中文摘要 目的：在本研究中，我们探究了术前纤维蛋白原与白蛋白比值（fibrinogen-to-albumin ratio，FAR）在胆囊癌（gallbladdercancer，GBC）患者中的预后意义。 方法：回顾性分析了 154 例于 2005 年 3 月至 2017 年 12 月在我院接受了手术治疗 的 GBC 患者。采用受试者工作特征（Receiveroperatingcharacteristic，ROC）曲线 来明确术前纤维蛋白原与白蛋白比值等生物学标记物的最佳临界值。单因素 Kaplan-Meier 法以及多因素 Cox 回归分析被用来进行 GBC 患者预后相关的分析。 结果：ROC 曲线显示术前 FAR 的最佳临界值为 0.08。术前 FAR 与年龄（P=0.045）、 黄疸（P<0.001）、肿瘤分化程度（P=0.002）、肿瘤切缘状态（P<0.001）、 T 分期（P<0.001）、 TNM 分期（P<0.001）、CA199（P<0.001）以及白蛋白水平（P<0.001）显著相关。 多因素分析表明肿瘤切缘状态[风险比（hazard ratio，HR）：2.343,95%置信区间 （confidenceinterval，CI）：1.532-3.581，P<0.001]，TNM 分期（P=0.035），术前白 蛋白水平（HR=0.595，95%CI：0.385-0.921，P=0.020）和 FAR（HR：2.813，95%CI： 1.765-4.484，P<0.001）是 GBC 患者的独立预后因素。 结论：术前 FAR 升高与 GBC 患者不良的总生存率（overall survival，OS）显著相 关，而术前白蛋白水平升高是 GBC 患者的保护性预后因素。术前 FAR 作为一种易 获取、高性价比且无创的指标，在临床上可用于预测 GBC 患者的预后。 中文摘要 目的：本研究探讨了联合应用术前血浆纤维蛋白原和 CA199 水平在胆囊癌 （gallbladdercarcinoma，GBC）患者中的预后价值。 方法：回顾性分析了 154 例 GBC 患者术后的临床病理资料。应用受试者工作特征 （receiveroperatingcharacteristic，ROC）曲线来确定术前血浆纤维蛋白原和 CA199 水平的最佳截断值。采用单因素和多因素生存分析来明确与 GBC 预后相关的危险 因素。根据通过多因素生存分析计算得到的风险比（Hazardratio，HR）值的相对值， 术前血浆纤维蛋白原和 CA199 水平同时升高的 GBC 患者被分配得分为 2.1；单独 血浆纤维蛋白原水平升高的患者得分为 1，单独 CA199 水平升高的患者得分为 1.1， 而没有这两者异常的患者得分为 0。 结果：ROC 曲线分析显示，术前血浆纤维蛋白原和 CA199 的最佳截断值分别为 3.47g/L 和 25.45U/ml。多因素分析表明，术前血浆纤维蛋白原和 CA199 水平升高与 更差的总体生存率（overall survival，OS）显著相关（HR=1.711,95%置信区间 （confidenceinterval，CI）：1.114-2.627，P=0.014 和 HR=1.842，95%CI：1.111-3.056， P=0.018）。当我们把这两个参数结合起来应用时，ROC 曲线下面积从 0.735（仅限 术前血浆纤维蛋白原）和 0.729（仅限术前 CA199）增加到 0.765。当该组合变量被 添加到多因素分析中时，联合应用血浆纤维蛋白原和 CA199 水平（P<0.001），肿瘤 切缘（P<0.001）和 TNM 分期（P=0.010）是接受手术治疗的 GBC 患者预后的独立 危险因素。 结论：与单独应用相比，联合应用血浆纤维蛋白原和 CA199 水平可以作为术后 GBC 患者更有效的、独立预后生物标志物。 中文摘要 背景：本研究旨在探讨淋巴细胞与单核细胞比率（lymphocyte-to-monocyteratio， LMR） 在胆囊癌（gallbladdercancer，GBC）患者中的预后价值。 方法：本研究回顾性分析了 2005 年至 2017 年间在我院住院进行手术治疗的 154 例 GBC 患者的临床资料。将术前外周血中的淋巴细胞计数除以单核细胞计数，来计算 患者术前血液样本的 LMR。采用受试者工作特征（receiveroperatingcharacteristic， ROC）曲线确定 LMR 在 GBC 患者总生存率（overallsurvival，OS）中的最佳截断 值。利用 Kaplan-Meier 方法来评估 OS，并采用对数秩检验比较组间患者 OS 的差 异。进行单因素和多因素 Cox 回归分析，来得到与 GBC 患者 OS 相关的独立的预 后指标。 结果：ROC 曲线表明术前外周血中 LMR 的最佳截断值为 4.76。与 LMR>4.76（风 险比（hazardratio，HR）： 0.399， 95%置信区间（confidenceinterval，CI）： 0.265-0.602， P<0.001）的患者相比，≤60 岁且 LMR≤4.76 的 GBC 患者 OS 明显更差；尽管如此， LMR 的预后价值在整个研究队列或 60 岁以上的患者中均未体现出统计学意义（均 P>0.05）。在年龄>60 岁的患者中，LMR 的最佳截断值为 4.21，与 LMR>4.21（HR： 1.830， 95%CI： 1.129-2.967， P=0.014）的患者相比，我们观察到在>60 岁且 LMR≤4.21 的患者中 OS 明显较差。多因素 Cox 回归分析显示，基于年龄分层产生较高和较低 的 LMR 截断值的生物标记物 LMR 为不同年龄段 GBC 患者的 OS 的独立危险因素 （HR：0.272，95%CI：0.105-0.704，P=0.007；和 HR：0.544，95%CI：0.330-0.895， P=0.017）。 结论：术前 LMR 作为 GBC 患者术后 OS 的独立预后指标之一，其最佳截断值具有 一定的年龄依赖性。 中文摘要 背景：竞争性内源性 RNA（competingendogenousRNA，ceRNA）作为一种全新的 基因表达调控模式，认为长链非编码 RNA（longnon-codingRNA，lncRNA）和基 因可以通过竞争性结合微小 RNA（microRNA，miRNA）从而在癌症的发病过程中 发挥重要的调节作用。然而， ceRNA 在肝内胆管细胞癌中的竞争机制尚不完全清楚。 材料和方法：通过检索 NCBIGEO 数据库获得有关人类肝内胆管细胞癌（intrahepatic cholangiocarcinoma，ICC）的 lncRNA、miRNA 和 mRNA 数据集表达数据。对上述 数据集进行差异表达分析并取交集以获得 ICC 差异表达的 lncRNA、miRNA 和 mRNA。通过差异表达的 lncRNA 和 mRNA 共表达分析、miRNA 靶基因预测分析 和 ceRNA 关系整合的方法构建与 ICC 相关的 ceRNA 调节网络（ceRNAregulating network，ceRNET），并对网络中的差异表达 mRNA 进行功能富集分析。然后根据 差异表达 RNA 的网络节点排名和在各 GEO 数据集之间的表达趋势是否一致，结合 其倍数变化的对数值（logfoldchange，logFC）及 ceRNA 关系，以及既往在其他肿 瘤中的研究结果，得到我们要验证的与 ICC 相关的核心调节通路。将此调节通路分 别用 ICC 患者的 10 对新鲜癌组织和癌旁组织、10 例外周血浆标本及 10 名配对的 健康受试者的外周血浆标本和 88 例 ICC 患者的石蜡切片标本进行实时定量聚合酶 链式反应、免疫印迹实验和免疫组织化学染色进行验证。 结果：构建的 ICC 相关 ceRNET 包含 340 个 lncRNA-miRNA-mRNA 调控关系，对 ceRNET 中的 44 个差异表达 mRNA 进行 GO 分析显示它们主要富集在“上皮细胞 增殖的负调控”和“活化的 T 淋巴细胞的增殖的正调控”等生物学过程，KEGG 分 析显示它们主要富集在“补体和凝血级联”通路。RP11-328K4.1-hsa-miR-27a3p-PROS1 是本研究确定的与 ICC 相关的 ceRNET 中的核心调节通路。