Leptin role in advanced lung cancer. A mediator of the acute phase response or a marker of the statu

科学技术进步奖公示内容一、项目名称：Leptin与SIRT1在骨肉瘤及骨转移瘤中的作用机制研究二、提名单位：河北省卫生和计划生育委员会三、项目简介：本研究应用Leptin与SIRT1对骨肉瘤细胞进行实验，采用蛋白质印迹法检测细胞中相关蛋白的表达；流式细胞技术检测各组细胞凋亡；采用MTT 比色法测定细胞增殖率；免疫组化检测Leptin与SIRT1在骨肉瘤标本中的表达；进行临床资料随访，完善相关临床病例的回顾，得出数据进行统计学分析。

应用Leptin对肺癌细胞侵袭转移的机制进行研究，发现Leptin 可通过促进肺癌细胞发生上皮间质转化（Epithelial-mesenchymal transition，EMT）促进肺癌细胞侵袭、骨转移。

应用免疫组化方法检测Leptin及其受体在肺癌及骨转移瘤中的表达，完善相关临床资料及随访结果进行数据统计分析。

本研究证实了Leptin与SIRT1对骨肉瘤细胞有促进增值、侵袭、转移的作用；Leptin与SIRT1免疫组化结果可以作为骨肉瘤的预后指标；Leptin与SIRT1均可以促进EMT的发生发展；Leptin 可以促进肺癌发生骨转移，可以作为肺癌及骨转移瘤的预后指标。

Leptin与SIRT1有可能成为骨肉瘤及骨转移瘤的药物设计靶点。

四、全部完成人及技术贡献（公示内容包括姓名、排名、技术职称、工作单位、对本项目技术创造性贡献、曾获科学技术奖励情况）：1、冯和林第一副主任医师河北医科大学第四医院指导临床及基础试验的设计，审核数据及统计分析结果，论文撰写与修改2、张宁第二副主任医师河北医科大学第四医院基础实验，统计分析，论文撰写与修改3、吴宏增第三主治医师河北医科大学第四医院观察病例，收集数据，论文撰写4、许建发第四主治医师河北医科大学第四医院基础实验，收集数据，统计分析，论文撰写5、张进明第五副主任医师河北医科大学第四医院观察病例，收集数据，论文撰写五、主要完成单位及创新推广贡献、推广应用及经济社会效益情况：Leptin与SIRT1免疫组化结果可以作为骨肉瘤及骨转移瘤的预后指标，在临床工作中能够以操作简单、价格便宜的方式创造出最大的社会效益。

三阴性乳腺癌是指雌激素受体（ER ）、孕激素受体（PR ）和人表皮生长因子受体（HER-2）均为阴性的一类乳腺癌，具有肿瘤体积大、分化低、转移率和复发率高等特点，发病率占乳腺癌总数的15%~25%［1-3］，并且呈现出较高的致死率［4-5］。

乳腺癌的治疗方式主要包括乳房切除、化疗、放疗以及联合疗法等［6］。

与其他乳腺癌相比，三阴性乳腺癌易发生远处转移且无靶向治疗药物，主要依赖化疗方法［7-9］，但总体预后较差，5年存活率低于30%［3］，且存在较高的复发风险［10］。

目前，临床上应用的Preparation of warangalone-loaded liposomes and its inhibitory effect on breast cancer cellsMAO Lianzhi 1,LIU Huiping 2,LIU Huahuan 1,BIAN Zhongbo 1,ZHANG Qiuyu 1,LIAO Wenzhen2,SUN Suxia 11Department of Nutrition and Food Hygiene,School of Public Health,Southern Medical University,Guangzhou 510515,China;2ERA (Shenzhen)Biotechonology,Shenzhen 518000,China摘要：目的制备和鉴定攀登鱼藤异黄酮温敏脂质体并研究其抗乳腺癌作用。

方法MTT 法检测攀登鱼藤异黄酮、大豆异黄酮和金雀异黄酮对人乳腺癌细胞（MDA-MB-231、MCF7、SKBR3）增殖活性影响；克隆形成实验探讨攀登鱼藤异黄酮对三阴性乳腺癌细胞（MDA-MB-231）克隆形成的影响；细胞划痕实验检测MDA-MB-231细胞迁移；蛋白印迹法检测MDA-MB-231细胞迁移和侵袭蛋白MMP2，MMP9表达量；薄膜水化法制备温敏脂质体及攀登鱼藤异黄酮温敏脂质体；透射电子显微镜、动态光散射扫描仪以及紫外分光光度计分别鉴定攀登鱼藤异黄酮温敏脂质体形貌、粒径、包封率及稳定性，并用MTT 法检测攀登鱼藤异黄酮温敏脂质体抗小鼠乳腺癌细胞（4T1）增殖活性。

褪黑素对脂多糖诱导的脓毒症大鼠肺损伤的保护作用宋洁琼;吴威;陈嵩;诸杜明;钟鸣【摘要】Objective:To investigate the protective effects of melatonin (MT)on lung injury induced by lipopolysaccharide (LPS)in rats with sepsis.Methods:Seventy-two rats were randomly divided into four groups with 18 rats in each group:control group (0.9%NS,i.v.),LPS group (LPS 1 mg/kg,i.v.),LPS+MT1 group (MT 0.1 mg/kg+LPS 1 mg/kg,i.v.)and LPS+MT2 group (MT 1 mg/kg+LPS 1 mg/kg,i.v.).Carotid arterial blood of all rats was collected at 6 h after administration and serum levels of tumor necrosis factor-α(TNF-α),interleukin-6 (IL-6)and interleukin-10 (IL-10) were detected by enzyme linked immunosorbent assay (ELISA ).The lung homogenate contents of superoxide dismutase (SOD),malondialdehyde(MDA)and myeloperoxidase (MPO)were also examined.Results:Compared with control group, the levels of serum TNF-α,IL-6 and IL-10 were significant higher in LPS group (P<0.01).With the MT intervention,the levels of TNF-αand IL-6 were significantly decreased but the IL-10 level was remarkably increased (P<0.05).This effect was more remarkable with the increase of the dose of MT.The level of SOD in LPS group was remarkably lower than in control group,but the levels of MDA and MPO were significantly higher(P<0.01).Compared with LPS group,the level of SOD in LPS+MT1 group was significantly increased,however,the contents of MDA and MPO were decreased (P<0.05).The same trend was more prominent in LPS+MT2 group.Conclusions:MT can decrease the lung injury by reducing theinflammatory response and lipid peroxidation induced by LPS in rats with sepsis.The protective effect was positively associated with the dose of MT.%目的：探讨褪黑素（MT）对脂多糖（LPS）诱导的脓毒症大鼠肺损伤组织的保护作用。

慢性肾衰竭血清瘦素、胰岛素样生长因子—1水平及意义瘦素(Leptin)是近几年来发现的一种由脂肪细胞产生的蛋白，它对调节机体食欲、体重和器官的能量消耗有重要作用。

肾脏是瘦素清除的主要器官，同时瘦素又可对肾脏直接发挥作用。

瘦素是慢性肾功能不全(CRF)时体内聚积的毒素之一，它与胰岛素样生长因子-1(IGF-1)共同作用于慢性肾功能衰竭患者的营养状况。

本文主要探讨慢性肾功能衰竭(CRF)血清瘦素和IGF-1的水平及意义。

一瘦素研究概况1994年hzang等首次鉴定并克隆出了人的肥胖基因，其与小鼠具有高度同源性，同时发现该基因编码的一种含167个酸的蛋白，分子量为16KD，为ob基因的表达产物，被命名为瘦(Leptin)[1]。

