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IntroductionPolychlorinated biphenyls (PCBs) are persistent environmental toxicants that have been implicated in numerous health disorders including liver diseases such as non-alcoholic fatty liver disease (NAFLD). Toxicant-associated NAFLD, also known as toxicant-associated fatty liver disease (TAFLD), consists of a spectrum of disorders ranging from steatosis and steatohepatitis to fibrosis and hepatocellular carcinoma. Previously, our group demonstrated that 12-week exposure to the PCB mixture, Aroclor 1260, exacerbated steatohepatitis in high-fat diet (HFD)-fed mice; however, the longer-term effects of PCBs on TAFLD remain to be elucidated. This study aims to examine the longer-term effects of Aroclor 1260 (>30 weeks) in a diet-induced obesity model to better understand how duration of exposure can impact TAFLD.MethodsMale C57BL/6 mice were exposed to Aroclor 1260 (20 mg/kg) or vehicle control by oral gavage at the beginning of the study period and fed either a low-fat diet (LFD) or HFD throughout the study period.ResultsAroclor 1260 exposure (>30 weeks) led to steatohepatitis only in LFD-fed mice. Several Aroclor 1260 exposed LFD-fed mice also developed hepatocellular carcinoma (25%), which was absent in HFD-fed mice. The LFD+Aroclor1260 group also exhibited decreased hepatic Cyp7a1 expression and increased pro-fibrotic Acta2 expression. In contrast, longer term Aroclor 1260 exposure in conjunction with HFD did not exacerbate steatosis or inflammatory responses beyond those observed with HFD alone. Further, hepatic xenobiotic receptor activation by Aroclor 1260 was absent at 31 weeks post exposure, suggesting PCB redistribution to the adipose and other extra-hepatic tissues with time.DiscussionOverall, the results demonstrated that longer-term PCB exposure worsened TAFLD outcomes independent of HFD feeding and suggests altered energy metabolism as a potential mechanism fueling PCB mediated toxicity without dietary insult. Additional research exploring mechanisms for these longer-term PCB mediated toxicity in TAFLD is warranted.

Background Many upper-middle-income countries (UMICs), including Malaysia, continue to face low breast cancer (BC) screening rates and patients with delayed presentation of BC. This study investigated the role of beliefs about BC and use of screening (e.g. beliefs about whether or not screening reduced the possibility of dying from BC). Methods A nationwide cross-sectional study was conducted in which a total of 813 women (aged ≥ 40 years old) were randomly selected and surveyed using the validated Awareness and Beliefs about Cancer (ABC) measure. The association between BC screening use, sociodemographic characteristics, and negative beliefs about BC screening were analysed using stepwise Poisson regressions. Results Seven out of ten Malaysian women believed that BC screening was necessary only if and when they started experiencing cancer symptoms. Women > 50 years and from households with more than one car or motorcycle were 1.6 times more likely to attend a mammogram or a clinical breast examination (mammogram: PR = 1.60, 95% CI = 1.19–2.14, CBE: PR = 1.61, 95%CI 1.29–1.99). Approximately one quarter of women (23%) reported anticipated anxiety about attending BC screening to the extent that they would avoid undergoing the procedure. Women who held negative beliefs about BC screening were 37% less likely to attend a mammogram (PR = 0.63, 95% CI = 0.42–0.94) and 24% less likely to seek a CBE (PR = 0.75, 95% CI = 0.60–0.95). Conclusions There is a need for public health strategies designed to change beliefs about BC screening among Malaysian women as a way of increasing uptake and impacting on late presentation and advanced cancer. The results provide insights about targeting of public health strategies – women with BC screening uptake-inhibiting beliefs tend to be under 50 years, in the lower income group (that do not own a car or a motorcycle) and more likely to be ethnic Malay or Indian (compared to Chinese-Malay).

RegHEC is a registration-based hand-eye calibration technique with no need for accurate calibration rig but arbitrary available objects, applicable for both eye-in-hand and eye-to-hand cases. It tries to find the hand-eye relation which brings multi-view point clouds of arbitrary scene into simultaneous registration under a common reference frame. RegHEC first achieves initial alignment of multi-view point clouds via Bayesian optimization, where registration problem is modeled as a Gaussian process over hand-eye relation and the covariance function is modified to be compatible with distance metric in 3-D motion space SE(3), then passes the initial guess of hand-eye relation to an Anderson Accelerated ICP variant for later fine registration and accurate calibration. RegHEC has little requirement on calibration object, it is applicable with sphere, cone, cylinder and even simple plane, which can be quite challenging for correct point cloud registration and sensor motion estimation using existing methods. While suitable for most 3-D vision guided tasks, RegHEC is especially favorable for robotic 3-D reconstruction, as calibration and multi-view point clouds registration of reconstruction target are unified into a single process. Our technique is verified with extensive experiments using varieties of arbitrary objects and real hand-eye system. We release an open-source C++ implementation of RegHEC.

