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Phosphatidylserine (PS), an anionic phospholipid enriched in the inner leaflet of the plasma membrane, is exposed to the outer leaflet during apoptosis. PS exposure was recently shown to be induced during tumor necrosis factor-induced necroptosis. We herein demonstrated that interferon (IFN)-γ induced necroptosis in Caspase-8-knockout mouse-derived embryonic fibroblasts (C8KO MEFs), as well as in WT MEFs co-treated with the pan-caspase inhibitor, z-VAD-fmk. PS exposure and necroptosis were significant after 6- and 24-h treatments with IFN-γ, respectively. To elucidate the molecular mechanisms underlying IFN-γ-induced PS exposure, we generated C8KO MEF-derived cell lines without the expression of RIPK3 (receptor-interacting protein kinase 3), an essential molecule in tumor necrosis factor-induced necroptosis, and IFN-γ-induced PS exposure and necrotic cell death were shown to be specifically inhibited by the loss of RIPK3 expression. Furthermore, the down-regulated expression of MLKL (mixed lineage kinase domain-like protein), a key molecule for inducing membrane rupture downstream of RIPK3 in necroptosis, abolished IFN-γ-induced PS exposure in C8KO MEFs. In human colorectal adenocarcinoma-derived HT29 cells, PS exposure and necroptosis were similarly induced by treatment with IFN-γ in the presence of Smac mimetics and z-VAD-fmk. The removal of IFN-γ from PS-exposing MEFs after a 6-h treatment completely inhibited necroptotic cell death but not the subsequent increase in the number of PS-exposing cells. Therefore, PS exposure mediated by RIPK3-activated MLKL oligomers was induced by a treatment with IFN-γ for a significant interval of time before the induction of necroptosis by membrane rupture. [ABSTRACT FROM AUTHOR]

This paper investigates the interactive influence between the local GDP and industrial structures of Shiyan City, Hubei Province between 1991 and 2014, by using the VAR Model, Johansen Co integration Test, Vector Error Correction Model, Granger Causality Test, Impulsive Response Function and Variation Decomposition analysis. The results indicate that there is interactive relationship between the primary industry and the tertiary industry in Hubei Shiyan. With the implementation of the Middle Route of the South-to-North Water Diversion Project, Water Pollution Prevention and Control as well as Water and Soil Conservation in Danjiangkou Reservoir and Upstream Areas (here in after referred as “DAN Comprehensive Treatment”) in Shiyan, strategy and policy suggestions on reshape and optimization of the three industrial structures of Shiyan are proposed. These can provide valuable advice or references for industrial structure reshape, economic and social development and ecological environment protection in Shiyan City, Hubei province and the similar reservoir areas and water source areas. [ABSTRACT FROM AUTHOR]

Abstract The aim of this paper was to identify DNA methylation based biomarkers for predicting overall survival (OS) of stage I–II lung adenocarcinoma (LUAD) patients. Methylation profile data of patients with stage I–II LUAD from The Cancer Genome Atlas (TCGA) database was used to determine methylation sites-based hallmark for stage I–II LUAD patients’ OS. The patients were separated into training and validation datasets by using median risk score as cutoff. Univariate Cox, least absolute shrinkage and selection operator (LASSO) and multivariate Cox analyses were employed to develop a DNA methylation signature for OS of patients with stage I–II LUAD. As a result, an 11-DNA methylation signature was determined to be critically associated with the OS of patients with stage I–II LUAD. Analysis of receiver operating characteristics (ROC) suggested a high prognostic effectiveness of the 11-DNA methylation signature in patients with stage I–II LUAD (AUC at 1, 3, 5 years in training set were (0.849, 0.879, 0.831, respectively), validation set (0.742, 0.807, 0.904, respectively), entire TCGA dataset (0.747, 0.818, 0.870, respectively). Kaplan–Meier survival analyses exhibited that survival was significantly longer in the low-risk cohort compared to the high-risk cohort in the training dataset (P = 7e − 07), in the validation dataset (P = 1e − 08), and in the all-cohort dataset (P = 6e − 14). In addition, a nomogram was developed based on molecular factor (methylation risk score) as well as clinical factors (age and cancer status) (AUC at 1, 3, 5 years entire TCGA dataset were 0.770, 0.849, 0.979, respectively). The result verified that our methylomics-associated nomogram had a strong robustness for predicting stage I–II LUAD patients’ OS. Furthermore, the nomogram combined clinical and molecular factors to determine an individualized probability of recurrence for patients with stage I–II LUAD, which stood for a major advance in the field of personalized medicine for pulmonary oncology. Collectively, we successfully identified a DNA methylation biomarker and a DNA methylation-based nomogram to predict the OS of patients with stage I–II LUAD.

