Background Individual lead or cadmium exposure can cause abnormal blood glucose level and changes in telomere length, and the role of telomere length in the relationship between heavy metal joint exposure and blood glucose level is still unclear. Objective To explore the role of telomere length in the relationship between lead and cadmium coexposure and blood glucose. Methods A cross-sectional study was conducted. By convenient sampling method, 600 residents living in two communities in a city in North China were selected as participants from April to June 2016. Face-to-face interviews were performed to collect general demographics and lifestyles of the participants. The peripheral blood samples of the participants were collected for blood glucose and telomere length detection, the urine samples were collected for urinary cadmium, urinary lead, and urinary creatinine measurement, and both urinary cadmium and urinary lead were corrected by urinary creatinine. The included participants were divided into a control group, a high-cadmium and low-lead group, a high-lead and low-cadmium group, and a high-lead and high-cadmium group, according to the median levels of urinary cadmium and urinary lead. A restricted cubic spline model was constructed to analyze the relationship between urinary lead/cadmium levels and blood glucose concentrations in the four groups and the relationship between cadmium exposure and telomere length in the high-lead and high-cadmium group. Intermediary model test was conducted to analyze the effect of telomere length on the relationship between exposures to lead and cadmium and blood glucose. Results The included participants were divided into the control group (n=99), the high-cadmium and low-lead group (n=91), the high-lead and low-cadmium group (n=145), and the high-lead and high-cadmium group (n=265). The differences in age, education level, per capita monthly household income, smoking, blood glucose, and telomere length were statistically significant among the four groups (P＜0.05). The high-lead and high-cadmium group had the highest blood glucose concentration, (5.63±1.68) mmol·L⁻¹, and the shortest telomere length, (2.63±1.05) Kb. The restricted cubic spline results showed that urinary cadmium level was correlated with blood glucose concentration in the high-lead and high-cadmium group (F=3.45, P=0.037), and there was a non-linear association (F=6.91, P=0.002); the association between urinary cadmium level and telomere length was also non-linear (F=5.93, P=0.043). The intermediary model test results showed that telomere length was a mediating variable between urinary cadmium level and blood glucose concentration, and the mediating effect size was 0.0192 (95%CI: 0.0007-0.0563), with a mediation ratio of 15.57%. Conclusion Correlations between urinary cadmium and blood glucose and between urinary cadmium and telomere length were observed in the high-lead and high-cadmium coexposure group, and telomere length may play a mediating role in the relationship between them.

Background Exposure to environmental lead can cause kidney damage and telomere wear. However, the relationship among lead, peripheral blood telomere length, and glomerular filtration rate (eGFR) are unclear. Objective This study is conducted to investigate the relationships of urinary lead level with peripheral blood telomere length and renal function index eGFR, and further explore whether peripheral blood telomere length plays an intermediary role in the relationship between urinary lead level and eGFR. Methods A case-control study was conducted to select 497 residents from two communities in a city, including 230 in the control group (eGFR≥80 mL·min⁻¹) and 267 in the abnormal eGFR group (eGFR<80 mL·min⁻¹). Basic information and health information of the subjects were collected through a face-to-face questionnaire survey. Fasting morning urine was collected, and urinary lead and urinary creatinine (UCr) were detected. Fasting peripheral venous blood was collected to detect telomere length and serum creatinine (SCr) in peripheral blood leukocytes. eGFR was estimated by the Levey formula. After further adjusting for age, gender, education level, family per capita monthly income, smoking, and drinking the relationship among urinary lead level, peripheral blood telomere length, and renal function index eGFR was evaluated by mediating effect analysis. Results The overall level of creatinine-adjusted urinary lead [M (P₂₅, P₇₅)] in the abnormal eGFR group was 3.85 (1.56, 7.34) μg·g⁻¹ which was higher than that in the control group, 1.57 (0.60, 3.62) μg·g⁻¹(P<0.001). In addition, the overall level of peripheral blood telomere length in the abnormal eGFR group was 2.42 (1.89, 3.10) Kb, lower than that in the control group, 2.69 (2.09, 3.64) Kb (P<0.001). The results of mediating effect analysis showed that the magnitude of mediating effect by peripheral blood telomere length was −0.276 (95%CI: −0.708-−0.001) and it contributed 3.35% to the relationship between urinary lead level and eGFR. In women, the magnitude of mediating effect by peripheral blood telomere length was −0.484 (95%CI: −1.160-−0.023) between urinary lead level and eGFR, and the proportion of the mediating effect was 5.34%. In men, no mediating role of peripheral blood telomere length was found between urinary lead and eGFR. Conclusion Urinary lead level is closely related to renal function index eGFR and telomere length in peripheral blood. Peripheral blood telomere length plays a mediating role in the relationship between female urinary lead and eGFR in women.