瘦素的生理功能包括:感受机营养状态[2]，进而抑制食物摄入:刺激或维持能量消耗;影响生殖泌系统;作为一种代谢激素促进一系列代谢过程，如胰岛素释放、糖的解作用、转运等。

瘦素缺乏或瘦素受体缺陷可导胖和垂体功能异常。

二 RCF患者血浆瘦素的变化及影响因素近期的研究认为肾功能衰竭患者同肥胖患者一样，血浆瘦素水平常明显高于正常。

由于瘦素分子量是16KD，可能通过肾小球滤过，假设人的瘦素清肾脏，那么有人做了这方面的研究，KumarS等测定了不同程度能损伤患者的主动脉和肾静脉血浆瘦素水平，发现瘦素的清除在与肾功能有关，同时连续测量通过肾脏的不同浓度和肾血流比率，计算出肾脏瘦素的净排出率为480ng/min，同时也发现在中度肾损伤患者肾脏没有瘦素清除[3]，另外监测到尿的瘦素水平低也表明在肾脏降解。

人体处于炎症状态时常常会表现食欲下降，有人用CRP(反应蛋白)增高代表机体存在炎症，研究发现尿毒症患者CRP瘦素确有相关关系，CRP高的患者往往血浆瘦素水平也高。

同时调查蛋白质摄入情况发现，CRP高的患者蛋白质摄入明显低于CRP正常患者。

提示炎症所致的食欲下降与它引起的瘦素增高有关[4]。

三瘦素水平相对增高对CRF病人的影响瘦素对慢性肾衰患者的不利影响可能不止是对机体营养状态的，瘦素增高交感神经兴奋性可能参与了慢性肾衰患者的血压异常，并且因为瘦素无法有效清除而致血压难以控制;慢性肾衰患者高瘦素血症与高胰岛素血症可能互为因果，互相促进;可能导致高脂血症。

基于网络药理学探讨白藜芦醇治疗肺癌的生物分子机制 张丽慧，耿其顺，朱子家，王文斌，沈志博，李砺锋，薛文华，赵杰郑州大学第一附属医院，河南郑州 450052摘要：目的 基于网络药理学，运用在线数据库研究白藜芦醇治疗肺癌的潜在作用机制。

方法 通过中药系统药理学数据库与分析平台（TCMSP）、PubChem、SwissTargetPrediction、GeneCards数据库分别获取白藜芦醇和肺癌的相关基因，取二者交集基因，使用String数据库获得交集基因的蛋白相互作用（PPI）网络图，使用DA VID6.8对交集基因进行GO和KEGG富集分析。

采用Cytoscape3.7.2软件构建化合物-靶点-通路-疾病网络模型。

使用AutoDock4.2.6软件对白藜芦醇和重要靶点进行分子对接。

Western blot检测白藜芦醇对人肺癌H1975细胞p-Akt蛋白表达的影响。

结果 获得白藜芦醇和肺癌交集基因78个，PPI网络图表明交集基因关系密切。

富集分析得到生物过程55项、分子功能26项、细胞组分18项，以及86条相关通路，其中以PI3K-Akt 通路富集靶点较多。

分子对接结果显示，白藜芦醇与PIK3CB、PIK3CA这2个重要靶点均能稳定结合。

Western blot检测结果显示，白藜芦醇能够显著降低人肺癌H1975细胞p-Akt蛋白表达。

结论 白藜芦醇可能主要通过作用于PIK3CB、PIK3CA靶点，介导PI3K-Akt信号通路发挥治疗肺癌作用。

关键词：白藜芦醇；肺癌；网络药理学；作用机制；分子对接中图分类号：R273.42；R285 文献标识码：A 文章编号：1005-5304(2021)06-0046-06DOI：10.19879/ki.1005-5304.202004113 开放科学（资源服务）标识码（OSID）：Biomolecular Mechanism of Resveratrol Against Lung Cancer Based on Network Pharmacology ZHANG Lihui, GENG Qishun, ZHU Zijia, WANG Wenbin, SHEN Zhibo, LI Lifeng, XUE Wenhua, ZHAO Jie First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China Abstract:Objective To use the online databases to study the potential mechanism of resveratrol in treating lung cancer based on network pharmacology. Methods The genes related to resveratrol and lung cancer were obtained from TCMSP, PubChem, SwissTargetPrediction and GeneCards database, and the related intersection genes of resveratrol and lung cancer were screened out. The String database was used to draw the PPI network diagram of the intersection genes, and the DA VID 6.8 was used to perform GO and KEGG enrichment analysis. The compound-target-signal pathway-disease network model was constructed by using Cytoscape 3.7.2 software. AutoDock 4.2.6 software was used to perform molecular docking of resveratrol and important targets. Western blot was used to detect the effect of resveratrol on the expression of p-Akt protein in human lung cancer H1975 cell line. Results Totally 78 intersection genes of resveratrol and lung cancer were obtained, and the PPI network diagram showed that there was a close relationship between them. The enrichment analysis mainly obtained 55 biological processes, 26 molecular functions, 18 cellular components, and 86 related pathways, among which the PI3K-Akt pathway enriched the most targets. Molecular docking results showed that resveratrol could stably bind to two important targets, PIK3CB and PIK3CA. Western blot test results showed that resveratrol could significantly reduce the expression of p-Akt protein in human lung cancer H1975 cells. Conclusion Resveratrol may mainly act on the targets of PIK3CB and PIK3CA, and mediates the PI3K-Akt signaling pathway to exert anti-lung cancer action.Keywords: resveratrol; lung cancer; network pharmacology; action mechanism; molecular docking研究表明，肿瘤的发生发展与基因突变及多条信号通路改变有关[1-2]。

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mTORC1/2双重抑制剂OSI -027抑制高氧诱导的肺成纤维细胞增殖和分化*吴黎虹， 唐坤， 党红星△， 符跃强， 刘成军， 李静， 许峰（重庆医科大学附属儿童医院重症医学科，国家儿童健康与疾病临床医学研究中心，儿童发育疾病研究教育部重点实验室，儿科学重庆市重点实验室，重庆 400014）［摘要］ 目的：分析哺乳动物雷帕霉素靶蛋白（mammalian target of rapamycin ， mTOR ）复合物1/2（mTORcomplex 1/2， mTORC1/2）双重抑制剂OSI -027对高体积分数氧（高氧）所致人胚肺成纤维细胞增殖和分化的抑制作用。

方法：高氧（95% O 2）处理人胚肺成纤维细胞MRC -5建立增殖分化模型，分为对照组、高氧组、高氧+OSI -027组和高氧+雷帕霉素组。

Western blot 检测α-平滑肌肌动蛋白（α-smooth muscle actin ， α-SMA ）、I 型胶原蛋白（collagen type I ， Col I ）、增殖细胞核抗原（proliferating cell nuclear antigen ， PCNA ）、细胞周期蛋白D1（cyclin D1）、RhoA 、Rho 相关含卷曲螺旋蛋白激酶1（Rho -associated coiled -coil -containing protein kinase 1， ROCK1）、蛋白激酶B （protein kinase B ， PKB/AKT ）、p -AKT 和mTOR 的表达； CCK -8实验检测细胞活力；流式细胞术检测细胞周期。

