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Tre2-Bub2-Cdc16 (TBC) proteins are conserved in eukaryotic organisms and function as negative feedback dominating the GAPs for Rab GTPases, while the function of TBC proteins in melanoma remains unclear. In this study, we observed the differential expression of 33 TBC genes in TCGA datasets classified by clinical features. Seven prognostic-associated TBC genes were identified by LASSO Cox regression analysis. Mutation analysis revealed distinctive frequency alteration in the seven prognostic-associated TBCs between cases with high and low scores. High-risk score and cluster 1 based on LASSO Cox regression and consensus clustering analysis were relevant to clinical features and unfavorable prognosis. GSVA analysis showed that prognostic-associated TBCs were related to metabolism and protein transport signaling pathway. Correlation analysis indicated the relationship between the prognostic-associated TBCs with RAB family members, invasion-related genes and immune cells. The prognostic nomogram model was well established to predict survival in melanoma. What’s more, interference of one of the seven TBC proteins TBC1D7 was confirmed to inhibit the proliferation, migration and invasion of melanoma cells in vitro. In summary, we preliminarily investigated the impact of TBCs on melanoma through multiple bioinformatics analysis and experimental validation, which is helpful for clarifying the mechanism of melanoma and the development of anti-tumor drugs.

Background Lower-grade gliomas (LGGs) is characteristic with great difference in prognosis. Due to limited prognostic biomarkers, it is urgent to identify more molecular markers to provide a more objective and accurate tumor classification system for LGGs. Methods In the current study, we performed an integrated analysis of gene expression data and genome-wide methylation data to determine novel prognostic genes and methylation sites in LGGs. Results To determine genes that differentially expressed between 44 short-term survivors (

Circular RNAs (circRNAs), which act as initiators and promoters of various diseases, were thought to be mostly noncoding RNAs (ncRNAs) in eukaryotes, until recent studies confirmed that some circRNAs have the function of encoding proteins. Accumulating research findings have proved that dysregulation of circRNAs is associated with the developmental process of multiple cancers. circHIPK3, an example of circRNA, is frequently expressed in many diseases, such as diabetes, age-related cataract, idiopathic pulmonary fibrosis, preeclampsia, osteoblasts, and retinal vascular dysfunction, leading to disease development and progression. In addition, circHIPK3 may also serve as a potential biomarker, to help us know more about the rules of occurrence and development of cancers. In recent studies, many circHIPK3-related cancers have been identified, including nasopharyngeal carcinoma, gallbladder cancer, lung cancer, hepatocellular carcinoma, osteosarcoma, glioma, colorectal cancer, ovarian cancer, bladder cancer, prostate cancer, gastric cancer, oral squamous cell carcinoma, and chronic myeloid leukemia. This review summarizes recent studies on the biological mechanisms of circHIPK3 and expounds the molecular mechanisms of circHIPK3 in these malignant tumors.

Objective There is a close association between erectile dysfunction (ED) and cardiovascular disease (CVD). This study aimed to investigate Chinese physicians’ understanding of this association. Methods A total of 651 physicians, including 245 cardiologists and 406 urologists, participated in our investigation through WeChat. Results Participants with more professional experience, a doctoral/postdoctoral degree, and an intermediate/senior title were significantly more likely to be aware of a close association between ED and CVD. Urologists had a significantly better understanding of the association of severity between both diseases, showed more positive attitudes towards phosphodiesterase type 5 inhibitor application in patients with CVD and systematic treatment, and gave greater consideration to both diseases during follow-up visits than did cardiologists. Men had a significantly better understanding of the associated severity of the two disorders and managed the two diseases together more actively than did women. Department, sex, professional experience, education, and affiliated hospital level significantly affected systematic management of ED and CVD. Conclusion Most physicians from cardiology and urology are aware of the association between ED and CVD, but this awareness may be insufficient. Department, sex, professional experience, education background, and professional title are significant factors associated with perception of this association.

Abstract Robot hands have been developing during the last few decades. There are many mechanical structures and analytical methods for different hands. But many tough problems still limit robot hands to apply in homelike environment. The ability of grasping objects covering a large range of sizes and various shapes is fundamental for a home service robot to serve people better. In this paper, a new grasping mode based on a novel sucked-type underactuated (STU) hand is proposed. By combining the flexibility of soft material and the effect of suction cups, the STU hand can grasp objects with a wide range of sizes, shapes and materials. Moreover, the new grasping mode is suitable for some situations where the force closure is failure. In this paper, we deduce the effective range of sizes of objects which our hand using the new grasping mode can grasp. Thanks to the new grasping mode, the ratio of grasping size between the biggest object and the smallest is beyond 40, which makes it possible for our robot hand to grasp diverse objects in our daily life. For example, the STU hand can grasp a soccer (220 mm diameter, 420 g) and a fountain pen (9 mm diameter, 9 g). What’s more, we use the rigid body equilibrium conditions to analysis the force condition. Experiment evaluates the high load capacity, stability of the new grasping mode and displays the versatility of the STU hand. The STU hand has a wide range of applications especially in unstructured environment.

