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Background. T cell-mediated antitumor immune response is the basis of colorectal cancer (CRC) immunotherapy. Cholesterol plays an important role in T cell signal transduction and function. Apolipoprotein E (APOE) plays a major role in cholesterol metabolism. Objective. To screen and analyze key markers involved in the anticolon cancer response of CD8+ T cells through the regulation of cholesterol metabolism. Methods. Based on the median cutoff of the expression value of APOE according to the data downloaded from The Cancer Genome Atlas and Gene Expression Omnibus database, patients were grouped into low and high expression groups. Differences in clinical factors were assessed, and survival analysis was performed. Differentially expressed genes (DEGs) in the high and low expression groups were screened, followed by the analysis of differences in tumor-infiltrating immune cells and weighted gene coexpression network analysis results. The closely related genes to APOE were identified, followed by enrichment analysis, protein–protein interaction (PPI) network analysis, and differential expression analysis. Immunohistochemical staining (IHC) was used to detect the expression of CD8 in CRC tissues. Results. There were significant differences in prognosis and pathologic_N between the APOE low and high expression groups. A total of 2,349 DEGs between the high and low expression groups were selected. A total of 967 genes were obtained from the blue and brown modules. The probability of distribution of CD8+ T cells differed significantly between the two groups, and 320 closely related DEGs of APOE were screened. Genes including the HLA gene family, B2M, IRF4, and STAT5A had a higher degree in the PPI network. GEO datasets verified the prognosis and the related DEGs of APOE. IHC staining verified the relationship between the distribution of CD8+ T cells and APOE expression. Conclusion. Genes including the HLA gene family, B2M, IRF4, and STAT5A might be the key genes involved in the anticolon cancer response of CD8+ T cells through the regulation of cholesterol metabolism.

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in the world. Therapeutic activity of icariin, a major bioactive component of Epimedii Herba, in NAFLD is still unknown. Herein, the C57BL/6J mice were fed with a high-fat diet for 16 weeks to establish a NAFLD model. Mice were assigned to five groups: control group, NAFLD group, and icariin treatment groups. Effects of icariin on blood indices, glucose tolerance, insulin sensitivity, histopathological morphology, cell apoptosis, lipid accumulation, and AMPK signaling were analyzed. In addition, another cohort of mice were assigned to five groups: control group, NAFLD group, dorsomorphin treatment group, icariin treatment group, and dorsomorphin + icariin treatment group. Expression of proteins in liver tissues associated with AMPK signaling, and levels of ALT and AST were evaluated. Icariin attenuated the NAFLD-induced increase of the TG, TC, LDL-C, ALT, AST levels. HDL-C levels were affected neither by NAFLD nor by icariin. Furthermore, icariin treatment (100-200 mg/kg) counteracted the NAFLD-reduced glucose tolerance and insulin sensitivity and modulated histopathological changes, cell apoptosis, and lipid accumulation in liver tissues. Additionally, icariin mitigated the NAFLD-induced up-regulation of the cleaved caspase 3/9, SREBP-1c, and DGAT-2 levels, and enhanced the expression level of CPT-1, p-ACC/ACC, AMPKα1, PGC-1α, and GLUT4. Effects of icariin on the AMPK signaling and levels of AST and ALT could be reversed by AMPK inhibitor, dorsomorphin. This paper investigates the glucose-reducing and lipid-lowering effects of icariin in NAFLD. Moreover, icariin might function through activating the AMPKα1/PGC-1α/GLTU4 pathway.

Metabolic syndrome (MetS) is characterized by a group of metabolic disturbances which leads to the enhanced risk of cancer development. Elucidating the mechanisms between these two pathologies is essential to identify the potential therapeutic molecular targets for colorectal cancer (CRC). 716 colorectal patients from the First and Second Affiliated Hospital of Wenzhou Medical University were involved in our study and metabolic disorders were proven to increase the risk of CRC. The prognostic value of the MetS factors was analyzed using the Cox regression model and a clinical MetS-based nomogram was established. Then by using multi-omics techniques, the distinct molecular mechanism of MetS genes in CRC was firstly systematically characterized. Strikingly, MetS genes were found to be highly correlated with the effectiveness of targeted chemotherapy administration, especially for mTOR and VEGFR pathways. Our results further demonstrated that overexpression of MetS core gene IL6 would promote the malignancy of CRC, which was highly dependent on mTOR-S6K signaling. In conclusion, we comprehensively explored the clinical value and molecular mechanism of MetS in the progression of CRC, which may serve as a candidate option for cancer management and therapy in the future.

Gastric cancer (GC) is a typical heterogeneous malignant tumor, whose insensitivity to chemotherapy is a common cause of tumor recurrence and metastasis. There is no doubt regarding the effectiveness of adjuvant chemotherapy (ACT) for GC, but the population for whom it is indicated and the selection of specific options remain the focus of present research. The conventional pathological TNM prediction focuses on cancer cells to predict prognosis, while they do not provide sufficient prediction. Enhanced computed tomography (CT) scanning is a validated tool that assesses the involvement of careful identification of the tumor, lymph node involvement, and metastatic spread. Using the radiomics approach, we selected the least absolute shrinkage and selection operator (LASSO) Cox regression model to build a radiomics signature for predicting the overall survival (OS) and disease-free survival (DFS) of patients with complete postoperative gastric cancer and further identifying candidate benefits from ACT. The radiomics trait-associated genes captured clinically relevant molecular pathways and potential chemotherapeutic drug metabolism mechanisms. Our results of precise surrogates using radiogenomics can lead to additional benefit from adjuvant chemotherapy and then survival prediction in postoperative GC patients.