分子生物学 实验结果显示：相对于正常对照，lncRNARP11-328K4.1 在 ICC 患者的癌组织和外 周血浆中显著低表达（p<0.05）；hsa-miR-27a-3p 在 ICC 患者的癌组织和外周血浆中 显著高表达（p<0.05）；mRNAPROS1 在 ICC 患者癌组织中显著低表达（p<0.05），然而在外周血浆中无明显降低（p>0.05）。mRNA 对应的蛋白在 ICC 患者的癌组织 中虽表达略有降低，但在 ICC 患者的外周血中表达确稍升高，差异均无统计学意义 （p>0.05）。ICC 患者的石蜡切片免疫组化染色显示，相较于癌旁组织，PROS1 蛋 白在癌组织中染色为阳性。 结论：构建 ceRNET 是研究 ICC 发病机制的有效手段，ICC 的发生与上皮细胞和活 化的 T 淋巴细胞的增殖的调控有关，补体和凝血级联通路参与了 ICC 的发病过程。 lncRNARP11-328K4.1的表达上调可通过海绵吸附作用去除致癌性miRNAhsa-miR27a 对 mRNAPROS1 表达的抑制，从而发挥 lncRNARP11-328K4.1 在 ICC 中的抑 癌基因的角色。核心调节通路中的 lncRNARP11-328K4.1，miRNAhsa-miR-27a-3p 和 mRNAPROS1 均为 ICC 相关的 ceRNET 中的连接度较高的中枢节点，是今后研 究和发现 ICC 患者诊断、预后和治疗靶点的理想候选生物标记物。

Abstract AIM To investigate the prognostic role of preoperative fibrinogen-to albumin ratio (FAR) on patients with gallbladder cancer(GBC)in this study. METHODS One hundred and fifty-four GBC patients were retrospectively analyzed, who received surgery in our hospital from March 2005 to December 2017. Receiver operating characteristic curve (ROC curve) was used to determine the optimal cut-offs for these biomarkers including preoperative fibrinogen to albumin ratio. Univariate Kaplan-Meier and multivariate Cox regression analyses were used to perform prognostic analysis of patients with GBC. RESULTS ROC curve revealed that the optimal cut-off value for preoperative FAR was 0.08. preoperative FAR was significantly correlated with age ( P= 0.045), jaundice ( P< 0.001), differentiation ( P = 0.002), resection margin status ( P < 0.001), T stage ( P < 0.001), TNM stage ( P< 0.001), and CA199 ( P< 0.001) as well as albumin levels ( P< 0.001).Multivariate analysis indicated that the resection margin status[hazard ratio (HR): 2.343, 95% confidence interval (CI): 1.532-3.581, P < 0.001], TNM stage ( P = 0.035), preoperative albumin level (HR = 0.595, 95%CI: 0.385-0.921, P= 0.020) and FAR (HR: 2.813, 95%CI: 1.765-4.484, P < 0.001) were independent prognostic factors in GBC patients. CONCLUSION An elevated preoperative FAR was significantly correlated with unfavorable overall survival(OS)in GBC patients, while an elevated preoperative albumin level was a protective prognostic factor for patients with GBC. The preoperative FAR could be used to predict the prognosis of GBC patients,which was easily accessible, cost effective and noninvasive. Abstract AIM To investigate the prognostic value of the combination of preoperative plasma fibrinogenandCA199inpatientswithgallbladdercarcinoma(GBC). METHODS The clinicopathological data of 154 GBC patients were retrospectively reviewed after surgery. A receiver operating characteristic (ROC) curve was plotted to verify the optimum cut-off values for plasma fibrinogen and CA199. Univariate and multivariate survival analyses were performed to identify the factors associated with GBC prognosis. based on the relative value of hazard ratios(HRs) calculated via multivariate survival analyses, patients with elevated plasma fibrinogen and CA199 levels were allocated a score of 2.1; those with an elevated plasma fibrinogen level only were allocated a score of 1, those with an elevated CA199 level only were allocated a scoreof1.1,andthosewithneitheroftheseabnormalitieswereallocatedascoreof0. RESULTS ROC curve analysis showed that the optimum cut-off values for preoperative plasma fibrinogen and CA199 were 3.47 g/L and 25.45 U/mL, respectively. Multivariate analysis indicated that elevated preoperative plasma fibrinogen and CA199 levels were significantly correlated with worse overall survival (OS) (HR = 1.711, 95% confidence