Clinical implications of PD-L1 expression and pathway-related molecular subtypes in advanced Asian colorectal cancer patients.

The expression level of PD-L1 does not accurately predict the prognosis of advanced colorectal cancer (CRC) patients, but it still reflects the tumor microenvironment to some extent. By stratifying PD-L1 status, gene subtypes in PD-L1 positivity-related pathological pathways were analyzed for their relationship to MSI or TMB to provide more individualized treatment options for CRCs. A total of 752 advanced CRCs were included, and their genomic variance was measured by a targeted next generation sequencing panel in this study. MSI and TMB were both measured by NGS, while PD-L1 expression level was measured using the PD-L1 colon 22C3 pharmDx kit. We found RTK/RAS pathway was positively related to high PD-L1 expression, with BRAF V600E and most KRAS mutations (G12 and G13) subtypes showing a significant correlation. Conversely, the Wnt and p53 pathways were negatively related to high PD-L1 expression, with APC C-terminal alterations and other non-inactivation mutations in TP53 making a primary contribution with significant statistical significance. Major subtypes showing a significantly higher proportion of TMB-H or MSI-H were irrespective of PD-L1 status. These findings demonstrate pathological pathways associated with high PD-L1 expression, suggesting that pathway-induced oncogenic constructive PD-L1 upregulation may be the reason for the corresponding patients' primary resistance to immune checkpoint inhibitors (ICIs), rather than a lack of pre-existing immune responses.

Path analysis to identify factors influencing osteoporosis: A cross-sectional study.

BACKGROUND: Osteoporosis is characterized by low bone mass and deterioration of bone tissue, which is influenced by both environmental factors and nutritional metabolism. The relationship between biochemical indicators and bone mineral density (BMD) is intricate and involves complex mechanisms. Path analysis, a statistical method that investigates causal relationships and the strength of associations among multiple factors, can be valuable in elucidating the connection between biochemical indicators and BMD. METHODS: In this study, we employed advanced statistical techniques, specifically structural equation modeling (SEM) to investigate the intricate interrelationships among a myriad of factors that exert influence on BMD. This analytical approach facilitated not only the identification of the direct relationships between specific variables and BMD but also the exploration of the intricate of indirect pathway through which other variables contribute to the oval impact on BMD. By delving into the direct and indirect effects, we aimed to unravel the complex influences that collectively shape the state of bone health, providing a nuanced understanding of the multifaceted nature of the factors affecting BMD. RESULTS: Our findings revealed that lipid levels had a significant indirect influence on BMD, which was mediated by body mass index (BMI). BMI exhibited both direct and indirect effects on BMD. Uric acid (UA) exerted a significant direct and indirect influence on BMD, with glomerular filtration rate (GFR) acting as the mediator. However, the total effect of UA on BMD was not significant due to the cancellation of positive effect UA on BMD but negative indirect effects of UA through GFR. For females, albumin had a significant direct effect on BMD, whereas this effect was not observed in males. The path analysis models generated results that demonstrated an acceptable fit for both female data (χ2 = 9.63, df = 7, p = 0.21, comparative fit index (CFI) = 0.98, root mean square error of approximation (RMSEA) = 0.05) and male data (χ2 = 6.26, df = 4, p = 0.18, CFI = 0.97, RMSEA = 0.06). CONCLUSIONS: Nutritional metabolism plays a crucial role in maintaining BMD in elderly females and males.

Application of Non-Ligation Technique in Thyroidectomy.