Medication nonadherence is associated with an increased risk of complications in hypertensive patients. We investigated behavioral factors associated with medication nonadherence in hypertensive patients in southern Taiwan. Using questionnaires, we collected data regarding clinicodemographic characteristics and nonadherence behaviors from 238 hypertensive patients. We assessed the self-reported prevalence of specific behaviors of medication nonadherence and investigated factors associated with each behavior using multivariable logistic regression analysis. The most common behavior of medication nonadherence was forgetting to take medication (28.6%), followed by discontinuing medication (9.2%) and reducing the medication dose (8.8%). Age ≥ 65 years (adjusted odds ratio [aOR] = 0.32, 95% confidence interval [CI] = 0.15–0.69) and male sex (aOR = 2.61, CI = 1.31–5.19) were associated with forgetting to take medication. The presence of comorbidities (diabetes, kidney disease, or both) and insomnia (aOR = 3.97, 95% CI = 1.30–12.1) was associated with reducing the medication dose. The use of diet supplements was associated with discontinuing the medication (aOR = 4.82, 95% CI = 1.50–15.5). Compliance with a low oil/sugar/sodium diet was a protective factor against discontinuing medication (aOR = 0.14, 95% CI = 0.03–0.75). The most pervasive behavior associated with medication nonadherence among hypertensive patients was forgetting to take medication. Age &lt, 65 years, male sex, comorbidities, insomnia, noncompliance with diet, and the use of dietary supplements were specifically associated with medication nonadherence.

BackgroundThe therapeutic efficacy of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in advanced EGFR-mutant lung squamous cell carcinoma (SCC) patients remains uncertain. Furthermore, the factors underlying the responsiveness have not been fully investigated. We therefore investigated the link between genomic profiles and EGFR-TKI efficacy.Material and MethodsWe consecutively enrolled stage IV, EGFR-mutant, and EGFR-TKI–treated patients with SCC. Patients with EGFR wild-type lung SCC and EGFR-mutant lung adenocarcinoma were consecutively enrolled as controls, and next-generation sequencing (NGS) was performed.ResultsIn total, 28 EGFR-mutant lung SCC, 41 EGFR-mutant lung adenocarcinoma, and 40 EGFR wild-type lung SCC patients were included. Among the patients with EGFR mutations, shorter progression-free survival (PFS) was observed in SCC compared to adenocarcinoma (4.6 vs. 11.0 months, PEGFR-mutant SCC patients had similar mutation characteristics to EGFR-mutant adenocarcinoma patients, but differed from those with EGFR wild-type SCC. Further exploration of EGFR-mutant SCC revealed that mutations in CREBBP (P = 0.005), ZNF217 (P = 0.016), and the Wnt (P = 0.027) pathway were negatively associated with PFS. Mutations in GRM8 (P = 0.025) were associated with improved PFS.ConclusionsEGFR-mutant lung SCC has a worse prognosis than EGFR-mutant adenocarcinoma. Mutations in other genes, such as CREBBP, ZNF217, GRM8, or Wnt that had implications on PFS raise the possibility of understanding mechanisms of resistance to EGFR-TKI in lung SCC, which will aid identification of potential beneficial subgroups of patients with EGFR-mutant SCCs receiving EGFR-TKIs.

Background Gastric cancer (GC) is the main malignancy affecting a large population worldwide. Lack of effective enough treatment is one of the leading factors contributing to the high mortality rate. Melatonin, a naturally occurring compound, has been proven to exert cytotoxic and antiproliferative effects on human gastric cancers. Nevertheless, the mechanisms of anti-gastric cancer of melatonin remain elucidated. It is believed that endoplasmic reticulum (ER) stress and its resultant unfolded protein response (UPR) are connected to the survival, progression, and chemoresistance of various tumor cells via multiple cellular procedures, such as autophagy. In this study, the effects of melatonin on human gastric cancer cell lines AGS and SGC-7901 was assessed to reveal the interaction between melatonin, endoplasmic reticulum stress, and autophagy in gastric cancer. Methods CCK-8, the wound healing analysis, colony formation assay, immunofluorescence analysis, Western blotting, flow cytometry, and animal models were used in the current study. Results The data demonstrated that melatonin could inhibit GC growth, proliferation, and invasion both in vivo and in vitro. Apoptosis and autophagy induced in a concentration-dependent manner is response to melatonin-induced ER stress. Melatonin induced the expression of apoptotic and autophagy-related proteins, which was markedly attenuated by the ER stress inhibitor 4-PBA and autophagy inhibitor 3-MA. In addition, we used the specific IRE1 inhibitor STF 083010, finding that inhibiting IRE1 could considerably relieve ER stress-induced autophagy activity, as revealed by the reduction of LC3-II and Beclin-1. Conclusion This study confirmed that melatonin-induced inhibition of GC cell proliferation is mediated by the activation of the IRE/JNK/Beclin1 signaling.

Relying on the Biomedical Big Data Center of West China Hospital, this paper makes an in-depth research on the construction method and application of breast cancer-specific database system based on full data lifecycle, including the establishment of data standards, data fusion and governance, multi-modal knowledge graph, data security sharing and value application of breast cancer-specific database. The research was developed by establishing the breast cancer master data and metadata standards, then collecting, mapping and governing the structured and unstructured clinical data, and parsing and processing the electronic medical records with NLP natural language processing method or other applicable methods, as well as constructing the breast cancer-specific database system to support the application of data in clinical practices, scientific research, and teaching in hospitals, giving full play to the value of medical big data of the Biomedical Big Data Center of West China Hospital.

Objective The malignant phenotypes of cancer are defined not only by its intrinsic tumor cells but also by the tumor-infiltrating immune cells activated and recruited to the cancer microenvironment. However, a comprehensive introduction of gastric cancer immune cell infiltration has not been identified so far. Methods In this study, we comprehensively analyzed the tumor-infiltrating immune cells abundance in gastric cancer for the first time by CIBERSORT. The meta-analysis, single-sample gene set enrichment analysis and hierarchical agglomerative clustering were used to measure and evaluate the respective proportions of 22 cell types of immune infiltration using normalized gene expression data. The fraction of tumor-infiltrating immune cells subpopulations was also evaluated to determine the associations with clinical features and molecular subtypes. Results Tumor-infiltrating immune cells are extensively involved in the pathogenesis and development of the gastric cancer. We discovered Tfh and activated CD4+ memory T cells were associated with poorer overall survival and Progression-free survival (PFS), but that naïve B cells were opposite for PFS. Unsupervised clustering analysis revealed there existed three tumor-infiltrating immune cells subgroups with distinct survival patterns. Specially, cluster 1 showed significantly better clinical outcome than other two clusters. Conclusions Collectively, our data explored the differences of tumor-infiltrating immune cells in gastric cancer, and these variations were likely to be important clues for prognosis and management of its future clinical implementation.

