The current management of advanced esophageal squamous cell carcinoma (ESCC) remains unsatisfactory. We investigated the safety, efficacy, and biomarkers of SHR-1210, an anti-PD-1 antibody, in patients with recurrent or metastatic ESCC. This study was part of a phase I trial in China. Patients with advanced ESCC who were refractory or intolerant to previous chemotherapy were enrolled. Eligible patients received intravenous SHR-1210 at a dose of 60 mg, with escalation to 200 and 400 mg (4-week interval after first dose followed by a 2-week schedule) until disease progression or intolerable toxicity. The associations between candidate biomarkers (PD-L1 and somatic mutation load) and the efficacy of SHR-1210 were also explored. Between May 11, 2016, and December 9, 2016, a total of 30 patients from one site in China were enrolled. Ten patients (33.3%) had an independently assessed objective response. Median progression-free survival was 3.6 months (95% CI, 0-7.2). Three (10.0%) treatment-related grade 3 adverse events were reported: two (6.7%) pneumonitis and one (3.3%) increased cardiac troponin I. No grade 4 or grade 5 treatment-related adverse events were reported. The exome sequencing and analysis showed that the mutational burden and the potential mutation-associated neoantigen count were associated with better responses. An objective response was more common in patients with PD-L1-positive tumors as defined by ≥5% staining (7 of 15 patients) than in those with PD-L1-negative tumors (1 of 9 patients). In this population of ESCC patients, SHR-1210 had a manageable safety profile and promising antitumor activity. .

The pitting and intergranular corrosion (IGC) behavior of various tempers of AA2024 was investigated in 1 M NaCl. The breakdown potentials associated with pitting or IGC were determined. The breakdown potentials were found to be almost independent of sample orientation for any given temper. Artificial aging had a strong effect on polarization behavior and localized corrosion morphology. The anodic polarization curves of AA2024 in the solution heat treated and water-quenched condition, T3, and T3+ tempers exhibited two breakdown potentials, whereas overaged AA2024-T8, T8+ , and solutionized and furnace cooled AA2024 exhibited only one breakdown potential. When two breakdown potentials were observed, the more active one was found to be related to the transient dissolution of S phase Al 2 CuMg particles leading to pitting while the noble one was thought to result primarily from initiation and growth of IGC. The breakdown potentials decreased with increasing aging time at 190°C, and only one breakdown potential was measured for T8 and T8+ tempers. Unlike the T3 temper, no sharp IGC was found for these tempers. Selected granular attack from breakdown of the copper-depleted matrix was believed to be the cause for localized corrosion in the T8 and T8+ tempers. The effect of nitrate and sulfate ions on the localized corrosion behavior was also studied.

BackgroundN6-methyladenosine (m6A) is an important epitranscriptomic mark with high abundance in the brain. Recently, it has been found to be involved in the regulation of memory formation and mammalian cortical neurogenesis. However, while it is now established that m6A methylation occurs in a spatially restricted manner, its functions in specific brain regions still await elucidation.ResultsWe identify widespread and dynamic RNA m6A methylation in the developing mouse cerebellum and further uncover distinct features of continuous and temporal-specific m6A methylation across the four postnatal developmental processes. Temporal-specific m6A peaks from P7 to P60 exhibit remarkable changes in their distribution patterns along the mRNA transcripts. We also show spatiotemporal-specific expression of m6A writers METTL3, METTL14, and WTAP and erasers ALKBH5 and FTO in the mouse cerebellum. Ectopic expression of METTL3 mediated by lentivirus infection leads to disorganized structure of both Purkinje and glial cells. In addition, under hypobaric hypoxia exposure, Alkbh5-deletion causes abnormal cell proliferation and differentiation in the cerebellum through disturbing the balance of RNA m6A methylation in different cell fate determination genes. Notably, nuclear export of the hypermethylated RNAs is enhanced in the cerebellum of Alkbh5-deficient mice exposed to hypobaric hypoxia.ConclusionsTogether, our findings provide strong evidence that RNA m6A methylation is controlled in a precise spatiotemporal manner and participates in the regulation of postnatal development of the mouse cerebellum.Electronic supplementary materialThe online version of this article (10.1186/s13059-018-1435-z) contains supplementary material, which is available to authorized users.

N6-methyladenosine (m6A) is the most abundant epitranscriptomic mark found on mRNA and has important roles in various physiological processes. Despite the relatively high m6A levels in the brain, its potential functions in the brain remain largely unexplored. We performed a transcriptome-wide methylation analysis using the mouse brain to depict its region-specific methylation profile. RNA methylation levels in mouse cerebellum are generally higher than those in the cerebral cortex. Heterogeneity of RNA methylation exists across different brain regions and different types of neural cells including the mRNAs to be methylated, their methylation levels and methylation site selection. Common and region-specific methylation have different preferences for methylation site selection and thereby different impacts on their biological functions. In addition, high methylation levels of fragile X mental retardation protein (FMRP) target mRNAs suggest that m6A methylation is likely to be used for selective recognition of target mRNAs by FMRP in the synapse. Overall, we provide a region-specific map of RNA m6A methylation and characterize the distinct features of specific and common methylation in mouse cerebellum and cerebral cortex. Our results imply that RNA m6A methylation is a newly identified element in the region-specific gene regulatory network in the mouse brain.

In this communication, the novel nonlinear optical crystal material Cd(4)BiO(BO(3))(3) with 3-chromophore asymmetric structures of CdO(n), BiO(6), and BO(3) groups has been prepared by a flux method, and the single crystal structure has been determined with the space group Cm. It is the largest NLO coefficient for Cd(4)BiO(BO(3))(3) among borate systems, and the strong NLO response originates from cooperation effects of the 3-chromophore asymmetric structures composed of the polar displacement of d(10) Cd(2+) ion, stereochemically active lone pair of Bi(3+), and pi-delocalization of BO(3). These evidence are provided in view of evaluations of calculated density of states and electron-density difference maps. The experimental measurements show that the features of a large SHG effect, phase-match, and high thermal stability will be favorable in industrial production and applications for Cd(4)BiO(BO(3))(3).