Abstract Rituximab in combination with chemotherapy has shown efficacy in patients with diffuse large B-cell lymphoma (DLBCL) for more than 15 years. HLX01 was developed as the rituximab biosimilar following a stepwise approach to demonstrate biosimilarity in analytical, pre-clinical, and clinical investigations to reference rituximab. With demonstrated pharmacokinetic similarity, a phase 3 multi-center, randomized, parallel, double-blind study (HLX01-NHL03) was subsequently conducted to compare efficacy and safety between HLX01 plus cyclophosphamide, doxorubicin, vincristine, and prednisone (H-CHOP) and reference rituximab plus CHOP (R-CHOP) in a total of 407 treatment-naïve, CD20-positive DLBCL patients aged 18–80 years. The primary efficacy endpoint was best overall response rate (ORR) within six cycles of treatment in the per-protocol set (PPS). Secondary endpoints included 1-year efficacy outcomes, safety, and immunogenicity profile. The results showed difference in ORRs [H-CHOP 94.1%; R-CHOP 92.8%] between two treatment groups was 1.4% (95% confidence interval [CI], − 3.59 to 6.32, p = 0.608) which falls within the pre-defined equivalence margin of ± 12%. The safety profile was comparable between the treatment groups, with a similar overall incidence of treatment-emergent adverse events (H-CHOP 99.5%, R-CHOP 99.0%, p = 1.000) and serious adverse events (H-CHOP 34.0%, R-CHOP 32.5%, p = 0.752). This study established bioequivalence in efficacy and safety between HLX01 and reference rituximab. The trial was registered at http://www.chinadrugtrials.org.cn on 26 August 2015 [#CTR20150583].

Urbanization is a process that is undergoing ail over the world, which will speed up in the forthcoming years, especially in China as the boom of economy. On average, urbanization level is not only depended on the speed, but theefficiency, particularly efficiency of using land resource which affects urbanization directly. This paper provided status quo of land resource utilization efficiency, indictors, methods and factors, and illustrated the reference of well land utilization, aiming at fostering urbanization in China. [ABSTRACT FROM AUTHOR]

BackgroundThe prognosis of pancreatic cancer (PC) is relatively dismal due to the lack of effective therapy. In this study, we explored the specific functions and molecular mechanisms of miR-107 to uncover effective therapeutic targets for PC.MethodThe miR-107 expression in PC cell lines was assessed via quantitative real-time polymerase chain reaction (qRT-PCR). Besides, online bioinformatics analysis was adopted to predict the underlying targets of miR-107. Meanwhile, TCGA database was employed to explore the prognosis of PC patients. In addition, MTT and transwell assays were conducted to explore the PC cells' biological functions.ResultMiR-107 was remarkably increased in PC cells which could promote the proliferation, invasion and migration of PC cells. In addition, miR-107 could directly down-regulate TGFBR3 expression through binding to TGFBR3 3'UTR. Survival analysis from TCGA suggested that PC patients with higher miR-107 expression was significantly involved in poorer prognosis.ConclusionWe concluded that miR-107 promoted proliferation, invasion and migration of PC cells via targeting TGFBR3, which may provide novel underlying therapeutic targets.