Objective: This study aimed to analyze the difference between non-ligation and traditional ligation techniques for papillary thyroid micro-carcinoma (PTMC) patients. Methods: Patients undergoing thyroidectomy in the Department of General Surgery, Ruijin Hospital, affiliated with Shanghai Jiao Tong University, Lu Wan Branch, were retrospectively enrolled. The gender, age, operation method, operation duration, tumor size, size of thyroidectomy specimen, postoperative bleeding, drainage volume on the first postoperative day, preoperative and postoperative levels of parathyroid hormone (PTH), and blood calcium were collected. Results: Compared with the traditional ligation technique, the non-ligation technique significantly shortened the operation time (69.36 ± 1.38 vs. 82.72 ± 2.12, P < .0001) and reached less variation of the serum calcium (2.32 ± 0.01 vs 2.28 ± 0.01, P < .001) and PTH (26.58 ± 0.08 vs 22.01 ± 1.04, P < .05) on the first postoperative day, and the above biochemical indicators returned to normal 3 weeks after surgery. The PTH in the No-ligation technique group was 7.20± 1.99, which was significantly lower than that in the Traditional ligation group (20.78± 3.78) (P < .01). Conclusion: No-ligation technique can significantly reduce the operation time in thyroidectomy but may temporarily affect the levels of parathyroid hormone and blood calcium, and the above changes returned to normal 3 weeks after surgery. These results highlighted that No-ligation technique can benefit patients and will be a favorable treatment method.

Efficacy of nasal irrigation and oral rinse with sodium bicarbonate solution on virus clearance for COVID-19 patients.

Background: Recent studies have shown that the infectivity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is reduced under alkaline conditions. The purpose of this study is to assess the effect of nasal irrigation and oral rinse with sodium bicarbonate solution on virus clearance among COVID-19 patients. Materials and methods: COVID-19 patients were recruited and randomly divided into two group, i.e., the experimental group and the control group. The experimental group received regular care plus nasal irrigation and oral rinse with 5% sodium bicarbonate solution, while the control group only received regular care. Nasopharyngeal and oropharyngeal swab samples were collected daily for reverse transcription-polymerase chain reaction (RT-PCR) assays. The negative conversion time and hospitalization time of the patients were recorded, and the results were statistically analyzed. Results: A total of 55 COVID-19 patients with mild or moderate symptoms were included in our study. There was no significant difference in gender, age and health status between the two groups. The average negative conversion time was 1.63 days after treatment with sodium bicarbonate, and the average hospitalization time of the control group and the experimental group were 12.53 and 7.7 days, respectively. Conclusions: Nasal irrigation and oral rinse with 5% sodium bicarbonate solution is effective in virus clearance for COVID-19 patients.

Assessment of PD-L1 mRNA expression in gastrointestinal tumors and the response to immunotherapy.

Background: Programmed death ligand 1 (PD-L1) immunohistochemistry (IHC) has been proposed as a predictive biomarker to predict response to immunotherapy. Given the limitations of IHC test in PD-L1 detection, this study aimed to investigate the technical feasibility of using quantitative RT-PCR (qRT-PCR) to replace IHC in PD-L1 detection in gastrointestinal tumors. Materials and methods: The Cancer Genome Atlas database was used to evaluate the relationship between PD-L1 expression in tumor tissue and the patient prognosis. In addition, 52 patients with gastrointestinal cancer were enrolled and divided into the stomach (STAD), colon (COAD), and rectum (READ) adenocarcinoma cohorts. IHC test was used to determine the PD-L1 level of the tissue specimens, and the qRT-PCR test was used to analyze the mRNA expression in both blood and tissue specimens. Moreover, the correlation between blood PD-L1 mRNA expression and immunotherapy efficacy was investigated in additional 15 patients with gastric cancer that further enrolled. Results: The expression level of PD-L1 in tumor tissue is related to the tumor stage of COAD (p-value = 0.001) and primary therapy outcomes in patients with READ (p-value = 0.003) but not significantly correlated to the overall survival (OS) time of patients with gastrointestinal cancer. Moreover, the concordance of PD-L1 mRNA expression level of tissue and paired blood samples is low, despite a weak linear relationship that was found in the STAD cohort (r = 0.43, p-value = 0.049). We further demonstrated that qRT-PCR results in both tissue and blood specimens were numerically but not statistically significant consistent with IHC results (corresponding to a p-value of 0.84 and 0.55, respectively). Remarkably, high PD-L1 expression in blood of patients with STAD shows a better response to immunotherapy (p-value = 0.04), which could be well identified at the relative expression cutoff of 1.5 (sensitivity of 85.7%, specificity of 75.0%, and AUC of 0.82). Conclusions: Our study established a novel strategy for rapidly distinguishing patients with gastrointestinal cancer with the response to immunotherapy and has potential clinical benefits.