结果：与对照组相比，PCNA 、cyclin D1、Col I 和α-SMA 表达随高氧处理时间增加而增加（P <0.05）。

与高氧组相比，OSI -027及雷帕霉素干预后，细胞活力下降，细胞周期被抑制在G 1期（P <0.05）。

抗肿瘤肽的研究及应用Anticancer Peptides: Research and ApplicationAbstract: Anticancer peptides are a promising class of therapeutic molecules that have gained increasing attention in the field of cancer treatment due to their selectivity and potency against cancer cells. In this article, we discuss the latest research and applications of anticancer peptides, including their sources, mechanisms of action, and promising preclinical and clinical data. We also examine the challenges and opportunities facing the field of anticancer peptides.Keywords: anticancer peptides, cancer therapy, peptide drugs, mechanism of action, preclinical research, clinical trials. IntroductionCancer is a major global health challenge, and traditional treatments such as chemotherapy, radiation therapy, and surgery have limitations due to their nonspecific nature and adverse side effects. Anticancer peptides, on the other hand, are a promising class of therapeutic molecules that have shown to be selective and effective against cancer cells with less toxicity. In this review, we discuss the latest research on anticancer peptides, including their sources, mechanisms of action, and promising preclinical and clinical data.Sources of Anticancer PeptidesAnticancer peptides can be found in a variety of sources, includingthe natural defense systems of animals, plants, and microbes, as well as designed peptides based on natural sequences. For example, the amphibian-derived peptide dermaseptin has been shown to exhibit potent anticancer activity through disruption of cancer cell membranes. Similarly, plant-derived peptides such as thionins and cyclotides have shown cytotoxic activity against cancer cells dueto their ability to penetrate the cell membrane. Microbial peptides such as lacticin 3147, designed based on bacterial lantibiotic peptides, have also demonstrated anticancer activity through multiple mechanisms of action.Mechanisms of ActionAnticancer peptides exert their cytotoxic effects through multiple mechanisms of action, including apoptosis, autophagy, necrosis, and senescence. Apoptosis is a programmed cell death mechanism that is activated when a cell is damaged, stressed, or infected. Anticancer peptides can induce apoptosis in cancer cells through various molecular pathways, such as mitochondrial pathway, death receptor pathway, and caspase-independent pathway. Autophagy is a process by which cells recycle damaged or unwanted cellular components through lysosomal degradation. Anticancer peptides such as tachyplesin can induce autophagy in cancer cells, leadingto their death. Necrosis is an uncontrolled form of cell death that occurs after severe cellular trauma or stress. Anticancer peptides can also induce necrosis in cancer cells through their ability to disrupt cell membranes. Senescence is a cellular state of irreversible growth arrest that can prevent the proliferation of cancer cells. Anticancer peptides such as p28 can induce senescence in cancer cells, leading to their growth arrest.Preclinical and Clinical DataPreclinical research on anticancer peptides has shown promising results in vitro and in animal models. For example, the amphibian-derived peptide caerin has shown potent anticancer activity against various cancer cell lines in vitro and reduced tumor growth in mouse xenograft models. Similarly, the microbial peptide lacticin 3147 has shown selective cytotoxicity against cancer cells in vitro and improved survival in mouse models of breast cancer. In addition, several natural and designed peptides have been found to have synergistic effects when combined with conventional chemotherapy drugs.Several anticancer peptides have also advanced to clinical trials, with some showing promising results. For example, the octapeptide d(KLAKLAK)2, which induces apoptosis in cancer cells, has been tested in phase I and phase II clinical trials for treatment of various types of cancer, including glioblastoma and multiple myeloma. Similarly, the cyclic peptide tasidotin has been tested in phase III clinical trials for the treatment of ovarian cancer, with promising results.Challenges and OpportunitiesDespite the promise of anticancer peptides, several challenges remain in their development and application. One challenge is the optimization of peptide pharmacokinetics and pharmacodynamics, including their stability, bioavailability, and selective targeting of cancer cells over normal cells. Another challenge is the high costof peptide production and purification, which can limit their accessibility and affordability. Furthermore, a better understanding of the mechanisms of action and resistance to anticancer peptidesis needed to select patients who are most likely to benefit from these therapies.In conclusion, anticancer peptides represent a promising class of therapeutic molecules for the treatment of cancer, with multiple mechanisms of action and potential for combination therapy. While several peptides have shown promising preclinical and clinical results, further research is needed to optimize their efficacy and safety for widespread clinical application.参考文献：1. Ghosh S et al. Anticancer Peptides: A Perspective. Frontiers in Biology. 2016; 11(1): 49-57.2. Jenssen H et al. Antimicrobial peptides for therapeutic use: obstacles and realistic outlook. Current Opinion in Pharmacology. 2006; 6(5): 468-472.3. Liu C et al. Anticancer Peptides. Biomedical Reports. 2016; 4(3): 319-324.4. Mann S et al. Anticancer peptides: Principles, diversity, and applications. Organic & Biomolecular Chemistry. 2021; 19(4): 668-684.5. Wang Y et al. Anticancer peptides: from design to clinic.Chemotherapy. 2017; 62(1): 1-13.Optimization of Peptide Pharmacokinetics and PharmacodynamicsOne of the major obstacles in the development of anticancer peptides is the optimization of their pharmacokinetics and pharmacodynamics. Peptides are generally less stable and have shorter half-lives than small molecule drugs, which can result in lower bioavailability and poorer pharmacokinetic properties. Peptide stability can be improved through modifications such as cyclization, amino acid substitutions, and the addition of chemical groups such as acetylation or amidation. Peptide bioavailability can be improved through formulations such as liposomes, nanoparticles, or conjugation to other molecules. In addition, selective targeting of cancer cells over normal cells can be achieved through conjugation to tumor-targeting peptides or antibodies.Cost of Peptide Production and PurificationAnother challenge in the development of anticancer peptides is the high cost of peptide production and purification. Peptide synthesis is often complex and time-consuming, requiring multiple steps and specialized equipment. In addition, peptide purification can also be challenging, as peptides can be difficult to separate from impurities. Strategies to reduce the cost of peptide production and purification include developing simplified synthesis methods or producing peptides using recombinant technologies, such as expression in bacteria or yeast.Mechanisms of Action and ResistanceA better understanding of the mechanisms of action and resistance to anticancer peptides is needed to optimize their efficacy and select patients who are most likely to benefit from these therapies. While the mechanisms of action of many anticancer peptides have been studied extensively, the mechanisms of resistance are less well understood. Mechanisms of resistance can include alterations in cellular uptake or efflux of peptides, changes in peptide binding or recognition by cancer cells, and activation of cellular defense mechanisms such as the unfolded protein response or autophagy.Clinical Testing of Anticancer PeptidesDespite these challenges, several anticancer peptides have advanced to clinical testing, with some showing promising results. The octapeptide d(KLAKLAK)2 has been tested in phase I and phase II clinical trials for treatment of various types of cancer, including glioblastoma and multiple myeloma, and has shown encouraging results. The cyclic peptide tasidotin has been tested in phase III clinical trials for the treatment of ovarian cancer, with promising results. In addition, several other peptides are currently in clinical trials, including AMP-514, a designed antimicrobial peptide with anticancer activity.ConclusionAnticancer peptides are a promising class of therapeutic molecules for the treatment of cancer, with multiple mechanisms of action and potential for combination therapy. While several peptides have shown promising preclinical and clinical results, further research isneeded to optimize their efficacy and safety for widespread clinical application. Optimization of peptide pharmacokinetics and pharmacodynamics, reduction of the cost of peptide production and purification, and a better understanding of the mechanisms of action and resistance will be crucial for the successful development of anticancer peptides as a new class of cancertherapies.Optimization of Peptide Pharmacokinetics and Pharmacodynamics:Peptide drugs, including anticancer peptides, face several challenges in terms of their pharmacokinetics and pharmacodynamics. Peptides are rapidly cleared from the bloodstream and can be rapidly degraded by enzymes, leading to a shorter half-life and lower bioavailability. This makes it difficult to achieve effective concentrations of the drug at the site of action within the body. To overcome these challenges, researchers have developed a range of strategies to enhance the pharmacological properties of peptides. For instance, cyclization or other chemical modifications can promote peptide stability, and conjugation to other molecules such as nanoparticles or polymers or coupling with tumor targeting peptides or antibodies can improve peptide distribution and drug efficacy. However, the optimization process still requires extensive preclinical testing and careful balancing of efficacy, toxicity and pharmacokinetics.Cost of Peptide Production and Purification:The cost of producing and purifying peptides can be prohibitive, particularly for rare or complex sequences of amino acids. Traditional synthetic approaches to peptide synthesis are slow andrequire expensive reagents, while biological methods rely on recombinant protein technology, which has its own limitations. To reduce costs, researchers are exploring alternative routes to peptide synthesis, such as incorporating modifications at the genetic level or using innovative methods such as microfluidics or solid-phase peptide synthesis. Purification of peptides from crude mixtures also presents challenges in terms of optimizing the purity and yield of the final product, with some purification techniques being expensive and time-consuming.Mechanisms of Action and Resistance:The mechanisms of action of anticancer peptides can be complex and varied, and some peptides may exert multiple functions, such as inhibiting tumor cell growth or inducing apoptosis. Understanding the specific mechanisms of action for a given peptide is essential for its clinical development, as well as the identification of potential resistance pathways. Some cancer cells are known to be resistant to some peptide drugs due to changes in cellular uptake or efflux, altered peptide binding or recognition, or activation of cellular defense mechanisms. Researchers are currently investigating the molecular mechanisms of resistance to gain deeper insights into how to circumvent these issues.Clinical Testing of Anticancer Peptides:Clinical trials play a critical role in the development of anticancer peptides. Phase I trials are typically used to evaluate the safety and toxicity of a peptide, while Phase II and III trials assess efficacy and drug performance under more realistic treatment scenarios.The clinical testing process for peptides is especially important, given that peptides are a relatively new therapeutic modality and require unique strategies for optimization of pharmacokinetics and pharmacodynamics. Strategies such as combination therapy are also under investigation to enhance the efficacy and reduce the risk of resistance. In addition, researchers are also exploring different cancer indications, including rare or orphan diseases, to identify new opportunities for the development of anticancer peptides. Overall, anticancer peptides hold huge promise as a new class of cancer therapies with multiple mechanisms of action and potential for combination therapy. While challenges still exist in terms of optimizing peptide pharmacokinetics, reducing costs, and developing a better understanding of the mechanisms of action and resistance, clinical trials are underway, suggesting that these peptides may offer a new and promising approach to fighting cancer in the future.。

