturation to late OLPs and the effect is mediated by cell cycle progression as well as Hes1 induction. [Copyright &y& Elsevier]

Abstract: The effect of local anisotropy due to the arrangement of anisotropic and arbitrary shaped grains of a directionally solidified superalloy on the J-integral is investigated by means of finite element analyses, where the models simulate the grain shape, its orientation, and the crack path of real material. The magnitudes of J aniso, obtained by a detailed model, where most of grains are simulated, shows a stepwise change against the crack length a. This is mainly caused by the anisotropy of the grain at the crack tip. J CV, obtained by a simplified model, where only the grains in the vicinity of the crack path are simulated, shows the same stepwise change as J aniso. It elucidates that the anisotropy in the vicinity of the crack path is the dominant factor for the fluctuation of J aniso. The magnitude of J aniso and J CV, however, are different from each other in detail. A large inhomogeneous area such as a cluster of grains and a large grain has a far-field influence and is mainly responsible for the differences between J aniso and J CV. [Copyright &y& Elsevier]

Abstract: To assist in understanding metal fuel performance at elevated temperatures, phase diagrams of the U–Pu–Zr, U–Pu–Fe, U–Zr–Fe and U–Pu–Zr–Fe systems at 800°C were calculated based on thermodynamic data that has been previously evaluated. The calculated phase diagrams were compared with phase composition data at the interdiffusion zones, which formed at the interface between the irradiated or unirradiated U–Pu–Zr metal fuel and stainless steel cladding at temperatures of 800°C or higher in literature. Each phase formed at the interface was successfully identified. It was confirmed that even in transient tests of the irradiated fuel pins, these phase diagrams are applicable to analysis of the multi-component interdiffusion zones between the metal fuel and the iron-based cladding. [Copyright &y& Elsevier]

PIEZO2 is a large stretch-gated ion channel highly expressed in specific sensory neurons which mediates human mechanosensation. Individuals with biallelic loss of function (LOF) variants in the PIEZO2 gene highlight the impact of the congenital absence of specific mechanotransduction-dependent senses, including proprioception aspects of touch and interception. We report on twelve unrelated individuals (except one sibling pair), ranging in age from 4 years to 42 years old with biallelic PIEZO2 LOF, and report on detailed neurological examination, neurophysiology, and evaluations of pulmonary, gastrointestinal and urinary function. We identified common early neonatal and developmental consequences of PIEZO2 LOF including: reduced fetal movements (n=6), hypotonia (n=12), neonatal respiratory distress (n=9), and feeding difficulty (n=11). The age at achievement of independent ambulation (n=8) was markedly delayed (5-16 years old). Pseudoathetosis was frequently clinically observed. Orthopedic and systemic findings included: congenital hip dysplasia (n=11), arthrogryposis (n=12), early progressive scoliosis (n=12), constipation (n=11), reduced voiding frequency (n=10). The findings in these participants with LOF in PIEZO2 recapitulates what is observed in preclinical models, and highlights the developmental, motor functional, systemic, and orthopedic consequences of absent mechanotransduction and proprioception. Initially slow but improving functional gains over time suggest that these maturational processes may rely on emerging executive and motor planning skills combined with visual compensatory input. This expanded series represents the largest cohort of individuals with PIEZO2 LOF across a wide age range. Recognizing and elucidating this PIEZO2-related phenotype improves our understanding of human sensory perception and allows for development of rehabilitative measures aimed at compensatory recruitment of intact sensory modalities to optimize function. [ABSTRACT FROM AUTHOR]

Although immune checkpoint inhibitors (ICI) targeting for PD-1 axis is a promising approach for advanced gastric cancer (GC) patients, the response rate is still limited. Induction of synergistic effect of irradiation with ICI targeting for the PD-1 axis can be an attractive strategy. We have conducted and reported a single-arm, phase 1/2 trial against advanced GC treated with combination of palliative radiotherapy and nivolumab, an anti-PD-1 antibody (CIRCUIT trial: NCT03453164). The 3-years follow-up results are presented herein. The eligible patients were unresectable advanced or recurrent GC who developed progression after primary and secondary chemotherapy with more than 1 lesions assessable (also, 1 lesion must be ≥ 2 cm) in diagnostic imaging. The number of enrolled patients was 41. Thirty-four patients were male and 7 were female. Median age was 70 years old (range = 36–86 years old). Thirty-three patients (81%) had 5 or more cancer lesions and 34 patients (83%) had 2 or more organs with cancer. The biggest or symptomatic tumors were irradiated in 22.5 Gy/5 fractions/5 days (EQD2 = 34.8Gy). Three patients had multiple sites irradiated. Ten patients had additional newly appeared tumors irradiated after first irradiation and 5 patients were re-irradiated after local recurrence (same site). The total number of irradiated field was 65 (primary tumor site (stomach): 11, metastatic lymph node site: 29, metastatic liver tumor site: 14, and other site: 11). Toxicities were graded based on the Common Terminology Criteria for Adverse Events version 4.0. The median survival time and progression-free survival time were 218 days (range = 21-1842 days) and 92 days (range = 21-1514 days), respectively. The overall survival rate and progression-free survival rate were 28% and 7% at 1-year, 15% and 7% at 2-year, and 13% and 7% at 3-year, respectively. Three patients have lived without disease progression for more than 3 years. The local control rate (LCR) at 1-, 2- and 3-years for the irradiated tumor were 80%, 67% and 67%, respectively. The LCR at 3-year according to sites were 100% at primary tumor (stomach), 48% at lymph node metastasis, 67% at liver metastasis, and 100% at other site. Severe adverse effect (≥ G3) was occurred in 18 patients (44%). However, severe adverse effect (≥ G3) caused by radiotherapy was not seen. Addition of radiotherapy to nivolumab therapy was safe and seemed to be beneficial for survival. Furthermore, good LCR was observed even though palliative irradiation dose. [ABSTRACT FROM AUTHOR]