PURPOSE: To validate the feasibility and efficacy of intratumoral radiofrequency hyperthermia (RFH)-enhanced herpes simplex virus (HSV) thymidine kinase (TK) and ganciclovir (GCV) (hereafter, HSV-TK/GCV) gene therapy for non–small-cell lung cancer (NSCLC). MATERIALS AND METHODS: This study was performed from November 11, 2015, to April 14, 2017, and included (a) in vitro experiments with human NSCLC cells to establish the proof of principle, (b) in vivo experiments using mice with subcutaneous NSCLC to further demonstrate the principle, and (c) in vivo experiments using rats with orthotopic NSCLC to validate the technical feasibility. Cells, nude mice, and nude rats were randomly divided into four groups (six animals per group): (a) combination therapy (HSV-TK/GCV combined with RFH), (b) RFH, (c) HSV-TK/GCV, and (d) phosphate-buffered saline. Data were analyzed by using the Dunnett t test or Kruskal–Wallis test. RESULTS: For in vitro experiments, the cell proliferation assay showed significantly diminished viable cells with combination therapy (mean, 0.56; 95% confidence interval [CI]: 0.44, 0.68) versus RFH (mean, 0.89; 95% CI: 0.82, 0.97), HSV-TK/GCV (mean, 0.71; 95% CI: 0.56, 0.86), and phosphate-buffered saline (mean, 1; 95% CI: 1, 1) (P < .05 for all). For in vivo experiments, optical imaging showed significantly decreased relative bioluminescence signal with combination therapy (mean, 0.71 [95% CI: 0.03, 1.39] in mice; 1.29 [95% CI: 0.51, 2.06] in rats) compared with RFH (mean, 2.66 [95% CI: 1.73, 3.59] in mice; 2.26 [95% CI: 1.51, 3.01] in rats), HSV-TK/GCV (mean, 1.37 [95% CI: 0.65, 2.08] in mice; 1.76 [95% CI: 1.20, 2.31] in rats), and phosphate-buffered saline (mean, 3.07 [95% CI: 2.50, 3.65] in mice; 2.94 [95% CI: 2.29, 3.58] in rats) (P < .001 for all). US showed that the smallest relative tumor volumes occurred with combination therapy (mean, 0.60; 95% CI: 0.15, 1.05) versus RFH (mean, 2.43; 95% CI: 1.80, 3.06), HSV-TK/GCV (mean, 1.32; 95% CI: 0.75, 1.89), and phosphate-buffered saline (mean, 2.56; 95% CI: 1.75, 3.38) (P < .05 for all) in the mouse subcutaneous model. CONCLUSION: Intratumoral radiofrequency hyperthermia–enhanced herpes simplex virus thymidine kinase and ganciclovir gene therapy for non–small-cell lung cancer is feasible and can be guided by molecular imaging. © RSNA, 2018

// Fu Xiong 1, 2, * , Feng Zhang 2, * , Yin Jin 2 , Qiaoyou Weng 2 , Jingjing Song 2 , Guofeng Zhou 1 , David Shin 2 , Chuansheng Zheng 1 and Xiaoming Yang 2 1 Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province 430022, China 2 Image-Guided Bio-Molecular Intervention Research and Section of Vascular & Interventional Radiology, Department of Radiology, University of Washington School of Medicine, Seattle, WA 98109, USA * These authors have contributed equally to this work Correspondence to: Xiaoming Yang, email: xmyang@uw.edu Chuansheng Zheng, email: hqzcsxh@sina.com Keywords: radiofrequency hyperthermia; gene therapy; hepatocellular carcinoma; molecular imaging Received: July 04, 2017 Accepted: September 08, 2017 Epub: December 22, 2017 Published: March 06, 2018 ABSTRACT Purpose: To validate the feasibility of using interventional radiofrequency hyperthermia(RFH) to enhance herpes simplex virus-thymidine kinase (HSV-TK)/ganciclovir (GCV) gene therapy of rat orthotopic hepatic cancer. Material and Methods : Rat hepatocellular carcinoma cells (MCA-RH-7777) were transduced with lentivirus/luciferase gene for optical imaging. In-vitro experiments with the luciferase cells and in-vivo experiments on rats with orthotopic hepatic tumors were divided into four treatment groups: (i) HSV-TK/GCV-mediated gene therapy combined with RFH; (ii) gene therapy alone; (iii) RFH alone; and (iv) phosphate buffered saline (PBS). Cell viability was evaluated by MTS assay and confocal microscopy, and HSV-TK gene expression in cells and tumors was quantified by western blotting. Bioluminescent optical imaging and ultrasound imaging were used to monitor and compare the photon signal and tumor size changes among different treatment groups overtime, respectively. The imaging findings were correlated with histology. Results: For in-vitro experiments, the combination therapy group (gene therapy + RFH) demonstrated the lowest cell proliferation by MTS assay, compared to the gene therapy alone, RFH alone, and PBS (26.1±3.2% vs 50.4±4.6% vs 82.9±6.3% vs 100%, p

// Qin-Fen Chen 1, * , Xiao-Dong Zhou 2, * , Dan-Hong Fang 3 , Yang-Jie Sun 1 , Qian Zhao 1 , Jun-Hua Huang 1 , Yin Jin 1 and Jian-Sheng Wu 3 1 Department of Gastroenterology, First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China 2 Department of Cardiovascular Medicine, First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China 3 Medical and Health Care Center, First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China * Co-first author Correspondence to: Jian-Sheng Wu, email: wenzhouwujs@163.com , wzwujs@wzhospital.cn Keywords: colorectal polyps, smoking, non-alcoholic fatty liver disease, health check Received: February 27, 2017 Accepted: July 25, 2017 Published: August 24, 2017 ABSTRACT Objectives: Non-alcoholic fatty liver disease (NAFLD) and smoking have similar mechanisms of promoting colorectal polyps. The potential link between NAFLD and smoking in men and colorectal polyps has not been adequately evaluated. The aim is to investigate this association. Methods: A retrospective cross-sectional study was conducted on 2409 individuals undergoing a health check. Univariate and multivariate logistic regression were performed for analyzing the association between risk factors and colorectal polyps. Individuals were divided into four groups: Q1: NAFLD (-)/smoking (-); Q2: NAFLD (+)/smoking (-); Q3: NAFLD (-)/smoking (+); Q4: NAFLD (+)/smoking (+). Logistic analyses were used to explore associations for the whole study population and stratified groups. Results: The prevalence of colorectal polyps was 38.8% in males, and that of colorectal polyps in smokers and individuals with NAFLD were 47.0% (428/911) and 42.9% (267/622), respectively. With Q1 as reference, subjects with NAFLD (+) and smoking habits (+) had the highest ORs for colorectal polyps (OR = 2.64, 95% CI: 1.91 - 3.64, P < 0.001), adenomatous polyps (OR = 2.06, 95% CI: 1.38 - 3.05, P < 0.05), non-adenomatous polyps (OR = 1.97, 95% CI: 1.39 - 2.80, P < 0.05), ≥ 3 polyps (OR = 2.05, 95% CI: 1.31 - 3.22, P < 0.05) and proximal polyps (OR = 1.58, 95% CI: 1.02 - 2.45, P < 0.05) after adjusting for confounding variables. Conclusions: Men with NAFLD and smoking habits have an increasing risk of colorectal polyps.