Deep learning for evaluation of microvascular invasion in hepatocellular carcinoma from tumor areas of histology images.

BACKGROUND: Microvascular invasion (MVI) is essential for the management of hepatocellular carcinoma (HCC). However, MVI is hard to evaluate in patients without sufficient peri-tumoral tissue samples, which account for over a half of HCC patients. METHODS: We established an MVI deep-learning (MVI-DL) model with a weakly supervised multiple-instance learning framework, to evaluate MVI status using only tumor tissues from the histological whole slide images (WSIs). A total of 350 HCC patients (2917 WSIs) from the First Affiliated Hospital of Sun Yat-sen University (FAHSYSU cohort) were divided into a training and test set. One hundred and twenty patients (504 WSIs) from Dongguan People's Hospital and Shunde Hospital of Southern Medical University (DG-SD cohort) formed an external test set. Unsupervised clustering and class activation mapping were applied to visualize the key histological features. RESULTS: In the FAHSYSU and DG-SD test set, the MVI-DL model achieved an AUC of 0.904 (95% CI 0.888-0.920) and 0.871 (95% CI 0.837-0.905), respectively. Visualization results showed that macrotrabecular architecture with rich blood sinus, rich tumor stroma and high intratumor heterogeneity were identified as the key features associated with MVI ( +), whereas severe immune infiltration and highly differentiated tumor cells were associated with MVI (-). In the simulation of patients with only one WSI or biopsies only, the AUC of the MVI-DL model reached 0.875 (95% CI 0.855-0.895) and 0.879 (95% CI 0.853-0.906), respectively. CONCLUSION: The effective, interpretable MVI-DL model has potential as an important tool with practical clinical applicability in evaluating MVI status from the tumor areas on the histological slides.

Prediction of microvascular invasion in hepatocellular carcinoma with expert-inspiration and skeleton sharing deep learning.

BACKGROUND AND AIMS: Radiological prediction of microvascular invasion (MVI) of hepatocellular carcinoma (HCC) is essential but few models were clinically implemented because of limited interpretability and generalizability. METHODS: Based on 2096 patients in three independent HCC cohorts, we established and validated an MVI predicting model. First, we used data from the primary cohort to train a 3D-ResNet network for MVI prediction and then optimised the model with "expert-inspired training" for model construction. Second, we implemented the model to the other two cohorts using three implementation strategies, the original model implementation, data sharing model implementation and skeleton sharing model implementation, the latter two of which used part of the cohorts' data for fine-tuning. The areas under the receiver operating characteristic curve (AUCs) were calculated to compare the performances of different models. RESULTS: For the MVI predicting model, the AUC of the expert-inspired model was 0.83 (95% CI: 0.77-0.88) compared to 0.54 (95% CI: 0.46-0.62) of model before expert-inspiring. Taking this model as an original model, AUC on the second cohort was 0.76 (95% CI: 0.67-0.84). The AUC was improved to 0.83 (95% CI: 0.77-0.90) with the data-sharing model, and further improved to 0.85 (95% CI: 0.79-0.92) with the skeleton sharing model. The trend that the skeleton sharing model had an advantage in performance was similar in the third cohort. CONCLUSIONS: We established an expert-inspired model with better predictive performance and interpretability than the traditional constructed model. Skeleton sharing process is superior to data sharing and direct model implementation in model implementation.

The Cancer-Associated Fibroblasts-Related Gene COMP Is a Novel Predictor for Prognosis and Immunotherapy Efficacy and Is Correlated with M2 Macrophage Infiltration in Colon Cancer.

