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Immune checkpoint blockade of programmed cell death protein 1 (PD-1) had an impressive long-lasting effect in a portion of advanced-stage melanoma patients, however, this therapy failed to induce responses in several patients; how to increase the objective response rate is very important. Cellular FLICE-inhibitory protein (c-FLIP) could inhibit apoptosis directly at the death-inducing signaling complex of death receptors and is also considered to be the main cause of immune escape. The overexpression of c-FLIPL occurs frequently in melanoma and its expression is associated with the prognosis. We found that the level of c-FLIPL expression was associated with the PD-1 blockade response rate in melanoma patients. Thus, we performed this research to investigate how c-FLIPL regulates immunotherapy in melanoma. We demonstrate that down regulation of c-FLIPL enhances the PD-1 blockade efficacy in B16 melanoma tumor model. Down regulation of c-FLIPL could increase the tumor apoptosis and enhance the antitumor response of T cells in the lymphocyte tumor cells co-culture system. Moreover, knockdown of c-FLIPL could decrease the expression of PD-L1 and recruit more effector T cells in the tumor microenvironment. Our results may provide a new combined therapeutic target for further improving the efficacy of PD-1 blockade in melanoma.

OBJECTIVE: To investigate possible correlations between apelin-12 levels and obesity in children in China and associations between apelin-12 and obesity-related markers, including lipids, insulin sensitivity and insulin resistance index (HOMA-IR). METHODS: Forty-eight obese and forty non-obese age- and gender-matched Chinese children were enrolled between June 2008 and June 2009. Mean age was 10.42 ± 2.03 and 10.86±2.23 years in obesity and control groups, respectively. Main outcome measures were apelin-12, BMI, lipids, glucose and insulin. HOMA-IR was calculated for all subjects. RESULTS: All obesity group subjects had significantly higher total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), insulin levels and HOMA-IR (all P

Introduction: To evaluate the prognostic value of the time-to-positivity in patients with culture-positive septic shock. Methods: Retrospective study using a prospective data registry was performed at the emergency department of a tertiary hospital. Consecutive adult patients with septic shock (N = 2499) were enrolled between 2014 and 2018. Bacteremia was defined using blood cultures, and viral and fungal pathogens were excluded. The primary outcome was the 28-day mortality. Results: In 803 (46.7%) septic shock patients with bacteremia, median TTP was 10.1 h. The most prevalent isolated bacterial pathogens were Escherichia coli (40.8%) and Klebsiella (23.4%). Although the TTP correlated with a higher sequential organ failure assessment score (Spearman’s rho = −0.12, p < 0.01), it showed no significant difference between the 28-day survivors and non-survivors (10.2 vs. 9.4 days, p = 0.35). In subgroup analysis of the Escherichia coli and Klebsiella bacteremia cases, a shorter TTP showed prognostic value for predicting the 28-day mortality. The optimal TTP cut-off for Escherichia coli and Klebsiella was 10 h and 8 h, respectively. Conclusions: The prognostic value of the TTP in septic shock patients receiving bundle therapy may be limited and its clinical interpretation should only be made on a pathogen-specific basis.

A real-time channel flood forecast model was developed to simulate channel flow in plain rivers based on the dynamic wave theory. Taking into consideration channel shape differences along the channel, a roughness updating technique was developed using the Kalman filter method to update Manning's roughness coefficient at each time step of the calculation processes. Channel shapes were simplified as rectangles, triangles, and parabolas, and the relationships between hydraulic radius and water depth were developed for plain rivers. Based on the relationship between the Froude number and the inertia terms of the momentum equation in the Saint-Venant equations, the relationship between Manning's roughness coefficient and water depth was obtained. Using the channel of the Huaihe River from Wangjiaba to Lutaizi stations as a case, to test the performance and rationality of the present flood routing model, the original hydraulic model was compared with the developed model. Results show that the stage hydrographs calculated by the developed flood routing model with the updated Manning's roughness coefficient have a good agreement with the observed stage hydrographs. This model performs better than the original hydraulic model.

A grid-based distributed hydrological model, the Block-wise use of TOPMODEL (BTOPMC), which was developed from the original TOPMODEL, was used for hydrological daily rainfall-runoff simulation. In the BTOPMC model, the runoff is explicitly calculated on a cell-by-cell basis, and the Muskingum-Cunge flow concentration method is used. In order to test the model's applicability, the BTOPMC model and the Xin'anjiang model were applied to the simulation of a humid watershed and a semi-humid to semi-arid watershed in China. The model parameters were optimized with the Shuffle Complex Evolution (SCE-UA) method. Results show that both models can effectively simulate the daily hydrograph in humid watersheds, but that the BTOPMC model performs poorly in semi-humid to semi-arid watersheds. The excess-infiltration mechanism should be incorporated into the BTOPMC model to broaden the model's applicability.

The main purpose of this study was to forecast the inflow to Hongze Lake using the Xin anjiang rainfall-runoff model. The upper area of Hongze Lake in the Huaihe Basin was divided into 23 sub-basins, including the surface of Hongze Lake. The influence of reservoirs and gates on flood forecasting was considered in a practical and simple way. With a one-day time step, the linear and non-linear Muskingum method was used for channel flood routing, and the least-square regression model was used for real-time correction in flood forecasting. Representative historical data were collected for the model calibration. The hydrological model parameters for each sub-basin were calibrated individually, so the parameters of the Xin anjiang model were different for different sub-basins. This flood forecasting system was used in the real-time simulation of the large flood in 2005 and the results are satisfactory when compared with measured data from the flood.