AIM To investigate the relationship between non-alcoholic fatty liver disease (NAFLD) and colorectal adenomatous and hyperplastic polyps. METHODS A retrospective cross-sectional study was conducted on 3686 individuals undergoing health checkups (2430 males and 1256 females). All subjects underwent laboratory testing, abdominal ultrasonography, colonoscopy, and an interview to ascertain the baseline characteristics and general state of health. Multinomial logistic regression analysis was performed to examine the association between NAFLD and the prevalence of colorectal adenomatous and hyperplastic polyps. Furthermore, the relationship was analyzed in different sex groups. Subgroup analysis was performed based on number, size, and location of colorectal polyps. RESULTS The prevalence of colorectal polyps was 38.8% in males (16.2% for adenomatous polyps and 9.8% for hyperplastic polyps) and 19.3% in females (8.4% for adenomatous polyps and 3.9% for hyperplastic polyps). When adjusting for confounding variables, NAFLD was significantly associated with the prevalence of adenomatous polyps (OR = 1.28, 95%CI: 1.05-1.51, P < 0.05) and hyperplastic polyps (OR = 1.35, 95%CI: 1.01-1.82, P < 0.05). However, upon analyzing adenomatous and hyperplastic polyps in different sex groups, the significant association remained in males (OR = 1.53, 95%CI: 1.18-2.00, P < 0.05; OR = 1.42, 95%CI: 1.04-1.95, P < 0.05) but not in females (OR = 0.44, 95%CI: 0.18-1.04, P > 0.05; OR = 1.18, 95%CI: 0.50-2.78, P > 0.05). CONCLUSION NAFLD is specifically associated with an increased risk of colorectal adenomatous and hyperplastic polyps in men. However, NAFLD may not be a significant factor in the prevalence of colorectal polyps in women.

Objective To explore stable and functional microRNA (miRNA)–disease relationships using a genome-wide expression profile pattern matching strategy. Methods We applied the ranked microarray pattern matching strategy Gene Set Enrichment Analysis to identify miRNA permutations with similar expression patterns to diseases. We also used quantitative reverse transcription PCR to validate the predicted expression levels of miRNAs in three diseases: inflammatory bowel disease (IBD), oesophageal cancer, and colorectal cancer. Results We found that hsa-miR-200 c was upregulated more than 40-fold in oesophageal cancer. The expression of miR-16 and miR-124 was not consistently upregulated in IBD or colorectal cancer. Conclusions Our results suggest that this expression profile matching strategy can be used to identify functional miRNA–disease relationships.

BACKGROUND Non-alcoholic fatty liver disease (NAFLD) is a common chronic liver disease worldwide. However, to date, there is no ideal therapy for this disease. AIM To study the effects of Si-Ni-San freeze-dried powder on high fat diet-induced NAFLD in mice. METHODS Twenty-four male C57BL/6 mice were randomized into three groups of eight. The control group (CON) was allowed ad libitum access to a normal chow diet. The high fat diet group (FAT) and Si-Ni-San group (SNS) were allowed ad libitum access to a high fat diet. The SNS group was intragastrically administered Si-Ni-San freeze-dried powder (5.0 g/kg) once daily, and the CON and FAT groups were intragastrically administered distilled water. After 12 wk, body weight, liver index, visceral fat index, serum alanine aminotransferase (ALT), portal lipopoly-saccharide (LPS), liver tumor necrosis factor (TNF)-α and liver triglycerides were measured. Intestinal microbiota were analyzed using a 16S r DNA sequencing technique. RESULTS Compared with the FAT group, the SNS group exhibited decreased body weight, liver index, visceral fat index, serum ALT, portal LPS, liver TNF-α and liver triglycerides (P < 0.05). Intestinal microbiota analysis showed that the SNS group had different bacterial composition and function compared with the FAT group. In particular, Oscillospira genus was a bacterial biomarker of SNS group samples. CONCLUSION The beneficial effects of Si-Ni-San freeze-dried powder on high fat diet-induced NAFLD in mice may be associated with its anti-inflammatory and changing intestinal microbiota effects.

Aim To identify the factors affecting the pharmacokinetics (PKs) of sirolimus in healthy Chinese subjects and renal transplant patients. Methods A population PK model of sirolimus was constructed using dense data from 22 healthy volunteers and sparse data from 105 renal transplant patients. Results The data were well described by a two-compartment model with first-order absorption. The estimates of absorption rate constant (Ka), clearance (CL/F), and central volume of distribution (V2/F) were 0.24 h(-1), 8.81 L/h, and 676 L, respectively. The CL/F in renal transplant patients was 45.5% lower than that in healthy subjects. Based on the final model, CL/F decreased significantly with increasing cyclosporine (CsA) daily dose and age. A decrease of 7.3% in CL/F for every 100-mg increase in the CsA daily dose and a decrease of 34.2% in CL/F for every 20-year increase in age was observed. Moreover, V2/F increased significantly with increasing serum creatinine in our study. However, the range of serum creatinine concentration and the interindividual variability for V2/F are large. Conclusion This is the first study to characterize the population PKs of sirolimus using a two-compartment model in healthy Chinese subjects and renal transplant patients. A decrease of 7.3% in the sirolimus CL/F for every 100-mg increase in the CsA daily dose and a decrease of 34.2% in the sirolimus CL/F for every 20-year increase in age was observed, which allowed us to better optimize sirolimus dosing regimens in Chinese renal transplant patients.