BACKGROUND: Colon cancer is characterized by a sophisticated tumor microenvironment (TME). Cancer-associated fibroblasts (CAFs), which make up the majority of the stromal cells in TME, participate in tumor development and immune regulation. Further investigations of CAFs would facilitate an in-depth understanding of its role in colon cancer TME. METHODS: In this study, we estimated CAF abundance based on The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases using the Microenvironment Cell Populations-counter (MCP-counter) algorithm. CAF-related genes were identified by differential gene expression analysis combined with weighted gene coexpression network analysis. For further selection, the least absolute shrinkage and selection operator (LASSO)-Cox regression was used, and the prognostic value of the selected gene was confirmed in numerous external cohorts. The function enrichment, immunological characteristics, tumor mutation signature, immunotherapy response, and drug sensitivity of the selected gene were subsequently explored. The bioinformatics analysis results were validated using immunohistochemistry on clinical samples from our institution. RESULTS: According to our findings, cartilage oligomeric matrix protein (COMP) was uncovered as a candidate CAFs-driven biomarker in colon cancer and plays an important role in predicting prognosis in colon cancer. COMP upregulation was associated with enhanced stromal and immune activation, and immune cell infiltration, especially M2 macrophages. Genes that mutated differently between the high- and low-COMP expression subgroups may be correlated with TME change. Following verification, COMP reliably predicted the immunotherapy response and drug response. In addition, our experimental validation demonstrated that COMP overexpression is associated with colon cancer carcinogenesis and is strongly associated with CAFs and M2 macrophage infiltration. CONCLUSION: Our study uncovered that COMP was a key CAFs-driven gene associated with M2 macrophage infiltration and acted as a convincing predictor for prognosis and immunotherapy response in colon cancer patients.

SuperTCM: A biocultural database combining biological pathways and historical linguistic data of Chinese Materia Medica for drug development.

AIM OF THE STUDY: Botanicals used in Traditional Chinese Medicine (TCM) are a rich source for drug discovery and provide models for multi-component drug development. To facilitate the studies of the actions of TCM drugs and expand their applications, a comprehensive database is urgently required. METHODS: One online resource connects all the relevant data from multiple scientific sources and languages. Drug information from published TCM databases and the official Chinese Pharmacopoeia as well as specialized meta-websites such as Kew's Medicinal Plant Names Service was integrated on a higher level. RESULTS: Our database, SuperTCM, covers the aspects of TCM derived from medicinal plants, encompassing pharmacological recipes up to chemical compounds. It provides the information for 6516 TCM drugs (or "herbs") with 5372 botanical species, 55,772 active ingredients against 543 targets in 254 KEGG pathways associated with 8634 diseases. SuperTCM is freely available at http://tcm.charite.de/supertcm.

The role of periampullary diverticulum on the incidence of pancreaticobiliary diseases and the outcome of endoscopic retrograde cholangiopancreatography.

INTRODUCTION: Periampullary diverticulum (PAD), although commonly discovered in patients undergoing endoscopic retrograde cholangiopancreatography (ERCP), remains controversial regarding its role in pancreaticobiliary diseases and the failure rate of cannulation. The aim of this study was to evaluate the association of PAD with pancreaticobiliary diseases and its impact on the outcome of ERCP. MATERIAL AND METHODS: A retrospective analysis was carried out on 1455 patients who underwent an ERCP. Patients were divided into a PAD group and a control group without PAD, and propensity score matching was performed to adjust for clinical differences. The comparison was focused on pancreaticobiliary diseases, technical success, and complications of ERCP. RESULTS: The occurrence of PAD is associated significantly with increasing age (p < 0.001). Incidences of acute pancreatitis (AP), suppurative cholangitis, and pancreatic head cancer were significantly higher in the PAD group (p < 0.05). After propensity score matching, the PAD group exhibited a higher rate of post-ERCP complications including haemorrhage, post-ERCP pancreatitis (PEP), and hyperamylasaemia (p < 0.05). However, the prevalence of perforation and the success rate of ERCP did not differ between groups (p > 0.05). CONCLUSIONS: Periampullary diverticulum develops with aging and seems to be associated with an increase in pancreaticobiliary diseases and post-ERCP complications except for perforation. Additionally, the presence of PAD does not affect the technical success of ERCP.

