Dendritic cells engineered to secrete anti-Dc R3 antibody augment cytotoxic T lymphocyte response against pancreatic cancer in vitro

AIM To investigate the enhanced cytotoxic T lymphocyte responses against pancreatic cancer(PC) in vitro induced by dendritic cells(DCs) engineered to secrete anti-DcR 3 monoclonal antibody(mA b).METHODS DCs, T lymphocytes and primary PC cells were obtained from PC patients. DCs were transfected with a designed humanized anti-Dc R3 monoclonal antibody heavy and light chain m RNA and/or total tumor RNA(DC-tumor-anti-Dc R3 RNA or DC-total tumor RNA) by using electroporation technology. The identification, concentration and function of anti-DcR 3 mA b secreted by DC-tumor-anti-Dc R3 RNA were determined by western blotting and enzyme-linked immunosorbent assay. After co-culturing of autologous isolated PC cells with target DCs, the effects of secreting anti-DcR 3 mA b on RNA-DCs' viability and apoptosis were assessed by MTT assay and flow cytometry. Analysis of enhanced antigen-specific immune response against PC induced by anti-DcR 3 mA b secreting DCs was performed using a 51 Cr releasing test. T cell responses induced by RNAloaded DCs were analyzed by measuring cytokine levels, including IFN-γ, IL-10, IL4, TNF-α and IL-12.RESULTS The anti-Dc R3 m Ab secreted by DCs reacted withrecombinant human Dc R3 protein and generated a band with 35 k Da molecular weight. The secreting m Ab was transient, peaking at 24 h and becoming undetectable after 72 h. After co-incubation with DCtumor-anti-Dc R3 RNA for designated times, the Dc R3 level in the supernatant of autologous PC cells was significantly down-regulated(P < 0.05). DCs secreting anti-Dc R3 m Ab could improve cell viability and slow down the apoptosis of RNA-loaded DCs, compared with DC-total tumor RNA(P < 0.01). The anti-Dc R3 m Ab secreted by DC-tumor-anti-Dc R3 RNA could enhance the induction of cytotoxic T lymphocytes(CTLs) activity toward RNA-transfected DCs, primary tumor cells, and PC cell lines, compared with CTLs stimulated by DC-total tumor RNA or control group(P < 0.05). Meanwhile, the antigen-specific CTL responses were MHC class I-restricted. The CD4+ T cells and CD8+ T cells incubated with anti-DcR 3 mA b secreting DCs could produce extremely higher level IFN-γ and lower level IL4 than those incubated with DC-total tumor RNA or controls(P < 0.01).CONCLUSION DCs engineered to secrete anti-Dc R3 antibody can augment CTL responses against PC in vitro, and the immune-enhancing effects may be partly due to their capability of down-regulating DC apoptosis and adjusting the Th1/Th2 cytokine network.

CTLA-4 and MDR1 polymorphisms increase the risk for ulcerative colitis:A meta-analysis

AIM:To evaluate the correlations between cytotoxic T lymphocyte-associated antigen-4(CTLA-4) and multidrug resistance 1(MDR1) genes polymorphisms with ulcerative colitis(UC) risk.METHODS:Pub Med,EMBASE,Web of Science,Cochrane Library,CBM databases,Springerlink,Wiley,EBSCO,Ovid,Wanfang database,VIP database,China National Knowledge Infrastructure,and Weipu Journal databases were exhaustively searched using combinations of keywords relating to CTLA-4,MDR1 and UC. The published studies were filtered using our stringent inclusion and exclusion criteria,the quality assessment for each eligible study was conducted using Critical Appraisal Skill Program and the resultant high-quality data from final selected studies were analyzed using Comprehensive Meta-analysis 2.0(CMA 2.0) software. The correlations between SNPs of CTLA-4 gene,MDR1 gene and the risk of UC were evaluated by OR at 95%CI. Z test was carried out to evaluate the significance of overall effect values. Cochran's Q-statistic and I2 tests were applied to quantify heterogeneity among studies. Funnel plots,classic fail-safe N and Egger's linear regression test were inspected for indication of publication bias.RESULTS:A total of 107 studies were initially retrieved and 12 studies were eventually selected for metaanalysis. These 12 case-control studies involved 1860 UC patients and 2663 healthy controls. Our major result revealed that single nucleotide polymorphisms(SNPs) of CTLA-4 gene rs3087243 G > A and rs231775 G > A may increase the risk of UC(rs3087243 G > A:allele model:OR = 1.365,95%CI:1.023-1.822,P = 0.035; dominant model:OR = 1.569,95%CI:1.269-1.940,P < 0.001; rs231775 G > A:allele model:OR = 1.583,95%CI:= 1.306-1.918,P < 0.001; dominant model:OR = 1.805,95%CI:1.393-2.340,P < 0.001). In addition,based on our result,SNPs of MDR1 gene rs1045642 C > T might also confer a significant increases for the risk of UC(allele model:OR = 1.389,95%CI:1.214-1.590,P < 0.001; dominant model:OR = 1.518,95%CI:1.222-1.886,P < 0.001).CONCLUSION:CTLA-4 gene rs3087243 G > A and rs231775 G > A,and MDR1 gene rs1045642 C > T might confer an increase for UC risk.