Background/Aims: Melatonin, which is mainly secreted by the pineal gland and released into blood, has anti-inflammatory properties in acute pancreatitis. Many studies show that melatonin can relieve inflammation in taurocholate-induced acute pancreatitis. However, the mechanisms of its anti-inflammatory effects are still undefined, especially the relationship between melatonin and endoplasmic reticulum stress. We explored the anti-inflammatory activity of melatonin in AR42J and rat models. Methods: The CCK-8 assay was used to assess effects of melatonin on AR42J cell viability. Inflammatory degree and the expressions of endoplasmic reticulum stress related molecules were examined by quantitative RT-PCR and western blotting. The degree of inflammation in the tissue was also accessed by pathological grading. Finally, we used the western blotting method to verify apoptosis and autophagy. Results: Endoplasmic reticulum stress was obviously activated in early stage inflammation in AR42J and rat models. Melatonin could induce anti-inflammatory effects via endoplasmic reticulum stress. Melatonin significantly inhibited inflammatory cytokines and the expression of ERS-related molecules. Finally, it played a protective role by promoting apoptosis and autophagy of the cells, which were damaged in the process of inflammatory reaction. Conclusion: Melatonin induces anti-inflammatory effects via endoplasmic reticulum stress in acute pancreatitis to play a protective role.

Background Moyamoya disease or syndrome (MMD or MMS) is a cerebrovascular disease characterized by stenosis or occlusion of the distal portion of the internal carotid arteries, with ultimate spread to the proximal portion of the anterior cerebral arteries and middle cerebral arteries (MCAs). In the present study, we wanted to evaluate the usefulness of conventional computed tomography (CT) and axial magnetic resonance (MR) T2-weighted imaging (T2WI) for the examination of horizontal segments of the MCAs (ie, M1 segments) in patients diagnosed with MMD or MMS. Methods This study enrolled 29 patients (n = 11 men; n = 18 women), who underwent conventional CT and/or MR T2WI. CT angiography, MR angiography, or digital subtraction angiography was used as a reference. CT and MR imaging data were reviewed by 2 experienced radiologists, who analyzed and recorded stenosis or occlusions of the M1 segments. We performed statistical analyses to compare the diagnostic accuracy of both techniques on M1 segments in MMD or MMS. Results Fifty-three steno-occlusive changes of M1 segments were revealed by angiography in the 29 patients. T2W-MRI allowed the identification of moyamoya vessels with 100% success rate. Stenosis and occlusion of M1 segments were better visualized on axial T2W-MRI compared to conventional CT (94.59% versus 71.43%; P = .008). Conclusions Our study showed that conventional CT and axial T2W-MRI could be used to identify the steno-occlusive changes of the horizontal segment of the MCA in MMD or MMS, which may have a significant impact on the accurate diagnosis of this disease at its early stage.

Background The aim of this study was to investigate and interpret the expression level and potential function of TCEA3 in gastric cancer. Material and methods qRT-PCR was used to determine the expression level of TCEA3 in gastric cancer tissues. Pearson χ2 test was performed to clarify the correlation between TCEA3 expression and patients' clinicopathologic characteristics. Biological function of TCEA3 was tested by proliferation assay and colony formation assay. Flow cytometry was used to study the potential function of TCEA3 in apoptosis induction. Results TCEA3 expression was significantly downregulated in gastric cancer tissues compared with paired normal tissues. Poor prognoses were observed in the low TCEA3 expression group of patients in contrast to the high TCEA3 expression group. Functionally, upregulation of TCEA3 inhibited gastric cancer cell proliferation and colony formation. We also found that TCEA3 may attenuate cell growth through apoptosis induction. Conclusions Our findings suggest that TCEA3 attenuates the proliferation and induces apoptosis of gastric cancer cells.

Colorectal neoplasm is considered to have a strong association with nonalcoholic fatty liver disease (NAFLD) and metabolic syndrome (MetS), respectively. The relationship among NAFLD, MetS, and colorectal neoplasm was assessed in 1793 participants. Participants were divided into 4 groups based on the status of NAFLD and MetS. Relative excess risks of interaction (RERI), attributable proportion (AP), and synergy index (SI) were applied to evaluate the additive interaction. NAFLD and MetS were significantly correlated with colorectal neoplasm and colorectal cancer (CRC), respectively. The incidence of CRC in NAFLD (+) MetS (+) group was significantly higher than other 3 groups. The result of RERI, AP, and SI indicated the significant additive interaction of NAFLD and MetS on the development of CRC. NAFLD and MetS are risk factors for colorectal neoplasm and CRC, respectively. And NAFLD and MetS have an additive effect on the development of CRC.

Recent studies have demonstrated that melatonin significantly decreased all studied acute pancreatitis-associated inflammatory parameters, in addition to reducing apoptosis and necrosis associated with pancreatic injury. However, the effect of melatonin on gut barrier dysfunction and bacterial translocation has not been fully elucidated. This study aimed to investigate the protective effects of melatonin on intestinal integrity in a rat model of severe acute pancreatitis (SAP) to evaluate whether melatonin prevented intestine barrier dysfunction and reduced bacterial translocation. Forty male Sprague Dawley (SD) rats were randomly divided into three groups, with 8 rats in the sham operation (SO) group, 18 rats in the SAP group and 14 SAP rats in the melatonin treatment (MT) group. SAP was induced by retrograde injection of 4% taurocholate into the biliopancreatic duct. Melatonin was administered 30 min prior to taurocholate injection in the melatonin-treated rats. All rats were sacrificed 24 h subsequent to pancreatitis induction. Real-time fluorescence quantitative polymerase chain reaction was used to detect and quantify Escherichia coli (E. coli) O157 in postcava blood. The microvilli structure was also analyzed with transmission electron microscopy. The level of E. coli DNA in the MT group was significantly lower than in rats in the SAP group. No E. coli DNA was detected in the control group. Villus height and crypt depth in the ileum were significantly higher in the MT and control groups compared to the SAP group, and were significantly higher in the MT group than in the SAP group. These results suggested that melatonin prevented gut barrier dysfunction and reduced bacterial translocation, resulting in reduced pancreatic-associated infections and decreased early mortality rates.

