Esophageal squamous cell carcinoma (ESCC) is a poor-prognosis cancer type with limited understanding of its molecular etiology. Using 508 ESCC genomes, we identified five novel significantly mutated genes and uncovered mutational signature clusters associated with metastasis and patients’ outcomes. Several functional assays implicated that NFE2L2 may act as a tumor suppressor in ESCC and that mutations in NFE2L2 probably impaired its tumor-suppressive function, or even conferred oncogenic activities. Additionally, we found that the NFE2L2 mutations were significantly associated with worse prognosis of ESCC. We also identified potential noncoding driver mutations including hotspot mutations in the promoter region of SLC35E2 that were correlated with worse survival. Approximately 5.9% and 15.2% of patients had high tumor mutation burden or actionable mutations, respectively, and may benefit from immunotherapy or targeted therapies. We found clinically relevant coding and noncoding genomic alterations and revealed three major subtypes that robustly predicted patients’ outcomes. Collectively, we report the largest dataset of genomic profiling of ESCC useful for developing ESCC-specific biomarkers for diagnosis and treatment.

Esophageal squamous cell carcinoma (ESCC) ranks fourth among cancer-related deaths in China due to the lack of actionable molecules. We performed whole-exome and T-cell receptor (TCR) repertoire sequencing on multi-regional tumors, normal tissues and blood samples from 39 ESCC patients. The data revealed 12.8% of ERBB4 mutations at patient level and functional study supported its oncogenic role. 18% of patients with early BRCA1 /2 variants were associated with high-level contribution of signature 3, which was validated in an independent large cohort ( n = 508). Furthermore, knockdown of BRCA1 /2 dramatically increased sensitivity to cisplatin in ESCC cells. 5% of patients harbored focal high-level amplification of CD274 that led to massive expression of PD-L1, and might be more sensitive to immune checkpoint blockade. Finally, we found a tight correlation between genomic and TCR repertoire intra-tumor heterogeneity (ITH). Collectively, we reveal high-level ITH in ESCC, identify several potential actionable targets and may provide novel insight into ESCC treatment.

International audienceThis brief presents a set of experimental results concerning the sliding mode control of an electropneumatic system. Two discrete-time control strategies are considered: an explicit and an implicit (that is very easy to implement with a projection on the interval [−1, 1]) Euler discretizations. While the explicit implementation is known to generate numerical chattering , the implicit one is expected to significantly reduce chattering while keeping the accuracy. The experimental results reported in this brief remarkably confirm that the implicit discrete-time sliding mode supersedes the explicit ones, with several important features: chattering in the control input is almost eliminated (while the explicit and saturated controllers behave like high-frequency bang–bang inputs), the input magnitude depends only on the perturbation size and is independent of the controller gain and sampling time

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High-quality AlPO-18 membranes were synthesized using low-cost symmetric alumina supports by a single hydrothermal step, and showed to be useful for light gas separation. Single-gas permeances of CO 2 , N 2 , CH 4 and C 3 H 8 decreased with increasing kinetic diameter. Single CO 2 and CH 4 permeance dependence of pressure drop was predicted by the Maxwell-Stefan diffusion model and was in agreement with experimental data. The best AlPO-18 membrane showed smaller-component permeances of 6.5, 6.3 and 1.0 Â 10 À7 mol (m 2 s Pa) À1 (equal to 1940, 1880 and 300 GPU) and mixture selectivities of 220, 45 and 22 for equimolar CO 2 /CH 4 , CO 2 /N 2 and H 2 /CH 4 binary mixtures at room temperature and 0.2 MPa pressure drop, respectively. The effects of temperature and pressure on the membrane's separation performance in the three binary mixtures were discussed.

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a b s t r a c tSeed bubbles are generated on microheaters located at the microchannel upstream and driven by a pulse voltage signal, to improve flow and heat transfer performance in microchannels. The present study investigates how seed bubbles stabilize flow and heat transfer in micro-boiling systems. For the forced convection flow, when heat flux at the wall surface is continuously increased, flow instability is self-sustained in microchannels with large oscillation amplitudes and long periods. Introduction of seed bubbles in time sequence improves flow and heat transfer performance significantly. Low frequency ($10 Hz) seed bubbles not only decrease oscillation amplitudes of pressure drops, fluid inlet and outlet temperatures and heating surface temperatures, but also shorten oscillation cycle periods. High frequency ($100 Hz or high) seed bubbles completely suppress the flow instability and the heat transfer system displays stable parameters of pressure drops, fluid inlet and outlet temperatures and heating surface temperatures. Flow visualizations show that a quasi-stable boundary interface from spheric bubble to elongated bubble is maintained in a very narrow distance range at any time. The seed bubble technique almost does not increase the pressure drop across microsystems, which is thoroughly different from those reported in the literature. The higher the seed bubble frequency, the more decreased heating surface temperatures are. A saturation seed bubble frequency of 1000-2000 Hz can be reached, at which heat transfer enhancement attains the maximum degree, inferring a complete thermal equilibrium of vapor and liquid phases in microchannels. Benefits of the seed bubble technique are the stabilization of flow and heat transfer, decreasing heating surface temperatures and improving temperature uniformity of the heating surface.