Genomic analysis of oesophageal squamous-cell carcinoma identifies alcohol drinking-related mutation signature and genomic alterations

Approximately half of the world's 500,000 new oesophageal squamous-cell carcinoma (ESCC) cases each year occur in China. Here, we show whole-genome sequencing of DNA and RNA in 94 Chinese individuals with ESCC. We identify six mutational signatures (E1–E6), and Signature E4 is unique in ESCC linked to alcohol intake and genetic variants in alcohol-metabolizing enzymes. We discover significantly recurrent mutations in 20 protein-coding genes, 4 long non-coding RNAs and 10 untranslational regions. Functional analyses show six genes that have recurrent copy-number variants in three squamous-cell carcinomas (oesophageal, head and neck and lung) significantly promote cancer cell proliferation, migration and invasion. The most frequently affected genes by structural variation are LRP1B and TTC28. The aberrant cell cycle and PI3K-AKT pathways seem critical in ESCC. These results establish a comprehensive genomic landscape of ESCC and provide potential targets for precision treatment and prevention of the cancer

Spatially and Temporally Complete Satellite Soil Moisture Data Based on a Data Assimilation Method

Multiple soil moisture products have been generated from data acquired by satellite. However, these satellite soil moisture products are not spatially or temporally complete, primarily due to track changes, radio-frequency interference, dense vegetation, and frozen soil. These deficiencies limit the application of soil moisture in land surface process simulation, climatic modeling, and global change research. To fill the gaps and generate spatially and temporally complete soil moisture data, a data assimilation algorithm is proposed in this study. A soil moisture model is used to simulate soil moisture over time, and the shuffled complex evolution optimization method, developed at the University of Arizona, is used to estimate the control variables of the soil moisture model from good-quality satellite soil moisture data covering one year, so that the temporal behavior of the modeled soil moisture reaches the best agreement with the good-quality satellite soil moisture data. Soil moisture time series were then reconstructed by the soil moisture model according to the optimal values of the control variables. To analyze its performance, the data assimilation algorithm was applied to a daily soil moisture product derived from the Advanced Microwave Scanning Radiometer for the Earth Observing System (AMSR-E), the Microwave Radiometer Imager (MWRI), and the Advanced Microwave Scanning Radiometer 2 (AMSR2). Preliminary analysis using soil moisture data simulated by the Global Land Data Assimilation System (GLDAS) Noah model and soil moisture measurements at a multi-scale Soil Moisture and Temperature Monitoring Network on the central Tibetan Plateau (CTP-SMTMN) was performed to validate this method. The results show that the data assimilation algorithm can efficiently reconstruct spatially and temporally complete soil moisture time series. The reconstructed soil moisture data are consistent with the spatial precipitation distribution and have strong positive correlations with the values simulated by the GLDAS Noah model over large areas of the region. Compared to the soil moisture measurements at the medium and large networks, the reconstructed soil moisture data have almost the same accuracy as the soil moisture product derived from AMSR-E/MWRI/AMSR2 for ascending and descending orbits

Comparison of mesenchymal stromal cells from peritoneal dialysis effluent with those from umbilical cords: characteristics and therapeutic effects on chronic peritoneal dialysis in uremic rats

Background A long-term of peritoneal dialysis (PD) using a hypertonic PD solution (PDS) leads to patient’s peritoneal membrane (PM) injury, resulting in ultrafiltration failure (UFF) and PD drop-out. Our previous study shows that PD effluent-derived mesenchymal stromal cells (pMSCs) prevent the PM injury in normal rats after repeated exposure of the peritoneal cavity to a PDS. This study was designed to compare the cytoprotection between pMSCs and umbilical cord-derived MSCs (UC-MSCs) in the treatment of both PM and kidney injury in uremic rats with chronic PD. Methods 5/6 nephrectomized (5/6Nx) Sprague Dawley rats were intraperitoneally (IP) injected Dianeal (4.25% dextrose, 10 mL/rat/day) and were treated with pMSCs or umbilical cord (UC)-MSCs (approximately 2 × 106/rat/week, IP). Ultrafiltration was determined by IP injection of 30 mL of Dianeal (4.25% dextrose) with 1.5-h dewell time, and kidney failure by serum creatinine (SCr) and blood urea nitrogen (BUN). The structure of the PM and kidneys was assessed using histology. Gene expression was examined using quantitative reverse transcription PCR, and protein levels using flow cytometric and Western blot analyses. Results We showed a slight difference in the morphology between pMSCs and UC-MSCs in plastic dishes, and significantly higher expression levels of stemness-related genes (NANOG, OCT4, SOX2, CCNA2, RAD21, and EXO1) and MSCs surface markers (CD29, CD44, CD90 and CD105) in UC-MSCs than those in pMSCs, but no difference in the differentiation to chondrocytes, osteocytes or adipocytes. pMSC treatment was more effective than UC-MSCs in the protection of the MP and remnant kidneys in 5/6Nx rats from PDS-induced injury, which was associated with higher resistance of pMSCs than UC-MSCs to uremic toxins in culture, and more reduction of peritoneal mesothelial cell death by the secretome from pMSCs than from UC-MSCs in response to PDS exposure. The secretome from both pMSCs and UC-MSCs similarly inactivated NOS2 in activated THP1 cells. Conclusions As compared to UC-MSCs, pMSCs may more potently prevent PDS-induced PM and remnant kidney injury in this uremic rat model of chronic PD, suggesting that autotransplantation of ex vivo-expanded pMSCs may become a promising therapy for UFF and deterioration of remnant kidney function in PD patients.Medicine, Faculty ofNon UBCMedicine, Department ofNephrology, Division ofUrologic Sciences, Department ofReviewedFacult