interval(CI): 1.114-2.627, P = 0.014, and HR = 1.842, 95%CI: 1.111-3.056, P = 0.018). When we combined these two parameters, the area under the ROC curve increased from 0.735(for preoperative plasma fibrinogen only) and 0.729(for preoperativeCA199 only) to 0.765. When this combined variable was added to the multivariate analysis, the combination of plasma fibrinogen and CA199 ( P<0.001), resection margin (P< 0.001) and TNM stage(P=0.010)were independent prognostic factors for GBC patients. CONCLUSION The combination of plasma fibrinogen and CA199 may serve as a more efficient independent prognostic biomarker for postoperative GBC patients than either parameter alone. Abstract Background: The purpose of the study is to discuss the prognostic value of lymphocyte-to-monocyte ratio(LMR)in patients with gallbladder carcinoma(GBC). Methods:In this study,we made a collection of154 consecutiveGBC patients who were hospitalized in our hospital for surgery from 2005 to 2017 retrospectively. Divide the lymphocyte count by the monocyte count in preoperative peripheral blood so as to calculate the LMR of preoperative blood samples. Employ receiver operating characteristic (ROC) curve in order to obtain the optimal cut-off value of LMR in overall survival (OS) determination. Utilize Kaplan-Meier method so as to assess OS and log-rank test compare difference in survival in different patitent groups. Conduct Univariate and multivariate Cox regression analyses to make detection of independent prognostic indicators for the GBC patients. Results: The ROC curve indicates that the optimal cut-off point for the LMR in preoperative peripheral blood reached 4.76. Compared to those with an LMR >4.76 (hazard ratio (HR): 0.399, 95% confidence interval (CI): 0.265–0.602, P<0.001), GBC patients who are≤60years old with an LMR ≤4.76hasevidentlyworseOS;nevertheless, the prognostic value of LMR has no detection among the whole study cohort or in patients>60yearsold(both P>0.05).Compared to those with an LMR>4.21(HR:1.830, 95% CI: 1.129–2.967, P=0.014), we have observed obviously poorer OS in patients >60 years with an LMR ≤4.21. Multivariate Cox regression analysis showed that biomarker LMR which yielded higher and lower LMR cutoff values based on age stratification was independent risk factor for OS in GBC patients of different age groups (HR: 0.272, 95% CI:0.105–0.704,P=0.007;HR:0.544,95%CI:0.330–0.895,P=0.017). Conclusions: LMR was an independent prognostic indicator of GBC patients, of which the optimal cut-off value has certaindependence on age Abstract Background: Competitive endogenous RNA (ceRNA) is a novel gene expression regulation model, and it is believed that long non-coding RNA(lncRNA) and genes can competitively bind microRNAs (microRNAs, miRNA) thus plays an important regulatory role in the pathogenesis of cancer. However, the competitive mechanism of ceRNA in intrahepatic cholangiocarcinoma is not fully understood. Materials and Methods: The lncRNA, miRNA and mRNA dataset expression data of ICC were obtained through retrieving the NCBI GEO database. The differential expression of the above datasets was analyzed and the intersections were taken, so as to obtain the differentially expressed lncRNAs, miRNAs and mRNAs of ICC. In addition, the ICC-related ceRNA regulating network (ceRNET) was constructed through co-expression analysis of the differentially expressed lncRNAs and mRNAs, miRNA target gene prediction analysis, and ceRNA relationship integration; besides, the differentially