This randomized controlled study aims to evaluate an educational intervention about breast cancer (BC) screening that navigates women to Clinical Breast Examination (CBE) services in a way that leads to an increase in BC screening uptake in Malaysia whilst taking account of the context of the COVID-19 pandemic.

Genus Rusa, belonging to the deer family Cervidae is native to the Indo-Malaya Archipelago (IMA). However, detailed information on the Rusa genus in the IMA is limited. This review provides comprehensive information on the Rusa genus in the IMA including, threats and conservation efforts. There are four species of deer in Rusa genus, which is Sambar deer (Rusa unicolor), Javan deer (Rusa timorensis), Visayan spotted deer (Rusa alfredi) and Philippine deer (Rusa marianna). Despite their wide distribution in the South Asian and Southeast Asian regions, they are under serious threats. Some conservation efforts that are being done to protect and conserve them among others are; 1) facilities protection, 2) habitat enrichment programme, 3) Ex-situ conservation, 4) legislations, and 5) captive breeding. Conservation through genetics is also an important step in conserving these species. Recommendations for conservation of the genus are also discussed; 1. maintenance of ecosystem. 2. more effective monitoring system on the existing protected area. 3. ex-situ conservation, and 4. habitat monitoring.

Oncogene-addicted cancers are predominantly driven by specific oncogenic pathways and display initial exquisite sensitivity to designer therapies, but eventually become refractory to treatments. Clear understanding of lung tumorigenic mechanisms is essential for improved therapies. Methods: Lysosomes were analyzed in EGFR-WT and mutant cells and corresponding patient samples using immunofluorescence or immunohistochemistry and immunoblotting. Microtubule organization and dynamics were studied using immunofluorescence analyses. Also, we have validated our findings in a transgenic mouse model that contain EGFR-TKI resistant mutations. Results: We herein describe a novel mechanism that a mutated kinase disrupts the microtubule organization and results in a defective endosomal/lysosomal pathway. This prevents the efficient degradation of phosphorylated proteins that become trapped within the endosomes and continue to signal, therefore amplifying downstream proliferative and survival pathways. Phenotypically, a distinctive subcellular appearance of LAMP1 secondary to microtubule dysfunction in cells expressing EGFR kinase mutants is seen, and this may have potential diagnostic applications for the detection of such mutants. We demonstrate that lysosomal-inhibitors re-sensitize resistant cells to EGFR tyrosine-kinase inhibitors (TKIs). Identifying the endosome-lysosome pathway and microtubule dysfunction as a mechanism of resistance allows to pharmacologically intervene on this pathway. Conclusions: We find that the combination of microtubule stabilizing agent and lysosome inhibitor could reduce the tumor progression in EGFR TKI resistant mouse models of lung cancer.

Additional file 1.

Additional file 1: Figure S1. Representative TEM images of (A) Sora-MNC-2 and (B) Sora-MNC-3. Figure S2. Zeta potential distribution profiles of (A) Sora-MNC formulations and (B) HA-EGCG, HA and sorafenib. HA-EGCG (10 mg mL−1) and HA (10 mg mL−1) were dissolved in deionized water. Sorafenib was first dissolved in methanol at 1 mg mL−1 and then 10-fold diluted with water for the zeta potential measurement. Figure S3. Stability of HA-EGCG micelles in 10% (v/v) fetal bovine serum over 5 days. Mean ± SD (n = 3). Figure S4. Anti-leukemic activity of Sora-MNC-1, HA-EGCG and EGCG on (A) MOLM-14 and (B) MV-4-11 cells as a function of EGCG unit concentration. Mean ± SD (n = 4). Figure S5. Median effect plots showing eradication of (A) MOLM-14 and (B) MV-4-11 cells treated with free sorafenib, HA-EGCG or their combination (Sora-MNC-1). Cytotoxicity data were plotted using the linearized median effect equation, log(fa/fu) = m log(D) – m log (Dm), where fa is the fraction of killed cells, fu is the fraction of survived cells, D is the dose applied, Dm is the median effective dose. The resultant plot gave the slope of m and the y-axis intercept of – m log (Dm). Figure S6. Hemolysis assay. (A) Representative photograph of mouse red blood cells treated with PBS, Triton X-100 (1%), or Sora-MNC-1 at various sorafenib doses for 1 h at 37 °C. (B) Effect of different treatments on the absorbance at 576 nm (an indicator of hemoglobin leakage from red blood cells). Figure S7. Flow cytometric detection of CD44 in MOLM-14, MV-4-11 and bone marrow stromal cells labeled without (left panel) or with FITC-tagged anti-CD44 antibody (right panel). Figure S8. (A) Z-average sizes and zeta potential values of Sora-MNC, DyLight 488-labeled MNC and DyLight 800-labeled MNC. (B) Fluorescence emission spectra (λex=400 nm) of DyLight 488 dye (0.312 µg mL−1) and DyLight 488-labeled MNC (Sorafenib concentration=0.8 µg mL−1). (C) Fluorescence emission spectra (λex=750 nm) of DyLight 800 dye (2.5 µg mL−1) and DyLight 800-labeled MNC (Sorafenib concentration=4 µg mL−1). Figure S9. KEGG map of differentially expressed genes (DEGs) involved in the tricarboxylic acid (TCA) cycle. The gradient color scale indicates upregulation (red) and downregulation (green) of gene expression calculated as log2 fold change. The names of DEGs selected for qPCR analysis are highlighted in blue. FH: Fumarate hydratase, SDHA: succinate dehydrogenase, OGDH: 2-oxoglutarate dehydrogenase, IDH1: isocitrate dehydrogenase 1. Figure S10. KEGG map of DEGs involved in the aminoacyl-tRNA biosynthesis. The gradient color scale indicates upregulation (red) and downregulation (green) of gene expression calculated as log2 fold change. The names of DEGs selected for qPCR analysis are highlighted in blue. LARS: leucyl-tRNA synthetase, FARSA: phenylalanyl-tRNA synthetase. Figure S11. Low-magnification images of H&E and immunohistochemical staining of the bone marrow specimen. AML cells were identified with anti-hCD45 antibody (brown area labeled “L”). Scale bars, 200 μm. The red boxes indicate the areas of the higher magnification images included in Figure 6F. Figure S12. (A) Albumin:globulin ratio and (B) blood urea nitrogen level in the experimental groups. Mean ± SD (n = 3); *P < 0.05; n.s.=nonsignificant. Figure S13. (A) Potassium and (B) sodium ion level in the experimental groups. Mean ± SD (n = 3); n.s.=nonsignificant. Table S1. Characteristics of Sora-MNC selected for in vitro studies. Table S2. Sequence of the primers used for qPCR analysis. Table S3. Pharmacokinetic parameters of Sora-MNC and free sorafenib.