Transcriptional regulators (TRs) participate in essential processes in cancer pathogenesis and are critical therapeutic targets. Identification of drug response-related TRs from cell line-based compound screening data is often challenging due to low mRNA abundance of TRs, protein modifications, and other confounders (CFs). In this study, we developed a regression-based pharmacogenomic and ChIP-seq data integration method (RePhine) to infer the impact of TRs on drug response through integrative analyses of pharmacogenomic and ChIP-seq data. RePhine was evaluated in simulation and pharmacogenomic data and was applied to pan-cancer datasets with the goal of biological discovery. In simulation data with added noises or CFs and in pharmacogenomic data, RePhine demonstrated an improved performance in comparison with three commonly used methods (including Pearson correlation analysis, logistic regression model, and gene set enrichment analysis). Utilizing RePhine and Cancer Cell Line Encyclopedia data, we observed that RePhine-derived TR signatures could effectively cluster drugs with different mechanisms of action. RePhine predicted that loss-of-function of EZH2/PRC2 reduces cancer cell sensitivity toward the BRAF inhibitor PLX4720. Experimental validation confirmed that pharmacological EZH2 inhibition increases the resistance of cancer cells to PLX4720 treatment. Our results support that RePhine is a useful tool for inferring drug response-related TRs and for potential therapeutic applications. The source code for RePhine is freely available at https://github.com/coexps/RePhine.

In order to assess the thermal effect of different holmium laser fiber during lithotripsy with WOLF F4.5/6.5 pediatric ureteroscope, we established an impacted ureter calculi model. Under 100mmHg irrigation pressure, regional temperature of different holmium laser fiber with varied working time and power were recorded. We found that the regional temperature was related with laser fiber diameters, power and working time settings. With 550 μm laser fiber, laser firing time longer than 3 s or 365 μm laser fiber firing more than 6 s, regional temperature exceeded 42℃, which would bring thermal injury towards ureter and subsequently cause ureter stricture.

This study analyzed the current status of the cultivation process of professional postgraduates of clinical medicine, combining with the case of the auxiliary teaching model of Academic Salons on the WeChat platform in Xiangya Hospital of Central South University. We collected students' satisfaction evaluation of this auxiliary teaching model by questionnaire survey. Through analyzing the results and feedback, we found that the overall satisfaction of this auxiliary teaching model is 71.43%, and the model has a remarkable effect in broadening knowledge, inspiring thinking of clinical diagnosis and treatment, improving ability of scientific research, increasing learning interest, enhancing the ability to link theory with practice, and using the knowledge flexibly. However, there are still some shortcomings in early publicity, understanding students' interests and needs, and improving students' autonomous learning ability. Therefore, using the WeChat platform to carry out academic salons is a good auxiliary teaching model for cultivating the scientific research ability of professional postgraduates of clinical medicine.

