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Malignant pleural mesothelioma (MPM) is a lung pleural cancer with very poor disease outcome. With limited curative MPM treatment available, it is vital to study prognostic biomarkers to categorise different patient risk groups.We defined gene signatures to separately characterise intrinsic and extrinsic features, and investigated their interactions in MPM tumour samples. Specifically, we calculated gene signature scores to capture the downstream pathways of major mutated driver genes (BAP1, NF2, SETD2 and TP53) as tumour-intrinsic features. Similarly, we inferred the infiltration levels for major immune cells in the tumour microenvironment to characterise tumour-extrinsic features. Lastly, we integrated these features with clinical factors to predict prognosis in MPM.The gene signature scores were more prognostic than the corresponding genomic mutations, mRNA and protein expression. High immune infiltration levels were associated with prolonged survival. The integrative model indicated that tumour features provided independent prognostic values than clinical factors and were complementary with each other in survival prediction.By using an integrative model that combines intrinsic and extrinsic features, we can more correctly predict the clinical outcomes of patients with MPM.

Acute kidney injury is common among hospitalized individuals, particularly those exposed to certain medications, and is associated with substantial morbidity and mortality. In a pragmatic, open-label, National Institutes of Health-funded, parallel group randomized controlled trial (clinicaltrials.gov NCT02771977), we investigate whether an automated clinical decision support system affects discontinuation rates of potentially nephrotoxic medications and improves outcomes in patients with AKI. Participants included 5060 hospitalized adults with AKI and an active order for any of three classes of medications of interest: non-steroidal anti-inflammatory drugs, renin-angiotensin-aldosterone system inhibitors, or proton pump inhibitors. Within 24 hours of randomization, a medication of interest was discontinued in 61.1% of the alert group versus 55.9% of the usual care group (relative risk 1.08, 1.04 – 1.14, p = 0.0003). The primary outcome – a composite of progression of acute kidney injury, dialysis, or death within 14 days - occurred in 585 (23.1%) of individuals in the alert group and 639 (25.3%) of patients in the usual care group (RR 0.92, 0.83 – 1.01, p = 0.09). Trial Registration Clinicaltrials.gov NCT02771977.

Despite mitochondrial DNA (mtDNA) mutations are common events in cancer, their global frequency and clinical impact have not been comprehensively characterized in patients with myelodysplastic neoplasia (also known as myelodysplastic syndromes, MDS). Here we performed whole-genome sequencing (WGS) on samples obtained before allogenic hematopoietic cell transplantation (allo-HCT) from 494 patients with MDS who were enrolled in the Center for International Blood and Marrow Transplant Research. We evaluated the impact of mtDNA mutations on transplantation outcomes, including overall survival (OS), relapse, relapse-free survival (RFS), and transplant-related mortality (TRM). A random survival forest algorithm was applied to evaluate the prognostic performance of models that include mtDNA mutations alone and combined with MDS- and HCT-related clinical factors. A total of 2666 mtDNA mutations were identified, including 411 potential pathogenic variants. We found that overall, an increased number of mtDNA mutations was associated with inferior transplantation outcomes. Mutations in several frequently mutated mtDNA genes (e.g., MT-CYB and MT-ND5) were identified as independent predictors of OS, RFS, relapse and/or TRM after allo-HCT. Integration of mtDNA mutations into the models based on the Revised International Prognostic Scores (IPSS-R) and clinical factors related to MDS and allo-HCT could capture more prognostic information and significantly improve the prognostic stratification efforts. Our study represents the first WGS effort in MDS receiving allo-HCT and shows that there may be clinical utility of mtDNA variants to predict allo-HCT outcomes in combination with more standard clinical parameters.

Background Duchenne muscular dystrophy (DMD) is a neuromuscular disease characterised by progressive muscular weakness and atrophy. Currently, studies on DMD muscle function mostly focus on individual muscles; little is known regarding the effect of gluteal muscle group damage on motor function. Objective To explore potential imaging biomarkers of hip and pelvic muscle groups for measuring muscular fat replacement and inflammatory oedema in DMD with multimodal quantitative magnetic resonance imaging (MRI). Materials and methods One hundred fifty-nine DMD boys and 32 healthy male controls were prospectively included. All subjects underwent MRI examination of the hip and pelvic muscles with T1 mapping, T2 mapping and Dixon sequences. Quantitatively measured parameters included longitudinal relaxation time (T1), transverse relaxation time (T2) and fat fraction. Investigations were all based on hip and pelvic muscle groups covering flexors, extensors, adductors and abductors. The North Star Ambulatory Assessment and stair climbing tests were used to measure motor function in DMD. Results T1 of the extensors (r = 0.720, P r = 0.558, P r = 0.697, P r = -0.711, P r = -0.753, P b = 0.013, t = 2.052, P = 0.042), T2 of the adductors (b = -0.234, t = -2.554, P = 0.012) and fat fraction of the extensors (b = -0.637, t = − 4.096, P Conclusion Magnetic resonance biomarkers of hip and pelvic muscle groups (particularly T1 values of the abductor muscles) have the potential to be used as independent risk factors for motor dysfunction in DMD.

