Tumor grade-associated genomic mutations in Chinese patients with non-small cell lung cancer

BackgroundLung cancer is the most prevalent cancer worldwide and accounts for approximately 20% of cancer-related death in China every year. High-grade lung cancer poses a significant threat to patients, and developing a novel treatment for these patients requires an understanding of its underlying mechanism.MethodsChinese patients with lung cancer were enrolled. The tumor samples were collected by surgery or puncture and applied for next-generation sequencing. A panel of pan-cancer genes was targeted, and the sequencing depth was set to over 1,000 to improve the sensitivity of detecting mutations. Short-length mutations (substitution, insertion, and deletion), copy number variation, and gene fusion were called. Gene mutations were compared between low-grade, middle-grade, and high-grade tumors using Fisher’s exact test. The enriched pathways in each grade of tumors were also inferred.ResultsThe study included 173 Chinese patients with non-small cell lung cancer, of whom 98 (56.6%) patients were female and 75 (43.4%) were male, with a mean age of 56.8 years. All patients were microsatellite stable; 66.4% were at the early stages (Stages 0, I, and II) with a tumor mutational burden of approximately 2.5 (confidence interval = [0, 48.3]). Compared to low-grade tumors, high-grade tumors had a significantly higher percentage of mutations in TP53 (75.9% vs 34.4%, p = 1.86e-3) and PIK3CA (24.1% vs. 0%, p = 3.58e-3). Pathway analysis found that high-grade tumors were enriched with mutations in bacterial invasion of epithelial cells (31% vs. 0%, p = 5.8e-4), Epstein–Barr virus infection (79.3% vs. 37.5%, p = 1.72e-3), and the Wnt signaling pathway (75.9% vs. 34.4%, p = 1.91e-3). High-grade tumors had a significantly higher tumor mutational burden than low-grade tumors (p-value = 0.0017). However, actionable mutations with high-level evidence were lower in high-grade tumors.ConclusionPatients with high-grade tumors from lung cancer may be more affected by bacteria and Epstein–Barr virus than low-grade tumors. High-grade tumors were specially mutated in TP53 and PIK3CA and may benefit more from immunotherapy. Further research on the underlying mechanism of high-grade lung cancer is necessary to develop new therapeutic options. Lung cancer, tumor grade, genomic mutations, Epstein–Barr virus, pathway analysi

A High Step-up Modular Isolated DC-DC Converter for Large Capacity Photovoltaic Generation System integrated into MVDC Grids

Nowadays, the research and design of the DC-DC conversion system has become more and more popular in the application of photovoltaic generation into the medium voltage DC (MVDC) grids. A novel high power modular isolated DC-DC converter with high step-up ratio is proposed as a module of the DC-DC conversion system in this paper. Based on the input parallel and output series (IPOS) connections of the proposed modular converters, the system is easy to achieve high capacity and high voltage. A two-stage structure is employed in the proposed converter. The interleaved boost topology is applied to the front-stage, which realizes MPPT for PV arrays with low input current ripples. The full-bridge LLC topology is employed as the back-stage, which lowers power losses by the implementation of soft-switching. The voltage gain of the proposed converter is derived in detail. The theoretical analysis and control strategy are studied in depth. Simulation and experiment verify the feasibility and effectiveness of the proposed converter.N

SARS-CoV-2 Variants Increase Kinetic Stability of Open Spike Conformations as an Evolutionary Strategy

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOCs) harbor mutations in the spike (S) glycoprotein that confer more efficient transmission and dampen the efficacy of COVID-19 vaccines and antibody therapies. S mediates virus entry and is the primary target for antibody responses, with structural studies of soluble S variants revealing an increased propensity toward conformations accessible to the human angiotensin-converting enzyme 2 (hACE2) receptor. However, real-time observations of conformational dynamics that govern the structural equilibriums of the S variants have been lacking. Here, we report single-molecule Förster resonance energy transfer (smFRET) studies of critical mutations observed in VOCs, including D614G and E484K, in the context of virus particles. Investigated variants predominately occupied more open hACE2-accessible conformations, agreeing with previous structures of soluble trimers. Additionally, these S variants exhibited slower transitions in hACE2-accessible/bound states. Our finding of increased S kinetic stability in the open conformation provides a new perspective on SARS-CoV-2 adaptation to the human population

Development and validation of prognostic dynamic nomograms for hepatitis B Virus-related hepatocellular carcinoma with microvascular invasion after curative resection

