Application of quality improvement techniques to the reduction of turnaround time for "STAT" and "ASAP" orders

This project educated a multidisciplinary team on the techniques of continuous quality improvement, which were then used to analyze the total medication cycle process in order to reduce the total turnaround time for STAT and ASAP orders. Members were trained in the appropriate analytical techniques, developed flow charts of the medication cycle, and developed and conducted a study of the turnaround time for STAT and ASAP orders. Three data collections were obtained: 1) baseline, 2) after flagging orders and medications to help quickly identify both, and 3) after implementation of guidelines for physicians to properly use the terms STAT and ASAP. The interventions seem to have resulted in system improvement based upon an overall decrease in turnaround time (70% for STAT orders, 54% for ASAP orders). The majority of the medication cycle time was on the patient care unit after medication delivery. Problems with the process were identified and recommendations made for future quality improvement teams.     

PTPMeg2抑制NIH3T3/STAT3CA细胞模型STAT3转录活性的研究

目的探讨磷酸酶PTPMeg2对NIH3T3/STAT3CA细胞模型的增殖及STAT3转录活性的影响。方法构建STAT3异常突变的细胞模型NIH3T3/STAT3CA,MTT法和裸鼠异体移植瘤实验分别用于观察PTPMeg2对NIH3T3/STAT3CA细胞体外和体内增殖的影响,免疫共沉淀实验用于PTPMeg2与STAT3CA相互作用的研究,双荧光素酶报告基因法用于转录活性的研究。结果 PTPMeg2对NIH3T3/STAT3CA细胞在体外和体内都具有增殖抑制作用,与对照组比较均具有明显的统计学意义。PTPMeg2对NIH3T3/STAT3CA细胞的转录活性具有抑制作用,而PTPMeg2的突变体(PTPMeg2C515S)和ShPTPMeg2则无效。结论 PTPMeg2对NIH3T3/STAT3CA细胞具有增殖抑制作用,其作用机制可能与抑制STAT3的转录活性有关。     

Dual inhibition of STAT1 and STAT3 activation downregulates expression of PD-L1 in human breast cancer cells

Objectives: Breast cancer is the most commonly diagnosed cancer, and it is a leading cause of cancer-related deaths in females worldwide. Triple-negative breast cancer (TNBC) constitutes 15% of breast cancer and shows distinct metastasis profiles with poor prognosis. Strong PD-L1 expression has been observed in some tumors, supporting their escape from immune surveillance. Targeting PD-L1 could be a promising therapeutic approach in breast cancer patients. We investigated potential molecular mechanisms for constitutive expression of PD-L1 by inhibiting upstream STAT1 and STAT3 signals.

Methods: PD-L1 expression in three breast cancer cell lines was measured using quantitative PCR and western blotting. Activation of STAT1 and STAT3 was blocked using pharmacological inhibitors and siRNA. The mechanism underlying the constitutive expression of PD-L1 was investigated using ChIP and co-immunoprecipitation assays.

Results: We found that individual inhibition of STAT1 and STAT3 activation partially downregulated PD-L1, while combined inhibition completely downregulated PD-L1 expression. Moreover, our results suggest that pSTAT1-pSTAT3 dimerize in cytosol and translocate to the nucleus, where they bind to PD-L1 promoter and induce PD-L1 expression.

Conclusion: These findings provide a rationale for combined targeting of STAT1 and STAT3 for the development of immune-based cancer therapies for down regulation of PD-L1 expression.     

STAT3基因shRNA真核表达载体的构建与鉴定

目的 构建携带信号传导和转录激活子3(STAT3)基因短发夹状干扰RNA(shRNA)的真核表达载体.方法 从GenBank STAT3 mRNA上寻找到3条符合特征的靶序列,合成靶序列的DNA寡核苷酸链,合成双链DNA,并和BamH Ⅰ和HindⅢ酶切后的pRNAT-U6.1/Neo载体质粒连接产生重组质粒,PCR筛选阳性克隆,并行测序鉴定.重组质粒转染大肠癌LoVo细胞,RT-PCR检测STAT3的表达.结果 PCR和测序证实重组质粒构建正确.3种重组质粒对大肠癌LoVo细胞STAT3的表达有较强的抑制作用.结论 成功构建了携带有STAT3基因的短发夹状干扰RNA的重组质粒.     

Novel STAT 3 inhibitors for treating gastric cancer

Introduction: Advanced gastric cancer has a poor prognosis, with a median survival of approximately 12 months. There is a continued need to explore the use of novel treatments for this disease. STAT3 inhibitors are under evaluation in a number of early phase trials, some showing promise in gastric cancer.