Background/Aims: Cholestasis is characterized by intrahepatic accumulation of cytotoxic bile acids (BAs), ultimately leading to fibrosis and cirrhosis, but the precise role of BAs in cholestasis-induced liver fibrosis remains largely elusive. In this study, we investigated the role and the potential mechanisms of BAs during cholestasis in vivo and in vitro. Methods: The effect of BAs during cholestasis was studied in bile duct ligation (BDL) rat models in vivo. We performed immunohistochemistry, Western blotting, and quantitative RT-PCR to investigate the expression of connective tissue growth factor (CTGF/CCN2) in rat liver during cholestasis. The hepatic cell lines AML12 and BRL were stimulated with taurocholate (TC) and the level of CTGF/CCN2, and activation of ERK, Akt, p38 MAPK, JNK, YAP, and TGF-β/Smad signaling were examined using Western blotting. Next, to elucidate the mechanism underlying bile acid-induced CTGF/CCN2, we treated the cells with MEK1/2 inhibitor (U0126), YAP function inhibitor (verteporfin), p38 kinase inhibitor (SB203580), Akt inhibitor (MK2206), and small interfering RNA (siRNA) targeting mek1, erk, and yap in cooperation with TC. Besides, we confirmed the activation of these signaling pathways in BDL and sham rat livers by immunohistochemistry, Western blotting, and quantitative RT-PCR. Results: In this study, we confirmed that the expression of CTGF/CCN2 was increased in BDL-induced rodent cholestatic liver fibrosis. In addition, we showed that TC, the main component of BAs, enhanced the synthesis of CTGF/ CCN2 in AML12 and BRL hepatic cell lines. Moreover, we demonstrated that TC activated ERK, Akt, and YAP signaling in hepatocytes, but the precise roles of these signaling cascades in the expression of CTGF/CCN2 were different: TC-induced expression of CTGF/CCN2 was mediated by ERK-YAP signaling, whereas Akt signaling inhibited ERK signaling and YAP and subsequently the expression of CTGF/CCN2 in hepatocytes. Furthermore, YAP functioned as a downstream regulator of ERK signaling in TC-induced CTGF/CCN2 expression in hepatocytes. Conclusion: Our report provides evidence for the role of conjugated BAs in liver fibrosis and suggests that the production of CTGF/CCN2, induced by conjugated BAs via ERK-YAP axis activation, may be a therapeutic target in cholestasis-induced liver fibrosis.

Abstract Background Posterior transfacet approach has been proved to be a safe and effective access to treat thoracic disc herniation. However, the therapeutic effect and safety of modified transfacet approach for treating thoracic spinal tuberculosis (TST) has not been reported in the clinical literature. In this study, the clinical efficacy and safety of a single-stage posterior modified transfacet debridement, posterior instrumentation, and interbody fusion for treating TST were retrospectively evaluated. Patients and methods From 2009 to 2014, 37 patients with TST underwent a posterior modified transfacet debridement, interbody fusion following posterior instrumentation, under the cover of 18 months of antituberculosis chemotherapy. The patients were evaluated preoperatively and postoperatively in terms of Frankel Grade, visual analog scale (VAS) pain score, kyphotic Cobb angle, and bony fusion. Results The follow-up time was 39.8 ± 5.1 months (29–50 months). No postoperative complication or recurrence of spinal tuberculosis was observed. Definitive bony fusion was achieved in all patients. At the final follow-up, 2 cases were rated as Frankel grade D, 35 as grade E. VAS was recovered from 8.4 ± 1.0 cm to 0.4 ± 0.8 cm. The kyphotic angles were corrected from 29.4 ± 10.9° to 17.6 ± 6.3°. Using the Kirkaldy-Willis criteria, functional outcome was excellent in 29 patients, good in 7, and fair in 1. Conclusions Our preliminary results showed that single-stage posterior modified transfacet debridement, posterior instrumentation, and interbody fusion are effective and safe surgical options for treating TST.