Expert Consensus on Cognitive Dysfunction in Diabetes

The incidence of diabetes is gradually increasing in China,and diabetes and associated complications,such as cognitive dysfunction have gained much attention in recent time.However,the concepts,clinical treatment,and prevention of cognitive dysfunction in patients with diabetes remain unclear.The Chinese Society of Endocrinology investigated the current national and overseas situation of cognitive dysfunction associated with diabetes.Based on research both in China and other countries worldwide,the Expert Consensus on Cognitive Dysfunction in Diabetes was established to guide physicians in the comprehensive standardized management of cognitive dysfunction in diabetes and to improve clinical outcomes in Chinese patients.This consensus presents an overview,definition and classification,epidemiology and pathogenesis,risk factors,screening,diagnosis,differential diagnosis,treatment,and prevention of cognitive dysfunction in patients with diabetes.

外泌体相关的microRNA在代谢性疾病诊断和治疗中的作用（英文）

代谢性疾病是指包括代谢综合征、肥胖和糖尿病在内的一系列复杂疾病。其中脂毒性、慢性炎症和氧化应激可以通过改变细胞功能,从而在代谢紊乱的病理进程中发挥重要作用。近期研究发现细胞可以分泌含有蛋白质、脂质、核酸的纳米级微小囊泡,介导相邻和远处细胞间的信号传导和物质转运。外泌体作为这类囊泡的一种,参与包括肿瘤转移、动脉粥样硬化、慢性炎症和胰岛素抵抗等多种病理过程。外泌体的研究大多集中于其所含的蛋白质,而近期关于外泌体相关microRNA的功能研究也日益受到关注。尤其是,现已证明外泌体相关microRNA参与了机体代谢的诸多生理、病理进程,为代谢性疾病的诊断和治疗提供了新的方向。本文总结了外泌体的结构、内容物及产生的机制(图1和图2);体液和细胞培养液中外泌体所含microRNA的种类、靶器官及其功能(表2);外泌体相关microRNA在代谢性疾病中的作用,以及在诊断和治疗方面的潜能。

Evaluation of a risk factor scoring model in screening for undiagnosed diabetes in China population

Objective:To develop a risk scoring model for screening for undiagnosed type 2 diabetes in Chinese population.Methods:A total of 5348 subjects from two districts of Jinan City,Shandong Province,China were enrolled.Group A (2985) included individuals from east of the city and Group B (2363) from west of the city.Screening questionnaires and a standard oral glucose tolerance test (OGTT) were completed by all subjects.Based on the stepwise logistic regression analysis of Group A,variables were selected to establish the risk scoring model.The validity and effectiveness of this model were evaluated in Group B.Results:Based on stepwise logistic regression analysis performed with data of Group A,variables including age,body mass index (BMI),waist-to-hip ratio (WHR),systolic pressure,diastolic pressure,heart rate,family history of diabetes,and history of high glucose were accepted into the risk scoring model.The risk for having diabetes increased along with aggregate scores.When Youden index was closest to 1,the optimal cutoff value was set up at 51.At this point,the diabetes risk scoring model could identify diabetes patients with a sensitivity of 83.3% and a specificity of 66.5%,making the positive predictive value 12.83% and negative predictive value 98.53%.We compared our model with the Finnish and Danish model and concluded that our model has superior validity in Chinese population.Conclusions:Our diabetes risk scoring model has satisfactory sensitivity and specificity for identifying undiagnosed diabetes in our population,which might be a simple and practical tool suitable for massive diabetes screening.

