Balloon Retrograde Transvenous Obliteration Versus Endoscopic Cyanoacrylate in Bleeding Gastric Varices: Comparison of Rebleeding and Mortality with Extended Follow-up

Purpose

To assess short- and long-term mortality and rebleeding with endoscopic cyanoacrylate (EC) versus balloon-occluded retrograde transvenous obliteration (BRTO).

New therapeutics based on emerging concepts in pulmonary fibrosis

Introduction: Fibrosis is an irreversible pathological endpoint in many chronic diseases, including pulmonary fibrosis. Idiopathic pulmonary fibrosis (IPF) is a progressive and often fatal condition characterized by (myo)fibroblast proliferation and transformation in the lung, expansion of the extracellular matrix, and extensive remodeling of the lung parenchyma. Recent evidence indicates that IPF prevalence and mortality rates are growing in the United States and elsewhere. Despite decades of research on the pathogenic mechanisms of pulmonary fibrosis, few therapeutics have succeeded in the clinic, and they have failed to improve IPF patient survival.

Areas covered: Based on a literature search and our own results, we discuss the key cellular and molecular responses that contribute to (myo)fibroblast actions and pulmonary fibrosis pathogenesis; this includes signaling pathways in various cells that aberrantly and persistently activate (myo)fibroblasts in fibrotic lesions and promote scar tissue formation in the lung.

Expert opinion: Lessons learned from recent failures and successes with new therapeutics point toward approaches that can target multiple pro-fibrotic processes in IPF. Advances in preclinical modeling and single-cell genomics will also accelerate novel discoveries for effective treatment of IPF.     

矽肺大鼠肺组织let-7d-3p和miRNA-21-5P差异表达及其初步分析

目的探索let-7d-3p和miRNA-21-5p在二氧化硅(SiO_2)诱导的大鼠纤维化肺组织中的差异表达及其意义。方法 SPF级Wistar雄性大鼠随机分为对照组和模型组,每组30只,采用一次性气管内灌注1 ml SiO_2悬浊液建立大鼠矽肺模型,对照组大鼠相同方法灌注1ml灭菌生理盐水。分别于染尘后1、7、14、21、28 d采集各组大鼠肺组织,每组取6只,对3只大鼠肺组织进行病理学观察,另外3只采用miRNA微阵列芯片技术筛选肺组织中差异表达的miRNA,通过miRNA芯片筛选结合反转录定量聚合酶链式反应(RT-qPCR)验证let-7d-3p和miRNA-21-5p在两组间的表达水平,对let-7d-3p和miRNA-21-5p进行靶基因预测并进行GO(gene ontology)富集分析和KEGG(kyoto encyclopedia of genes and genomes)通路分析。结果对照组大鼠1、7、14和21 d Masson染色均可见正常肺组织,未发现胶原纤维,28 d大鼠肺间质和支气管周围仅有少量纤细的胶原分布;模型组大鼠1 d和7 d未发现胶原纤维,14 d染色可见较多以淋巴细胞为主的炎症细胞浸润,未见明显纤维组织,21 d和28 d模型组大鼠肺间质内可见大片状密集的胶原纤维沉积,在肉芽组织、支气管及血管壁周围胶原蛋白增生明显。模型组中let-7d-3p的表达水平均显著下调,miRNA-21-5p表达水平均显著上调,与对照组相比差异均有统计学意义(P0.05)。结论模型组中let-7d-3p和miRNA-21-5p表达变化明显,可能与早期矽肺的发生发展有关。     

Does prenylation predict progression in NAFLD?