Objective To analyze the cases of medical disputes involving prenatal examination from a point of view of forensic expertise, and to discuss the risk of medical disputes and the preventive measures. Methods A retrospective analysis was conducted on 49 forensic expertise cases of medical disputes in prenatal examination which were identified in Academy of Forensic Science and Shanghai Di’an Forensic Science Limited Company from 2010 to 2017. Results In recent years, the number of medical disputes involving prenatal examination showed an increasing trend year by year. The common causes of medical disputes were: uninformed or insufficiently informed disclosure （20 cases）; the propaganda and application of three-dimensional, four-dimensional ultrasound were not standardized （14 cases）; ultrasound examination and serological screening process were not standardized （12 cases）; no antenatal counseling （2 cases）, etc. Conclusion In order to minimize the occurrence of such medical disputes, hospitals or related associations should avoid the risk of prenatal examination through the standardization of management and operation.

Abstract Background Synchronous primary cancers in gallbladder and liver are rarely reported. Here we report an unusual case of synchronous cancers of gallbladder carcinoma and combined hepatocellular cholangiocarcinoma. Case presentation Several lesions in the gallbladder and in adjacent parenchyma of liver were discovered in a 65-years-old woman by imaging examination. Surgical resection was performed following a diagnosis of primary gallbladder carcinoma with local hepatic metastasis. Histological examination confirmed the diagnosis of primary gallbladder carcinoma, and the lesions in the liver consisted of hepatocellular carcinoma simultaneously with cholangiocarcinoma. Adjuvant chemoradiation therapy was not performed due to the patient’s refusal of the treatment. Unfortunately, the patient died of widespread metastasis 8 months after the operation. Conclusions The disease needed to be differentially diagnosed from gallbladder carcinoma with hepatic metastasis. Aggressive surgical approach should be based on a balance between the risk of surgery (morbidity and mortality) and the outcome.

Abstract Background This study explored the effect of liver resection on perioperative circulating tumor cells (CTCs) and found that the prognostic significance of surgery was associated with changes in CTC counts in patients with hepatocellular carcinoma (HCC). Methods One hundred thirty-nine patients with HCC were consecutively enrolled. The time-points for collecting blood were one day before operation and three days after operation. CTCs in the peripheral blood were detected by the CellSearch™ System. Results Both CTC detection incidence and mean CTC counts showed greater increases postoperatively (54%, mean 1.54 cells) than preoperatively (43%, mean 1.13 cells). The postoperative CTC counts increased in 41.7% of patients, decreased in 25.2% of patients and did not change in 33.1% of patients. The increase in postoperative CTC counts was significantly associated with the macroscopic tumor thrombus status. Patients with increased postoperative CTC counts (from preoperative CTC

Abstract Backgrounds UDP-glucuronosyltransferase 1A subfamily (UGT1A) enzymes can inactivate cytarabine (Ara-C) by glucuronidation, and thus serves as candidate genes for interindividual difference in Ara-C response. UGT1A1 is a major UGT1A isoform expressed in human liver. Methods UGT1A1*6 and *28 polymorphisms resulting in reduced UGT1A1 activity were genotyped in 726 adult acute myeloid leukemia (AML) patients treated with Ara-C based regimens. Influences of both polymorphisms on chemosensitivity and disease prognosis of the patients were evaluated. Results After one or two courses of Ara-C based induction chemotherapy, the complete remission (CR) rate was significantly higher in patients carrying the UGT1A1*6 (77.0%) or the UGT1A1*28 (76.4%) alleles as compared with corresponding wild-type homozygotes (66.9 and 68.5%, respectively). Carriers of the UGT1A1*6 or *28 alleles showed significantly decreased risk of non-CR (OR = 0.528, 95% CI 0.379–0.737, P = 1.7 × 10−4) and better overall survival (HR = 0.787, 95% CI 0.627–0.990, P = 0.040) as compared with homozygotes for both polymorphisms. Conclusion Our results suggest that UGT1A1*28 and UGT1A1*6 are associated with improved clinical outcomes in Chinese AML patients treated with Ara-C.