expressed mRNAs in the network were performed functional enrichment analysis. Subsequently, the ICC-related core regulatory pathway to be verified was obtained according to the network node ranking of the differentially expressed RNAs and consistency of the expression trend of each GEO dataset, based on the relationship of log-fold change (logFC) with ceRNA as well as the previous research results in other tumors. Afterwards, such regulatory pathway was experimentally verified using 10 pairs of fresh carcinoma and para-carcinoma tissues from ICC patients, 10 peripheral plasma specimens from ICC patients and matched peripheral plasma specimens from 10 healthy subjects, as well as 88 paraffin sections from ICC patients through real-time quantitative polymerase chain reaction(PCR),Western blotting and immunohistochemicalstaining. Results: The constructed ICC-related ceRNET had contained 340 lncRNA-miRNAmRNA regulatory relationships. GO analysis of the 44 differentially expressed mRNAs in ceRNET suggested that, they were mainly enriched in the biological processes such as “negative regulation of epithelial cell proliferation” and “positive regulation of the activated T-lymphocyte proliferation”; in addition, KEGG analysis indicated that they were mainly enriched in the “complement and coagulation cascade” pathway. RP11328K4.1-hsa-miR-27a-3p-PROS1 was the ICC-related core regulatory pathway in ceRNET determined in this study. Molecular biological experiment verified that, compared with normal control, lncRNA RP11-328K4.1 expression in cancer tissues and peripheral plasma of ICC patients was down-regulated, and the differences were statistically significant (p=0.000007 and 0.036093). hsa-miR-27a-3p expression in cancer tissues and peripheral plasma of ICC patients was up-regulated, and the differences were of statistical significance (p= 0.00016 and 0.049420345). Meanwhile, low mRNA PROS1 expression could be detected in cancer tissues and peripheral plasma of ICC patients, and the difference between cancer and para-carcinoma tissues was statistically significant (p=0.006611), while that between peripheral plasma was not statistically significant (p=0.171259). The expression of proteins corresponding to mRNA PROS1 was down-regulated relative to that of adjacent normal tissues, whereas, in the peripheral plasma of ICC patients was up-regulated relative to that of normal subjects, but the difference was not statistically significant in either group (p=0.668353048 and 0.597799476); in the ICC paraffin pathological sections, the staining of protein PROS1 incancertissueswaspositivecomparedwiththatinpara-carcinomatissues. Conclusions: Constructing ceRNET is an effective approach to investigate the pathogenesis of ICC. The occurrence of ICC is related to the regulation of proliferation of epithelial cells and the activated T lymphocytes, and the complement and coagulation cascade pathway is involved in the pathogenesis of ICC. The up-regulated lncRNA RP11-328K4.1 expression can remove the suppression of the oncogenic miRNA hsa-miR-27a on mRNA PROS1 expression through the sponge adsorption effect, thus exerting the role of lncRNARP11-328K4.1 in ICC as a tumor suppressor gene. lncRNA RP11-328K4.1, miRNA hsa-miR-27a-3p and mRNA PROS1 in the core regulatory pathway are the ICC-related pivot nodes with high connectivity in ceRNET, which are the ideal candidate biomarkers to investigate and discover the diagnostic, prognostic and therapeutic targets forICC patients in the future.