IL-10 contributes to gemcitabine resistance in extranodal NK/T-cell lymphoma cells via ABCC4

Investigational New Drugs - Background Chemotherapy resistance is a main reason for treatment failure in extranodal NK/T-cell lymphoma (ENKTL). Interleukin-10 (IL-10) is closely related to...     

滋肾育胎丸加减方预防ACA阳性者不良妊娠结局的效果及机制研究＊

目的 探讨滋肾育胎丸加减方预防抗磷脂抗体（ACA）阳性者不良妊娠结局的效果及机制研究。方法 选取2016年2月至2019年2月我院收治的89例ACA阳性，先兆性流产或有习惯性流产（RSA）史患者，将采用西医治疗的40例作为对照组，将采用西医联合滋肾育胎丸加减方治疗的49例作为观察组，比较两组中医证候疗效、中医证候积分、ACA-IgA、ACA-IgM、ACA-IgG、凝血指标［血小板聚集功能（PAF）、活化蛋白C（PC）、抗凝血酶（AT）、纤溶酶原激活抑制物-1（PAI-1）］、Th1/Th2细胞因子［干扰素γ（IFN-γ）、白介素-2（IL-2）、白介素-4（IL-4）、白介素-10（IL-10）］、妊娠结局、安全性。结果 治疗2周后检测ACA，观察组2例未降低，对照组11例未降低，观察组未降低患者占比低于对照组（P<0.05）；观察组总有效率100.00%高于对照组85.00%（P<0.05）；观察组治疗4周、7周后中医证候积分低于对照组（P<0.05）；观察组治疗4周、7周后ACA-IgA、ACA-IgM、ACA-IgG低于对照组（P<0.05）；观察组治疗4周、7周后PAF、PAI-1低于对照组，PC、AT高于对照组（P<0.05）；观察组治疗4周、7周后IFN-γ、IL-2低于对照组，IL-4、IL-10高于对照组（P<0.05）；观察组活产率95.92%高于对照组80.00%（P<0.05）；组间不良反应总发生率比较，差异无统计学意义（P>0.05）。结论 动态监测ACA对滋肾育胎丸加减方精准应用具有指导意义，指导滋肾育胎丸加减方通过调理脏腑、气血、经络功能，改善先兆性流产或有RSA史患者临床症状及凝血因子指标，降低ACA水平，并可改善患者免疫耐受功能，提高胎儿活产率，且安全性高。     

化浊清解愈溃煎对溃疡性结肠炎大鼠p38MAPK、TNF-α、IL-4的影响

目的观察化浊清解愈溃煎对溃疡性结肠炎(UC)大鼠血清及结肠组织p38MAPK、肿瘤坏死因子-α(TNF-α)、白细胞介素-4(IL-4)含量的影响。方法清洁级Wistar雄性大鼠50只按随机数字表法分为两组,空白组8只,其余大鼠均为造模组。采用TNBS/乙醇联合造模法构建UC大鼠模型。造模成功后按照随机数字表法将模型大鼠分为模型组、西药组(予美沙拉嗪肠溶片混悬液0.42 g/kg)及中药高、中、低剂量组。中药高、中、低剂量组予化浊清解愈溃煎中药混悬液,剂量分别为22、11、5.5 g/(kg·d),每日灌胃1次,疗程14 d。采用免疫组化法检测各组大鼠结肠组织内p38MAPK的蛋白表达量。ELISA法检测各组大鼠血清内TNF-α、IL-4含量。结果与空白组比较,模型组一般情况较差,血清中TNF-α含量显著升高(P<0.05),IL-4含量则明显降低(P<0.05),结肠组织中p38MAPK水平明显升高(P<0.05)。与模型组比较,西药组、中药各剂量组大鼠一般生存状况改善明显,血清中TNF-α含量下降,IL-4含量明显升高,尤以中药高剂量组和西药组疗效显著(P<0.05)。结论化浊清解愈溃煎高、中剂量可改善UC大鼠一般生存状况,并通过调节血清中IL-4含量,下调TNF-α表达水平和结肠组织中p38MAPK蛋白表达水平而达到保护结肠黏膜和治疗UC的作用。     

Dysregulation in nucleic acid‐sensing pathway genes is associated with cancer patients’ prognosis

The innate immune system, the first line of defense against pathogens, is activated by nucleic acids from microbial invaders that are recognized by nucleic acid‐sensing receptors. Recent evidence affirms the ability of these receptors to respond to nucleic acids released by damaged cancer cells. The innate immune system is also involved in cancer immunosurveillance, and could be modulated for devising effective antitumor therapies by targeting nucleic acid‐sensing pathways. A systematic, comprehensive analysis of dysregulation in nucleic acid‐sensing pathways in cancer is required to fully understand its role. Based on multidimensional data of The Cancer Genome Atlas pan‐cancer cohort, we revealed that upregulation of cytosolic DNA‐sensing genes like AIM2 and CGAS was common in tumor tissues. We used 15 genes in the nucleic acid‐sensing pathway to cluster all tumor patients into 2 subgroups and found that the subgroup with higher expression of nucleic acid‐sensing pathway genes was associated with poorer prognosis across cancer types. However, in homologous recombination deficient patients, the nucleic acid recognition activated subgroup was associated with better prognosis, which confirms the therapeutic effect of nucleic acid recognition. This study contributes to a better understanding of the functions and mechanisms of nucleic acid recognition in cancer, lays the foundation for new therapeutic strategies, and enlarges the scope of development of new drugs.     

