Background and Purpose
Indoleamine 2,3‐dioxygenase 1 (IDO1) is emerging as an important new therapeutic target for treatment of malignant tumours characterized by dysregulated tryptophan metabolism. ...However, the antitumour efficacy of existing small‐molecule inhibitors of IDO1 is still unsatisfactory and the underlying mechanism remains largely undefined. Hence, we discovered a novel potent small‐molecule inhibitor of IDO1, LW106, and studied its antitumour effects and the underlying mechanisms in two tumour models.
Experimental Approach
C57BL6 mice, athymic nude mice or Ido1−/− mice were inoculated with IDO1‐expressing and ‐nonexpressing tumour cells and treated with vehicle, epacadostat or increasing doses of LW106. Xenografted tumours, plasma, spleens and other vital organs were harvested and subjected to kynurenine/tryptophan measurement and flow cytometric, histological and immunohistochemical analyses.
Key Results
LW106 dose‐dependently inhibited the outgrowth of xenografted tumours that were inoculated in C57BL6 mice but not nude mice or Ido1−/− mice, showing a stronger antitumour efficacy than epacadostat, an existing IDO1 inhibitor. LW106 substantially elevated intratumoural infiltration of proliferative Teff cells, while reducing recruitment of proliferative Treg cells and non‐haematopoietic stromal cells such as endothelial cells and cancer‐associated fibroblasts. LW106 treatment resulted in a reduced subpopulation of cancer stem cells (CSCs) in xenografted tumours in which fewer proliferative/invasive tumour cells and more apoptotic tumour cells were observed.
Conclusions and Implications
LW106 inhibits tumour outgrowth by limiting stroma‐immune crosstalk and CSC enrichment in the tumour micro‐environment. LW106 has potential as a immunotherapeutic agent for use in combination with immune checkpoint inhibitors and (or) chemotherapeutic drugs for cancer treatment.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
The present study was designed to evaluate the dynamic survival and recurrence of remnant gastric cancer (RGC) after radical resection and to provide a reference for the development of personalized ...follow‐up strategies. A total of 298 patients were analyzed for their 3‐year conditional overall survival (COS3), 3‐year conditional disease‐specific survival (CDSS3), corresponding recurrence and pattern changes, and associated risk factors. The 5‐year overall survival (OS) and the 5‐year disease‐specific survival (DSS) of the entire cohort were 41.2% and 45.8%, respectively. The COS3 and CDDS3 of RGC patients who survived for 5 years were 84.0% and 89.8%, respectively. The conditional survival in patients with unfavorable prognostic characteristics showed greater growth over time than in those with favorable prognostic characteristics (eg, COS3, ≥T3: 46.4%‐83.0%, Δ36.6% vs ≤T2: 82.4%‐85.7%, Δ3.3%; P < 0.001). Most recurrences (93.5%) occurred in the first 3 years after surgery. The American Joint Committee on Cancer (AJCC) stage was the only factor that affected recurrence. Time‐dependent Cox regression showed that for both OS and DSS, after 4 years of survival, the common prognostic factors that were initially judged lost their ability to predict survival (P > 0.05). Time‐dependent logistic regression analysis showed that the AJCC stage independently affected recurrence within 2 years after surgery (P < 0.05). A postoperative follow‐up model was developed for RGC patients. In conclusion, patients with RGC usually have a high likelihood of death or recurrence within 3 years after radical surgery. We developed a postoperative follow‐up model for RGC patients of different stages, which may affect the design of future clinical trials.
Patients with RGC usually have a high likelihood of death or recurrence within 3 years after radical surgery. We developed a postoperative follow‐up model for RGC patients of different stages.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Most mines choose the drilling and blasting method which has the characteristics of being a cheap and efficient method to fragment rock mass, but blast-induced ground vibration damages the ...surrounding rock mass and structure and is a drawback. To predict, analyze and control the blast-induced ground vibration, the random forest (RF) model, Harris hawks optimization (HHO) algorithm and Monte Carlo simulation approach were utilized. A database consisting of 137 datasets was collected at different locations around the Tonglvshan open-cast mine, China. Seven variables were selected and collected as the input variables, and peak particle velocity was chosen as the output variable. At first, an RF model and a hybrid model, namely a HHO-RF model, were developed, and the prediction results checked by 3 performance indices to show that the proposed HHO-RF model can provide higher prediction performance. Then blast-induced ground vibration was simulated by using the Monte Carlo simulation approach and the developed HHO-RF model. After analyzing, the mean peak particle velocity value was 0.98 cm/s, and the peak particle velocity value did not exceed 1.95 cm/s with a probability of 90%. The research results of this study provided a simple, accurate method and basis for predicting, evaluating blast-induced ground vibration and optimizing the blast design before blast operation.