Background and AimThe prediction models of postoperative survival for hepatitis B virus-related hepatocellular carcinoma (HBV-HCC) with microvascular invasion (MVI) have not been well established. The study objective was the development of nomograms to predict disease recurrence and overall survival (OS) in these patients.MethodsData were obtained from 1046 HBV-related MVI-positive HCC patients who had undergone curative resection from January 2014 to December 2017. The study was approved by the Eastern Hepatobiliary Surgery Hospital and Jinling Hospital ethics committee, and patients provided informed consent for the use of their data. Nomograms for recurrence and OS were created by Cox regression model in the training cohort (n=530). The modes were verified in an internal validation cohort (n= 265) and an external validation cohort (n= 251).ResultsThe nomograms of recurrence and OS based on preoperative serological indicators (HBV-DNA, neutrophil-lymphocyte ratio, a-fetoprotein), tumor clinicopathologic features (diameter, number), surgical margin and postoperative adjuvant TACE achieved high C-indexes of 0.722 (95% confidence interval [CI], 0.711-0.732) and 0.759 (95% CI, 0.747-0.771) in the training cohort, respectively, which were significantly higher than conventional HCC staging systems (BCLC, CNLC, HKLC).The nomograms were validated in the internal validation cohort (0.747 for recurrence, 0.758 for OS) and external validation cohort(0.719 for recurrence, 0.714 for OS) had well-fitted calibration curves. Our nomograms accurately stratified patients with HBV-HCC with MVI into low-, intermediate- and high-risk groups of postsurgical recurrence and mortality. Prediction models for recurrence-free survival (https://baishileiehbh.shinyapps.io/HBV-MVI-HCC-RFS/) and OS (https://baishileiehbh.shinyapps.io/HBV-MVI-HCC-OS/) were constructed.ConclusionsThe two nomograms showed good predictive performance and accurately distinguished different recurrence and OS by the nomograms scores for HBV-HCC patients with MVI after resection

Research on Energy-Saving Optimization for the Performance Parameters of Rural-Building Shape and Envelope by TRNSYS-GenOpt in Hot Summer and Cold Winter Zone of China

The aim of this paper is to optimize the building shape parameters and envelope parameters influencing the rural building energy consumption in cold winter and hot summer climate. Several typical models are established and optimized by integrated TRNSYS and GenOpt. Single-objective optimization has provided guidance to the multi-dimensional optimization. Building shape and envelope parameters are considered simultaneously by multi-dimensional optimization. Results of the optimization showed significant reduction in terms of EC (energy consumption). When O (building orientation) was SW (south by west) 10°, LWR (length-width ratio) was 1.1, WWRS (window-wall ratio in south) with the range of 0.6–0.8, ITE (insulation thickness of exterior wall) and ITR (insulation thickness of roof) was 0.05 m and 0.08 m respectively, the building had minimal energy consumption. The results also indicated that the optimal EWT (exterior window type) was plastic single-frame Low-E insulating glazing filled with inert gas, and the optimal shape of building is Re (rectangle). An effective method was provided to optimize the design of the rural building for the purpose of reducing building energy consumption in cold winter and hot summer climate

A System to Pre-Evaluate the Suitability of Energy-Saving Technology for Green Buildings

Rating systems for green buildings often give assessments from the perspective of the overall performance of a single building or architecture complex but rarely target specific green building technologies. As some of the rating systems are scored according to whether the technologies are used or not, some developers tend to pile up energy-saving technologies blindly just for the sake of certifications without considering their suitability for the application. Such behavior may lead to the failure of achieving the energy goals for green buildings. To solve this problem, a system that pre-evaluates the suitability of green building energy-saving technologies is devised based on modified TOPSIS (Technique for Order Preference by Similarity to an Ideal Solution) method, SA (simulated annealing) algorithm and unascertained theory-based data analysis method. By setting indices from technology performance, economy, human satisfaction aspects and by using the building prior information and measured database of technology usage, this system can make a quantifiable and multi-dimensional grading assessment for the target green building energy-saving technologies in the design stage. The system aims at helping the designer choose technologies in the design phase that best enhance the performance of the finished green building. It also helps prevent the sub-optimal performance of unsuitable technologies caused by the “pile up” behavior mentioned earlier. To verify this evaluation system, two building designs which use energy-recovery technology are evaluated, and the predicted performance for both designs matched the actual operation of the technology in the buildings themselves well