Plastin 1 drives metastasis of colorectal cancer through the IQGAP1/Rac1/ERK pathway

Tumor metastasis is the dominant cause of death in colorectal cancer (CRC) patients, and it often involves dysregulation of various cytoskeletal proteins. Plastin 1 (PLS1) is an actin‐bundling protein that has been implicated in the structure of intestinal epithelial microvilli; however, its role in CRC metastasis has not yet been determined. In this study, we demonstrated that PLS1 is highly expressed in 33.3% (45/135) of CRC patients and is correlated with lymph node metastasis and poor survival. In in vitro and in vivo experiments, PLS1 induced the migration and invasion of CRC cells and the metastases to the liver and lung in mice. Moreover, the expressions of key factors for CRC metastases, matrix metalloproteinase (MMP) 9 and 2, were enhanced by PLS1, which was dependent on phosphorylating ERK1/2 activated by IQGAP1/Rac1 signaling. The connection between these signals and PLS1 was further confirmed in CRC tissues of patients and the metastatic nodules from a mouse model. These findings suggest that PLS1 promotes CRC metastasis through the IQGAP1/Rac1/ERK pathway. Targeting PLS1 may provide a potential approach to inhibit the metastasis of CRC cells.     

Altered resting‐state functional connectivity and effective connectivity of the habenula in irritable bowel syndrome: A cross‐sectional and machine learning study

Irritable bowel syndrome (IBS) is a disorder involving dysfunctional brain–gut interactions characterized by chronic recurrent abdominal pain, altered bowel habits, and negative emotion. Previous studies have linked the habenula to the pathophysiology of negative emotion and pain. However, no studies to date have investigated habenular function in IBS patients. In this study, we investigated the resting‐state functional connectivity (rsFC) and effective connectivity of the habenula in 34 subjects with IBS and 34 healthy controls and assessed the feasibility of differentiating IBS patients from healthy controls using a machine learning method. Our results showed significantly enhanced rsFC of the habenula‐left dorsolateral prefrontal cortex (dlPFC) and habenula‐periaqueductal grey (PAG, dorsomedial part), as well as decreased rsFC of the habenula‐right thalamus (dorsolateral part), in the IBS patients compared with the healthy controls. Habenula‐thalamus rsFC was positively correlated with pain intensity (r = .467, p = .005). Dynamic causal modeling (DCM) revealed significantly decreased effective connectivity from the right habenula to the right thalamus in the IBS patients compared to the healthy controls that was negatively correlated with disease duration (r = ?.407, p = .017). In addition, IBS was classified with an accuracy of 71.5% based on the rsFC of the habenula‐dlPFC, habenula‐thalamus, and habenula‐PAG in a support vector machine (SVM), which was further validated in an independent cohort of subjects (N = 44, accuracy = 65.2%, p = .026). Taken together, these findings establish altered habenular rsFC and effective connectivity in IBS, which extends our mechanistic understanding of the habenula's role in IBS.     

胆囊肝样腺癌的临床影像病理分析

目的总结胆囊肝样腺癌临床病理学特征及影像学表现。 方法回顾性分析2010年1月至2019年10月海军军医大学第三附属医院收治的经手术病理诊断的6例胆囊肝样腺癌患者的临床资料、病理检查结果、影像学资料及术后随访资料。 结果本组6例胆囊肝样腺癌患者的发病年龄为49~69岁，男女发病率为2∶1，3例发生于肝脏或淋巴结转移。6例患者血清甲胎蛋白（AFP）水平均升高、肝细胞抗原（Hep-1）染色均呈阳性。1例患者MRI和CT表现动脉期呈中度-明显强化，门静脉期及延迟期强化减退，1例为轻度强化；1例为不均匀明显强化。6例患者中2例患者失访；2例患者术后5年未见复发，存活至今；1例患者术后2年发现肝转移，治疗后存活至今；1例患者术后1年复发，治疗6个月后死亡。 结论胆囊肝样腺癌好发于中老年男性，且容易发生肝脏或淋巴结转移，并通常伴有血清AFP水平升高，预后差，结合临床和影像学特征可提高对该病的诊断准确率。     

肝细胞癌肝移植供肝选择策略

供肝数量不足是制约肝移植发展的主要因素,更是制约肝细胞癌肝移植治疗的突出因素。既往对肝细胞癌肝移植的研究多集中在受者选择标准、降期治疗、免疫抑制方案等方面,近年来研究发现供肝的选择对肝细胞癌肝移植术后肿瘤复发也有显著影响。笔者从临床供肝的主要类型、肝细胞癌肝移植适应证的把握、适应证内肝细胞癌肝移植和超适应证肝细胞癌肝移植的供肝选择以及供肝选择对肝细胞癌肝移植预后的影响进行深入探讨。     

Inhibition of Cdc42–intersectin interaction by small molecule ZCL367 impedes cancer cell cycle progression,proliferation, migration,and tumor growth

Cdc42 is a member of the Rho family of small GTPases that are at the crossroads of major oncogenic signaling pathways involved in both lung and prostate cancers. However, the therapeutic potential of Cdc42 regulation is still unclear due to the lack of pharmacological tools. Herein, we report that ZCL367 is a bona fide Cdc42 inhibitor that suppressed cancer development and ZCL278 can act as a partial Cdc42 agonist. In lung cancer cell lines with varying EGFR and Ras mutations as well as both androgen-independent and androgen-dependent prostate cancer cell lines, ZCL367 impeded cell cycle progression, reduced proliferation, and suppressed migration. ZCL367 decreased Cdc42–intersectin interactions and reduced Cdc42-mediated filopodia formation. ZCL367 showed increased potency and selectivity for Cdc42 when compared to Rac1 and RhoA. ZCL367 reduced A549 tumorigenesis in a xenograft mouse model. Altogether, ZCL367 is a selective Cdc42 inhibitor and an excellent candidate for lead compound optimization for further anticancer studies.