甲状腺癌中p-STAT1和STAT1蛋白表达及意义

目的 探讨p-STAT1及STAT1蛋白在甲状腺癌中的表达及其与肿瘤临床病理的关系.方法 选取浙江省诸暨市人民医院江东普外科保存的甲状腺癌及对应癌旁组织80例,采用免疫组织化学SP法检测磷酸化STAT1（p-STAT1）及STAT1蛋白的表达,分析其与甲状腺癌临床病理特征的关系;随访其中74例,观察p-STAT1及STAT1蛋白与甲状腺癌无复发生存率之间的关系.结果 p-STAT1及STAT1蛋白在甲状腺癌组织及正常甲状腺组织中的阳性表达率分别为28.8％ （23/80）和90.0％ （72/80）、85.0％（68/80）和50.0％（40/80）,差异均有统计学意义（P＜0.05）.相对于Ⅰ＋Ⅱ期甲状腺癌患者,p-STAT1蛋白在Ⅲ＋Ⅳ期的甲状腺癌患者中显著下降（P＜0.05）,而STAT1则无明显变化.p-STAT1蛋白在有淋巴结转移的甲状腺癌中的阳性表达率显著低于无淋巴结转移者（P＜0.05）.p-STAT1蛋白阳性患者中无复发生存率为100％,而STAT1阳性的患者中为92.65％,提示p-STAT1表达与甲状腺癌患者预后相关.结论 p-STAT1蛋白表达与甲状腺癌的发生发展、浸润转移及无复发生存率相关,检测p-STAT1蛋白的表达可能作为评估甲状腺癌预后和指导临床靶向治疗的重要指标.     

高糖培养下系膜细胞JAK2／STAT3信号转导通路活性变化及与活性氧簇作用的研究

目的：通过观察高糖培养条件下大鼠肾小球系膜细胞P-STAT3的表达变化,探讨糖尿病状态下JAK2／STAT3途径活性的变化及该通路与活性氧簇（ROS之间的相互作用。方法：用传代培养的大鼠肾小球系膜细胞同步化后分组：（1）正常糖浓度组（含5．5mmol／L）,高糖浓度组（25mmol／L）,甘露醇组（5．5mmot／L糖＋19．5mmol甘露醇）,正常糖＋AG-490（浓度10／μmol／L）组,高糖＋AG-490（浓度10μmol／L）组。继续观察培养后用Westem Blot及细胞免疫化学方法检测系膜细胞STAT3、P-STAT3表达的变化。（2）正常糖浓度组（N）,高糖浓度组（H）,甘露醇组（M）,正常糖＋Apocynin组（N＋A,Apocynin浓度为100μmol／L）,高糖＋Apocynin组（H＋A,Atx）cynin浓度为100μmol／L）,收集上清液,用比色法检测系膜细胞ROS水平。（3）NADPH氧化酶抑制剂Apocynin预处理,分组同（2）,Apocynin提前1h加入,与正常糖或高糖同时培养后,用Westem Blot方法检测系膜细胞P-STAT3表达。结果：（1）高糖培养大鼠肾小球系膜细胞P-STAT3的表达较正常糖浓度组明显升高,甘露醇组与正常糖浓度组相比差异无统计学意义;各组之间STAT3表达差异无统计学意义。（2）高糖条件下,ROS产生明显升高,NADPH氧化酶抑制剂Apocynin可明显降低ROS的产生。（3）高糖条件下,Apocynin经预处理,在正常糖浓度和高糖浓度同时培养48h后,正常糖浓度组和正常糖＋Apocynin组对比P-NTAT3的表达差异无明显区别;高糖十Apocynin组较正常糖浓度组有明显区别,但与高糖组相比明显降低。结论：高糖通过磷酸化方式激活大鼠肾小球系膜细胞JAK2／STAT3信号转导通路;高糖作用下,肾小球系膜细胞ROS产生增加,并具有时间依赖性;高糖状态下ROS可激活肾小球系膜细胞的JAK2／STAL信号传导通路,证明ROS可能参与糖尿病肾病的发生和发展过程。     

Periodontal pathogens Porphyromonas gingivalis and Fusobacterium nucleatum promote tumor progression in an oral-specific chemical carcinogenesis model

Oral squamous cell carcinoma (OSCC) is a lethal disease whose incidence is increasing. Epidemiologic studies demonstrate an association between periodontitis and oral cancer, and periodontal pathogens are implicated in the pathogenesis of numerous disorders, including rheumatoid arthritis, cardiovascular diseases, diabetes and gastrointestinal malignancies. Nevertheless, a causal role for periodontal pathogens in OSCC has not been shown, partly due to the lack of an appropriate animal model. Here, utilizing a newly-established murine model of periodontitis-associated oral tumorigenesis, we report that chronic bacterial infection promotes OSCC, and that augmented signaling along the IL-6-STAT3 axis underlies this effect. Our results indicate that periodontal pathogens P. gingivalis and F. nucleatum stimulate tumorigenesis via direct interaction with oral epithelial cells through Toll-like receptors. Furthermore, oral pathogens stimulate human OSCC proliferation and induce expression of key molecules implicated in tumorigenesis. To the best of our knowledge, these findings represent the first demonstration of a mechanistic role for oral bacteria in chemically induced OSCC tumorigenesis. These results are highly relevant for the design of effective prevention and treatment strategies for OSCC.     