Abstract Background Centenarians refer to a special group who have outlived most of their fellows. Body shape and abdominal obesity have been identified as cardiovascular disease (CVD) risk factors. Our study aimed to evaluate the relationship between body mass index (BMI), waist circumference (WC), waist-to-hip ratio (WHR), and waist-to-height ratio (WHtR) and CVD risk factors among male and female centenarians in Hainan province. Methods Five hundred thirty-seven centenarians aged between 100 and 115 (Mage = 107 years old) years participated in this study. Each participant received a standardized questionnaire and physical examination. We measured anthropometric variables (BMI, WC, WHR, WHtR, SBP and DBP) and serum lipid (TC, TG, HDL-C and LDL-C). Results 76.9% (n = 413) of the study subjects were female. TC, TG, LDL-C and HDL-C were significantly higher in female group than that of male group. BMI, WC and WHtR were well-correlated with the CVD risk factors. The anthropometric measures were negatively related with HDL-C levels and positively related with the other CVD risk factors. Conclusions Hainan centenarians were short in stature and underweight. Moreover, female centenarians were often pear-shaped, while male centenarians were often apple-shaped. Further, BMI, WC and WHtR were well-correlated with the serum lipid, and TC, TG, LDL-C and HDL-C were significantly higher in females than males. Also, BMI, WC and WHtR were closely related to the incidence of dyslipidemia in females, including high TG, high LDL-C and low HDL-C.

Background/Aims: In the current study, we performed an integrated analysis of genome-wide methylation and gene expression data to find novel prognostic genes for lower-grade gliomas (LGGs). Methods: First, TCGA methylation data were used to identify prognostic genes associated with promoter methylation. Second, candidate genes that were stably regulated by promoter methylation were explored. Third, Cox proportional hazards regression analysis was used to generate a prognostic signature, and the signature genes were used to construct a survival risk score system. Results: Three genes (EMP3, GSX2 and EMILIN3) were selected as signature genes. These three signature genes were used to construct a survival risk score system. The high-risk group exhibited significantly worse overall survival (OS) and relapse-free survival (RFS) as compared to the low-risk group in the TCGA dataset. The association of the three-gene prognostic signature with patient’ survival was then validated using the CGGA dataset. Moreover, Kaplan-Meier plots showed that the three-gene prognostic signature risk remarkably stratified grade II and grade III patients in terms of both OS and RFS in the TCGA cohort. There was also a significant difference between the low- and high-risk groups in IDH wild-type glioma patients, indicating that the three-gene signature may be able to help in predicting prognosis for patients with IDH wild-type gliomas. Conclusion: We identified and validated a three-gene (EMP3, GSX2 and EMILIN3) prognostic signature in LGGs by integrating multidimensional genomic data from the TCGA and CGGA datasets, which may help in fine-tuning the current histology-based tumors classification system and providing better stratification for future clinical trials.

Abstract Background Cytarabine arabinoside (Ara-C) has been the core of chemotherapy for adult acute myeloid leukemia (AML). Ara-C undergoes a three-step phosphorylation into the active metabolite Ara-C triphosphosphate (ara-CTP). Several enzymes are involved directly or indirectly in either the formation or detoxification of ara-CTP. Methods A total of 12 eQTL (expression Quantitative Trait Loci) single nucleotide polymorphisms (SNPs) or tag SNPs in 7 genes including CMPK1, NME1, NME2, RRM1, RRM2, SAMHD1 and E2F1 were genotyped in 361 Chinese non-M3 AML patients by using the Sequenom Massarray system. Association of the SNPs with complete remission (CR) rate after Ara-C based induction therapy, relapse-free survival (RFS) and overall survival (OS) were analyzed. Results Three SNPs were observed to be associated increased risk of chemoresistance indicated by CR rate (NME2 rs3744660, E2F1 rs3213150, and RRM2 rs1130609), among which two (rs3744660 and rs1130609) were eQTL. Combined genotypes based on E2F1 rs3213150 and RRM2 rs1130609 polymorphisms further increased the risk of non-CR. The SAMHD1 eQTL polymorphism rs6102991 showed decreased risk of non-CR marginally (P = 0.055). Three SNPs (NME1 rs3760468 and rs2302254, and NME2 rs3744660) were associated with worse RFS, and the RRM2 rs1130609 polymorphism was marginally associated with worse RFS (P = 0.085) and OS (P = 0.080). Three SNPs (NME1 rs3760468, NME2 rs3744660, and RRM1 rs183484) were associated with worse OS in AML patients. Conclusion Data from our study demonstrated that SNPs in Ara-C and dNTP metabolic pathway predict chemosensitivity and prognosis of AML patients in China.