The aim of the present study was to investigate the protective mechanism underlying of melatonin in severe acute pancreatitis (SAP). A total of 64 male Sprague‑Dawley rats were randomly divided into four groups: The sham operation (SO) group, SAP group, melatonin treatment (MLT) group and p38 inhibitor (SB203580) treatment (SB) group. Acute pancreatitis was induced by 5% taurocholate through retrograde infusion into the biliopancreatic ducts. The melatonin and SB203580 treatment groups were administered with MLT and SB 30 min before operation the induction of SAP. Rats in each group were euthanized at 6 and 12 h following SAP induction. Blood and pancreatic tissues were removed for inflammatory examination. Peripheral blood mononuclear cells (PBMCs) were isolated following sacrifice to measure the phosphorylation of p38 and nuclear factor‑κB (NF‑κB was measured as p65 and phosphorylation of p65). The pretreatment of melatonin significantly attenuated the severity of pancreatitis. In addition, melatonin also reduced serum amylase and proinflammatory cytokine levels, including tumor necrosis factor‑α, interleukin (IL)‑1 and IL‑6. The mean pathological scores for pancreatic tissues in the MLT group were higher than those for samples in the SO group, but were lower than those for samples in the SAP group at each time-point. Phosphorylation of p38 and p65 levels in the melatonin treatment group were lower than that in the SAP group, and higher in the SAP group than in the SO group, and the SB203580 treatment group. Furthermore, melatonin significantly inhibited the activation of p38 and NF‑κB in PBMCs. The authors revealed that melatonin may attenuate inflammatory reactions by inhibiting the activation of p38 MAPK and NF‑κB in both acute pancreatitis rats and PBMCs. SAP is a severe disease with a high risk of morbidity and mortality. It is important to attenuated inflammatory reaction in acute pancreatitis. Thus, the authors studied melatonin, which is synthesized by the pineal gland and released into the blood. Previous studies have shown that melatonin serves a protective role in the early course of human acute pancreatitis, and melatonin concentration variations are closely related to the severity of acute pancreatitis. It may be concluded that melatonin may attenuates inflammatory reactions by inhibiting the activation of p38 MAPK and NF‑κB in both acute pancreatitis rats and PBMCs.

Magnetic resonance (MR) contrast agents focusing on special functions are required to improve cancer diagnosis, particularly in the early stages. Here, we designed multifunctional solid lipid nanoparticles (SLNs) with simultaneous loading of gadolinium (Gd) diethylenetriaminepentaacetic acid (Gd-DTPA) and octadecylamine fluorescein isothiocyanate (FITC) to obtain Gd-FITC-SLNs as a tumor-absorbable nanoparticle contrast agent for the histological confirmation of MR imaging (MRI) findings. Colorectal tumors were evaluated in vitro and in vivo via direct uptake of this contrast agent, which displayed reasonable T1 relaxivity and no significant cytotoxicity at the experimental concentrations in human colon carcinoma cells (HT29) and mouse colon carcinoma cells (CT26). In vitro cell uptake experiments demonstrated that contrast agent absorption by the two types of cancer cells was concentration-dependent in the safe concentration range. During in vivo MRI, transrectal infusion of Gd-FITC-SLNs showed more significant enhancement at the tumor site compared with the infusion of Gd-DTPA in female C57/BL mice with azoxymethane/dextran sulfate sodium-induced colorectal highgrade intraepithelial neoplasia. Subsequent confocal fluorescence microscopy demonstrated Gd-FITC-SLNs as highly concentrated green fluorescent spots distributed from the tumor capsule into the tumor. This study establishes the "proof-of-principle" of a new MRI technique wherein colorectal tumors are enhanced via direct absorption or uptake of the nanoparticle contrast agent.

Anastomotic complications such as leakage and bleeding remain among the most serious complications of laparoscopic colorectal surgery. No perfect method exists for accurate and reliable avoidance of these catastrophes. This study aimed to study the usefulness of routine intraoperative endoscopy (RIOE) by comparing the surgical outcomes for RIOE patients with those for selective intraoperative endoscopy (SIOE) patients. A retrospective chart review was performed for consecutive patients who underwent elective laparoscopic colorectal resections with distal anastomosis between January 2004 and May 2007. One surgeon performed RIOE, whereas the other three surgeons performed SIOE as necessary. All the abnormalities of IOE patients were managed with a subsequent salvage procedure, and the postoperative outcomes were compared between the RIOE and SIOE groups. The study included 107 patients in the RIOE group and 137 patients in the SIOE group. Abnormalities were detected in 11 RIOE patients (10.3%) (six with staple line bleeding, three with positive air leak test results, and two with additional pathology identified). All but one abnormality was laparoscopically managed without conversion to laparotomy. Whereas one patient experienced postoperative staple line bleeding that required a second operation, the remaining 10 patients recovered uneventfully. The mean hospital stay was 6 days (range, 4–9) days. The RIOE group had overall rates of 0% for anastomotic leakage and 0.9% for staple line bleeding. Intraoperative endoscopies were performed for 30 (21.9%) of the 137 patients in the SIOE group. The postoperative outcomes comparison between the RIOE and SIOE groups showed a tendency toward more overall anastomotic complications (0.9% vs. 5.1%) in the SIOE group, which due to the small sample size did not translate into significant differences in terms of staple line bleeding and anastomotic leakage. There also were no significant differences in other outcomes such as ileus, abdominal or pelvic sepsis, reoperation, positive distal margin, distance from distal margins, length of hospital stay, or mortality. Routine IOE for patients undergoing elective laparoscopic colorectal surgery with distal anastomosis can detect abnormalities at or around the anastomosis. Although the RIOE group had fewer postoperative anastomotic complications, due to the small sample size, the 5.7-fold increase in anastomotic failure did not translate into significantly better postoperative outcomes than the SIOE group experienced. A larger-scale single or multicenter prospective randomized study or a metaanalysis including similar studies is necessary for further investigation of this issue.