不可切除胰腺癌的分子靶向药物治疗进展胡润，李俊蒽，姚沛，桂仁捷，段华新湖南师范大学附属第一医院，湖南省人民医院肿瘤科，长沙 410005通信作者：段华新，****************（ORCID： 0000-0001-9596-5013）摘要：胰腺癌作为消化系统最常见的恶性肿瘤之一，其发病率及死亡率正逐年上升，大多数胰腺癌患者因分期较晚而失去了手术机会。

尽管以吉西他滨、氟尿嘧啶为主的化疗方案在一定程度上延长了患者的生存期，但仍有部分患者因无法耐受化疗而失去治疗机会。

随着精准医疗时代的来临，分子靶向药物治疗展现出的优异疗效使其成为对抗肿瘤的重要治疗手段之一，但由于胰腺癌高度的异质性及复杂的免疫微环境，针对胰腺癌的分子靶向治疗并未取得显著效果，因此亟需探寻新的治疗靶点及药物攻克这一难题。

本综述基于胰腺癌常见分子靶点及肿瘤免疫相关靶点探究在不可切除胰腺癌中分子靶向药物治疗研究的最新进展，为胰腺癌患者提供新的治疗策略。

关键词：胰腺肿瘤；分子靶向治疗；免疫疗法基金项目：湖南省自然科学基金（2020JJ8084）Advances in molecular-targeted therapy for unresectable pancreatic cancerHU Run，LI Junen，YAO Pei，GUI Renjie，DUAN Huaxin.（Department of Oncology，The First Affiliated Hospital of Hunan Normal University， Hunan Provincial People’s Hospital， Changsha 410005， China）Corresponding author： DUAN Huaxin，****************（ORCID： 0000-0001-9596-5013）Abstract：Pancreatic cancer is one of the most prevalent malignant tumors of the digestive system， and its incidence and mortality rates are increasing year by year. Most patients with pancreatic cancer are unable to receive surgery due to the advanced stage. Although chemotherapy regimens based on gemcitabine and fluorouracil have prolonged the survival time of patients to some extent，some patients cannot tolerate chemotherapy and hence lose the opportunity for treatment. With the advent of the era of precision medicine， molecular-targeted therapy has exhibited an excellent therapeutic efficacy and has thus become one of the most important treatment techniques for tumors； however， due to the high heterogeneity of pancreatic cancer and its complicated tumor microenvironment， molecular-targeted therapy for pancreatic cancer has not achieved notable results. Therefore， it is imperative to seek new therapeutic targets and medications to overcome this issue. This article reviews the latest advances in the research on molecular-targeted therapy for unresectable pancreatic cancer based on common molecular targets and tumor immunity-related therapeutic targets， in order to provide new treatment strategies for patients with pancreatic cancer.Key words：Pancreatic Neoplasms； Molecular Targeted Therapy； ImmunotherapyResearch funding：Natural Science Foundation of Hunan Province of China （2020JJ8084）胰腺癌是一种起病隐匿、进展迅速、疗效及预后极差的恶性肿瘤，大多数患者确诊时已经属于晚期。

贝伐单抗联合顺铂胸腔灌注治疗肺腺癌恶性胸腔积液张娜，何文娴，杨雪梅，李桂萍，崔妍婷，毋江洪（昆明市第二人民医院肿瘤科，云南昆明650204）［摘要］目的探讨贝伐单抗与顺铂胸腔灌注联合治疗肺腺癌恶性胸腔积液的临床价值。

方法将昆明市第二人民医院2015年8月至2017年8月期间所收治的68例肺腺癌恶性胸腔积液患者，按照计算机表法将其分为研究组和对照组，对照组应用顺铂，研究组在此基础上加用贝伐单抗，对比分析2组治疗1周后的近期疗效，观察2组治疗4周后的胸水血管内皮生长因子（vascular endothelial growth factor ，VEGF ）测定结果与不良反应发生情况。

结果研究组近期总有效率（85.29%）显著高于对照组（61.76%），组间比较有统计学意义（＜0.05），研究组不良反应发生率为23.53%（2例I °骨髓抑制，6例消化道反应），对照组为32.35%（3例I °骨髓抑制，8例消化道反应），研究组治疗后VEGF 水平显著下降，对照组无统计学意义的变化（＞0.05）。