Additional file 1. The list of southern and northern provinces in the mainland of China

Additional file 1. Supplemental Figures.

Additional file 4: Supplementary Table 1. Total number of potentially pathogenic variants discovered in each prioritized gene; and support for these genes across different cancer gene databases. Supplementary Table 2. Patient IDs for the patients with rare pathogenic variants in each gene. Supplementary Table 3. Clinical features and pathogenic variants identified in 89 breast cancer patients. Supplementary Table 4. Involvement in cancer for seven of our selected variants, as reported in the literature. Supplementary Table 5. PCR primers and cycling conditions used for Sanger sequencing.

Automatic assessment and understanding of facial skin condition have several applications, including the early detection of underlying health problems, lifestyle and dietary treatment, skin-care product recommendation, etc. Selfies in the wild serve as an excellent data resource to democratize skin quality assessment, but suffer from several data collection challenges.The key to guaranteeing an accurate assessment is accurate detection of different skin features. We present an automatic facial skin feature detection method that works across a variety of skin tones and age groups for selfies in the wild. To be specific, we annotate the locations of acne, pigmentation, and wrinkle for selfie images with different skin tone colors, severity levels, and lighting conditions. The annotation is conducted in a two-phase scheme with the help of a dermatologist to train volunteers for annotation. We employ Unet++ as the network architecture for feature detection. This work shows that the two-phase annotation scheme can robustly detect the accurate locations of acne, pigmentation, and wrinkle for selfie images with different ethnicities, skin tone colors, severity levels, age groups, and lighting conditions., Accepted by the conference of Electronic Imaging (EI) 2022

This paper proposes FREEtree, a tree-based method for high dimensional longitudinal data with correlated features. Popular machine learning approaches, like Random Forests, commonly used for variable selection do not perform well when there are correlated features and do not account for data observed over time. FREEtree deals with longitudinal data by using a piecewise random effects model. It also exploits the network structure of the features by first clustering them using weighted correlation network analysis, namely WGCNA. It then conducts a screening step within each cluster of features and a selection step among the surviving features, that provides a relatively unbiased way to select features. By using dominant principle components as regression variables at each leaf and the original features as splitting variables at splitting nodes, FREEtree maintains its interpretability and improves its computational efficiency. The simulation results show that FREEtree outperforms other tree-based methods in terms of prediction accuracy, feature selection accuracy, as well as the ability to recover the underlying structure.

This paper investigates simultaneous arrival planning of multiple unmanned vehicles. Problem of simultaneous arrival planning is introduced and formulated. First, a Temporal–Spatial (T–S) Bezier curve is constructed by considering time as a one-dimensional variable of Bezier curve. Second, constraints of minimum curvature radius, tangent acceleration and velocity are addressed to design the suboptimal T–S Bezier curve. Subsequently, the suboptimal simultaneous arrival time for multiple unmanned vehicles is calculated and obtained. Finally, simultaneous arrival planning by using a T–S Bezier is summarized. Simulations and comparisons are conducted to demonstrate the effectiveness of the proposed method.