Longitudinal radiomics algorithm of posttreatment computed tomography images for early detecting recurrence of hepatocellular carcinoma after resection or ablation.

OBJECTIVES: To develop a radiomics algorithm, improving the performance of detecting recurrence, based on posttreatment CT images within one month and at suspicious time during follow-up. MATERIALS AND METHODS: A total of 114 patients with 228 images were randomly split (7:3) into training and validation cohort. Radiomics algorithm was trained using machine learning, based on difference-in-difference (DD) features extracted from tumor and liver regions of interest on posttreatment CTs within one month after resection or ablation and when suspected recurrent lesion was observed but cannot be confirmed as HCC during follow-up. The performance was evaluated by area under the receiver operating characteristic curve (AUC) and was compared among radiomics algorithm, change of alpha-fetoprotein (AFP) and combined model of both. Five-folded cross validation (CV) was used to present the training error. RESULTS: A radiomics algorithm was established by 34 DD features selected by random forest and multivariable logistic models and showed a better AUC than that of change of AFP (0.89 [95% CI: 0.78, 1.00] vs 0.63 [95% CI: 0.42, 0.84], P = .04) and similar with the combined model in detecting recurrence in the validation set. Five-folded CV error in the validation cohort was 21% for the algorithm and 26% for the changes of AFP. CONCLUSIONS: The algorithm integrated radiomic features of posttreatment CT showed superior performance to that of conventional AFP and may act as a potential marker in the early detecting recurrence of HCC.

The lncRNA MCF2L-AS1 controls osteogenic differentiation by regulating miR-33a.

Bone homeostasis is maintained by balanced osteoblast-mediated tissue production and osteoclast-mediated tissue destruction, and is disrupted in pathological conditions such as osteoporosis. The mechanisms underlying osteogenic differentiation of bone marrow mesenchymal stem cells, which is critical to bone homeostasis, are not completely clear, despite extensively studies. Long noncoding RNAs (lncRNAs) have recently emerged as novel therapeutic targets in various diseases. However, the expression pattern and biological function of lncRNAs in osteogenic differentiation remain unclear. In this study, we aimed to determine the role of lncRNAs in osteogenic differentiation of human bone marrow mesenchymal stem cells. We found high lncRNA MCF2L-AS1 expression in human bone marrow mesenchymal stem cells, and used bioinformatics analysis to analyze its function. MCF2L-AS1 knockdown induced inhibition of osteoblast differentiation. Silencing of MCF2L-AS1 increased the expression of miR-33a and subsequently inhibited Runx2 expression at the post-transcriptional level. Moreover, MCF2L-AS1 directly interacted with miR-33a, and downregulation of miR-33a efficiently reversed the suppression of Runx2 induced by MCF2L-AS1 short hairpin RNA (shRNA). Thus, MCF2L-AS1 positively regulated the expression of Runx2 by sponging miR-33a, and promoted osteogenic differentiation in BMSCs. Our results indicated that the lncRNA MCF2L-AS1 plays a critical role in the osteogenic differentiation of BMSCs, and targeting lncRNA MCF2L-AS1 could be a promising strategy to promote osteogenic differentiation.

Computational Prediction of Potential Inhibitors of the Main Protease of SARS-CoV-2.