BackgroundThis study aimed to use single-cell RNA-seq (scRNA-seq) to discover marker genes in endothelial cells (ECs) and construct a prognostic model for glioblastoma multiforme (GBM) patients in combination with traditional high-throughput RNA sequencing (bulk RNA-seq).MethodsBulk RNA-seq data was downloaded from The Cancer Genome Atlas (TCGA) and The China Glioma Genome Atlas (CGGA) databases. 10x scRNA-seq data for GBM were obtained from the Gene Expression Omnibus (GEO) database. The uniform manifold approximation and projection (UMAP) were used for downscaling and cluster identification. Key modules and differentially expressed genes (DEGs) were identified by weighted gene correlation network analysis (WGCNA). A non-negative matrix decomposition (NMF) algorithm was used to identify the different subtypes based on DEGs, and multivariate cox regression analysis to model the prognosis. Finally, differences in mutational landscape, immune cell abundance, immune checkpoint inhibitors (ICIs)-associated genes, immunotherapy effects, and enriched pathways were investigated between different risk groups.ResultsThe analysis of scRNA-seq data from eight samples revealed 13 clusters and four cell types. After applying Fisher’s exact test, ECs were identified as the most important cell type. The NMF algorithm identified two clusters with different prognostic and immunological features based on DEGs. We finally built a prognostic model based on the expression levels of four key genes. Higher risk scores were significantly associated with poorer survival outcomes, low mutation rates in IDH genes, and upregulation of immune checkpoints such as PD-L1 and CD276.ConclusionWe built and validated a 4-gene signature for GBM using 10 scRNA-seq and bulk RNA-seq data in this work.

The interaction between pancreatic cancer cells (PCCs) and pancreatic stellate cells (PSCs) promotes aggressive progression of pancreatic cancer, and disrupting the tumor-stromal crosstalk is a promising therapeutic strategy. Integrin α5 (ITGA5) is specifically overexpressed in pancreatic cancer stroma and activated PSCs. ITGA5 acts as a mediator in PCCs-PSCs interaction, but its role in regulating biological behaviors of PSCs and PCCs is still not quite clear. In this study, ITGA5 in PSCs was inhibited using its specific inhibitor AV3 peptide or siRNA knockdown technique. Pancreatic cancer SW1990 cells conditioned medium (SW1990-CM) and an indirect co-culture system were used to mimic the environment of the in vitro tumor-stromal crosstalk. Our results showed that ITGA5 inhibition impaired the proliferation and migration of PSCs, but enhanced autophagy. After co-culture with PSCs, SW1990 cells gained some cancer stem cells (CSCs)-like characteristics, such as increased drug resistance, migration and invasion ability, but PSCs with ITGA5 knockdown were incapable of producing these effects. The present results suggested that ITGA5 was involved in the development of the malignant biological behaviors of PSCs and PCCs, and ITGA5 inhibition in PSCs might benefit the treatment of pancreatic cancer by re-educating PCCs-PSCs interaction.

Objective To evaluate the efficacy and safety of SBRT for localized prostate cancer (PCa) with CyberKnife in China. Moreover, it is the largest-to-date pilot study to report 5-year outcomes of SBRT for localized PCa from China. Methods In this retrospective study, 133 PCa patients in our center were treated by SBRT with CyberKnife (Accuray Inc., Sunnyvale, USA) from October 2012 to July 2019. Follow-up was performed every 3 months for efficacy and toxicity evaluation. Biochemical progression-free survival (bPFS) and toxicities were assessed using the Phoenix definition and the Common Terminology Criteria for Adverse Events (CTCAE) v.5.0, respectively. Factors predictive of bPFS were identified with COX regression analysis. Results 133 patients (10 low-, 21 favorable intermediate-, 31 unfavorable intermediate-, 45 high-, and 26 very high risk cases on the basis of NCCN risk classification) with a median age of 76 years (range 54–87 years) received SBRT. The median dose was 36.25 Gy (range 34–37.5 Gy) in 5 fractions. Median follow-up time was 57.7 months (3.5–97.2 months). The overall 5-year bPFS rate was 83.6% for all patients. The 5-year bPFS rate of patients with low-, favorable intermediate-, unfavorable intermediate-, high-, and very high risk PCa was 87.5%, 95.2%, 90.5%, 86.3%, and 61.6%, respectively. Urinary symptoms were all alleviated after SBRT. All patients tolerated SBRT with 1 (0.8%) patient reporting grade-3 acute and 1 (0.8%) patient reporting grade-3 late genitourinary (GU) toxicity, respectively. There were no grade 4 toxicities. Gleason score (P Conclusion SBRT is an efficient and safe treatment modality for localized PCa with high 5-year bPFS rates and acceptable toxicities.

