Nanotherapy: New Approach for Impeding Hepatic Cancer Microenvironment via Targeting Multiple Molecular Pathways

Objective: Hepatocellular carcinoma (HCC) microenvironment has been recognized as a key contributor for cancer progression, metastasis, and drug resistance. The crosstalk between tumor cells, the vascular endothelial growth factor (VEGF), and the chemokine (C-C motif) ligand 2 (CCL2) signaling networks mediates immunoinhibitory impact and facilitates tumor angiogenesis. The current investigation aimed at exploring the potent anti-cancer activity of the newly designed nano-based anti-cancer therapy comprising anti-VEGF drug, avastin (AV), and CCR2 antagonist (CR) to counteract HCC and tracking its mode of action in vivo. Methods: The prepared AV, CR, and AVCR nanoprototypes were characterized by nanoscale characterization techniques in our previous work. Here, they are applied for unearthing their anti-cancer properties / mechanisms in hepatic cancer-induced rats via analyzing protein levels and genetic expression of the elements incorporated in the angiogenesis, apoptosis, and metastasis signalling pathways. Results: The present results revealed a significant down-regulation in the angiogenesis, survival and metastasis indices along with up-regulation in the pro-apoptotic mediators upon treatment of hepatic cancer-bearing rats with the novel synthesized nanomaterials when compared with the untreated counterparts. We showed across HCC model that anti-VEGF in combination with CCR2 antagonism therapy leads to sensitization and enhanced tumor response over anti-VEGF or CCR2 antagonism monotherapy, particularly in its nanoscale formulation. Conclusion: The present approach provides new mechanistic insights into the powerful anti-hepatic cancer advantage of the novel nanoprototypes which is correlated with modulating critical signal transduction pathways implicated in tumor microenviroment such as angiogenesis, apoptosis and metastasis. This research work presents a substantial foundation for future studies focused on prohibiting cancer progression and recovery by targeting tumor microenviroment.     

Role of surgical treatments in high-grade or advanced gastroenteropancreatic neuroendocrine neoplasms

Over the last 40 years, the incidence and prevalence of gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) have continued to increase. Compared to other epithelial neoplasms in the same organ, GEP-NENs exhibit indolent biological behavior, resulting in more chances to undergo surgery. However, the role of surgery in high-grade or advanced GEP-NENs is still controversial. Surgery is associated with survival improvement of well-differentiated high-grade GEP-NENs, whereas poorly differentiated GEP-NENs that may benefit from resection require careful selection based on Ki67 and other tissue biomarkers. Additionally, surgery also plays an important role in locally advanced and metastatic disease. For locally advanced GEP-NENs, isolated major vascular involvement is no longer an absolute contraindication. In the setting of metastatic GEP-NENs, radical intended surgery is recommended for patients with low-grade and resectable metastases. For unresectable metastatic disease, a variety of surgical approaches, including cytoreduction of liver metastasis, liver transplantation, and surgery after neoadjuvant treatment, show survival benefits. Primary tumor resection in GEP-NENs with unresectable metastatic disease is associated with symptom control, prolonged survival, and improved sensitivity toward systemic therapies. Although there is no established neoadjuvant or adjuvant strategy, increasing attention has been given to this emerging research area. Some studies have reported that neoadjuvant therapy effectively reduces tumor burden, improves the effectiveness of subsequent surgery, and decreases surgical complications.     

脾脏ARFI弹性联合血小板计数预测乙肝肝硬化食管静脉曲张的价值

目的 本研究应用声辐射力脉冲成像(Acoustic Radiation Force Impulse ARFI)技术对慢性乙型肝炎肝硬化患者进行脾脏弹性检测和分析,探讨和对比脾脏ARFI弹性及脾脏ARFI弹性联合血小板计数(Platelet Count PC)在预测乙肝肝硬化食道静脉曲张的临床应用价值。方法 对232例慢性乙型肝炎肝硬化患者应用ARFI技术检测脾脏实时超声弹性,并测量PC,所有患者均于检测前后一周内行胃镜检查明确食管静脉曲张情况,以胃镜结果为金标准,应用受试者工作特征(receiver operating characteristic, ROC)曲线比较脾脏ARFI弹性、PC、及脾ARFI弹性联合PC诊断肝硬化食管静脉曲张的临床价值。结果 食道静脉曲张组脾脏ARFI弹性和PC分别为3.52(3.16-3.87)m/s 和62(41-88.25),无食道静脉曲张组脾脏ARFI弹性和PC分别为2.91(2.35-3.35)m/s和129.5(87.25-196.25)。脾脏ARFI弹性和PC在两组间比较的差异均具有统计学意义(P＜0.001 )。单独脾脏ARFI弹性及脾脏ARFI弹性联合PC的ROC曲线下面积分别为0.76和0.83,差异具有统计学意义(P = 0.0021)。结论 脾脏ARFI弹性测值联合PC较单纯脾脏ARFI弹性能更准确的无创预测慢性乙型肝炎肝硬化食管静脉曲张的存在,具有良好的临床应用前景。     