Circulating YKL‐40 in myelofibrosis a potential novel biomarker of disease activity and the inflammatory state

Chronic myeloproliferative neoplasms (MPN), encompassing essential thrombocythaemia (ET), polycythaemia vera (PV) and myelofibrosis (PMF), are featured by a chronic inflammatory state which is pronounced in myelofibrosis The value of YKL‐40 as a biomarker of disease burden has been demonstrated in several different diseases, including cancer, diabetes mellitus and cardiovascular diseases. A state of chronic inflammation is shared by them all, YKL‐40 also being involved in the severity of chronic endothelial inflammation, which today is considered of crucial importance for the development of atherosclerosis. The MPNs being cancers with a heavy burden of cardiovascular diseases we hypothesised that circulating YKL‐40 might reflect the inflammatory process and potentially serve as a novel disease marker. Using ELISA, we measured YKL‐40 in 15 patients with ET, 16 patients with PV, 17 patients with PMF and 30 healthy controls. YKL‐40 was significantly elevated in PMF vs. control subjects, PMF levels median 43 ng/mL vs. controls median 28 ng/mL, P = 0.033. An increase from ET over PV may reflect the integrated impact of disease processes in MPNs.     

骨髓增殖性肿瘤研究进展:JAK2 V617F基因突变发现后10年

结合大量的临床实践和近10年来对骨髓增殖性肿瘤(MPN)[骨髓增殖性疾病(MPD)]在JAK2 V617F基因突变等分子水平的大量研究,更加深了对MPN(MPD)的分子发病机制和临床价值的认识.研究者们探讨了JAK2 V617F基因突变如何促进MPN(MPD)发病的机制,分析了JAK2 V617F基因突变的分子机制和JAK2 V617F基因突变如何引起MPN(MPD)不同临床表型,以及MPN(MPD)基因组突变图谱及其生物学意义,指出了MPN(MPD)病理克隆的复杂性.JAK2 V617F基因突变在研究和诊治MPN(MPD)的过程中发挥着重大作用,其促使MPN(MPD)的研究和应用深入到基因/分子水平,治疗更趋于靶向性,更加精确,特别是使那些常规检验无法明确诊断的患者获得了及时诊治,避免了合并疾病的发生.MPN(MPD)的防治焦点是及时诊治,预防并避免血栓/出血性并发症的发生.推荐首选干扰素α(IFN-α)治疗,对于年龄大于60岁的患者,羟基脲是可以采用的.MPN(MPD)患者的预后大多数良好,发生恶变的风险不高,这是反复建议对中国MPD患者避免使用MPN称谓的主要理由.     

p-STAT3与缺氧诱导因子在结肠癌组织中的表达及其临床意义

目的检测信号转导和转录激活子3(STAT3)的活化形式-p-STAT3及缺氧诱导因子-1α(HIF-1α)在结肠癌及癌旁组织中的表达,探究p-STAT3和HIF在结肠癌诊断中的临床意义。方法采用免疫组织化学SABC法检测40例结肠癌及癌旁组织中p-STAT3和HIF-1α的表达情况及二者的相关性。结果在40例结肠癌组织中p-STAT3阳性表达率为92.5%,HIF-1α的阳性表达率为87.5%,两者呈正相关,p-STAT3和HIF-1α的表达在结肠癌组织均明显高于癌旁组织(P<0.05)。结论 p-STAT3和HIF-1α的过度表达在结肠癌的诊断中具有重要价值,p-STAT3可能通过HIF的转录共同促进结肠癌的发生和发展。     

Allogeneic Stem Cell Transplant vs. Janus Kinase Inhibition in the Treatment of Primary Myelofibrosis or Myelofibrosis After Essential Thrombocythemia or Polycythemia Vera

Primary myelofibrosis is one of the Philadelphia chromosome–negative myeloproliferative neoplasms and is the member of that group with the worst survival and the most significant limitations in quality of life. Hepatosplenomegaly due to extramedullary hematopoiesis, constitutional symptoms, and cytopenias are the main manifestations. The natural history is highly variable, and up to 30% of patients can experience acceleration to acute myelogenous leukemia. Conventional therapy is only palliative and not always effective. However, huge advances have been achieved in the past 2 decades toward a better understanding of the pathogenesis of this disease, as well as improved management. Powerful risk stratification systems are now available and can reliably separate the patients into different prognostic categories to aid clinical management. Allogeneic stem cell transplant can offer cure but is still not universally applicable owing to the treatment-related mortality and toxicity. Nevertheless, outcomes of transplant are improving, owing to the introduction of reduced-intensity conditioning regimens and the optimization of remission monitoring techniques and relapse prevention strategies. The discovery of the V617F mutation of JAK2 (Janus kinase 2) and some other molecular aberrations has shed more light on the molecular pathogenesis of the disease and has led to the introduction of novel therapies such as JAK2 inhibitors. In fact, JAK inhibitors have shown promising symptomatic efficacy, and the JAK inhibitor ruxolitinib has also shown a potential survival benefit. Future effort should be made to combine allogeneic stem cell transplant with JAK inhibition.