AIM To explore the association between Helicobacter pylori (H. pylori) infection status, intestinal metaplasia (IM), and colorectal adenomas. METHODS We retrospectively reviewed 1641 individuals aged ≥ 40 years who underwent physical examination, laboratory testing, 13C-urea breath testing, gastroscopy, colonoscopy, and an interview to ascertain baseline characteristics and general state of health. Histopathological results were obtained by gastric and colorectal biopsies. RESULTS The prevalence of H. pylori infection and adenomas was 51.5% (845/1641) and 18.1% (297/1641), respectively. H. pylori infection was significantly correlated with an increased risk of colorectal adenomas (crude OR = 1.535, 95%CI: 1.044-1.753, P = 0.022; adjusted OR = 1.359, 95%CI: 1.035-1.785, P = 0.028). Individuals with IM had an elevated risk of colorectal adenomas (crude OR = 1.664, 95%CI: 1.216-2.277, P = 0.001; adjusted OR = 1.381, 95%CI: 0.998-1.929, P = 0.059). Stratification based on H. pylori infection stage and IM revealed that IM accompanied by H. pylori infection was significantly associated with an increased risk of adenomas (crude OR = 2.109, 95%CI: 1.383-3.216, P = 0.001; adjusted OR = 1.765, 95%CI: 1.130-2.757, P = 0.012). CONCLUSION H. pylori-related IM is associated with a high risk of colorectal adenomas in Chinese individuals.

Background Glucose-insulin-potassium (GIK) has been advocated in the setting of acute coronary syndrome (ACS) to reduce ischemia-related arrhythmias and myocardial injury. We conducted a meta-analysis of randomized controlled trials (RCTs) to assess whether the use of GIK infusions >3 or 3 hours after the onset of symptoms, on mortality and/or cardiac arrest. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated for each outcome. Results Nine trials were identified and eligible for review. The summary OR for in-hospital mortality was 1.01 (95% CI 0.94 to 1.09), based on 2,542 deaths among 27,294 patients. The subgroup analysis according to the study enrollment time (within 3 hours [OR, 0.77, 95% CI 0.50-1.16], vs. >3 hours [OR, 0.90; 95% CI, 0.67-1.21]) did not reveal any difference in mortality. Conclusions Administration of GIK in ACS patients does not significantly reduce mortality whether or not GIK administration >3 or

Background Ovarian hyper stimulation syndrome (OHSS) is an iatrogenic complication associated with fertility drugs. It is characterized by increased vascular permeability and substantial fluid shift with accumulation in the body cavity. The pathogenesis of OHSS remains obscure, and no definitive treatments are currently available. Results Using western blot and short-circuit current (Isc) techniques, we investigate the potential coactions of analysis in cystic fibrosis transmembrane conductance regulator (CFTR) and aquaporin 1 (AQP1) on the hyper permeability of body cavity peritoneal epithelial cells in the pathogenesis of OHSS. The rats develop OHSS symptoms, with the up regulation of both CFTR and AQP1 expression and enhanced CFTR channel activity in peritoneal epithelial cells, can also be mimicked by administration of estrogen, alone in ovariectomized rats. Administration of progesterone suppresses CFTR activity, OHSS symptoms as well as CFTR and AQP1 expression. Besides, AQP1 inhibitor, HgCl2, can suppress CFTR channel activity. Therefore, antisera against CFTR or AQP1 to OHSS animals may result in alleviation of the symptom. Conclusion This study confirms the coactions of CFTR and AQP1 play a critical role in the development and progression of increased peritoneal epithelial permeability in severe OHSS. These findings may provide grounds for ameliorating assisted reproduction treatment strategy to reduce the risk of OHSS in in vitro fertilization (IVF).

Cytochrome P450 2S1 (CYP2S1) is a drug-metabolizing enzyme that shows interindividual variations in response to treatments for psoriasis and is regarded as a putative prognostic marker for colorectal cancer treatment. To gain insight into the genetic basis for the interindividual variations, CYP2S1 gene polymorphisms were analyzed in Korean subjects. Using direct sequencing of the CYP2S1 gene, 12 genetic variations, which included the two novel nonsynonymous mutations CYP2S1 S61N (0.3%) and CYP2S1 L230R (0.8%), were identified in 50 Korean subjects. Homology modeling predicted the location of the L230R change to be near two conserved alpha-helices in the hood of the substrate-binding site. Linkage disequilibrium (LD) analysis with seven common CYP2S1 variations showed two discrete LD blocks in CYP2S1 gene and consequently a limited number of haplotypes. Although the importance of novel CYP2S1 variants and haplotypes remains to be discovered, CYP2S1 polymorphisms would provide useful information on interindividual variations with respect to CYP2S1 function, which facilitates drug response predictions and disease prognosis.

BACKGROUND: With the rapid development of real-time elastography (RTE), a variety of measuring methods have been developed for the assessment of hepatic fibrosis. We evaluated the overall performance of four methods based on RTE by performing meta-analysis of published literature. METHODS: Online journal databases and a manual search from April 2000 to April 2014 were used. Studies from different databases that meet inclusion criteria were enrolled. The statistical analysis was performed using a random-effects model and fixed-effects model for the overall effectiveness of RTE. The area under the receiver operating characteristic curve (AUROC) was calculated for various means. Fagan plot analysis was used to estimate the clinical utility of RTE, and the heterogeneity of the studies was explored with meta-regression analysis. RESULTS: Thirteen studies from published articles were enrolled and analyzed. The combined AUROC of the liver fibrosis index (LFI) for the evaluation of significant fibrosis (F≥2), advanced fibrosis (F≥3), and cirrhosis (F = 4) were 0.79, 0.94, and 0.85, respectively. The AUROC of the elasticity index (EI) ranged from 0.75 to 0.92 for F≥2 and 0.66 to 0.85 for F = 4. The overall AUROC of the elastic ratio of the liver for the intrahepatic venous vessels were 0.94, 0.93, and 0.96, respectively. The AUROC of the elastic ratio of the liver for the intercostal muscle in diagnosing advanced fibrosis and cirrhosis were 0.96 and 0.92, respectively. There was significant heterogeneity in the diagnostic odds ratio (DOR) for F≥2 of LFI mainly due to etiology (p