扶正化瘀方含药血清对肝星状细胞activinA/smad信号通路活化的影响

目的　探讨扶正化瘀方含药血清对肝星状细胞（HSC）激活素A（activinA）/smad信号通路活化的影响。方法　20只SD大鼠按照随机数字表法分为对照组及扶正化瘀（Fzhy）-低、中、高剂量含药血清组，每组5只，分别以蒸馏水，0.75、1.5、3.0 g/kg扶正化瘀溶液（扶正化瘀胶囊药物粉末与蒸馏水配制）灌胃1次/d，连续3 d，取血制备空白血清（对照组）和含药血清。以大鼠HSC-T6细胞为研究对象，分别用5%、10%、20%体积分数的各组含药血清培养细胞。CCK-8检测细胞存活率，选取细胞存活率在50%左右的体积分数重新分为对照组及Fzhy-低、中、高剂量组。流式细胞术检测细胞周期及凋亡率、线粒体膜电位变化和活性氧（ROS）水平；实时荧光定量聚合酶链反应检测细胞中activinA、smad3、samd7、核因子（NF）-κB的mRNA水平；蛋白质印迹法检测细胞中activinⅡA受体（ActRⅡA）、smad3、NF-κB p65、胱天蛋白酶（caspase）-3的蛋白水平。结果　各扶正化瘀含药血清组的细胞存活率均低于对照组（P＜0.05），选择体积分数为10%的含药血清进行后续实验。对照组和各扶正化瘀方含药血清组细胞周期和凋亡率差异均无统计学意义。对照组及Fzhy-低、中、高剂量组细胞内ROS水平及线粒体膜电位水平降低比例逐次升高（P＜0.05）。与对照组比较，Fzhy-中、高剂量组smad3 mRNA表达水平降低，smad7 mRNA升高，Fzhy-低、中、高剂量组NF-κB、activinA mRNA，smad3、NF-κB p65、ActRⅡA蛋白表达水平降低，Fzhy-低剂量组、中剂量组caspase-3蛋白表达水平升高（P＜0.05）；与Fzhy-低剂量组相比，Fzhy-中、高剂量组smad3 mRNA表达水平降低，Fzhy-中剂量组activinA及smad7 mRNA升高（P＜0.05）。结论　扶正化瘀方含药血清可通过影响HSC-T6细胞增殖、参与细胞的氧化应激以及调节细胞activinA/smad信号转导通路来实现抗纤维化作用。     

奥美拉唑的不良反应及其与其他药物间的相互作用研究

目的探究奥美拉唑所引起的不良反应及其与其他药物间的相互作用。方法122例接受奥美拉唑治疗并出现不良反应的患者,分析患者所处的环境状况、情绪状况、过敏史、年龄、过敏体质、生活习惯、饮酒情况等临床资料,探讨不良反应的发生原因,并分析不良反应累及系统分布情况及临床症状、导致不良反应的药物使用类型以及预后情况。结果122例奥美拉唑所致不良反应患者中,男性患者、年龄40~50岁、过敏体质、过敏史、情绪不稳定、药后饮酒、环境状况差占比相对较高。122例患者奥美拉唑所致不良反应中免疫系统占27.87%、消化道系统占23.77%、心脑血管系统占7.38%、神经系统占9.02%、血液系统占21.31%、肝胆系统占10.66%。患者常见临床症状为皮疹、瘙痒、皮炎、过敏性休克、恶心、呕吐、腹泻、心动过速、心律不齐、头晕、头痛、意识模糊、血小板下降、白细胞减少、血尿、肝功能障碍等。奥美拉唑与抗癫痫药苯妥英、抗惊厥药卡马西平、抗焦虑抗癫痫药地西泮以及安替比林药物相互作用,会使机体代谢功能降低,其发生可能与抑制钠离子内流有关。结论奥美拉唑所致不良反应会累及机体多个系统,因此医护人员应加强对患者的问诊,了解患者的相关情况,设计合理的用药方案,减少不良反应的发生。     