Tumour heterogeneity leads to the development of multiple resistance mechanisms during targeted therapies. Identifying the dominant driver(s) is critical for treatment decision. We studied the relative dynamics of multiple oncogenic drivers in longitudinal plasma of 50 EGFR‐mutant non‐small‐cell lung cancer patients receiving gefitinib and hydroxychloroquine. We performed digital PCR and targeted sequencing on samples from all patients and shallow whole‐genome sequencing on samples from three patients who underwent histological transformation to small‐cell lung cancer. In 43 patients with known EGFR mutations from tumour, we identified them accurately in plasma of 41 patients (95%, 41/43). We also found additional mutations, including EGFR T790M (31/50, 62%), TP53 (23/50, 46%), PIK3CA (7/50, 14%) and PTEN (4/50, 8%). Patients with both TP53 and EGFR mutations before treatment had worse overall survival than those with only EGFR. Patients who progressed without T790M had worse PFS during TKI continuation and developed alternative alterations, including small‐cell lung cancer‐associated copy number changes and TP53 mutations, that tracked subsequent treatment responses. Longitudinal plasma analysis can help identify dominant resistance mechanisms, including non‐druggable genetic information that may guide clinical management., EMBO Molecular Medicine, 10 (6), ISSN:1757-4676, ISSN:1757-4684

Patients with advanced stage non-small cell lung cancer with sensitizing epidermal growth factor receptor (EGFR) mutations using EGFR tyrosine kinase inhibitors (TKIs) such as erlotinib, gefitinib and afatinib as first-line treatment had better progression-free survival, overall response rate and quality of life than those on chemotherapy. Although EGFR TKIs are commonly associated with skin-related (rash, xerosis and paronychia) and gastrointestinal-related (diarrhea and stomatitis) adverse events (AEs), these effects are usually mild. But severe cases can occur, significantly affecting patient's well-being, treatment compliance and quality of life. Therefore, patient education, early diagnosis, and prophylactic treatment are important strategies to optimally manage EGFR TKI-related adverse effects. In this review, we summarize the commonly encountered EGFR TKI-related AEs and provide a current overview of AE management in local practice with a focus on Asian patients.

To investigate the effects of microRNA-137 (miRNA-137) in proliferation and migration of placenta trophoblast cells of preeclampsia and the targeting gene of miRNA-137.A total of 134 cases of puerperants were divided into normal pregnancy (n = 50), mild preeclampsia (n = 38), and severe preeclampsia groups (n = 46). MiRNA-137, estrogen-related receptor α (ERRα), and wingless INT (WNT)11 messenger RNAs (mRNAs) were measured in placental tissue and trophoblast cells after transfection, and ERRα protein in placental tissues was detected by immunohistochemistry. The target genes of miRNA-137, trophoblast cell proliferation, migration, and invasion abilities were detected. Both ERRα and WNT11 proteins in the trophoblast cells were measured after transfection.Relative expressions of miRNA-137 were higher, and positive expression rates and relative expression levels of ERRα protein were lower in mild and severe preeclampsia and early- and late-onset preeclampsia than in normal pregnancy group (all P.05). MiRNA-137 in the placental tissues was negatively correlated with ERRα protein ( P.05). Luciferase reporter gene assay analysis showed that ERRα was a direct target gene of miRNA-137. Absorbance values, relative scratch-covered areas, cell membrane permeable rate, ERRα, and WNT11 mRNA and protein relative expressions were significantly lower, while cells at G1/G0 phase were higher in miRNA-137 mimic group than those in the blank, negative control, and miRNA-137 inhibitor group.MiRNA-137 significantly reduced the proliferation and migration of placenta trophoblast cells of preeclampsia by targeting ERRα, which might be a potential target for gene therapy.

This paper presents an algorithmic solution for depth control. Depth control for Underwater Vehicle-Manipulator System (UVMS) is essential to complete a specific underwater manipulation. A large number of algorithms have been designed to tackle the depth control problem. However, because of water currents, algorithm for depth control is required strong robustness. This work describes an adaptive sliding mode control (SMC) method to implement the depth control. The designed SMC method combining the proposed adaptive algorithm can alleviate influence of uncertain parameters of system and external disturbances. The stability is proven by a Lyapunov function. Then, we build a ROS-based underwater simulation environment–UWSim. Real-time depth and velocity of UVMS can be obtained by depth gauge and IMU via ROS nodes. Finally, we conduct a depth control simulation with our proposed hybrid-driven underwater vehicle-manipulator system (HD-UVMS). A comparative simulation is also implemented to verify the effectiveness of the proposed method.

Video summarization targets the challenge of finding the smallest subset of frames, while still conveying the whole story of a given video. Thus it is of great significance for large-scale video understanding, allowing efficient processing of the large amount of videos that are uploaded every day. In this paper, we introduce a Dilated Temporal Relational Adversarial Network (DTR-GAN) to achieve frame-level video summarization. The dilated temporal relational units in the generator aim to exploit multi-scale temporal context in order to select key frames. To ensure that the model predicts high quality summaries, we present a discriminator that learns to enhance both the information completeness and compactness via a three-player loss. Experiments on the public TVSum dataset demonstrate the effectiveness of the proposed approach.