This paper presents a novel solution of coverage path planning for robotic mowing applications. The planning algorithm is based on the Boustrophedon motions and the rapid Voronoi diagram. The coordinate conversion and the sweeping vector is defined by minimum bounding box and the Voronoi travel paths are designed to reduce the computational cost and execution time compared to conventional heuristic methods. The tracked path is controlled via dynamic feedback in standard lawn mowing robots under robot operating system (ROS). Within ROS, the information exchanging among different tasks of both extensive simulation cases and experimental field tests can be conducted easily. When meeting unknown obstacles, the proposed algorithm can re-plan its paths dynamically. The performance of the proposed algorithm is compared to several conventional coverage algorithms in terms of time efficiency, coverage, repetition, and robustness with respect to both concave and convex shapes. The field tests are conducted to demonstrate that the applicability of the sensor fusion and robustness of the proposed algorithm for the complete coverage tasks by robotic mowers.

BACKGROUND: The function of major histocompatibility complex (MHC) molecules is to bind peptide fragments derived from genomic mutations or pathogens and display them on the cell surface for recognition by cognate T cells to initiate an immune response. METHODS: In this study, we provide a comprehensive investigation of HLA gene expression in a pan-cancer manner involving 33 cancer types. We utilised gene expression data from several databases and immune checkpoint blockade-treated patient cohorts. RESULTS: We show that MHC expression varies strongly among cancer types and is associated with several genomic and immunological features. While immune cell infiltration was generally higher in tumours with higher HLA gene expression, CD4+ T cells showed significantly different correlations among cancer types, separating them into two clusters. Furthermore, we show that increased HLA gene expression is associated with prolonged survival in the majority of cancer types. Lastly, HLA gene expression is associated with patient response to immune checkpoint blockade, which is especially prominent for HLA class II expression in tumour biopsies taken during treatment. CONCLUSION: We show that HLA gene expression is an important feature of tumour biology that has significant impact on patient prognosis.

Simultaneously possessed high energy-storage and power density dielectric ceramics are promising materials for pulsed power capacitor applications. In this work, the (1 − x)K0.5Bi0.5TiO3–xCa0.7La0.2TiO3 ((1 − x)KBT–xCLT, x = 0, 0.24, 0.29, and 0.34) ceramics were prepared by conventional solid-state reaction method. The structural, dielectric, and energy storage properties of the ceramics were systematically studied. All ceramics exhibit a main perovskite phase with dense microstructure accompanied by little secondary phase. With the increasing of CLT content, relaxor behavior appears and gradually becomes notable in the samples. A high recoverable energy storage density of 2.57 J/cm3 together with outstanding power density of 47 MW/cm3 can be achieved simultaneously in the 0.66KBT–0.34CLT ceramic. In addition, the ceramic also shows a rapid discharge time of 41 ns. This study provides a strategy for achieving high recoverable energy storage and power density simultaneously for pulsed capacitor applications.

Pancreatic ductal adenocarcinoma (PDAC) and autoimmune pancreatitis (AIP) are diseases with a highly analogous visual presentation that are difficult to distinguish by imaging. The purpose of this research was to create a radiomics-based prediction model using dual-time PET/CT imaging for the noninvasive classification of PDAC and AIP lesions. This retrospective study was performed on 112 patients (48 patients with AIP and 64 patients with PDAC). All cases were confirmed by imaging and clinical follow-up, and/or pathology. A total of 502 radiomics features were extracted from the dual-time PET/CT images to develop a radiomics decision model. An additional 12 maximum intensity projection (MIP) features were also calculated to further improve the radiomics model. The optimal radiomics feature set was selected by support vector machine recursive feature elimination (SVM-RFE), and the final classifier was built using a linear SVM. The performance of the proposed dual-time model was evaluated using nested cross-validation for accuracy, sensitivity, specificity, and area under the curve (AUC). The final prediction model was developed from a combination of the SVM-RFE and linear SVM with the required quantitative features. The multimodal and multidimensional features performed well for classification (average AUC: 0.9668, accuracy: 89.91%, sensitivity: 85.31%, specificity: 96.04%). The radiomics model based on 2-[18F]fluoro-2-deoxy-D-glucose (2-[18F]FDG) PET/CT dual-time images provided promising performance for discriminating between patients with benign AIP and malignant PDAC lesions, which shows its potential for use as a diagnostic tool for clinical decision-making. • The clinical symptoms and imaging visual presentations of PDAC and AIP are highly similar, and accurate differentiation of PDAC and AIP lesions is difficult. • Radiomics features provided a potential noninvasive method for differentiation of AIP from PDAC. • The diagnostic performance of the proposed radiomics model indicates its potential to assist doctors in making treatment decisions.