The rapidly developing pandemic, known as coronavirus disease 2019 (COVID-19) and caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has recently spread across 213 countries and territories. This pandemic is a dire public health threat-particularly for those suffering from hypertension, cardiovascular diseases, pulmonary diseases, or diabetes; without approved treatments, it is likely to persist or recur. To facilitate the rapid discovery of inhibitors with clinical potential, we have applied ligand- and structure-based computational approaches to develop a virtual screening methodology that allows us to predict potential inhibitors. In this work, virtual screening was performed against two natural products databases, Super Natural II and Traditional Chinese Medicine. Additionally, we have used an integrated drug repurposing approach to computationally identify potential inhibitors of the main protease of SARS-CoV-2 in databases of drugs (both approved and withdrawn). Roughly 360,000 compounds were screened using various molecular fingerprints and molecular docking methods; of these, 80 docked compounds were evaluated in detail, and the 12 best hits from four datasets were further inspected via molecular dynamics simulations. Finally, toxicity and cytochrome inhibition profiles were computationally analyzed for the selected candidate compounds.

Efficacy and safety of endoscopic submucosal dissection for large gastric stromal tumors.

BACKGROUND AND AIM: Endoscopic submucosal dissection (ESD) of gastric stromal tumors is becoming increasingly common. However, there have been few studies analyzing the therapeutic efficacy and safety of this technique on large (≥ 3 cm) gastric stromal tumors (LGSTs). The aim of this study was to determine the feasibility of ESD for the removal of LGSTs and to investigate the clinical safety and efficacy of ESD for this indication. METHODS: A retrospective analysis was carried out on 82 patients with LGSTs who underwent an ESD. Data on therapeutic outcomes and follow-up were collected for an analysis of the rates of en block resection and complete resection. A logistic regression model was used to identify potential risk factors for ESD-related complications, and a receiver operating characteristic (ROC) curve was generated for qualifying independent risk factors. RESULTS: En bloc resection was achieved in 81 lesions (98.8%), and complete resection was achieved in 80 lesions (97.6%). The rates of intraoperative and postoperative bleeding were 6.1% and 3.7%, respectively. The accidental perforation rate was 12.2%, the postoperative perforation rate was 3.7%, the intentional perforation rate was 28.0%, and the postoperative infection rate was 12.2%. There was no postoperative mortality. LGSTs originating from the deep muscularis propria (MP) layer (OR = 4.905, 95% CI: 1.362-17.658, P = 0.015), located at the gastric fundus (OR = 4.927, 95% CI:1.308-18.558, P = 0.018) and with an irregular shape (OR = 4.842, 95% CI: 1.242-18.870, P = 0.023) increased the rate of complications. The prediction model that incorporated these factors demonstrated an area under the ROC curve of 0.77 (95% CI: 0.66-0.89). No tumor recurrence or distant metastasis was observed during the follow-up period, which ranged from 6-36 months. CONCLUSIONS: ESD is a feasible, safe, effective and minimally invasive approach for the resection of LGSTs. Tumors originating from the deep MP layer, located at the fundus and with an irregular shape were identified as risk factors for the development of complications.

The Effect of Sulforaphane on the Activity and Mineralization of Osteoblasts under Oxidative Stress.

Sulforaphane (SFN) is considered an antioxidant agent, but the biological effects on hypoxia-treated osteoblasts remain unclear. Therefore, the aims of this study were to investigate the effects of SFN on the activity and mineralization of osteoblasts in hypoxia. Osteoblasts were treated with hypoxia with or without SFN, and apoptosis was assayed with caspase 3 Activity Assay Kit and flow cytometer. The levels of reactive oxygen species (ROS) were measured with DCFH-DA. The levels of glutathione (GSH) and glutathione disulphide were determined by the o-phthalaldehyde fluorimetric assay. Mineralization of Osteoblasts was detected by Alizarin red staining and alkaline phosphatase (ALP) staining, and the relative proteins levels were examined by Western blotting. Our results showed that SFN reduced the hypoxia-mediated apoptosis and ROS levels in osteoblasts. The utilization of SFN improved the inhibitory effect of osteoblast mineralization by hypoxia. Additionally, the effect of alleviating hypoxia by SFN will be an increase in osteoblast activity. These findings clarify the effects of SFN on hypoxia-treated osteogenesis and will help identify novel therapeutic strategies for the protection of skeletal health.