We develop two cooperative robots for power transmission lines (PTLs) inspection – a light climbing robot (CBR) which can stably move on the overhead ground wire (OGW) for sensor data collection and an unmanned aerial vehicle (UAV) with a grabbing mechanism, which can automatically put the CBR on the OGW and take it off. In order to guarantee the safety, the mechanical structures of the connectors are designed in the shape of a trumpet. Further, a self-locked structure of the CBR is developed to automatically seize and release the OGW. For autonomous navigation, the UAV is equipped with a movable sliding rail and a 2D Laser Range Finder (LRF). The LRF can not only detect the position and orientation of the OGW but also detect the top beam of the CBR and the grabbing position in it. Furthermore, the action of the grabbing mechanism is automatically triggered by a microswitch. Finally, by the developed UAV and CBR platforms, we test the whole loading and unloading strategy in an artificially constructed PTLs environment outdoors and achieve an encouraging result1. Combining the flexible motion of the UAV and the high inspection accuracy of the CBR, the CBR can negotiate any obstacle by flying and abandon the traditional heavy obstacle crossing mechanism to effectively realize close-proximity inspection. Due to the light weight and low power consumption, the CBRs can be deployed once in many power corridors to conduct a long-term inspection.1https://www.youtube.com/watch?v=2Bg98wnyqJg

Hepatocellular carcinoma (HCC) affects approximately half a million patients worldwide and is the most rapidly increasing cause of cancer death in the United States owing to the lack of effective treatment options for advanced disease [1]. Numerous lines of clinical and histopathologic evidence suggest that HCC is a heterogeneous disease, but a coherent molecular explanation for this heterogeneity has yet to be reported [2]. Due to the phenotypic and molecular diversity of HCC, it is a challenge to determine a patient’s prognosis [3]. It would be ideal to increase monitoring of patients with poor prognosis. Thus the inability to accurately predict prognosis leads to excessive or insufficient time spent following patients, resulting in unnecessary anxiety and cost for patients, and inefficient allocation of resources for hospitals.

Eighty-four specimens collected from 13 populations from Malaysia, Thailand, and Vietnam were analysed, revealing 21 putative haplotypes with overall estimated haplotype and nucleotide diversities of 0.79 and 0.0079, respectively. High levels of diversity and an absence of founder effects were observed among populations in peninsular Malaysia. In contrast, populations from Sarawak exhibited low genetic diversity, which is a typical sign of colonies introduced from a single source. Historical translocation of Trichopodus pectoralis from Thailand to Malaysia, as well as to the Philippines, Indonesia, and Myanmar was apparent. Historical introduction of T. pectoralis from Vietnam was also detected in peninsular Malaysia.

Employing unmanned aerial vehicles (UAV) to conduct close proximity inspection of transmission tower is becoming increasingly common. This paper aims to solve the key problem of close proximity navigation - estimating the UAV positions. To this end, we propose a novel monocular-vision-based environmental perception approach and implement it in a hierarchical embedded UAV system. The proposed framework is an improved point-line-based SLAM framework consisting of feature matching, frame tracking, local mapping, loop closure, and nonlinear optimization. In order to enhance frame association, the prominent line feature of tower is heuristically extracted and matched followed by the intersections of lines are processed as point feature. Then the bundle adjustment optimization leverages the intersections of lines and the point-to-line distance to improve the accuracy of UAV localization. Additionally, two reasonable paths are planned for the refined inspection. In experiments, the whole UAV system developed on Robot Operating System (ROS) network is evaluated along the paths in a real-world inspection environment, which achieves a satisfactory result.

Pluripotent stem cells are uniquely positioned for regenerative medicine, but their clinical potential can only be realized if their tumorigenic tendencies are decoupled from their pluripotent properties. Deploying small molecules to remove remnant undifferentiated pluripotent cells, which would otherwise transform into teratomas and teratomacarcinomas, offers several advantages over non-pharmacological methods. Dioxonapthoimidazolium YM155, a survivin suppressant, induced selective and potent cell death of undifferentiated stem cells. Herein, the structural requirements for stemotoxicity were investigated and found to be closely aligned with those essential for cytotoxicity in malignant cells. There was a critical reliance on the quinone and imidazolium moieties but a lesser dependence on ring substituents, which served mainly to fine-tune activity. Several potent analogues were identified which, like YM155, suppressed survivin and decreased SOX2 in stem cells. The decrease in SOX2 would cause an imbalance in pluripotent factors that could potentially prompt cells to differentiate and hence decrease the risk of aberrant teratoma formation. As phosphorylation of the NF-κB p50 subunit was also suppressed, the crosstalk between phospho-p50, SOX2, and survivin could implicate a causal role for NF-κB signaling in mediating the stem cell clearing properties of dioxonaphthoimidazoliums.