Abstract Background Erythropoietin (EPO) is a hypoxia-inducible stimulator of erythropoiesis. Besides its traditional application in anemia therapy, it offers an effective treatment in the cancer patients, especially those who receive chemotherapy. Several reports indicated that it could promote the tumor cell proliferation through its specific receptor (EPOR). Unfortunately, the role of EPO/EPOR in hepatocellular carcinoma (HCC) progressing is still uncertain. Methods Protein in tumor tissue from HCC patients or H22 tumor-bearing mice was detected with immunohistochemistry. Cells were cultured under 1% oxygen to establish hypoxia. RT-PCR and western blotting were used to measure mRNA and protein of EPO/EPOR, respectively. MTT, flow cytometry and PCNA staining were used to detect cell proliferation. Immunofluorescence staining was applied to study the expression and location of cellular EPOR. The EPOR binding studies were performed with 125I-EPO radiolabeling assay. Results EPO and EPOR protein were up-regulated in HCC tissue of patients and H22-bearing mice. These were positively correlated with hypoxia-inducible factor -1 α and ki-67. Hypoxia up-regulated the expression of EPO and EPOR in HepG2 cells. It also induced the proliferation and increased the percentage of divided cells after 24, 48 and 72 h treatment. These were inhibited in cells pre-treated with 0.5 μg/mL soluble-EPOR. Immunofluorescence staining presented that EPOR was obviously translocated from nucleus to cytoplasm and membrane under hypoxia. EPOR binding activity was also increased after exposure to hypoxia. Recombinant human erythropoietin obviously elevated cell proliferation rate and the percentage of divided under hypoxia but not normoxia, which were also inhibited by soluble-EPOR. Conclusions Our result indicated for the first time that EPO promoted the proliferation of HCC cells through hypoxia induced translocation of it specific receptor. Trial registration TJC20141113, retrospectively registered

This study aimed to evaluate the effect of PRKCH rs2230500 genetic polymorphism on efficacy of amlodipine and telmisartan for patients with hypertension. A total of 136 essential hypertension (EH) patients were treated with amlodipine (70 patients) or telmisartan (66 patients), respectively. Genetic polymorphism was genotyped by Sanger sequencing. Both baseline and post-treatment blood pressure (BP) and heart rate were measured to evaluate the influence of genetic polymorphism on the antihypertensive response. No significant difference in the absolute decrease in diastolic blood pressure (DBP),systolic blood pressure (SBP), and mean arterial pressure (MAP) was observed among PRKCH rs2230500 genotypes after 4-week amlodipine or telmisartan therapy (p > 0.05). However, when compared with carriers or GG genotype, the antihypertensive effect of PRKCH rs2230500 GA/AA carriers was superior in telmisartan treatment group. PRKCH rs2230500 gene polymorphism is significantly related to the efficiency in telmisartan therapy (p = 0.02). The PRKCH rs2230500 may influence the antihypertensive efficacy of telmisartan in Chinese EH patients, and further studies are needed to confirm these findings.

Background/Aims: Acute myeloid leukemia (AML) is a heterogeneous clonal disease and patients with AML who harbor an FMS-like tyrosine kinase 3 (FLT3) mutation present several dilemmas for the clinician. This study aims to identify novel targets for explaining the dilemmas. Methods: We analyzed four microarray gene expression profiles to investigate changes in whole genome expression associated with FLT3-ITD mutation. Results: We identified 22 differentially expressed genes which are commonly expressed among all four profiles. Kaplan-Meier analysis of the dataset GSE12417 revealed that low expression of AHSP, EPB42, GYPC and HEMGN predicted poor prognosis (AHSP: P=0.0317, HR=1.894; EPB42: P=0.0382, HR=1.859; GYPC: P=0.0015, HR=2.051; HEMGN: P=0.0418, HR=1.838 in GSE12417 test cohort; AHSP: P=0.0279, HR=1.548; EPB42: P=0.0398, HR=1.505; GYPC: P=0.0408, HR=1.501; HEMGN: P=0.0143, HR=1.630 in GSE12417 validation cohort). When patients were FLT3-ITD positive, the expression of FLT3 was significantly increased (all P

Abstract Dysregulated long noncoding RNAs (lncRNAs) are potential markers of several tumor prognoses. This study aimed to develop a lncRNA expression signature that can predict chemotherapeutic sensitivity for patients with advanced stage and high-grade serous ovarian cancer (HGS-OvCa) treated with platinum-based chemotherapy. The lncRNA expression profiles of 258 HGS-OvCa patients from The Cancer Genome Atlas were analyzed. Results revealed that an eight-lncRNA signature was significantly associated with chemosensitivity in the multivariate logistic regression model, which can accurately predict the chemosensitivity of patients [Area under curve (AUC) = 0.83]. The association of a chemosensitivity predictor with molecular subtypes indicated the excellent prognosis performance of this marker in differentiated, mesenchymal, and immunoreactive subtypes (AUC > 0.8). The significant correlation between ZFAS1 expression and chemosensitivity was confirmed in 233 HGS-OvCa patients from the Gene Expression Omnibus datasets (GSE9891, GSE63885, and GSE51373). In vitro experiments demonstrated that the ZFAS1 expression was upregulated by cisplatin in A2008, HeyA8, and HeyC2 cell lines. This finding suggested that ZFAS1 may participate in platinum resistance. Therefore, the evaluation of the eight-lncRNA signature may be clinically implicated in the selection of platinum-resistant HGS-OvCa patients. The role of ZFAS1 in platinum resistance should be further investigated.