结论贝伐单抗与顺铂胸腔灌注联合治疗肺腺癌恶性胸腔积液的效果明显，能够有效提高患者的近期疗效率，另外，胸水VEGF 也可能作为肺腺癌恶性胸腔积液的疗效检测因素，值得临床应用。

［关键词］贝伐单抗；顺铂胸腔灌注；肺腺癌恶性胸腔积液；血管内皮生长因子［中图分类号］R734［文献标志码］A ［文章编号］2095－610X （2019）04－0117－04Analysis of the Clinical Effects of Bevacizumab Combined withCisplatin Intrapleural Infusion on the Treatment of MalignantPleural Effusion of Lung AdenocarcinomaZHANG Na ，HE Wen-xian ，YANG Xue-mei ，LI Gui-ping ，CUI Yan-ting ，WU Jiang-hong （Dept.of Oncology ，The 2nd People's Hospital of Kunming ，Kunming Yunnan 650204，China ）［Abstract ］Objective To study the clinical value of bevacizumab combined with cisplatin in the treatment of malignant pleural effusion of lung adenocarcinoma.Methods 68patients with malignant pleural effusion of lung adenocarcinoma admitted to our hospital from August 2015to August 2017were included in the study and divided into study group and control group according to computer table method.The control group was given cisplatin,and the study group was given cisplatin and bevacizumab.Then the short-term effects were compared in the two groups after 1week of treatment.The results of vascular endothelial growth factor （VEGF ）measurement and adverse reactions in the pleural effusion after 4weeks of treatment were observed.Results The total effective rate （85.29%）in the study group was significantly higher than that in the control group （61.76%）.There was a statistically significant difference between the two groups.The incidence of adverse reactions in the study group was 23.53%（2cases of I °myelosuppression ，6cases ）of gastrointestinal reaction ，），32.35%in the control group （3cases of I °myelo-suppression ，8cases of digestive tract reaction ）；the VEGF level of the study group decreased significantly after treatment ，and there was no statistically significant change in the control group.Conclusion Bevacizumab com-Journal of Kunming Medical UniversityCN 53-1221R［收稿日期］2018－12－12收稿［基金项目］昆明市卫生科技人才培养暨技术中心建设基金资助项目[2015-SW(技)-32]；昆明市卫生科技人才培养暨“十百千”工程基金资助项目[2015-SW(后备)-37]［作者简介］张娜（1987～），女，山西运城人，医学硕士，主治医师，主要从事恶性肿瘤姑息及内科综合治疗研究工作。

晚期肺癌患者肺部感染病原菌特征及预测模型构建和验证王亚平 李小月［摘 要］　目的　探讨晚期肺癌患者肺部感染的病原菌特征以及预测模型的构建。

方法　统计分析安庆市第一人民医院2019年3月至2021年12月收治的208例晚期肺癌患者肺部感染发生率、感染病原菌分布特点，K-B 扩散纸片法分析病原菌对抗菌药物的耐药性，采用多因素logistic 逐步回归分析患者肺部感染的危险因素，并根据其回归系数构建晚期肺癌肺部感染预测模型，使用受试者工作特征（ROC ）曲线、Hosmer-Lemeshow 检验对预测模型进行效能评估。

结果　208例晚期肺癌患者中，并发肺部感染49例（23.56%），革兰阴性菌37株（60.66%）、革兰阳性菌20株（32.79%）、真菌4株（6.56%）；铜绿假单胞菌、鲍曼不动杆菌、肺炎克雷伯菌对亚胺培南的耐药性低，表皮葡萄球菌、金黄色葡萄球菌对万古霉素、氨苄西林的耐药性低。

logistic 逐步回归分析结果显示，糖尿病、低蛋白血症、KPS 评分<80分、放疗及化疗是晚期肺癌患者肺部感染的危险因素（P <0.05）；患者肺部感染预测模型为P =1/1+exp （-2.686+1.566χ糖尿病+1.838χ低蛋白血症+1.336χKPS 评分+1.236χ放疗+0.874χ化疗），预测模型的ROC 下面积（AUC ）为0.817，且Hosmer-Lemeshow 检验P =0.529。

结论　晚期肺癌患者肺部感染以革兰阴性菌为主，合并糖尿病、低蛋白血症、Karnofsky 评分<80分、放化疗是患者肺部感染的危险因素，基于上述因素建立的预测模型有较高的预测效能。

［关键词］晚期肺癌；肺部感染；病原菌；危险因素；预测模型doi:10.3969/j.issn.1000-0399.2023.04.006Characteristics of lung infection pathogens and construction of prediction model for lung infection in advanced lung cancer WANG Yaping ，LI XiaoyueDepartment of Clinical laboratory,Anqing First People's Hospital,Anqing 246003,ChinaFunding project:Project of Anhui Provincial Department of Science and Technology(NO.201904a 07020016)Correspondingauthor:LIXiaoyue,***************[Abstract] Objective To investigate the characteristics of lung infection pathogens and construction of prediction model in patients with advanced lung cancer. Methods The incidence of lung infection and distribution characteristics of pathogens were statistically analyzed in the 208 patients with advanced lung cancer admitted to Anqing First People ’s Hospital between March 2019 and December 2021. The drug resis⁃tance of pathogens to antibiotics was analyzed by Kirby-Bauer (K-B) method. The risk factors of lung infection were analyzed by multivariate logistic stepwise regression analysis, and the prediction model for lung infection was constructed based on their regression coefficients. The pre⁃dictive efficiency of the model was evaluated by receiver operating characteristic (ROC) curves and Hosmer-Lemeshow test. Results In the 208 patients with advanced lung cancer, there were 49 cases (23.56%) with lung infection. There were 37 strains of Gram-negative bacte⁃ria (60.66%), 20 strains of Gram-positive bacteria (32.79%) and 4 strains of fungi (6.56%). The drug resistance of Pseudomonas aeruginosa, Acinetobacter baumannii and Klebsiella pneumoniae was low to imipenem, and drug resistance of Staphylococcus epidermidis and Staphylococ⁃cus aureus was low to vancomycin and ampicillin. The results of logistic stepwise regression analysis showed that diabetes, hypoproteinemia, KPS score <80 points, radiotherapy and chemotherapy were independent risk factors of lung infection in patients with advanced lung cancer (P <0.05). The prediction model for lung infection was as follows: P =1/1+exp (-2.686+1.566 χdiabetes +1.838 χhypoproteinemia +1.336χKPS score +1.236 χradio⁃therapy+0.874 χchemotherapy ). The area under the ROC curve (AUC) of the prediction model was 0.817 (P =0.529 in Hosmer-Lemeshow test). Conclu⁃sions The main pathogen of lung infection is Gram-negative bacteria in patients with advanced lung cancer. Diabetes, hypoproteinemia, KPS score <80 points, radiotherapy and chemotherapy are independent risk factors of lung infection. The prediction model for lung infection of ad⁃vanced lung cancer constructed based on the above factors has high predictive efficiency.[Key words ] Advanced lung cancer; Lung infection; Pathogen; Risk factors; Prediction model基金项目：安徽省科学技术厅基金项目（编号：201904a07020016）作者单位：246003　安徽安庆　安庆市第一人民医院检验科通信作者：李小月，***************本文引用格式：王亚平，李小月.晚期肺癌患者肺部感染病原菌特征及预测模型构建和验证［J ］.安徽医学，2023，44（4）：388-393.DOI ：10.3969/j.issn.1000-0399.2023.04.006第 44 卷第 4 期 2023 年4 月388安徽医学Anhui Medical Journal第 44 卷第 4 期2023 年4 月安徽医学Anhui Medical Journal肺癌可分为非小细胞肺癌和小细胞肺癌，肺癌中晚期患者已出现癌细胞扩散或病灶转移［1］，可采用化学治疗（简称化疗）和放射治疗（简称放疗）治疗方式，但伴随副作用较强［2］。