A whole-body MRI (WB-MRI) including T1, short time inversion recovery (STIR), diffusion-weighted imaging (high b value) was applied in our center for the detection of bone metastasis in prostate cancer (PCa) patients. We intended to assess the diagnostic performance of this examination. 547 cases of PCa patients with higher risk of metastasis were referred to bone scintigraphy with SPECT/CT (BS + SPECT/CT) and whole-body MRI in Shanghai Changhai Hospital. Best valuable comparator (BVC) was applied for the final diagnosis of metastasis. A panel of radiologists interpreted the results. Decision curve analysis (DCA) and receiver operating characteristic curve (ROC) analysis were applied. Bone metastasis was diagnosed in 110 cases, and others were non-metastatic by BVC. The area under the receiver operating characteristic curve (AUC) was higher in WB-MRI (0.778) than BS + SPECT/CT (0.634, p

Background Estriol (E3) is a steroid hormone formed only during pregnancy in primates including humans. Although E3 is synthesized at large amounts through a complex pathway involving the fetus and placenta, it is not required for the maintenance of pregnancy and has classically been considered virtually inactive due to associated very weak canonical estrogen signaling. However, estrogen exposure during pregnancy may have an effect on organs both within and outside the reproductive system, and compounds with binding affinity for estrogen receptors weaker than E3 have been found to impact reproductive organs and the brain. Here, we explore potential effects of E3 on fetal development using mouse as a model system. Results We administered E3 to pregnant mice, exposing the fetus to E3. Adult females exposed to E3 in utero (E3-mice) had increased fertility and superior pregnancy outcomes. Female and male E3-mice showed decreased anxiety and increased exploratory behavior. The expression levels and DNA methylation patterns of multiple genes in the uteri and brains of E3-mice were distinct from controls. E3 promoted complexing of estrogen receptors with several DNA/histone modifiers and their binding to target genes. E3 functions by driving epigenetic change, mediated through epigenetic modifier interactions with estrogen receptors rather than through canonical nuclear transcriptional activation. Conclusions We identify an unexpected functional role for E3 in fetal reproductive system and brain. We further identify a novel mechanism of estrogen action, through recruitment of epigenetic modifiers to estrogen receptors and their target genes, which is not correlated with the traditional view of estrogen potency.

Expression quantitative trait loci (eQTLs) analyses have been widely used to identify genetic variants associated with gene expression levels to understand what molecular mechanisms underlie genetic traits. The resultant eQTLs might affect the expression of associated genes through transcriptional or post-transcriptional regulation. In this study, we attempt to distinguish these two types of regulation by identifying genetic variants associated with mRNA stability of genes (stQTLs). Specifically, we computationally inferred mRNA stability of genes based on RNA-seq data and performed association analysis to identify stQTLs. Using the Genotype-Tissue Expression (GTEx) lung RNA-Seq data, we identified a total of 142,801 stQTLs for 3,942 genes and 186,132 eQTLs for 4,751 genes from 15,122,700 genetic variants for 13,476 genes, respectively. Interesting, our results indicated that stQTLs were enriched in the CDS and 3’UTR regions, while eQTLs are enriched in the CDS, 3’UTR, 5’UTR, and upstream regions. We also found that stQTLs are more likely than eQTLs to overlap with RNA binding protein (RBP) and microRNA (miRNA) binding sites. Our analyses demonstrate that simultaneous identification of stQTLs and eQTLs can provide more mechanistic insight on the association between genetic variants and gene expression levels.Author SummaryIn the past decade, many studies have identified genetic variants associated with gene expression level (eQTLs) in different phenotypes, including tissues and diseases. Gene expression is the result of cooperation between transcriptional regulation, such as transcriptional activity, and post-transcriptional regulation, such as mRNA stability. Here, we present a computational framework that take advantage of recently developed methods to estimate mRNA stability from RNA-Seq, which is widely used to estimate gene expression, and then to identify genetic variants associated with mRNA stability (stQTLs) in lung tissue. Compared to eQTLs, we found that genetic variants that affects mRNA stability are more significantly located in the CDS and 3’UTR regions, which are known to interact with RNA-binding proteins (RBPs) or microRNAs to regulate stability. In addition, stQTLs are significantly more likely to overlap the binding sites of RBPs. We show that the six RBPs that most significantly bind to stQTLs are all known to regulate mRNA stability. This pipeline of simultaneously identifying eQTLs and stQTLs using only RNA-Seq data can provide higher resolution than traditional eQTLs study to better understand the molecular mechanisms of genetic variants on the regulation of gene expression.