Small nucleolar RNAs (SnoRNAs) are a class of non-coding RNAs divided into two classes: C/D box snoRNAs and H/ACA box snoRNAs. The canonical function of C/D box and H/ACA box snoRNAs are 2'-O-ribose methylation and pseudouridylation of ribosomal RNAs (rRNAs), respectively. Emerging evidence has demonstrated that snoRNAs are involved in various physiological and pathological cellular processes. Mutations and aberrant expression of snoRNAs have been reported in cell transformation, tumorigenesis, and metastasis, indicating that snoRNAs may serve as biomarkers and/or therapeutic targets of cancer. Hence, further study of the functions and underlying mechanism of snoRNAs is valuable. In this review, we summarize the biogenesis and functions of snoRNAs, as well as the association of snoRNAs in different types of cancers and their potential roles in cancer diagnosis and therapy.

Objective: A large portion of non-metastatic colorectal cancers (non-mCRCs) recur after curative surgery. In addition to the traditional tumor-related factors, host-related factors are also required to accurately predict prognosis. A few studies have shown an association between the serum lipid profile and the survival and treatment response of patients with colorectal cancer. Methods: We retrospectively evaluated the prognostic significance of the preoperative serum lipid profile [total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C)] in patients with non-mCRC treated with curative surgery. The Spearman rank correlation test was used to analyze associations between lipid levels and categorical variables. Lipid levels were modeled as four equal-sized quartiles based on the distribution among the whole cohort. Kaplan-Meier curves were used to estimate survival probabilities, and the log-rank test was used to detect differences between them. Multivariate fractional polynomial (MFP) analysis was used to model any non-linear effects and avoid categorization. To evaluate the added prognostic value of lipids, the predictive power of two models (with and without lipids as covariates) was compared by using Harrell's C-statistic and the Akaike information criterion (AIC). Results: A total of 266 patients with non-mCRC were enrolled in the present study. Spearman rank correlation test showed that TGÂ levels inversely correlated with N stage (r = â0.20, PÂ =Â 0.00) and Tumor-Node-Metastasis (TNM) stage (r = â0.19, P = 0.00). HDL-C levels positively correlated with perineural invasion (PNI) (r = 0.15, PÂ = 0.02), and LDL-C levels inversely correlated with lymphovascular invasion (LVI) (r = â0.12, PÂ =Â 0.04). None of the four lipids predicted overall survival (OS) in univariate or multivariate analyses adjusted for age, gender, T stage, N stage, TNM stage, histological grade, tumor deposits, LVI, PNI, and adjuvant treatment (all P > 0.05). In agreement, the Kaplan-Meier curves for OS according to the lipid quartiles were not significantly different, as confirmed by the log-rank test (all P > 0.05). MFPÂ analysis also found no significant associations between lipid levels and OS (all P > 0.05). A prognostic model that included lipids had a higher Harrell's C-statistic and a lower AIC value than did a model that did not include lipids (for Harrell's C-statistic: 0.82 vs. 0.77; for AIC: 398 vs. 432). Conclusion: Measuring preoperative serum lipid levels may be a simple and cost-effective way of increasing prognostic accuracy in patients with non-mCRC treated with curative surgery. Keywords: Serum lipids, Colorectal cancer, Overall survival, Prognostic model

Background: Aldehyde dehydrogenase 2 (ALDH2) is involved in the pathophysiological processes of cardiovascular diseases. Recent studies showed that mutant ALDH2 could increase oxidative stress and is a susceptible factor for hypertension. In addition, wild-type ALDH2 could improve the endothelial functions, therefore reducing the risk of developing atherosclerosis. The aim of the present study was to explore the frequency of the Glu504Lys polymorphism of the ALDH2 gene and its relation to carotid intima-media thickness (CIMT) in a group of patients with essential hypertension (EH) and to investigate the association between the Glu504Lys polymorphism and CIMT in Chinese Han patients with EH. Methods: In this study, 410 Chinese Han patients with EH who received physical examinations at the People's Hospital of Sichuan Province (China) were selected. DNA microarray chip was used for the genotyping of the Glu504Lys polymorphism of the ALDH2 gene. The differences in CIMT among patients with different Glu504Lys ALDH2 genotypes were analyzed. Results: The mean CIMT of the patients carrying AA/AG and GG genotypes was 1.02 ± 0.31 mm and 0.78 ± 0.28 mm, respectively. One-way ANOVA showed that the CIMT of the patients carrying the AA/AG genotype was significantly higher than in the ones carrying the GG genotype (P < 0.001). Multivariate logistic regression showed that the Glu504Lys AA/AG genotype of the ALDH2 gene was one of the major factors influencing the CIMT in patients with EH (odds ratio = 3.731, 95% confidence interval = 1.589–8.124, P = 0.001). Conclusions: The Glu504Lys polymorphism of the ALDH2 gene is associated with the CIMT of Chinese Han patients with EH in Sichuan, China.