// Si Han Sherman Ho 1, * , Azhar Ali 2, * , Tan Min Chin 2 , Mei Lin Go 1 1 Department of Pharmacy, Faculty of Science, National University of Singapore, Singapore 2 Cancer Science Institute, Yong Loo Lin School of Medicine, Singapore * These authors have contributed equally to this work Correspondence to: Mei Lin Go, e-mail: meilin.go@nus.edu.sg Keywords: non-small cell lung cancer, YM155, survivin suppressant, NF-κB signaling, p50 phosphorylation Received: June 13, 2015 Accepted: January 27, 2016 Published: February 10, 2016 ABSTRACT The NF-κB pathway is overexpressed in non-small cell lung cancers (NSCLC) and contributes to the poor prognosis and high mortality characterizing this malignancy. Silencing the p50 and p65 NF-κB subunits in the NSCLC H1299 cell line led to profound loss in cell viability and downregulated anti-apoptotic proteins survivin and Mcl1. We also showed that a survivin suppressant, the dioxonaphthoimidazolium YM155, and its structural analog AB1 arrested the growth of H1299 cells at nanomolar concentrations. Both compounds were apoptogenic and suppressed survivin and other anti-apoptotic proteins (Mcl1, Bcl-2, Bcl-xl) in a dose- and/or time-dependent manner. YM155 and AB1 did not affect the expression of key proteins (IκBα, p65, p50) involved in NF-κB signaling. Stable IκBα levels suggest that the NF-κB/IκB complex and proteins upstream of IκBα, were not targeted. Neither did the compounds intercept the nuclear translocation of the p50 and p65 subunits. On the other hand, YM155 and AB1 suppressed the phosphorylation of the p50 subunit at Ser337 which is critical in promoting the binding of NF-κB dimers to DNA. Both compounds duly impeded the binding of NF-κB dimers to DNA and attenuated transcriptional activity of luciferase-transfected HEK293 cells controlled by NF-κB response elements. We propose that the “silencing” the NF-κB pathway effected by these compounds contributed to their potent apoptogenic effects on H1299. Notwithstanding, the mechanism(s) involved in their ability to abolish phosphorylation of p50 remains to be elucidated. Taken together, these results disclose a novel facet of functionalized dioxonaphthoimidazoliums that could account for their potent cell killing property.

The extremely large upper critical field in PdS2-related superconductors has been a puzzling problem in recent years. In this work, we grow a series of high-quality Nb2Pd0.77S5 filamentary samples with different diameters and investigate the influence of size of the sample on the upper critical field. It is interesting to find that the upper critical field is significantly enhanced with the decreasing of the diameter of the filamentary sample. The extremely large upper critical field in Nb2Pd0.77S5 compounds can be attributed to the thin superconducting shapes.

e21516 Background: The utility of a liquid biopsy test for diagnosis and treatment is determined by its accuracy, molecular target coverage and timeliness to a clinically informative result. We describe our clinical experience of providing comprehensive next-generation sequencing (NGS) plasma testing for advanced lung cancer cases, including parallel testing with allele-specific PCR (AS-PCR) for rapid EGFR mutation detection. Methods: Plasma cell-free DNA (cfDNA) from advanced lung cancer patients (n = 374) underwent real-world testing with an amplicon-based NGS assay, in a CAP and ISO15189 accredited central laboratory. The assay covers 51 genes, including 8 guideline recommended biomarkers- EGFR, BRAF, MET, ALK, RET, ROS1, ERBB2 and KRAS. 168 cases (44.9%) were treatment-naïve (baseline) and 206 cases (55.1%) had received one or more lines of treatment. Parallel testing with AS-PCR for 10 specific EGFR mutations was done for 151 cases (90 baseline, 61 non-baseline). Concordance of EGFR mutation detection by the two methods, and the frequency of detection of clinically actionable (driver) mutations by NGS were assessed. Turnaround time (TAT) was calculated from sample receipt. Results: An overall concordance of 97.4% was observed for EGFR mutations between AS-PCR and NGS. When restricted to baseline cases, concordance was 100%. Among baseline cases which were concordant with AS-PCR for EGFR negativity (n = 63), driver mutations were identified in EGFR (n = 7 rarer mutations), KRAS, ERBB2, MET, NRAS, BRAF and ALK (n = 16 total) by NGS, providing an additional 37% diagnostic yield (23/63 cases). Among all baseline cases tested by NGS, a driver gene mutation was found in 64.28% of cases, including EGFR (36.9%) and KRAS mutations (11.9 %). Among non-baseline cases which were EGFR-negative by NGS and by AS-PCR, added diagnostic yield provided by NGS was 33.3% (10 of 30 cases), and included 16.7% rarer EGFR mutations. Overall, detection rate of ALK, RET, ROS1 fusions was 2.4% (n = 5, 3 and 1, respectively). Median TAT for EGFR results by AS-PCR was 1 day (range 1-2 days), while median TAT for NGS results was 10 days (range 4-13 days). Conclusions: We report excellent real-world performance of blood-based liquid biopsy testing for detecting recommended biomarkers in lung cancers, including an approach combining two orthogonal platforms for quick decision making. Clinically meaningful diagnostic yields can be obtained using a timely comprehensive NGS assay, either individually or in parallel with rapid AS-PCR testing.