Non-alcoholic fatty liver disease (NAFLD) often develops in concert with related metabolic diseases, such as obesity, dyslipidemia and insulin resistance. Prolonged lipid accumulation and inflammation can progress to non-alcoholic steatohepatitis (NASH). Although factors associated with the development of NAFLD are known, triggers for the progression of NAFLD to NASH are poorly understood. Recent findings published in The Journal of Pathology reveal the possible regulation of NASH progression by metabolites of the mevalonate pathway. Mevalonate can be converted into the isoprenoids farnesyldiphosphate (FPP) and geranylgeranyl diphosphate (GGPP). GGPP synthase (GGPPS), the enzyme that converts FPP to GGPP, is dysregulated in humans and mice during NASH. Both FPP and GGPP can be conjugated to proteins through prenylation, modifying protein function and localization. Deletion or knockdown of GGPPS favors FPP prenylation (farnesylation) and augments the function of liver kinase B1, an upstream kinase of AMP-activated protein kinase (AMPK). Despite increased AMPK activation, livers in Ggpps-deficient mice on a high-fat diet poorly oxidize lipids due to mitochondrial dysfunction. Although work from Liu et al provides evidence as to the potential importance of the prenylation portion of the mevalonate pathway during NAFLD, future studies are necessary to fully grasp any therapeutic or diagnostic potential. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

调控TGFβ1/SMAD通路的microRNAs在失神经支配骨骼肌中的表达

目的:本研究拟探讨骨骼肌失神经支配后差异性表达的microRNAs,并明确其是否参与调控TGFβ1/SMAD信号通路。方法:C57/BL6J小鼠,随机分为正常对照组和实验组,实验组小鼠切断右下肢坐骨神经为手术组,左下肢游离坐骨神经作为假手术组。4周后处死小鼠取腓肠肌Masson染色观察肌纤维形态变化,比较各组肌纤维横截面积。以TGFβ1/SMAD为靶基因,通过生物信息学分析寻找到18个可能的miRNAs指标。定量PCR检测其表达,并针对表达升高的microRNAs采用荧光素酶报告基因实验确认其靶基因。结果:手术组肌纤维横截面积比对照组明显缩小,对照组与假手术组肌肉之间的差异无统计学意义。在失神经骨骼肌中特异性高表达的有miR-424、miR-744、miR-15a。在C2C12细胞系中行报告基因实验显示,与对照组比较,转染miR-744后,SMAD3的荧光素酶强度下降;转染miR-15a后,TGFβ1的荧光素酶强度下降;转染miR-424后,SMAD3的荧光素酶强度变化无统计学意义。PCR验证microRNAs的靶基因显示,转染miR-744、miR-15a的模拟物后,分别对应的SMAD3、TGFβ1表达下调,差异有统计学意义。结论:miR-424、miR-744、miR-15a可能参与调控失神经支配导致的骨骼肌萎缩纤维化,其中miR-744的靶基因是SMAD3,miR-15a的靶基因是TGFβ1。     

Role of surgery in colorectal cancer liver metastases

Colorectal carcinoma (CRC) is the third most common cancer, and approximately 35%-55% of patients with CRC will develop hepatic metastases during the course of their disease. Surgical resection represents the only chance of long-term survival. The goal of surgery should be to resect all metastases with negative histological margins while preserving sufficient functional hepatic parenchyma. Although resection remains the only chance of long-term survival, management strategies should be tailored for each case. For patients with extensive metastatic disease who would otherwise be unresectable, the combination of advances in medical therapy, such as systemic chemotherapy (CTX), and the improvement in surgical techniques for metastatic disease, have enhanced prognosis with prolongation of the median survival rate and cure. The use of portal vein embolization and preoperative CTX may also increase the number of patients suitable for surgical treatment. Despite current treatment options, many patients still experience a recurrence after hepatic resection. More active systemic CTX agents are being used increasingly as adjuvant therapy either before or after surgery. Local tumor ablative therapies, such as microwave coagulation therapy and radiofrequency ablation therapy, should be considered as an adjunct to hepatic resection, in which resection cannot deal with all of the tumor lesions. Formulation of an individualized plan, which combines surgery with systemic CTX, is a necessary task of the multidisciplinary team. The aim of this paper is to discuss different approaches for patients that are treated due to CRC liver metastasis.