Background: G-protein β-polypeptide 3 (GNB3) is a β subunit isoform of G-protein that plays important role in signal transduction of membrane G-protein coupled receptors (GPCRs). The GNB3 splice variant C825T (rs5443) is associated with risk for essential hypertension (EH) and efficacy of therapeutic drugs targeting GPCRs. It is unknown whether the polymorphism is associated with blood pressure (BP) response to telmisartan or amlodipine, two widely prescribed antihypertensive drugs. Methods: A total of 93 subjects initially diagnosed as EH were recruited and underwent a 4-week treatment with telmisartan (42 patients) or amlodipine (51 patients) monotherapy. Both baseline and after-treatment BP were measured. GNB3 C825T polymorphism was genotyped by polymerase chain reaction-restriction fragment length polymorphism. Results: Baseline systolic BP (SBP) and diastolic BP (DBP) were comparable among C825T genotypes in both telmisartan and amlodipine treatment groups. Patients with the CT or TT genotypes showed significantly lower body mass index (BMI) as compared with CC homozygotes in both groups (P < 0.05, respectively). GNB3 825TT homozygotes showed significantly higher after-treatment DBP and mean arterial pressure (MAP) than those carrying at least one 825C allele (P < 0.01) in the telmisartan treatment group. No difference in after-treatment SBP, DBP, and MAP levels among C825T genotypes was observed in the amlodipine treatment group. No significant difference in absolute changes in BP levels was observed among the genotypes in either treatment group. Conclusion: The GNB3 C825T splice variant is associated with the DBP-lowering effect of telmisartan but not amlodipine in Chinese EH patients.

Dual antiplatelet treatment with aspirin and clopidogrel is the standard therapy for patients undergoing percutaneous coronary intervention (PCI). However, a portion of patients suffer from clopidogrel resistance (CR) and consequently with recurrence of cardiovascular events. Genetic factors such as loss-of-function variants of CYP2C19 contribute a lot to CR. Recently, the N-6-adenine-specific DNA methyltransferase 1 (N6AMT1) rs2254638 polymorphism is reported to be associated with clopidogrel response. To validate the association between N6AMT1 rs2254638 polymorphism and clopidogrel response, 435 Chinese CAD patients receiving aspirin and clopidogrel were recruited. N6AMT1 rs2254638 and CYP2C19*2/*3 polymorphisms were genotyped. Platelet reaction index (PRI) was measured by VASP-phosphorylation assay after treated with a 300 mg loading dose (LD) clopidogrel or 75 mg daily maintenance dose (MD) clopidogrel for at least 5 days. There was a significant difference in PRI between LD cohort and MD cohort. Carriers of CYP2C19*2 allele showed significantly increased PRI in the entire cohort and in respective of the MD and LD cohorts (p < 0.001, p = 0.003, p < 0.001, respectively). However, carriers of CYP2C19*3 allele exhibited significantly higher PRI only in the entire cohort and LD cohort (p = 0.023, p = 0.023 respectively). PRI value was significantly higher in CYP2C19 PM genotyped patients as compared with those carrying the IM genotypes and EM genotype (p < 0.001). Besides, carriers of the rs2254638 C allele showed significantly higher PRI in entire cohort and in the LD cohort (p = 0.023, p = 0.008, respectively). When the patients were grouped into clopidogrel resistance (CR) and non-clopidogrel resistance (non-CR) groups, CYP2C19*2 was associated with increased risk of CR in the entire cohort, the LD cohort and the MD cohort (p < 0.001, p < 0.001, and p = 0.019, respectively). Carriers of the rs2254638 C allele also showed increased risk of CR in the entire cohort and the LD cohort (p = 0.024, and p = 0.028, respectively). N6AMT1 rs2254638 remained as a strong predictor for CR (TC vs. TT: OR = 1.880, 95% CI = 1.099–3.216,p = 0.021; CC vs. TT: OR = 1.930, 95% CI = 1.056-3.527, p = 0.032; TC + CC vs. TT: OR = 1.846, 95%CI = 1.126–3.026, p = 0.015) after adjustment for confounding factors. Our study confirmed the influence of CYP2C19*2 and rs2254638 polymorphisms on clopidogrel resistance in Chinese CAD patients. Both CYP2C19*2 and N6AMT1 rs2254638 polymorphism may serve as independent biomarkers to predict CR.