α-cells, which synthesize glucagon, also support β-cell survival and have the capacity to transdifferentiate into β-cells. However, the role of α-cells in pathological conditions and their putative clinical applications remain elusive due in large part to the lack of mature α-cells. Here, we present a new technique to generate functional α-like cells. α-like cells (iAlpha cells) were generated from mouse fibroblasts by transduction of transcription factors, including Hhex, Foxa3, Gata4, Pdx1 and Pax4, which induce α-cell-specific gene expression and glucagon secretion in response to KCl and Arg stimulation. The cell functions in vivo and in vitro were evaluated. Lineage-specific and functional-related gene expression was tested by realtime PCR, insulin tolerance test (ITT), glucose tolerance test (GTT), Ki67 and glucagon immunohistochemistry analysis were done in iAlpha cells transplanted nude mice. iAlpha cells possess α-cell function in vitro and alter blood glucose levels in vivo. Transplantation of iAlpha cells into nude mice resulted in insulin resistance and increased β-cell proliferation. Taken together, we present a novel strategy to generate functional α-like cells for the purposes of disease modeling and regenerative medicine.
Animals ; Blood Glucose ; Fibroblasts* ; Gene Expression ; Glucagon ; Glucose Tolerance Test ; Immunohistochemistry ; In Vitro Techniques ; Insulin ; Insulin Resistance ; Mice* ; Mice, Nude ; Polymerase Chain Reaction ; Regenerative Medicine ; Transcription Factors

OBJECTIVETo summarize the treatment status of gastric gastrointestinal stromal tumor (GIST) in Shandong province,by analyzing the clinicopathological features and prognostic factors.

METHODSClinicopathological and follow-up data of 1 165 patients with gastric GIST between January 2000 and December 2013 from 23 tertiary referral hospitals in Shandong Province were collected to establish a database. The risk stratification of all cases was performed according to the National Institutes of Health(NIH) criteria proposed in 2008. Kaplan-Meier method was used to calculate the survival rate. Log-rank test and Cox regression model were used for univariate and multivariate prognostic analyses.

RESULTSAmong 1 165 cases of gastric GIST, 557 were male and 608 were female. The median age of onset was 60 (range 15-89) years. Primary tumors were located in the gastric fundus and cardia in 623 cases(53.5%), gastric body in 346 cases(29.7%), gastric antrum in 196 cases(16.8%). All the cases underwent resection of tumors, including endoscopic resection (n=106), local resection (n=589), subtotal gastrectomy(n=399), and total gastrectomy(n=72). Based on the NIH risk stratification, there were 256 cases (22.0%) at very low risk, 435 (37.3%) at low risk, 251 cases (21.5%) at intermediate risk, and 223 cases (19.1%) at high risk. A total of 1 116 cases(95.8%) were followed up and the median follow-up period was 40 (range, 1-60) months. During the period, 337 patients relapsed and the median time to recurrence was 34 (range 1-60) months. The 1-, 3-, and 5-year survival rates were 98.6%, 86.1% and 73.4%, respectively. The 5-year survival rates of patients at very low, low, intermediate, and high risk were 93.1%, 85.8%, 63.0% and 42.3% respectively, with a statistically significant difference (P=0.000). Multivariate analysis showed that primary tumor site (RR=0.580, 95%CI:0.402-0.835), tumor size (RR=0.450, 95%CI:0.266-0.760), intraoperative tumor rupture(RR=0.557, 95%CI:0.336-0.924), risk classification (RR=0.309, 95%CI:0.164-0.580) and the use of imatinib after surgery (RR=1.993, 95%CI:1.350-2.922) were independent prognostic factors.

CONCLUSIONSThe choice of surgical procedure for gastric GIST patients should be based on tumor size. All the routine procedures including endoscopic resection, local excision, subtotal gastrectomy and total gastrectomy can obtain satisfactory curative outcomes. NIH classification has a high value for the prediction of prognosis. Primary tumor site, tumor size, intraoperative tumor rupture, risk stratification and postoperative use of imatinib are independent prognostic factors in gastric GIST patients.