To evaluate and compare the efficacy of two techniques for the treatment of acute acromioclavicular joint dislocation, the charts of 60 patients diagnosed with acute Rockwood type IV and V acromioclavicular joint dislocation that undergone arthroscopic fixation procedure with single tunnel technique (N = 30, 30.7 ± 5.7 years old) or coracoid sling technique (N = 30, 30.1 ± 5.4 years old) fixation were retrospectively reviewed. The Visual Analog Scale pain score, Constant shoulder functionality score, Karlsson acromioclavicular joint score, the time of return to sports and activity, and plain radiographs of the affected shoulder at different time points of follow-up were recorded for a minimum of 2 years post-op. The majority of the patients recovered to their preoperative activity levels with few complications. The average postoperative acromioclavicular and coracoclavicular distances were significantly narrower than preoperative measurements in both groups without significant difference between the two groups at 2 years post-op (P

Mesenchymal stem cell–derived EVs (MSC-EVs) are demonstrated to have similar therapeutic effect as their cells of origin and represent an attractive cell-free stem cell therapy. With the potential to be the future medical regimen, the information of fate and behavior of MSC-EVs in the living subject should be urgently gathered. This study aimed to track MSC-EVs by 111In-labeling and μSPECT/CT imaging. Wharton’s jelly-MSC-EVs (WJ-MSC-EVs) were isolated using Exo-Prep kit followed by characterization of expressing markers and size. After labeled by 111In-oxine, 111In-EVs were injected into C57BL/6 mice followed by μSPECT/CT imaging. Organs were then taken out for ex vivo biodistribution analysis. The radiochemical purity of 111In-EVs was > 90 % and remained stable up to 24 h. The image results showed that with injection of 111In-EVs, the signal mainly accumulated in the liver, spleen, and kidney, compared to that in lung and kidney after 111In-oxine injection. The ex vivo biodistribution showed the similar pattern to that of imaging. Chelation of free 111In with EDTA was found necessary to reduce the nonspecific accumulation of signal. This study demonstrated the feasibility of radiolabeling WJ-MSC-EVs with 111In-oxine for in vivo imaging and quantitative analysis in a mouse model. This simple and quick labeling method preserves the characteristics of WJ-MSC-EVs. The results in this study provide a thorough and objective basis for future clinical study.

Gene expression is regulated by a large variety of mechanisms. Previous studies attempting to model the quantitative relationships between gene expression levels and regulatory mechanisms have considered only one or a few mechanisms at a time, which cannot provide a full picture of the complex interactions among different mechanisms. This was partially due to the heterogeneity of the mechanisms, which involve different types of biological objects and data representations, making it hard to study them in a unified way. Here, we describe a flexible framework that can integrate very different types of data for studying their joint effects on gene expression. In this framework, domain knowledge is represented by metapaths, while the manifestations of their effects in actual data are summarized by an embedding of the biological objects in a latent space. We demonstrate the use of our framework in integrating several diverse types of data that are related to gene expression in different ways, including DNA contacts in three-dimensional genome architecture, protein–protein interactions, genomic neighbourhoods and broad chromatin accessibility domains. The modelling results reveal that these several types of data are able to model gene expression fairly well individually, but even better when integrated. Gene expression is regulated by a variety of mechanisms, which have been difficult to study in a unified way. The authors propose a flexible framework that can integrate different types of data for studying their joint effects on gene expression. The framework uses a general network representation for data integration, metapaths for inputting prior knowledge of gene regulatory mechanisms, and embedding techniques for capturing complex structures in the data.