Rapamycin (sirolimus) is a mTOR kinase inhibitor and is widely used as an immunosuppressive drug to prevent graft rejection in organ transplantation currently. However, some recent investigations have reported that it had profibrotic effect in the progression of organ fibrosis, and its precise role in the liver fibrosis is still poorly understood. Here we showed that rapamycin upregulated connective tissue growth factor (CTGF) expression at the transcriptional level in hepatic progenitor cells (HPCs). Using lentivirus-mediated small hairpin RNA (shRNA) we demonstrated that knockdown of mTOR, Raptor, or Rictor mimicked the effect of rapamycin treatment. Mechanistically, inhibition of mTOR activity with rapamycin resulted in a hyperactive PI3K-Akt pathway, whereas this activation inhibited the expression of CTGF in HPCs. Besides, rapamycin activated the TGF-β-Smad signaling, and TGF-β receptor type I (TGFβRI) serine/threonine kinase inhibitors completely blocked the effects of rapamycin on HPCs. Moreover, Smad2 was involved in the induction of CTGF through rapamycin-activated TGF-β-Smad signaling as knockdown completely blocked CTGF induction, while knockdown of Smad4 expression partially inhibited induction, whereas Smad3 knockdown had no effect. Rapamycin also induced ROS generation and latent TGF-β activation which contributed to TGF-β-Smad signaling. In conclusion, this study demonstrates that rapamycin upregulates CTGF in HPCs and suggests that rapamycin has potential fibrotic effect in liver.

In the original publication of this article [1], Fig. 6 is wrong and the updated figure is shown below.

Objective(s): Angiotensin Ⅱ type 1 receptor blockers (ARBs) represent one of the widely used antihypertensive agents. In addition to anti-hypertension effect, some ARBs also show other molecular effects such as activating peroxisome proliferator-activated receptor-γ and so on. Here we studied the effects of telmisartan on the rat isolated mesenteric artery rings pre-contracted by phenylephrine (PE). Materials and Methods:Rat mesenteric artery rings were pre-contracted with 10 μM PE, and cumulative concentration-response curves to telmisartan were obtained. The endothelium-dependent mechanisms were investigated by mechanical removal of the endothelium. K+ channels were investigated by pretreatment of the artery rings with various K+ channel blockers. Results:Telmisartan produced concentration-dependent relaxation of the artery rings pre-contracted by 10 μM PE. Denudation of the endothelium did not affect the relaxant effect of telmisartan. Pretreatment with BaCl2 nearly inhibited the relaxation induced by the 0.5, 1, 5 and 10 μM telmisartan, but did not affect the relaxation induced by the 50 and 100 μM telmisartan. While the relaxation induced by telmisartan was not affected by pretreatment with TEA, 4-AP and glibenclamide. Conclusion:These findings demonstrated that telmisartan produces concentration dependent vasodilation in isolated rat mesenteric artery rings with or without endothelium pre-contracted by PE. KIR channel may be involved in such a relaxant effect of telmisartan.

Abstract Background It has been well accepted that glycans present in schistosomes are highly antigenic. However, it is not clear what kind of worm glycans can affect the infected host to mount IgG responses and whether mounted anti-glycan IgG responses are protective. Methods The contribution of antigenicity by glycans was measured by using competitive ELISA assay in sera from infected mice and humans. Monoclonal antibodies towards soluble Schistosoma japonicum egg antigens (SjEA) were generated from SjEA immunizated mice. The expression of glycans on surfaces of cercaria or young worm and their distributions were examined by immunofluorescence assay. The protective roles of glycans-specific mAbs were assayed by determination of the worm and egg burden in infected mice. Results Both periodate-resistant glycans and periodate-sensitive glycans are antigenic in schistosome infections. When monoclonal antibodies against either periodate-sensitive or periodate-resistant glycans were administered prior to schistosome infections in mice, both kinds of anti-glycan antibodies were found to successfully provide protective immunity to infected mice. Conclusions Both periodate-resistant and periodate-sensitive glycans are antigenic, and dominant anti-glycan IgG responses can play important roles in protective immunity in schistosome infected hosts.