Outcomes of endoscopic sphincterotomy vs open choledochotomy for common bile duct stones.

BACKGROUND: Endoscopic sphincterotomy (EST) for the management of common bile duct stones (CBDS) is used increasingly widely because it is a minimally invasive procedure. However, some clinical practitioners argued that EST may be complicated by post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP) and accompanied by a higher recurrence of CBDS than open choledochotomy (OCT). Whether any differences in outcomes exist between these two approaches for treating CBDS has not been thoroughly elucidated to date. AIM: To compare the outcomes of EST vs OCT for the management of CBDS and to clarify the risk factors associated with stone recurrence. METHODS: Patients who underwent EST or OCT for CBDS between January 2010 and December 2012 were enrolled in this retrospective study. Follow-up data were obtained through telephone or by searching the medical records. Statistical analysis was carried out for 302 patients who had a follow-up period of at least 5 years or had a recurrence. Propensity score matching (1:1) was performed to adjust for clinical differences. A logistic regression model was used to identify potential risk factors for recurrence, and a receiver operating characteristic (ROC) curve was generated for qualifying independent risk factors. RESULTS: In total, 302 patients undergoing successful EST (n = 168) or OCT (n = 134) were enrolled in the study and were followed for a median of 6.3 years. After propensity score matching, 176 patients remained, and all covariates were balanced. EST was associated with significantly shorter time to relieving biliary obstruction, anesthetic duration, procedure time, and hospital stay than OCT (P < 0.001). The number of complete stone clearance sessions increased significantly in the EST group (P = 0.009). The overall incidence of complications and mortality did not differ significantly between the two groups. Recurrent CBDS occurred in 18.8% (33/176) of the patients overall, but no difference was found between the EST (20.5%, 18/88) and OCT (17.0%, 15/88) groups. Factors associated with CBDS recurrence included common bile duct (CBD) diameter > 15 mm (OR = 2.72; 95%CI: 1.26-5.87; P = 0.011), multiple CBDS (OR = 5.09; 95%CI: 2.58-10.07; P < 0.001), and distal CBD angle ≤ 145° (OR = 2.92; 95%CI: 1.54-5.55; P = 0.001). The prediction model incorporating these factors demonstrated an area under the receiver operating characteristic curve of 0.81 (95%CI: 0.76-0.87). CONCLUSION: EST is superior to OCT with regard to time to biliary obstruction relief, anesthetic duration, procedure time, and hospital stay and is not associated with an increased recurrence rate or mortality compared with OCT in the management of CBDS.

Novel role of microRNA-126 in digestive system cancers: From bench to bedside.

MicroRNAs (miRNAs) are ubiquitously expressed, small, non-coding RNAs that regulate the expression of approximately 30% of the human genes at the post-transcriptional level. miRNAs have emerged as crucial modulators in the initiation and progression of various diseases, including numerous cancer types. The high incidence rate of cancer and the large number of cancer-associated cases of mortality are mostly due to a lack of effective treatments and biomarkers for early diagnosis. Therefore there is an urgent requirement to further understand the underlying mechanisms of tumorigenesis. MicroRNA-126 (miR-126) is significantly downregulated in a number of tumor types and is commonly identified as a tumor suppressor in digestive system cancers (DSCs). miR-126 downregulates various oncogenes, including disintegrin and metalloproteinase domain-containing protein 9, v-crk sarcoma virus CT10 oncogene homolog and phosphoinositide-3-kinase regulatory subunit 2. These genes are involved in a number of tumor-associated signaling pathways, including angiogenesis, epithelial-mensenchymal transition and metastasis pathways. The aim of the current review was to summarize the role of miR-126 in DSCs, in terms of its dysregulation, target genes and associated signaling pathways. In addition, the current review has discussed the potential clinical application of miR-126 as a biomarker and therapeutic target for DSCs.

The Catch-22 of Predicting hERG Blockade Using Publicly Accessible Bioactivity Data.