逐级减压套扎法治疗胃底静脉曲张临床观察

目的比较逐级减压套扎法与硬化剂治疗胃底静脉曲张的疗效差异,以期为临床提供参考。方法选择萍乡市第二人民医院消化内科2018年9月～2019年3月收治的胃底静脉曲张病例80例,随机分为两组,每组各40例,治疗组采取逐级减压套扎治疗。对照组采用传统硬化剂注射法治疗。治疗结束后比较两组患者治疗有效率、并发症发生情况、静脉曲张消除率及再出血率。结果 (1)治疗后,治疗组总有效率高于对照组,差异有统计学意义(P0.05)。(2)两组间并发症发生率比较,差异均无统计学意义(均P0.05)。(3)首次治疗后治疗组静脉曲张消除率高于对照组,两组差异具有统计学意义(P0.05)。全部患者随访3个月,治疗组再出血率低于对照组,两组差异具有统计学意义(P0.05)。结论逐级减压套扎法革新手术方式明显提高疗效,减少复发率,减轻患者负担,具有明显的实用性和先进性,值得在医疗机构推广,尤其是在基层医院,具有良好的社会效益和经济效益。     

系统免疫炎症指数和骨骼肌质量指数与肝硬化合并肝癌患者术后预后的关系

目的:探讨系统免疫炎症指数（SII）和骨骼肌质量指数（SMI）与肝硬化合并肝癌患者术后预后的关系。方法:选取2015年1月至2017年12月我院收治的128例肝癌合并肝硬化患者。比较不同水平SII和SMI组患者临床病理特征和预后，分析影响肝硬化合并肝癌患者术后预后的危险因素。结果:术前SII高水平组的BCLC分期、脉管癌栓占比、低分化占比高于低水平组，差异均有统计学意义（P＜0.05）。术前SMI高水平组的年龄、美国麻醉医师协会分级、BCLC分期、肿瘤个数、脉管癌栓占比均低于或少于低水平组，差异有统计学意义（P＜0.05）。术前SII低水平组1年、2年、3年累积总生存率分别为90.8%、75.5%、47.3%，术前SII高水平组1年、2年、3年累积总生存率分别为70.7%、58.2%、39.1%，差异有统计学意义（P=0.045）。术前SMI低水平组1年、2年、3年累积总生存率分别为73.3%、55.3%、34.8%，术前SMI高水平组1年、2年、3年累积总生存率分别为90.4%、77.8%、49.7%，差异有统计学意义（P=0.010）。Cox多因素分析结果显示，BCLC B-C期、多发肿瘤、低分化、脉管癌栓、术前高水平SII是患者术后预后的独立危险因素（P＜0.05），根治性切除和术前高水平SMI是其独立保护因素（P＜0.05）。结论:术前SII和SMI水平与肝硬化合并肝癌患者预后密切相关，高水平SII是其独立危险因素，而高水平SMI是其独立保护因素。     

Recent advances in preclinical in vitro approaches towards quantitative prediction of hepatic clearance and drug-drug interactions involving organic anion transporting polypeptide (OATP) 1B transporters

Hepatic uptake mediated by organic anion transporting polypeptide (OATP) 1B1 and 1B3 can serve as a major elimination pathway for various anionic drugs and as a site of drug-drug interactions (DDIs). This article provides an overview of the in vitro approaches used to predict human hepatic clearance (CL_h) and the risk of DDIs involving OATP1Bs. On the basis of the so-called extended clearance concept, in vitro–in vivo extrapolation methods using human hepatocytes as in vitro systems have been used to predict the CL_h involving OATP1B-mediated hepatic uptake. CL_h can be quantitatively predicted using human donor lots possessing adequate OATP1B activities. The contribution of OATP1Bs to hepatic uptake can be estimated by the relative activity factor, the relative expression factor, or selective inhibitor approaches, which offer generally consistent outcomes. In OATP1B1 inhibition assays, substantial substrate dependency was observed. The time-dependent inhibition of OATP1B1 was also noted and may be a mechanism underlying the in vitro–in vivo differences in the inhibition constant of cyclosporine A. Although it is still challenging to quantitatively predict CL_h and DDIs involving OATP1Bs from only preclinical data, understanding the utility and limitation of the current in vitro methods will pave the way for better prediction.