OBJECTIVE:To study and analyze the impact of rosuvastatin on function changes of endothelial cell. METHODS:30 patients with coronary heart disease were selected from our hospital during Jun. 2013 to Jun. 2014,and 15 healthy persons were included. They were divided into healthy control group,drug intervention of coronary heart disease group and coronary heart disease group with 15 cases in each group. The levels of asymmetric dimethylarginine (ADMA),NO and nitric oxide synthase (NOS) were determined by ELISA and compared among those groups. Its relationship with OD value was analyzed. After cultured for 4 h and 8 h,human umbilical vein endothelial cells (HUVEC) were divided into 5 groups,i.g. control group 0 μmol/L,0.1 μmol/L group,1 μmol/L group,10 μmol/L group,100 μmol/L group. The change of DDAH mRNA expression in endothelial cells treated with different concentrations of rosuvastatin was detected. RESULTS:The level of ADMA in drug intervention of coronary heart disease group were significantly lower than in coronary heart disease group,but still higher than that in healthy control group;NO and NOS levels were significantly higher than coronary heart disease group,but still lower than healthy control group,with statisti-cal significance (P<0.05). According to Pearson method correlation analysis,OD value was positively correlated to ADMA,NO and NOS. 4h after HUVEC culture,RT-PCR showed that mRNA expression of DDAH were increased in 0.1 μmol/L,1 μmol/L, 10μmol/L and 100μmol/L rosuvastatin groups,there was statistically significant difference between 10μmol/L and 100μmol/L ro-suvastatin groups and control group (P<0.05). 8 h after HUVEC culture,RT-PCR showed mRNA expression of DDAH were in-creased in 0.1 μmol/L,1 μmol/L,10 μmol/L and 100 μmol/L rosuvastatin groups,and there was statistically significant difference between 10 μmol/L rosuvastatin group and control group(P<0.05). CONCLUSIONS:Rosuvastatin is a new type of lipid-lowering drugs,which has a good protective effect on endothelial cells,it is worthy of attention in the clinic.

Objective To investigate the changes of plasma bone morphogenetic protein-4 (BMP-4) levels in patients with coronary heart disease (CHD) and rosuvastatin intervention effect on BMP-4 level.Methods Fifty-two patients with CHD and 35 health people were enrolled in this study as CHD group and control group.ELISA method was used to detect the concentration of plasma BMP-4.Analyzed the relationship between plasma BMP-4 and blood lipids,flow-mediated dilation (FMD),nitric oxide (NO),cyclooxygenase-2 (COX-2),malondialdehyde (MDA) and superoxide dismutase (SOD).And observed the changing of plasma BMP-4 before and after rosuvastatin intervention.Results Plasma BMP-4 level in CHD patients was (7.53 ± 1.20) μg/L,higher than that of control group ((3.81 ± 0.79) μ g/L,t =3.541,P =0.006).After rosuvastatin treatment,plasma BMP-4 level in CHD patient was decreased from (7.53 ± 1.20) μg/L to (5.40± 0.98) μg/L (t =1.436,P =0.001).Plasma BMP-4 level was positively correlated with COX-2,MDA,low-density lipoprotein cholesterol,total cholesterol (r =0.395,0.350,0.274,0.288 respectively,P ＜ 0.01 or P ＜0.05).But,it was negatively correlated with NO,high-density lipoprotein cholesterol,SOD,FMD (r =-0.291,-0.253,-0.476,-0.320 respectively,P ＜0.01 or P ＜0.05).COX-2,SOD and FMD were independent risk factors of plasma BMP-4 in patients with CHD.Conclusion Oxidative stress and endothelial dysfunction are in patients with CHD.Rosuvastatin treatment can remarkably reduce plasma BMP-4 level,alleviate vascular endothelium injury induced by oxidative stress and improve endothelial function in patients with CHD.

Mitogen-activated protein (MAP) kinases comprise a family of protein-serine/threonine kinases, which are highly conserved in protein structures from unicellular eukaryotic organisms to multicellular organisms, including mammals. These kinases, including ERKs, JNKs and p38s, are regulated by a phosphorelay cascade, with a prototype of three protein kinases that sequentially phosphorylate one another. MAPKs transduce extracellular signals into a variety of cellular processes, such as cell proliferation, survival, death, and differentiation. Consistent with their essential cellular functions, MAPKs have been shown to play critical roles in embryonic development, adult tissue homeostasis and various pathologies. In this review, we discuss recent findings that reveal the profound impact of these pathways on chronic inflammation and, particularly, inflammation-associated cancer development.
Animals ; Extracellular Signal-Regulated MAP Kinases ; metabolism ; Humans ; Inflammation ; complications ; enzymology ; JNK Mitogen-Activated Protein Kinases ; metabolism ; MAP Kinase Signaling System ; Mice ; Neoplasms ; enzymology ; etiology ; p38 Mitogen-Activated Protein Kinases ; metabolism