Drug-induced inhibition of the human ether-à-go-go-related gene (hERG)-encoded potassium ion channels can lead to fatal cardiotoxicity. Several marketed drugs and promising drug candidates were recalled because of this concern. Diverse modeling methods ranging from molecular similarity assessment to quantitative structure-activity relationship analysis employing machine learning techniques have been applied to data sets of varying size and composition (number of blockers and nonblockers). In this study, we highlight the challenges involved in the development of a robust classifier for predicting the hERG end point using bioactivity data extracted from the public domain. To this end, three different modeling methods, nearest neighbors, random forests, and support vector machines, were employed to develop predictive models using different molecular descriptors, activity thresholds, and training set compositions. Our models demonstrated superior performance in external validations in comparison with those reported in the previous studies from which the data sets were extracted. The choice of descriptors had little influence on the model performance, with minor exceptions. The criteria used to filter bioactivity data, the activity threshold settings used to separate blockers from nonblockers, and the structural diversity of blockers in training data set were found to be the crucial indicators of model performance. Training sets based on a binary threshold of 1 µM/10 µM to separate blockers (IC50/ Ki ≤ 1 µM) from nonblockers (IC50/ Ki > 10 µM) provided superior performance in comparison with those defined using a single threshold (1 µM or 10 µM). A major limitation in using the public domain hERG activity data is the abundance of blockers in comparison with nonblockers at usual activity thresholds, since not many studies report the latter.

Short-chain chlorinated paraffins (SCCPs) in a freshwater food web from Dianshan Lake: Occurrence level, congener pattern and trophic transfer.

Short-chain chlorinated paraffins (SCCPs) are new group of persistent organic pollutants (POPs) listed in the Stockholm Convention. The Yangtze River Delta is among the industrially most developed areas in China, supporting a large production and consumption of chlorinated paraffins (CPs). Despite this, there is very limited data on the environmental exposure of SCCPs from the region. This study analyzed SCCPs in 14 wild aquatic organisms from Dianshan Lake, Shanghai, China. The concentrations of total SCCPs ranged from 10 to 1300µgg-1 lipid weight, with significantly higher levels (p<0.05) in benthic (benthic fish and invertebrates) than in non-benthic species (pelagic and mesopelagic fish). The abundance of C10 congeners was much higher in the benthic species compared to in the non-benthic species. The calculated trophic magnification factors (TMFs) of SCCP congeners varied from 1.19 (C10H12Cl10) to 1.57 (C13H20Cl8). The TMFs were significantly correlated (p<0.01) with carbon-chain length in a positive linear relationship and with Log Kow in a parabolic curve relationship. Considering the high concentrations of SCCPs in wild aquatic organisms and the trophic magnification observed in the freshwater food web, further studies should be undertaken to assess the environmental fate of SCCPs and the public health risk in the Yangtze River Delta.

SuperDRUG2: a one stop resource for approved/marketed drugs.

Regular monitoring of drug regulatory agency web sites and similar resources for information on new drug approvals and changes to legal status of marketed drugs is impractical. It requires navigation through several resources to find complete information about a drug as none of the publicly accessible drug databases provide all features essential to complement in silico drug discovery. Here, we propose SuperDRUG2 (http://cheminfo.charite.de/superdrug2) as a comprehensive knowledge-base of approved and marketed drugs. We provide the largest collection of drugs (containing 4587 active pharmaceutical ingredients) which include small molecules, biological products and other drugs. The database is intended to serve as a one-stop resource providing data on: chemical structures, regulatory details, indications, drug targets, side-effects, physicochemical properties, pharmacokinetics and drug-drug interactions. We provide a 3D-superposition feature that facilitates estimation of the fit of a drug in the active site of a target with a known ligand bound to it. Apart from multiple other search options, we introduced pharmacokinetics simulation as a unique feature that allows users to visualise the 'plasma concentration versus time' profile for a given dose of drug with few other adjustable parameters to simulate the kinetics in a healthy individual and poor or extensive metabolisers.