白藜芦醇抑制膀胱癌细胞生长增殖及影响miR-34a表达的研究王伟;李覃;李瑛;李辉【摘要】Objective To invesligale the effects of resveralrol on proliferation of human bladder cancer cell line T24,and the role of miR - 34a in its mechanism. Methods T24 cells were trealed with resveralrol in differenl concenlralions for 24 h. Cell proliferation was validated by MTT. Flow cylomelry was used Lo analyse apoptosis. The expression of miR - 34a was delet by real - lime PCR. Results Resveralrol could inhibit the proliferation of T24 in a dose dependenl manner, induce apoplosis and increase the expression of p53 significantly. Furthermore, the level of miR - 34a in T24 cells was higher in resveralrol - trealed group than that in the conlrol group. Conclusions Resveralrol can suppress the proliferation of human bladder cancer cells, which may be allribuled lo inducing apoplosis, up - regulating miR - 34a and p53.%目的观察白藜芦醇( resveratrol,Res) 对人膀胱癌细胞T24 生长增殖的影响,初步探讨miR-34a 在Res影响T24 细胞中的作用.方法不同浓度Res分别作用T24细胞24 h,采用甲基噻唑基四唑(methyl thiazolyl tetrazolium,MTT)法检测细胞增殖,流式细胞术检测细胞凋亡,Western blotting检测p53蛋白水平,实时定量PCR(Real-time PCR)检测T24 细胞miR-34a 的基因表达.结果 Res剂量依赖性地抑制T24细胞增殖,诱导细胞凋亡,明显增加p53的蛋白表达.此外,Res处理后T24 细胞中miR-34a 的基因表达亦显著升高.结论 Res能够有效抑制膀胱癌细胞生长增殖,可能与诱导细胞凋亡、上调miR-34a及p53表达有关.【期刊名称】《武警医学》【年(卷),期】2012(023)012【总页数】3页(P1062-1064)【关键词】白藜芦醇;膀胱癌;细胞凋亡;miR-34a;p53【作者】王伟;李覃;李瑛;李辉【作者单位】300162,天津,武警后勤学院附属医院肾病科;300162,天津,武警后勤学院免疫学教研室;300162,天津,武警后勤学院附属医院肾病科;300162,天津,武警后勤学院附属医院肾病科【正文语种】中文【中图分类】R737.14白藜芦醇(resveratrol，Res)是非黄酮类多酚化合物，具有抗肿瘤、抗感染、抑制血小板聚集、调节脂质代谢等多种生物学活性［1］。

[18]张铁山，赵刚，陈杰，等.切开与闭合复位空心钉内固定治疗移位股骨颈骨折的疗效比较[J].中国骨与关节损伤杂志，2015，30（2）：130-132.[19]梁凡，彭昊，胡巍，等.股骨颈骨折术后继发股骨头坏死的危险因素分析[J].中华创伤杂志，2016，32（9）：813-817.[20] Lee J H，Zhou L，Kwon K S，et al.Role of leptin in legg-calv é-perthes disease[J].J Orthop Res，2013，31（10）：1605-1610.（收稿日期：2018-01-08）　（本文编辑：程旭然）①广东省东莞市常平医院　广东　东莞　523560通信作者：袁柏强不同胸腔闭式引流管疗效对比分析袁柏强①　杨培文①　黄爱仪①　利桂河①　李秋明①　陈效强① 【摘要】　目的：探讨两种不同胸腔引流管治疗自发性气胸的临床效果及适用人群。

方法：选取2015年1月-2017年6月本院收治的自发性气胸患者112例。

按照随机数字表法将其分为细管组和粗管组，各56例。

两组均行胸腔闭式引流，细管组采用一次性使用中心静脉导管（舒贝康），粗管组采用22F 硅胶胸腔引流管。

观察两组复张拔管时间、住院时间、伤口愈合时间、3 d 肺复张率、管道堵塞率、皮下气肿发生率及需要干预的疼痛发生率；分析3 d 肺复张率的影响因素；比较两组不同年龄及是否合并基础肺部疾病患者的拔管时间、3 d 肺复张率、堵管率。

结果：细管组伤口愈合时间、住院时间均短于粗管组，皮下气肿及需要干预的疼痛发生率均低于粗管组，比较差异均有统计学意义（P <0.05）；两组复张拔管时间、管道堵塞率、3 d 肺复张率比较，差异均无统计学意义（P >0.05）；年龄>60岁、合并基础肺部疾病的细管组拔管时间均长于粗管组，3 d 肺复张率均低于粗管组，堵管率均高于粗管组，比较差异均有统计学意义（P <0.05）；Logistic 回归分析显示，引流管粗细、合并基础肺病是影响3 d 肺复张的独立因素（P <0.05）。