Areas covered: This article explores the role of STAT 3 in gastric cancer and highlights some early phase clinical trials on STAT3 inhibition. The STAT3 protein and signalling pathway are discussed. STAT3 in the pathogenesis of gastric cancer is reviewed; pre-clinical data on the role of STAT3 in the development of cancer is presented together with early and emerging data on STAT3 inhibitors under investigation in the clinical setting. In this review, the authors searched PubMed, clinicaltrials.gov and ASCO abstracts on STAT3 inhibitors, focusing on trials recruiting gastric cancer patients.

Expert opinion: Activated STAT3 in gastric cancer is correlated with poor survival. It plays a critical role in regulating tumour growth and metastases. STAT3 inhibitors are emerging as an interesting drug in gastric cancer. However, trials utilising these agents remain in their early phase with one agent currently under evaluation in the phase III setting.     

信号转导和转录激活因子3在肝病中的研究进展

信号转导和转录激活因子3（STAT3）是一种重要的转录因子,可被多种细胞因子和生长因子激活,在细胞生长、增殖和分化中发挥关键作用。研究表明,几乎所有的人类肝脏疾病和肝损伤动物模型中均存在STAT3过度激活的现象。通过抑制STAT3的激活可治疗急性肝损伤和肝纤维化,故STAT3抑制剂具有预防和治疗肝脏疾病的潜力。针对STAT3在肝损伤、肝炎、肝再生、肝纤维化和肝癌发生方面的研究进展作一综述。     

Therapeutic Targeting of the JAK/STAT Pathway

Antibodies that block cytokine function provide a powerful therapeutic tool especially for the treatment of autoimmune diseases. Cytokines are a group of small hydrophilic glycoproteins that bind their receptors on the cell surface and subsequently activate intracellular signalling cascades, such as the JAK/STAT pathway. A bulk of evidence has demonstrated that genetic mutations in signalling molecules can cause immunodeficiencies and malignant cell growth. As a result, several drug companies have begun to develop therapeutics that inhibit the function of JAK tyrosine kinases. Currently, two JAK inhibitors, tofacitinib and ruxolitinib, are used in the clinic for treating rheumatoid arthritis and myeloproliferative diseases, respectively. Inhibiting JAK function has been shown to efficiently prevent the uncontrolled growth of cancerous cells and to harness overly active immune cells. In the future, other small molecule compounds are likely to come into clinical use, and intense work is ongoing to develop inhibitors that specifically target the constitutively active mutant JAKs. This MiniReview will summarize the basic features of the JAK/STAT pathway, its role in human disease and the therapeutic potential of JAK/STAT inhibitors.     

缬沙坦对高糖培养系膜细胞信号转导和转录活化因子1、3表达的影响

目的探讨高糖状态下肾小球系膜细胞中信号转导和转录活化因子1、3的改变以及血管紧张素受体1拮抗剂(AT1Ra)缬沙坦的影响。方法体外培养大鼠肾小球系膜细胞,分别给予高糖和缬沙坦干预,采用W estern印迹检测信号转导和转录活化因子1、3(STAT1、STAT3)及其磷酸化蛋白(p-STAT1、p-STAT3)的表达,酶联免疫吸附实验(ELISA)和放免法测定细胞上清液中TGF-β1、纤维连接蛋白(F ibronectin,FN)和IV型胶原的含量,逆转录-聚合酶链反应(RT-PCR)检测TGF-β1mRNA的表达。结果与低糖对照组相比,高糖组系膜细胞p-STAT1和p-STAT3表达明显上调,TGF-β1、FN和IV型胶原含量增加,TGF-β1mRNA的表达增加。缬沙坦组p-STAT1和p-STAT3的表达明显下调,TGF-β1、FN和IV型胶原的含量减少,同时TGF-β1mRNA的表达降低。结论高糖状态下p-STAT1和p-STAT3表达明显升高,缬沙坦抑制肾小球系膜细胞TGF-β1和细胞外基质的分泌可能部分是通过影响STAT1和STAT3的激活而实现。     

STAT3抑制剂抗肿瘤研究进展

信号转导和转录激活因子3（STAT3）是参与多种生物学功能的转录因子,可将细胞外信号传导到细胞核,进而激活靶基因的转录。STAT3异常激活可诱导肿瘤的发生,促进肿瘤的发展,是一个有吸引力的抗癌靶点。目前STAT3抑制剂快速发展,其主要包括STAT3上游信号抑制剂和STAT3直接抑制剂。重点综述近几年靶向STAT3药物的抗肿瘤研究进展。