AIM: To assess the value of plasma melatonin in predicting acute pancreatitis when combined with the acute physiology and chronic health evaluation II (APACHEII) and bedside index for severity in acute pancreatitis (BISAP) scoring systems. METHODS: APACHEII and BISAP scores were calculated for 55 patients with acute physiology (AP) in the first 24 h of admission to the hospital. Additionally, morning (6:00 AM) serum melatonin concentrations were measured on the first day after admission. According to the diagnosis and treatment guidelines for acute pancreatitis in China, 42 patients suffered mild AP (MAP). The other 13 patients developed severe AP (SAP). A total of 45 healthy volunteers were used in this study as controls. The ability of melatonin and the APACHEII and BISAP scoring systems to predict SAP was evaluated using a receiver operating characteristic (ROC) curve. The optimal melatonin cutoff concentration for SAP patients, based on the ROC curve, was used to classify the patients into either a high concentration group (34 cases) or a low concentration group (21 cases). Differences in the incidence of high scores, according to the APACHEII and BISAP scoring systems, were compared between the two groups. RESULTS: The MAP patients had increased melatonin levels compared to the SAP (38.34 ng/L vs 26.77 ng/L) (P = 0.021) and control patients (38.34 ng/L vs 30.73 ng/L) (P = 0.003). There was no significant difference inmelatoninconcentrations between the SAP group and the control group. The accuracy of determining SAP based on the melatonin level, the APACHEII score and the BISAP score was 0.758, 0.872, and 0.906, respectively, according to the ROC curve. A melatonin concentration ≤ 28.74 ng/L was associated with an increased risk of developing SAP. The incidence of high scores (≥ 3) using the BISAP system was significantly higher in patients with low melatonin concentration (≤ 28.74 ng/L) compared to patients with high melatonin concentration (> 28.74 ng/L) (42.9% vs 14.7%, P = 0.02). The incidence of high APACHEII scores (≥ 10) between the two groups was not significantly different. CONCLUSION: The melatonin concentration is closely related to the severity of AP and the BISAP score. Therefore, we can evaluate the severity of disease by measuring the levels of serum melatonin.

To investigate whether therapeutic treatment with melatonin could protect rats against acute pancreatitis and its associated lung injury.Seventy-two male Sprague-Dawley rats were randomly divided into three groups: the sham operation (SO), severe acute pancreatitis (SAP), and melatonin treatment (MT) groups. Acute pancreatitis was induced by infusion of 1 mL/kg of sodium taurocholate (4% solution) into the biliopancreatic duct. Melatonin (50 mg/kg) was administered 30 min before pancreatitis was induced, and the severity of pancreatic and pulmonary injuries was evaluated 1, 4 and 8 h after induction. Serum samples were collected to measure amylase activities, and lung tissues were removed to measure levels of mRNAs encoding interleukin 22 (IL-22) and T helper cell 22 (Th22), as well as levels of IL-22.At each time point, levels of mRNAs encoding IL-22 and Th22 were significantly higher (P0.001) in the MT group than in the SAP group (0.526 ± 0.143 vs 0.156 ± 0.027, respectively, here and throughout, after 1 h; 0.489 ± 0.150 vs 0.113 ± 0.014 after 4 h; 0.524 ± 0.168 vs 0.069 ± 0.013 after 8 h, 0.378 ± 0.134 vs 0.122 ± 0.015 after 1 h; 0.205 ± 0.041 vs 0.076 ± 0.019 after 4 h; 0.302 ± 0.108 vs 0.045 ± 0.013 after 8 h, respectively) and significantly lower (P0.001) in the SAP group than in the SO group (0.156 ± 0.027 vs 1.000 ± 0.010 after 1 h; 0.113 ± 0.014 vs 1.041 ± 0.235 after 4 h; 0.069 ± 0.013 vs 1.110 ± 0.213 after 8 h, 0.122 ± 0.015 vs 1.000 ± 0.188 after 1 h; 0.076 ± 0.019 vs 0.899 ± 0.125 after 4 h; 0.045 ± 0.013 vs 0.991 ± 0.222 after 8 h, respectively). The mean pathological scores for pancreatic tissues in the MT group were significantly higher (P0.01) than those for samples in the SO group (1.088 ± 0.187 vs 0.488 ± 0.183 after 1 h; 2.450 ± 0.212 vs 0.469 ± 0.242 after 4 h; 4.994 ± 0.184 vs 0.513 ± 0.210 after 8 h), but were significantly lower (P0.01) than those for samples in the SAP group at each time point (1.088 ± 0.187 vs 1.969 ± 0.290 after 1 h; 2.450 ± 0.212 vs 3.344 ± 0.386 after 4 h; 4.994 ± 0.184 vs 6.981 ± 0.301 after 8 h). The severity of SAP increased significantly (P0.01) over time in the SAP group (1.088 ± 0.187 vs 2.450 ± 0.212 between 1 h and 4 h after inducing pancreatitis; and 2.450 ± 0.212 vs 4.994 ± 0.184 between 4 and 8 h after inducing pancreatitis).Melatonin protects rats against acute pancreatitis-associated lung injury, probably through the upregulation of IL-22 and Th22, which increases the innate immunity of tissue cells and enhances their regeneration.

Background: With high morbidity, mortality and disability rate, brain infarction brings a huge economic and health burden to the whole society in China. Although some previous studies suggested that telerehabilitation may facilitate rehabilitation for stroke survivors at home, the evidence is insufficient for clinical application; additionally, as yet no trial evaluates efficacy of telerehabilitation for brain infarction patients. Therefore, more high quality trials are needed to provide practice evidence for this novel rehabilitation strategy. Methods/Design: Based on recruitment criteria, this assessor blinded, paralleled randomized controlled trial will recruit 210 brain infarction patients. After being randomly allocated into two groups, participants will receive home-based tele-supervising rehabilitation or conventional rehabilitation. Outcome measurement will be conducted at the end of intervention and 90-day follow-up. Among which, Barthel index assessment will be considered as primary outcome measurement, secondary outcome measurements include NIHSS score, mRS score, 3-oz water swallow test and surface electromyography. Adverse events will also be recorded during the whole process of the trial for safety assessment. Discussion: The HTRBIP trial will evaluate efficacy and safety of home-based tele-supervising rehabilitation for brain infarction patients. It is expected to provide new evidence for telerehabilitation application. Trial registration: Registration date: 17 September 2014; Registration number: ChiCTR-TRC-14005233