㊃综述㊃基金项目:2023年广州市科技局市校(院)联合资助项目肠道菌群代谢产物S C F A s 通过N F -κB 信号通路在帕金森病发病中的作用及机制研究(S L 2023A 03J 00590)通信作者:陈江瑛,E m a i l :1447369530@q q.c o m 胰高血糖素样肽-1在帕金森病肠-脑轴 中的作用研究进展周正新,梁秋雄,陈江瑛(暨南大学附属广州红十字会医院神经内科,广东广州510220) 摘 要:帕金森病(P D )是中老年时期常见的神经退行性疾病之一㊂P D 患者出现肠道炎症㊁便秘等胃肠道症状可能早于运动障碍㊂B r a a k 假说假设异常的α-突触核蛋白在肠道中开始积累,并通过迷走神经以类似朊病毒的方式传至大脑,且这一观点得到病理生理学证据的支持㊂P D 中 肠-脑轴 的关联在于代谢㊁免疫和炎症等相关机制,通过探讨其中机制可能成为治疗P D 的新思路㊂胰高血糖素样肽-1(G L P -1)作为研究较多的代谢物质之一,广泛参与在神经退行性病变中㊂本文对G L P -1在P D 肠-脑轴 中的作用进行综述,以期为P D 提供新的诊疗及研究思路㊂关键词:帕金森病;胰高血糖素样肽-1;肠-脑轴中图分类号:R 742.5 文献标志码:A 文章编号:1004-583X (2023)09-0855-04d o i :10.3969/j.i s s n .1004-583X.2023.09.015 帕金森病(P a r k i n s o n s d i s e a s e ,P D )是常见的运动障碍疾病,是一种表现有运动症状(运动迟缓㊁震颤㊁肌强直㊁步态异常)和非运动症状(胃肠功能紊乱㊁认知障碍㊁精神障碍㊁睡眠障碍和感觉障碍)的神经退行性疾病,其病因尚不完全清楚,亦缺乏根治手段㊂近年来, 肠-脑轴 这一概念的提出给包括P D 在内的神经疾病发病机制的探究提供了新思路㊂研究P D 与肠道系统相互联系的途径与其靶点,是丰富P D 研究的重点㊂2型糖尿病(t y pe 2d i a b e t e s m e l l i t u s ,T 2D M )是P D 发病的危险因素,且两者均与淀粉样多肽经过非正常折叠成纤维并随后聚集成淀粉样沉积有关[1]㊂因此,可以假设糖代谢异常可能是P D 的重要机制之一㊂P D 模型研究[2]表明,降糖药物胰高血糖素样肽-1(g l u c a g o n -l i k e p e p t i d e -1,G L P -1)受体激动剂具有神经保护作用㊂其中G L P -1,不只是一种可促进胰岛素信号传导㊁调节血糖水平且抑制食欲的肠促胰岛素激素[3],还是 肠-脑轴 的重要介质之一[4]㊂本文就G L P -1在P D肠-脑轴 中的作用进行综述,进一步探讨G L P -1与P D 的关系,以期为P D 的诊治提供新思路和依据㊂1 P D 的肠-脑轴 在大脑㊁肠道和肠道菌群存在着1种尚未被完全了解的交流系统,即 肠-脑轴 ㊂基于此轴,肠道菌群的改变被证明与一些神经疾病有关,如对P D 来说,肠道菌群的改变就是其突出的特征之一㊂1.1 病理联系 作为P D 黑质中形成的标志性聚集物,α-突触核蛋白(α-s y n u c l e i n ,α-s yn )不只在大脑中表达,且在肠道中也有表达[5];甚至其在肠道中的聚集比在大脑中病理形成更早[6]㊂B r a a k 等[7]提出,P D 是起源于中枢神经系统以外的病理模型㊂在该模型中,α-s yn 的错误折叠起自肠道,并通过迷走神经以朊病毒样的行为方式传至大脑[8]㊂且α-s yn 增加在P D 患者前驱阶段和早期无发病阶段的肠上皮中被发现[9]㊂可见,肠道中出现异常的α-s yn 发生在中枢神经退行性变的临床症状出现前㊂这表明,肠道可能是P D 发生的起源场所㊂虽然B r a a k 的观点备受争议,但中枢神经系统外α-s y n 错误折叠和聚集仍是P D 发病机制的经典假说,同时也是P D 肠-脑轴 的病理基础㊂1.2 肠道中介 细菌及其代谢产物除影响免疫系统外,还影响神经系统㊂F r i e d l a n d 等[10]提出了1个新的术语 m a p r a n o s i s 来描述微生物群相关的蛋白质病和神经炎症的过程( -o s i s )㊂尽管目前还未完全明确影响P D 的肠道菌群,但P D 的肠道状态和健康的肠道状态存在差异㊂临床研究[11]显示,P D 患者肠道出现异常改变,既有肠黏膜通透性增加㊁炎症迹象和受到细菌入侵,同时也有异常肠道菌群组成㊂在过表达α-s yn 小鼠大脑中小胶质细胞的激活和α-s yn 的病理形成及这些小鼠运动缺陷的产生都需肠道菌群参与,说明肠道菌群是P D 的危险因素[12]㊂P D 肠道菌群含有外膜脂多糖(l i p o p o l y s a c c h a r i d e s ,L P S )的细菌之相对丰度增加,而产生短链脂肪酸㊃558㊃‘临床荟萃“ 2023年9月20日第38卷第9期 C l i n i c a l F o c u s ,S e pt e m b e r 20,2023,V o l 38,N o .9(s h o r t-c h a i n f a t t y a c i d s,S C F A)的细菌之相对丰度降低,这是因为含有L P S的细菌与免疫激活和炎症有关,而产生S C F A的细菌与可能存在的抗炎性质有关[13]㊂一方面,L P S等促炎细菌成分激活小胶质细胞引发神经退行性变[14],暴露在L P S的全身效应随肠道屏障缺损(即肠道高渗透性)而增加,这是P D 的1个特征;另一方面,菌群的代谢产物S C F A与神经炎症的减轻㊁神经退行性变的减少和运动功能的改善有一定关系,在P D患者中这些菌群相对丰度往往减少[15]㊂位于肠道里的细菌代谢产物S C F A在P D的 肠-脑轴 假说中也发挥重要作用㊂S C F A的受体既存在于免疫细胞上,也存在于大脑细胞上,这为S C F A介导的 肠-脑轴 提供了物质联系[16]㊂目前,1个探索程度相对较低的机制就是S C F A对神经系统的影响㊂研究[17]发现,S C F A可引起G L P-1分泌,且对P D有神经保护作用㊂以上均提示,肠道菌群及其代谢产物对P D的产生有不可忽视的影响㊂2G L P-1在P D 肠-脑轴 中的作用肠-脑轴 与内分泌激素的产生与释放相关㊂研究[18]表明,T2D M是P D的危险因素,且胰岛素抵抗可能存在于大脑中,是神经退行性疾病的常见特征㊂作为与糖尿病相关的内分泌激素,G L P-1是肠促胰素信号系统成员之一,目前对其研究较为热门,其作用机制的研究最为深入也最为复杂㊂大量研究已证实,G L P-1广泛参与了P D的发生发展㊂可见,G L P-1可能在P D的 肠-脑轴 中发挥了重要作用㊂2.1 G L P-1受体在神经系统的分布 G L P-1作用于外周组织中的G L P-1受体(g l u c a g o n-l i k e p e p t i d e-1r e c e p t o r,G L P-1R)㊂这种受体遍布肠道㊁胃部㊁胰腺㊁心脏㊁肾脏㊁骨骼㊁血管和脂肪细胞[19]㊂G L P-1R 也广泛分布于中枢神经系统中,如与P D相关的黑质,其中也包括表达酪氨酸羟化酶(t y r o s i n e h y d r o x y l a s e,T H)的多巴胺能神经元[20],且神经元周围的小胶质细胞和星形胶质细胞也可表达G L P-1R[21],这些为G L P-1与神经退行性变的关系提供了物质基础㊂2.2肠道菌群对G L P-1的作用内源性G L P-1是由肠道L细胞产生㊂L细胞的数量沿胃肠道的纵轴逐渐增加;结肠腔内有大量肠道菌群,L细胞在其中比例最高,L细胞由于与肠道菌群直接接触而受到刺激㊂由此可见,肠道L细胞分泌的G L P-1受肠道菌群的影响;同时,其也受到细菌产生的S C F A影响㊂S C F A通过与L细胞上的跨膜游离脂肪酸受体(f r e e f a t t y a c i d r e c e p t o r2,F F A R2)结合发挥促分泌作用㊂L细胞中的法尼醇X受体(f a r n e s o i d Xr e c e p t o r, F X R)的激活通过减少F F A R2的表达和信号传导以减少S C F A诱导的G L P-1分泌;相反,S C F A诱导G L P-1分泌在敲除F X R小鼠中增强[17]㊂这提示,肠内分泌系统可能是调节G L P-1水平的主要调节位点,即对F X R的拮抗作用可能增强G L P-1的分泌㊂利用这种方法可增加G L P-1的产生,进而获得治疗益处㊂如前所述,P D肠道的特征是产生S C F A细菌丰度减低[15],这引起了各项研究对P D肠道G L P-1分泌的关注㊂因此,有研究[22]表明,与食用相同餐食的对照组相比,P D组餐后G L P-1水平较低㊂说明P D患者G L P-1分泌可能存在障碍,且这种障碍可能是由于产生S C F A的细菌较少所致㊂可以说,肠道菌群可通过G L P-1来影响大脑功能,即形成了 肠-脑轴 的联系㊂2.3 G L P-1对P D的作用 T2D M是P D的危险因素[1],G L P-1R激动剂能降低T2D M患者血糖[23]㊂这提示,G L P-1的稳态失调可能是P D的潜在机制㊂因此,存在将G L P-1信号的增强用于预防神经退行性病变的可能㊂研究[2]发现,G L P-1R激动剂恢复了合成多巴胺的限速酶T H在黑质的表达,还能进一步降低作为脂质过氧化产物和氧化应激标志物的4-羟基壬烯醛的产生[24],提高了神经营养因子,如神经胶质细胞系来源的神经营养因子和脑源性的神经营养因子的合成[25],并阻止体内T H阳性纹状体和中脑多巴胺能神经元中α-s