Tumour heterogeneity leads to the development of multiple resistance mechanisms during targeted therapies. Identifying the dominant driver(s) is critical for treatment decision. We studied the relative dynamics of multiple oncogenic drivers in longitudinal plasma of 50

BACKGROUND A germline deletion in the BIM (BCL2L11) gene has been shown to impair the apoptotic response to tyrosine kinase inhibitors (TKIs) in vitro but its association with poor outcomes in TKI-treated non-small cell lung cancer (NSCLC) patients remains unclear. We conducted a systematic review and meta-analysis on both aggregate and individual patient data to address this issue. RESULTS In an aggregate data meta-analysis (n = 1429), the BIM deletion was associated with inferior PFS (HR = 1.51, 95%CI = 1.06-2.13, P = 0.02). Using individual patient data (n = 1200), we found a significant interaction between the deletion and ethnicity. Amongst non-Koreans, the deletion was an independent predictor of shorter PFS (Chinese: HR = 1.607, 95%CI = 1.251-2.065, P = 0.0002; Japanese: HR = 2.636, 95%CI = 1.603-4.335, P = 0.0001), and OS (HR = 1.457, 95% CI = 1.063-1.997, P = 0.019). In Kaplan-Meier analyses, the BIM deletion was associated with shorter survival in non-Koreans (PFS: 8.0 months v 11.1 months, P < 0.0005; OS: 25.7 v 30.0 months, P = 0.042). In Koreans, the BIM deletion was not predictive of PFS or OS. MATERIALS AND METHODS 10 published and 3 unpublished studies that reported survival outcomes in NSCLC patients stratified according to BIM deletion were identified from PubMed and Embase. Summary risk estimates were calculated from aggregate patient data using a random-effects model. For individual patient data, Kaplan-Meier analyses were supported by multivariate Cox regression to estimate hazard ratios (HRs) for PFS and OS. CONCLUSIONS In selected populations, the BIM deletion is a significant predictor of shorter PFS and OS on EGFR-TKIs. Further studies to determine its effect on response to other BIM-dependent therapeutic agents are needed, so that alternative treatment strategies may be devised.

Introduction: Religion/Spirituality has been shown to be salutary on health, and a possible link between religion and positive health outcomes is diet. Research has shown that religiosity is associated with better diet but most studies were conducted in a multi-denominational context, which might be confounded with theological differences. Thus, the first aim of this study was to examine the relationship between individual religiosity and diet within a homogenous group of believers. Neighbourhood characteristics have an effect on health above and beyond the effect of the individual characteristics of those living in the neighbourhood. Neighbourhood might affect the health of its residents by influencing the adoption and maintenance of health behaviours. People of the same faith often practice religious activities together and religious congregation could be considered a community of faith and similar to neighbourhoods. Thus, the characteristics of a religious congregation might influence the health behaviour and health of the congregants. The second aim of this study was to examine whether congregational conservativeness would be significantly associated with the diet of congregants even after taking account of their demographics and individual levels of religiosity. This study also examined whether social gradient exists in a group of health-conscious Christian and whether health behaviours (dietary habits, alcohol consumption and exercise) mediate the relationship between religiosity and health outcomes (systolic and diastolic blood pressure and blood glucose level). Methods: The study population was all Seventh-Day Adventists residing in West Malaysia, aged 18-80. This study used a cross-sectional, multilevel survey design. There were two surveys; the first was congregational and the second, individual. In the first survey, 45 congregations returned questionnaires about congregational conservativeness. In the second survey, 574 Adventists returned questionnaires about religiosity, diet, lifestyle, self-reported history of diseases and demographics. One hundred of the 574 Adventists also participated in a healthy screening where their blood pressure, blood glucose level, weight and height, and waist and hip circumferences were measured. To examine the relationship between individual religiosity and diet and whether social gradient existed in the diet of the participants, multiple regressions were conducted. Multilevel linear regressions were conducted to determine whether congregational conservativeness was significantly associated with the diet of the congregants above and beyond individual factors. To examine whether health behaviours mediated the relationship between religiosity and health outcomes, path analysis was conducted. Results: While none of the religious variables were significantly associated with fruit and vegetable intake, a higher level of religiosity was associated with better dietary habits and vegetarian status. Congregational conservativeness predicted individual dietary habit above and beyond individual characteristics; a higher congregational conservativeness was positively associated with better individual dietary habits scores. None of the religious variables were associated with fruit and vegetable intake at individual and congregational level. Social gradient still existed in the dietary habits of the participants. Health behaviours did not mediate the relationship between religiosity and health outcomes; the direct effect of religiosity on health outcomes was more important than the indirect effect. Conclusions: The finding supports the role of religion as a potential channel to promote health by encouraging the believers to adopt a healthy diet.