Hierarchical hollow structures show particular properties and promising applications, and therefore have been attracting attention. To the best of our knowledge, ZnO/C hollow sphere constructed by octahedron has not been reported so far. In this paper, a solvothermal process has been developed to prepare precursor hollow spheres constructed by octahedron. The precursor can be converted to hollow ZnO/C spheres with well-preserved morphology via thermal decomposing. In order to research the formation mechanism, intermediate precursors were acquired at different reaction times, and a possible growth mechanism was also proposed. When the hierarchical ZnO/C hollow spheres constructed by octahedron were used as the adsorbents, the Langmuir model can well describe the adsorption isotherms. For Congo red and Pb(II), the maximum adsorption capacities are up to 392 and 314 mg g−1, respectively. Furthermore, the as-prepared ZnO/C displays good recyclability in the removal of Congo red. Our results provide new strategy for the synthesis of novel ZnO/C hollow sphere, which has promising adsorption ability for water treatment.

Lung adenocarcinoma (LUAD) has become the most frequent histologic type of lung cancer in the past several decades. Recent successes with immune checkpoint blockade therapy have demonstrated that the manipulation of the immune system is a very potent treatment for LUAD. This study aims to explore the role of immune-related genes in the development of LUAD and establish a signature that can predict overall survival for LUAD patients. To identify the differential expression genes (DEGs) between normal and tumor tissues, we developed an analysis strategy to combine an independent-sample design and a paired-sample design using RNA-seq transcriptomic profiling data of The Cancer Genome Atlas LUAD samples. Further, we selected prognostic markers from DEGs and evaluated their prognostic value in a prediction model. We identified and validated PD1, PDL1 and CTLA4 genes as prognostic markers, which are well-known immune checkpoints, and revealed two new potential prognostic immune checkpoints for LUAD, HHLA2 (logFC = 2.55, FDR = 1.89 × 10–6) and VTCN1 (logFC = −2.86, FDR = 1.72 × 10–11). Furthermore, we identified an 18-gene LUAD prognostic biomarker panel and observed that the classified high-risk group presented a significantly shorter overall survival time (HR = 3.57, p value = 4.07 × 10–10). The prediction model was validated in five independent high-throughput gene expression datasets. The identified DEG features may serve as potential biomarkers for prognosis prediction of LUAD patients and immunotherapy. Based on that assumption, we identified a gene expression-based immune signature for lung adenocarcinoma prognosis.

EGFR mutations occur most frequently in patients with lung adenocarcinoma in East Asia. However, the prognostic and therapeutic impact of co-mutational status of EGFR and tumor suppressor genes is not fully understood. This study aims to provide a deeper understanding of lung adenocarcinoma patients with co-mutation of EGFR and tumor suppressor genes. From November 2009 to May 2016, 675 patients with lung adenocarcinoma who underwent complete surgery were included in this study. Samples were collected and pathologically examined. Whole-exome sequencing was performed on 197 samples, while direct sequencing of major driver genes, including EGFR, KRAS, ERBB2 and BRAF and Ion-torrent targeted sequencing of tumor suppressor genes, including TP53, KEAP1, MGA, NF1, RB1, SMARCA4 and STK11, were performed on 478 samples. Tumor mutational burden was calculated and survival analyses were performed. The frequency of EGFR and TP53 mutation was 409 (60.6%) and 215 (31.9%), respectively. Co-mutation of EGFR and TP53 occured in 151 patients (22.4%), while co-mutation of EGFR and at least one tumor suppressor gene occured in 184 patients (27.3%). Compared with patients with only EGFR mutations, patients with co-mutations of EGFR and TP53 had a higher tumor mutational burden (p = 0.007) and worse recurrence-free survival (p = 0.010), while patients with co-mutations of EGFR and at least one tumor suppressor gene had a higher tumor mutational burden (p = 0.007), worse recurrence-free survival (p = 0.016) and worse overall survival (p = 0.018). Lung adenocarcinoma patients harboring EGFR and co-mutational tumor suppressor genes should be regarded as a unique subgroup.

A series of Ti-29Nb-(4, 7, 10, 13)Zr-2Cr alloys were fabricated to investigate the influence of Zr content on microstructures and mechanical properties. All the four alloys present a single β phase after solution treatment. With the increase in Zr content, the 0.2% proof stress is gradually increased from 388 MPa in Ti-29Nb-4Zr-2Cr to 713 MPa in Ti-29Nb-13Zr-2Cr. The Young’s modulus gradually is decreased from 80 GPa in Ti-29Nb-4Zr-2Cr to 63 GPa in Ti-29Nb-13Zr-2Cr. The elongation shows the same trend as that of Young’s modulus. The changes of mechanical properties are influenced by the β stability and solid solution strengthening effect, which are both enhanced by Zr addition. The Ti-29Nb-13Zr-2Cr alloy presents a Young’s modulus of 63 GPa, tensile strength of 730 MPa and elongation of 18% and is a promising biomedical material.