We have compiled a sample of 26 metal-poor galaxies with 12 + log(O/H) < 8.1 with both infrared continuum and 1.4 GHz radio continuum data. By comparing to galaxies at higher metallicity, we have ...investigated the IR-radio relationship's dependence on metallicity at the 24, 70, 100, and 160 m bands, as well as the integrated FIR luminosity. It is found that metal-poor galaxies have on average lower than metal-rich ones, with larger offsets at longer IR wavelengths, from −0.06 dex in to −0.6 dex in . The of all galaxies as a whole at 160 m show positive trends with the metallicity and IR-to-FUV ratio and negative trends with the IR color, while those at lower IR wavelengths show weaker correlations. We propose a mechanism that invokes the combined effects of low obscured-SFR-to-total-SFR fraction and warm dust temperature at low metallicity to interpret the above behavior of , with the former reducing the IR radiation and the latter further reducing the IR emission at longer IR wavelengths. Other mechanisms that are related to the radio emission, including the enhanced magnetic field strength and increased thermal radio contribution, are unable to reconcile the IR-wavelength-dependent differences of between metal-poor and metal-rich galaxies. In contrast to , the mean total-SFR-to-radio ratio of metal-poor galaxies is the same as that for metal-rich galaxies, indicating the 1.4 GHz radio emission is still an effective tracer of SFRs at low metallicity.
Biodegradable poly（butylene succinate） （PBS） and layered double hydroxide （LDH） nanocomposites were prepared via melt blending in a twin-screw extruder. The morphology and dispersion of LDH ...nanoparticles within PBS matrix were characterized by transmission electron microscopy （TEM）, which showed that LDH nanoparticles were found to be well distributed at the nanometer level. The nonisothermal crystallization behavior of nanocomposites was extensively studied using differential scanning calorimetry （DSC） technique at various cooling rates. The crystallization rate of PBS was accelerated by the addition of LDH due to its heterogeneous nucleation effect; however, the crystallization mechanism and crystal structure of PBS remained almost unchanged. In kinetics analysis of nonisothermal crystallization, the Ozawa approach failed to describe the crystallization behavior of PBS/LDH nanocomposites, whereas both the modified Avrami model and the Mo method well represented the crystallization behavior of nanocomposites. The effective activation energy was estimated as a function of the relative degree of crystallinity using the isoeonversional analysis. The subsequent melting behavior of PBS and PBS/LDH nanocomposites was observed to be dependent on the cooling rate. The POM showed that the small and less perfect crystals were formed in nanocomposites.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
For maximum metal recovery, considering the movement of ore and waste during the blasting process in loading design is meaningful for reducing ore loss and ore dilution in an open-pit mine. The ...blast-induced rock movement (BIRM) can be directly measured; nevertheless, it is time-consuming and relative expensive. To solve this problem, a novel intelligent prediction model was proposed by using dimensional analysis and optimized artificial neural network technique in this paper based on the BIRM monitoring test in Husab Uranium Mine, Namibia and Phoenix Mine, USA. After using dimensional analysis, five input variables and one output variable were determined with both considering the dimension and physical meaning of each dimensionless variable. Then, artificial neural network technique (ANN) technique was utilized to develop an accurate prediction model, and a metaheuristic algorithm namely the Equilibrium Optimizer (EO) algorithm was applied to search the optimal hyper-parameter combination. For comparison aims, a linear model and a non-linear regression model were also performed, and the comparison results show that the provided hybrid ANN-based model can yield better prediction performance. As a result, it can be concluded that the developed intelligent model in this article has the potential to predict BIRM during bench blasting, and the analysis method and modeling process in this paper can provide a reference for solving other engineering problems.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Artificial neural network (ANN) combined with signal decomposing methods is effective for long‐term streamflow time series forecasting. ANN is a kind of machine learning method utilized widely for ...streamflow time series, and which performs well in forecasting nonstationary time series without the need of physical analysis for complex and dynamic hydrological processes. Most studies take multiple factors determining the streamflow as inputs such as rainfall. In this study, a long‐term streamflow forecasting model depending only on the historical streamflow data is proposed. Various preprocessing techniques, including empirical mode decomposition (EMD), ensemble empirical mode decomposition (EEMD) and discrete wavelet transform (DWT), are first used to decompose the streamflow time series into simple components with different timescale characteristics, and the relation between these components and the original streamflow at the next time step is analyzed by ANN. Hybrid models EMD‐ANN, EEMD‐ANN and DWT‐ANN are developed in this study for long‐term daily streamflow forecasting, and performance measures root mean square error (RMSE), mean absolute percentage error (MAPE) and Nash–Sutcliffe efficiency (NSE) indicate that the proposed EEMD‐ANN method performs better than EMD‐ANN and DWT‐ANN models, especially in high flow forecasting.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
To evaluate the efficacy and safety of low molecular weight heparin (LMWH) prophylaxis for venous thromboembolism (VTE) after lumbar decompression surgery.