A study on the effect of water salinity ranging from 0-30 ppt on hatching success of snake head fish, Channa striatus was conducted in a 15-liter glass aquarium (water volume 10 liters) containing 500 eggs for various levels of water salinity. Fertilization rates at 0, 5, 10, 11, 12, 13 and 14 ppt were 69.33, 72.67, 71.33, 72.67, 82.00, 73.33 and 10.67%, respectively. The fertilization rate at 12-13 ppt salinity was significantly (P0.05) among 0, 5 and 10 ppt.

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The transport and magnetic properties of BaFe2−x Mn x As2 single crystal samples are investigated by means of resistivity, magnetic susceptibility, thermopower, and electron spin resonance studies. No superconductivity is observed in these compounds. Our electron spin resonance study reveals that the intensity of a paramagnetic signal monotonously increases with increasing Mn doping content, indicating that the introduction of Mn leads to the localization of the Mn/Fe 3d electrons. It is suggested that the Mn ions act as the local scatterers, which hardly interact with neighboring Fe ions. The present results partially explain why the BaFe2−x Mn x As2 samples are not superconducting.

Curcumin is known to trigger ER-stress induced cell death of acute promyelocytic leukemic (APL) cells by intercepting the degradation of nuclear co-repressor (N-CoR) protein which has a key role in the pathogenesis of APL. Replacing the heptadienedione moiety of curcumin with a monocarbonyl cross-conjugated dienone embedded in a tetrahydrothiopyranone dioxide ring resulted in thiopyranone dioxides that were more resilient to hydrolysis and had greater growth inhibitory activities than curcumin on APL cells. Several members intercepted the degradation of misfolded N-CoR and triggered the signaling cascade in the unfolded protein response (UPR) which led to apoptotic cell death. Microarray analysis showed that genes involved in protein processing pathways that were germane to the activation of the UPR were preferentially up-regulated in treated APL cells, supporting the notion that the UPR was a consequential mechanistic pathway affected by thiopyranone dioxides. The Michael acceptor reactivity of the scaffold may have a role in exacerbating ER stress in APL cells.

To better understand stress tolerance of the White leg shrimp, Litopenaeus vannamei, RNA interference (RNAi) was used to assess the role of the molecular chaperone, Hsp70 in protecting post larvae against low pH and salinity. As revealed by SDS-polyacrylamide gel electrophoresis and immunoprobing of western blots, injection of L. vannamei post larvae with Hsp70 and Hsc70 dsRNA reduced Hsp70 but had no apparent effect on survival. However, the survival of post larvae lacking Hsp70, as compared to those containing the heat shock protein, was reduced more than two-fold 48 h after exposure to low salinity and pH, strongly indicating that Hsp70 is required for protection against these abiotic stressors. This is the first time to our knowledge that RNAi has been used to demonstrate a role for Hsp70 in protecting L. vannamei post larvae against salinity and pH stress, an effect undoubtedly due to the importance Hsp70 assumes in maintaining protein homeostasis within cells. Information generated in this work provides further understanding of Hsp70 function in the stress response of Penaeid shrimp and will assist in the development of strategies to mitigate abiotic stresses experienced by aquatic invertebrates during aquaculture.

Aqueduct is a common water conveyance buildings, this paper adopts finite element method to carry out three-dimensional finite element simulation analysis for Liye reinforced concrete rectangular-sectioned aqueduct. Researching variation law of the aqueducts stress and displacement in construction process and operational process. Analysis results show that, structure of Liye reinforced concrete rectangular-sectioned aqueduct is reasonable, force of aqueduct structure is explicit, it meets the requirements for engineering.

Purpose Sensitivity to a tyrosine kinase inhibitor (TKI) is correlated with the presence of somatic mutations that affect the kinase domain of epidermal growth factor receptor (EGFR). Development of resistance to TKI is a major therapeutic problem in non-small cell lung cancer (NSCLC). Aim of this study is to identify agents that can overcome TKI resistance in NSCLC. Methods We used a carefully selected panel of 12 NSCLC cell lines to address this clinical problem. Initially, the cell lines were treated with a variety of 10 compounds. Cellular proliferation was measured via MTT assay. We then focused on the gefitinib-resistant, EGFR mutant cell lines [H1650: exon 19 and PTEN mutations; and H1975: exons 20 (T790M) and 21 (L858R)] to identify agents that could overcome TKI resistance. Results Both 17-DMAG (Hsp90 inhibitor) and belinostat (histone deacetylase inhibitor, HDACi) effectively decreased the growth of almost all NSCLC lines. Also, belinostat markedly decreased the expression of EGFR and phospho-Akt in the cells. Combination of 17-DMAG and belinostat synergistically inhibited in vitro proliferation of these cells. Furthermore, both agents and their combination almost completely prevented TKI-resistant tumor formation (EGFR T790M mutation) in a xenograft model. Conclusion These results suggest that the combination of 17-DMAG and belinostat should be examined in a clinical trial for TKI-resistant NSCLC cell. Electronic supplementary material The online version of this article (doi:10.1007/s00280-013-2132-y) contains supplementary material, which is available to authorized users.