A type of trust region-sequential quadratic programming (TRSQP) approach with superlinearly convergent property is first proposed, investigated, and implemented on bipedal robots based on nonlinear model predictive control (NMPC). NMPC is utilized to predict the system behavior and optimize the control move in a receding horizon way, which will result in recursive efficiency and stability. Considering that the classical line search rules are expensive or hard in particular applications, the attempted trust region search is leveraged to avoid the drawbacks of the classical line search rules. Moreover, the feasible descent direction is contained in the trust region via a novelly truncated technique which avoids to recompute the quadratic programming subproblem (QPS) for the main search direction. Owing to some suitable conditions, the globally/superlinearly convergent performance and well-defined properties are analyzed and verified for the TRSQP. The main result is illustrated on a simple bipedal robot which is called as compass-like bipedal robot (CLBR) through numerical simulations and is used to generate dynamic locomotion via TRSQP and NMPC. Furthermore, to demonstrate the feasibility and superiority of a complex bipedal robot which is called as a high-dimensional bipedal robot, numerical simulations are conducted on the model of a three-link bipedal robot (TLBR) and a five-link robot (RABBIT). Furthermore, simulation results show that the TRSQP approach is effectiveness and superiority through comparing with the classical approaches, which included discrete mechanics and optimal control (DMOC) and hybrid zero dynamic (HZD), and control Lyapunov function-quadratic programming (CLF-QP) for the optimal gait of bipedal robot. In addition, to verify the robustness, the TLBR model with parameter’s disturbance 1.5 times is investigated and analyzed via TRSQP with NMPC technique. Last,this study develops an interesting framework to exploiting control methods on bipedal robots through accurately and effectively solving nonlinear programming problems.

To improve cancer precision medicine, prognostic and predictive biomarkers are critically needed to aid physicians in deciding treatment strategies in a personalized fashion. Due to the heterogeneous nature of cancer, most biomarkers are expected to be valid only in a subset of patients. Furthermore, there is no current approach to determine the applicability of biomarkers. In this study, we propose a framework to improve the clinical application of biomarkers. As part of this framework, we develop a clinical outcome prediction model (CPM) and a predictability prediction model (PPM) for each biomarker and use these models to calculate a prognostic score (P-score) and a confidence score (C-score) for each patient. Each biomarker’s P-score indicates its association with patient clinical outcomes, while each C-score reflects the biomarker applicability of the biomarker’s CPM to a patient and therefore the confidence of the clinical prediction. We assessed the effectiveness of this framework by applying it to three biomarkers, Oncotype DX, MammaPrint, and an E2F4 signature, which have been used for predicting patient response, pathologic complete response versus residual disease to neoadjuvant chemotherapy (a classification problem), and recurrence-free survival (a Cox regression problem) in breast cancer, respectively. In both applications, our analyses indicated patients with higher C scores were more likely to be correctly predicted by the biomarkers, indicating the effectiveness of our framework. This framework provides a useful approach to develop and apply biomarkers in the context of cancer precision medicine.

Ovarian carcinoma is the most lethal type of gynecologic malignancies. Alterations of Notch pathway are prevalent in ovarian carcinogenesis. This study investigated the expression profile and function of delta-like 1 homolog (DLK1), a non-canonical Notch ligand, during ovarian carcinogenesis. Tissue microarray (TMA) consisting of surgically resected samples from 221 patients with ovarian carcinoma was constructed for DLK1 expression. DLK1 overexpression or knockdown was achieved by adenovirus gene delivery to evaluate the effect of DLK1 on the oncogenic behaviors in ovarian cancer cells and in xenografted tumors. TMA analysis revealed that elevated DLK1 expression was correlated with stages, lymph node metastasis and E-cadherin downregulation. Despite no influence on survival among ovarian carcinoma patients, DLK1 overexpression was specially associated with overall survival and progression free survival in high-grade serous carcinoma (HGSC) patients, constituting an independent prognostic factor for these patients. By adenovirus gene delivery, it was found modulation of cellular DLK1 level regulated the tumorigenic behaviors and epithelial-mesenchymal transition (EMT) in vitro and in vivo. Immunohistochemical analysis further showed that DLK1 overexpression resulted in escalated proliferation, angiogenesis, EMT and Notch activities. Application of recombinant DLK1 extracellular domain (rDLK1-EC) recapitulated the tumorigenic behaviors of DLK1 in ovarian cancer cells. By using neutralizing antibody or pharmaceutical inhibitor, blockade of Notch signaling attenuated the tumorigenic behaviors evoked by DLK1 overexpression. The present study indicates that DLK1 overexpression participates in ovarian carcinogenesis through Notch activation and EMT induction. Moreover, DLK1 may constitute a novel diagnostic biomarker and therapeutic target for HGSC.