Long-Term Outcomes of Bioprosthetic and Mechanical Valve Replacement for Patients Aged between 50 and 70 Years

Background: The choice between bioprosthetic and mechanical valves for aortic valve replacement (AVR) and mitral valve replacement (MVR) among patients aged 50–70 years is controversial. We compared the long-term outcomes of patients using bioprosthetic or mechanical valves to provide clinical evidence for valve selection. Methods: From 2002 to 2007, patients aged 50–70 years who underwent isolated AVR or MVR at the Fuwai Hospital were enrolled. After inverse probability-weighted (IPW) propensity balancing, we evaluated long-term mortality, stroke, and bleeding events between patients receiving mechanical and biological prostheses for MVR or AVR. Results: A total of 1639 patients were included in the study, including 1181 patients undergoing MVR (median follow-up: 11.6 years) and 458 patients undergoing AVR (median follow-up: 11.4 years). After IPW adjustment, there was no significant difference in long-term mortality and stroke rate between patients using bioprosthetic and mechanical valves for MVR [mortality: log-rank p = 0.802; stroke: log-rank p = 0.983] and AVR [mortality: log-rank p = 0.815; stroke: log-rank p = 0.537]. Landmark analysis at 12.5 years yielded significantly lower mortality in the patients receiving mechanical valves compared with bioprosthetic valves in the MVR cohort (p = 0.028). Patients receiving mechanical aortic valves displayed an increased risk of bleeding compared with those who received bioprosthetic aortic valves [Hazard Ratio (95% Confidence interval): 2.51 (1.06–5.93) p = 0.036]. Conclusions: For patients aged 50–70, there was no significant difference in overall long-term mortality between mechanical and bioprosthetic valve recipients. Patients receiving mechanical valves for MVR displayed lower mortality after 12.5 years follow-up. For AVR, bioprosthetic valves were associated with a lower risk of bleeding

Association of GWAS-identified lung cancer susceptibility loci with survival length in patients with small-cell lung cancer treated with platinum-based chemotherapy.

Genetic variants have been shown to affect length of survival in cancer patients. This study explored the association between lung cancer susceptibility loci tagged by single-nucleotide polymorphisms (SNPs) identified in the genome-wide association studies and length of survival in small-cell lung cancer (SCLC). Eighteen SNPs were genotyped among 874 SCLC patients and Cox proportional hazards regression was used to examine the effects of genotype on survival length under an additive model with age, sex, smoking status and clinical stage as covariates. We identified 3 loci, 20q13.2 (rs4809957G >A), 22q12.2 (rs36600C >T) and 5p15.33 (rs401681C >T), significantly associated with the survival time of SCLC patients. The adjusted hazard ratio (HR) for patients with the rs4809957 GA or AA genotype was 0.80 (95% CI, 0.66-0.96; P = 0.0187) and 0.73 (95% CI, 0.55-0.96; P = 0.0263) compared with the GG genotype. Using the dominant model, the adjusted HR for patients carrying at least one T allele at rs36600 or rs401681 was 0.78 (95% CI, 0.63-0.96; P = 0.0199) and 1.29 (95% CI, 1.08-1.55; P = 0.0047), respectively, compared with the CC genotype. Stratification analyses showed that the significant associations of these 3 loci were only seen in smokers and male patients. The rs4809957 SNP was only significantly associated with length of survival of patients with extensive-stage but not limited-stage tumor. These results suggest that some of the lung cancer susceptibility loci might also affect the prognosis of SCLC

Kaplan–Meier estimates of overall survival of patients with small-cell lung cancer according to rs4809957G >A (a), rs36600C >T (b) or rs401681C >T (c) genotypes.

<p>Kaplan–Meier estimates of overall survival of patients with small-cell lung cancer according to rs4809957G >A (a), rs36600C >T (b) or rs401681C >T (c) genotypes.</p

Clinical characteristics of 874 patients with small-cell lung cancer.

<p>Abbreviation: No., number of patients; MST, median survival time.</p><p>^†<i>P</i> values for log-rank test.</p><p>*Classified according to the Veterans' Administration Lung Study Group.</p><p>Clinical characteristics of 874 patients with small-cell lung cancer.</p