Initiating Characteristics of Early-onset Type 2 Diabetes Mellitus in Chinese Patients

Background： Type 2 diabetes mellitus （T2DM） has traditionally been considered to affect mainly the elderly; however, the age at diagnosis has gradually reduced in recent years. Although the incidence of young-onset T2DM is increasing, it is still not fully clear the onset characteristics and risk factors of early-onset T2DM. The aim of this study was to describe the initiating characteristics of early-onset T2DM in Chinese patients and evaluate the risk factors fbr diabetes mellitus. Methods： This cross-sectional controlled study was performed using a questionnaire survey method in outpatients of multiple centers in China. A total of 1545 patients with T2DM with an age at onset of 〈40 years were included, and the control group consisted of subjects aged 〈40 years with normal blood glucose level. Results： In patients with young-onset T2DM, the mean age and initial hemoglobin IAc at diagnosis were 32.96 ± 5.40 years and 9.59 ± 2.71%, respectively. Most of the patients were obese, followed irregular diet pattern and sedentary lifestyle, had life or work pressure, and had a family history of diabetes mellitus. Compared with subjects with normal blood glucose level, logistic regression analysis showed that waist-to-hip ratio （odds ratio [OR] 446.99, 95% confidence interval [CI] 42.37±4714.87）, family history of diabetes mellitus （OR 23.46, CI71 14.47- 38.03）, dyslipidemia （OR 2.65, U1 1.54-4.56）, diastolic blood pressure （OR 1.02, CI 1.00 1.04）, and body mass index （OR 0.95, C1 0.92-0.99） are independent factors tbr early-onset T2DM. Conclusions： We observed that abdominal obesity, family history of diabetes mellitus, and medical history of hypertension and dyslipidemia are independent risk factors for early-onset T2DM. It is, therefore, necessary to apply early lifestyle intervention in young people with risk of diabetes mellitus.

Efficacy and Safety of Avandamet or Uptitrated Metformin Treatment in Patients with Type 2 Diabetes Inadequately Controlled with Metformin Alone： A Multicenter, Randomized,Controlled Trial

Background：At present,China has listed the compound tablet containing a fixed dose ofrosiglitazone and metformin,Avandamet,which may improve patient compliance.The aim of this study was to evaluate the efficacy and safety of Avandamet or uptitrated metformin treatment in patients with type 2 diabetes inadequately controlled with metformin alone.Methods：This study was a 48-week,multicenter,randomized,open-labeled,active-controlled trial.Patients with inadequate glycaemic control （glycated hemoglobin [HbA1c] 7.5-9.5%） receiving a stable dose of metformin （≥1500 mg） were recruited from 21 centers in China （from 19 November,2009 to 15 March,2011）.The primary objective was to compare the proportion of patients who reached the target of HbA1c ≤7% between Avandamet and metformin treatment.Results：At week 48,83.33% of patients reached the target of HbA 1 c ≤7% in Avandamet treatment and 70.00% in uptitrated metformin treatment,with significantly difference between groups.The target of HbAlc ≤6.5% was reached in 66.03% of patients in Avandamet treatment and 46.88% in uptitrated metformin treatment.The target of fasting plasma glucose （FPG） ≤6.1 mmol/L was reached in 26.97% of patients in Avandamet treatment and 19.33% in uptitrated metformin treatment.The target of FPG ≤7.0 mmol/L was reached in 63.16% of patients in Avandamet treatment and 43.33% in uptitrated metformin treatment.Fasting insulin decreased 3.24 ±0.98 μU/ml from baseline in Avandamet treatment and 0.72 ＆#177; 1.10 μU/ml in uptitrated metformin treatment.Overall adverse event （AE） rates and serious AE rates were similar between groups.Hypoglycaemia occurred rarely in both groups.Conclusions：Compared with uptitrated metformin,Avandamet treatment provided significant improvements in key parameters ofglycemic control and was generally well tolerated.Registration number：ChiCTR-TRC-13003776.

Consensus on clinical management of tumor-induced osteomalacia

Tumor-induced osteomalacia(TIO)is a rare paraneoplastic syndrome caused by excessive fibroblast growth factor 23(FGF23)production by a tumor,which often arises from a mesenchymal origin.[1-3]Most clinical symptoms of TIO are the consequences of prolonged FGF23-mediated hypophosphatemia as muscle weakness,bone pain,impaired mobility,and fractures.[4]Clinical diagnosis and management of TIO are challenging because knowledge about this condition is still restricted to a few specialized centers,leading to delay in diagnosis and appropriate treatment.The scope of the present consensus is to provide up-to-date guidance on the assessment and treatment of TIO.

Consensus on the Prevention of Type 2 Diabetes in Chinese Adults

INTRODUCTIONHigh-risk population of Type 2 diabetes mellitus （T2DM） includes both euglycemic （normal glucose tolerance [NGT]） population with high risk of diabetes （EPWHROD） and prediabetic population. Between these two groups,