Background Altica (Coleoptera: Chrysomelidae) is a highly diverse and taxonomically challenging flea beetle genus that has been used to address questions related to host plant specialization, reproductive isolation, and ecological speciation. To further evolutionary studies in this interesting group, here we present a draft genome of a representative specialist, Altica viridicyanea, the first Alticinae genome reported thus far. Results The genome is 864.8 Mb and consists of 4490 scaffolds with a N50 size of 557 kb, which covered 98.6% complete and 0.4% partial insect Benchmarking Universal Single-Copy Orthologs. Repetitive sequences accounted for 62.9% of the assembly, and a total of 17,730 protein-coding gene models and 2462 non-coding RNA models were predicted. To provide insight into host plant specialization of this monophagous species, we examined the key gene families involved in chemosensation, detoxification of plant secondary chemistry, and plant cell wall-degradation. Conclusions The genome assembled in this work provides an important resource for further studies on host plant adaptation and functionally affiliated genes. Moreover, this work also opens the way for comparative genomics studies among closely related Altica species, which may provide insight into the molecular evolutionary processes that occur during ecological speciation.

Recent studies suggest that rare variants exhibit stronger effect sizes and might play a crucial role in the etiology of lung cancers (LC). Whole exome plus targeted sequencing of germline DNA was performed on 1045 LC cases and 885 controls in the discovery set. To unveil the inherited causal variants, we focused on rare and predicted deleterious variants and small indels enriched in cases or controls. Promising candidates were further validated in a series of 26,803 LCs and 555,107 controls. During discovery, we identified 25 rare deleterious variants associated with LC susceptibility, including 13 reported in ClinVar. Of the five validated candidates, we discovered two pathogenic variants in known LC susceptibility loci, ATM p.V2716A (Odds Ratio [OR] 19.55, 95%CI 5.04–75.6) and MPZL2 p.I24M frameshift deletion (OR 3.88, 95%CI 1.71–8.8); and three in novel LC susceptibility genes, POMC c.*28delT at 3′ UTR (OR 4.33, 95%CI 2.03–9.24), STAU2 p.N364M frameshift deletion (OR 4.48, 95%CI 1.73–11.55), and MLNR p.Q334V frameshift deletion (OR 2.69, 95%CI 1.33–5.43). The potential cancer-promoting role of selected candidate genes and variants was further supported by endogenous DNA damage assays. Our analyses led to the identification of new rare deleterious variants with LC susceptibility. However, in-depth mechanistic studies are still needed to evaluate the pathogenic effects of these specific alleles.

BackgroundCuticular wax plays important role in protecting plants from drought stress. In ArabidopsisWRI4improves drought tolerance by regulating the biosynthesis of fatty acids and cuticular wax.Cyperus esculentus(yellow nutsedge) is a tough weed found in tropical and temperate zones as well as in cooler regions. In the current study, we report the molecular cloning of aWRI4-like gene fromCyperus esculentusand its functional characterization in Arabidopsis.ResultsUsing RACE PCR, full-lengthWRI-like gene was amplified from yellow nutsedge. Phylogenetic analyses and amino acid comparison suggested it to be aWRI4-like gene. According to the tissue-specific expression data, the highest expression ofWRI4-like gene was found in leaves, followed by roots and tuber. Transgenic Arabidopsis plants expressing nutsedgeWRI4-like gene manifested improved drought stress tolerance. Transgenic lines showed significantly reduced stomatal conductance, transpiration rate, chlorophyll leaching, water loss and improved water use efficiency (WUE). In the absence of drought stress, expression of key genes for fatty acid biosynthesis was not significantly different between transgenic lines and WT while that of cuticular wax biosynthesis genes was significantly higher in transgenic lines than WT. The PEG-simulated drought stress significantly increased expression of key genes for fatty acid as well as wax biosynthesis in transgenic Arabidopsis lines but not in WT plants. Consistent with the gene expression data, cuticular wax load and deposition was significantly higher in stem and leaves of transgenic lines compared with WT under control as well as drought stress conditions.ConclusionsWRI4-like gene fromCyperus esculentusimproves drought tolerance in Arabidopsis probably by promoting cuticular wax biosynthesis and deposition. This in turn lowers chlorophyll leaching, stomatal conductance, transpiration rate, water loss and improves water use efficiency under drought stress conditions. Therefore,CeWRI4-like gene could be a good candidate for improving drought tolerance in crops.