Patients at high or the highest risk of VTE ...who underwent lumbar spine surgery in Peking Union Medical College Hospital from January 2004 to April 2011 were included in the present study. All the patients received a half dose of LMWH 6 hours after surgery followed by a full dose LMWH once per day until discharge. We recorded incidences of deep venous thrombosis (DVT), pulmonary embolism (PE), bleeding complications, and medication side effects.
Seventy-eight consecutive patients were eligible and enrolled in this study. The mean hospital stat was 8.5±4.5 days. No symptomatic DVT, PE, or major bleeding events were observed. One patient developed wound ecchymosis, another developed wound bleeding, four had mild hepatic aminotransferase level elevation, and one developed a suspicious allergic reaction.
LMWH may be applied as an effective and safe prophylaxis for VTE in high-risk patients undergoing lumbar decompression surgery.
Decoupled charge structures are widely used in contour blasting because of their lower peak value and loading rate of the borehole wall pressure (BWP), which plays an important role in the contour ...blasting effect. The filling medium and decoupling ratio are the two key factors of decoupled charge blasting, and their effects on the peak value, rise time and loading rate of BWP need to be investigated. In the present study, physical model tests of decoupled charge blasting on cement mortar blocks (400 × 400 × 200 mm) were conducted under different filling mediums and decoupling ratios, and polyvinylidene fluoride (PVDF) gauges were used to directly measure the BWP. In addition, a numerical model was developed and verified to simulate the same decoupled charge blasting tests and some other tests with additional decoupling ratios. The measured and simulated results both showed that the peak value and the loading rate decreased with increasing decoupling ratio. Compared with the theoretical formulas, the modified power function formulas provide more accurate peak values. The peak pressure, rise time and loading rate were higher in water-coupled blasting, and the ratio of the peak pressure in water-coupled blasting to that in air-coupled blasting was between 2.35 and 4.28 under decoupling ratios of 2∼5. When the peak pressure was the same, the loading rate in the water coupling blasting was always lower than that in the air coupling blasting.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
•An effective raise blast technique with vertically parallel and dense bunch holes.•An accurate numerical model for raise blasting under in-situ stress.•In-situ stress governs the radial cracks but ...has little effect on the crush zone.•In-situ stress can reduce PPA and frequency of the blast-induced vibration.•Short-delay blast can effectively reduce the cut blasting induced vibration.
In deep underground mining, the damage evolution and vibration response mechanisms of rock caused by cut blasting are different from those of shallow rock. It is essential to understand the mechanisms for underground engineering safety. In this study, field raise blasting with vertically parallel and dense bunch longholes was designed and performed at the Shaxi underground mine in China. The raise contour and the blasting vibration were measured in the field, and regression analyses of the peak particle acceleration (PPA) were performed. Then, a numerical model considering the effect of in situ stress was developed and calibrated to simulate raise blasting excavation. The damage contours show that the in-situ stress can reduce the radial fractures outside the raise, but has little influence on the crater. The vibration analyses indicate that the PPA and the average frequency (AF) decrease with an increasing in-situ stress. The confinement effect of in-situ stress on vibration characteristics is discussed, and blast loading relative pressure curves are presented for a demonstration. It is determined that the relative pressure peak value decreases, and the rising time and duration time increase with an increasing the in-situ stress; as a result, the blast-induced vibration is lower in amplitude and AF. In terms of the frequency, the vibration from a higher in-situ stress is more harmful to structures. A short-delay blasting model was conducted, and the results show that it can effectively reduce the structural vibration damage caused by cut blasting.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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