y n[2,25]的积累㊂目前,已有研究进一步证明G L P-1R信号增强带来有益作用的机制㊂有研究[26]表明,G L P-1通过抑制核因子κB (n u c l e a r f a c t o rk a p p a-B,N F-κB)信号传导以发挥抗炎作用;而所对应的炎症正是在含有L P S的细菌的相对丰度增加和肠道屏障功能障碍下发生的㊂G L P-1R的激活通过调节细胞内线粒体活性氧(r e a c t i v e o x y g e n s p e c i e s,R O S)抑制P D的氧化应激(o x i d a t i v e s t r e s s,O S)㊂G L P-1R的激活增强了丝氨酸/苏氨酸激酶(t h r e o n i n e k i n a s e,A k t)的磷酸化并诱导转录因子环磷酸腺苷(c y c l i c a d e n o s i n e m o n o p h o s p h a t e,c AM P)反应元件结合蛋白[27],增强了抗凋亡B淋巴细胞瘤2(b-c e l l l y m p h o m a2,B c l-2)合成并降低促凋亡B c l-2相关X蛋白(b c l-2a s s o c i a t e d X p r o t e i n,B a x)[25,28]和细胞色素C (c y t o c h r o m eC,C y t C)[28]水平,使降低的B c l-2/B a x 比例正常化同时还降低了具有凋亡效应的天冬氨酸㊃658㊃‘临床荟萃“2023年9月20日第38卷第9期 C l i n i c a l F o c u s,S e p t e m b e r20,2023,V o l38,N o.9特异性半胱氨酸蛋白酶3(c a s p a s e3)水平[25]㊂这些研究为G L P-1对P D的作用提供了机制方面的支持证据㊂最近1项针对T2D M患者基于人群的纵向队列研究[29]结果显示,接受G L P-1R激动剂治疗组与其他降糖药物组比较,P D发病率降低㊂该研究为使用G L P-1R激动剂治疗的T2D M患者预防P D提供了可靠的流行病学证据,证明了G L P-1对P D神经保护和抗炎作用㊂3小结P D是发病率第2的神经退行性疾病,在全球范围内,P D导致的残疾和死亡人数高于其他神经系统疾病㊂目前的治疗方案仍未能满足临床需求,加之发病机制尚未完全明确,给P D患者预后带来极大挑战㊂作为目前研究最多且广泛参与T2D M和神经疾病发病机制中的肠促胰素,G L P-1为从肠道与神经系统角度分析 肠-脑轴 的形成开创了新的研究方向㊂期待未来会有更多关于G L P-1对P D 肠-脑轴 作用的研究,以更好地为防控P D等神经疾患奠定研究基础㊂参考文献:[1] N g u y e nP H,R a m a m o o r t h y A,S a h o o B R,e ta l.A m y l o i do l i g o m e r s:A j o i n t e x p e r i m e n t a l/c o m p u t a t i o n a l p e r s p e c t i v eo na l z h e i m e r'sd i s e a s e,p a r k i n s o n'sd i s e a s e,t y p e i i d i ab e t e s,a n da m y o t r o p h i c l a t e r a ls c l e r o s i s[J].C h e m R e v,2021,121(4):2545-2647.[2] Z h a n g L Y,J i nQ Q,Höl s c h e rC,e t a l.G l u c a g o n-l i k e p e p t i d e-1/g l u c o s e-d e p e n d e n ti n s u l i n o t r o p i c p o l y p e p t i d ed u a lr e c e p t o ra g o n i s tD A-C H5i s s u p e r i o r t o e x e n 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R o d r i g u e s P V,d e G o d o y J V P,B o s q u e B P,e t a l.T r a n s c e l l u l a r p r o p a g a t i o n o f f i b r i l l a rα-s y n u c l e i n f r o me n t e r o e n d o c r i n e t on e u r o n a lc e l l sr e q u i r e sc e l l-t o-c e l lc o n t a c ta n d i sR a b35-d e p e n d e n t[J].S c i R e p,2022,12(1):4168.[7] B r a a k H,Rüb U,G a i W P,e ta l.I d i o p a t h i c p a r k i n s o n'sd i se a s e:p o s s i b l er o u t e sb y w h i c hv u l n e r a b l en e u r o n a lt y p e sm a y b e s u b j e c t t o n e u r o i n v a s i o n b y a n u n k n o w n p a t h o g e n[J].JN e u r a lT r a n s m(V i e n n a),2003,110(5):517-536. [8] B o r g h a mm e r P.H o w d o e s p a r k i n s o n's d i s e a s e b e g i n?p e r s p e c t i v e s o n n e u r o a n a t o m i c a l p a t h w a y s,p r i o n s,a n dh i s t o l o g y[J].M o vD i s o r d,2018,33(1):48-57.[9]S h a n n o n KM,K e s h a v a r z i a n A,M u t l u E,e t a l.A l p h a-s y n u c l e i n i nc o l o n i cs u b m u c o s a i ne a r l y u n t r e a t e dP a r k i n s o n'sd i se a s e[J].M o v e m e n tD i s o r d e r s,2012,27(6):709-715.[10] F r i e d l a n dR P,C h a p m a nM R.T h e r o l e o fm i c r o b i a l a m y l o i d i nn e u r o d e g e n e r a t i o n[J].P L o S P a t h o g,2017,13(12): e1006654.[11] D u m i t r e s c uL,M a r t a D,D췍n췍u A,e ta l.S e r u m a n df e c a lm a r k e r s o f i n t e s t i n a l i n f l a mm a t i o n a n d i n t e s t i n a l b a r r i e r p e r m e a b i l i t y a r ee l e v a t e di n p a r k i n s o n's d i s e a s e[J].F r o n tN e u r o s c i.2021,18(15):689723.[12]S a m p s o n T,D e b e l i u sJ,T h r o n T,e ta l.G u t m i c r o b i o t ar e g u l a t em o t o rd e f i c i t sa n dn e u r o i n f l a mm a t i o ni na m o d e lo f p a r k i n s o n's d i s e a s e[J].C e l l,2016,167(6):1469-1480,e12.[13]J o e r s V,M a s i l a m o n i G,K e m p f D,e t a l.M i c r o g l i a,i n f l a mm a t i o na n d g u t m i c r o b i o t ar e s p o n s e si na p r o g r e s s i v em o n k e y m o d e lo f p a r k i n s o n's d i s e a s e:A c a s es e r i e s[J].N e u r o b i o lD i s,2020,144:105027.[14] A b d e l-H a q R,S c h l a c h e t z k i J C M,G l a s s C K,e t a l.M i c r o b i o m e-m i c r o g l i a c o n n e c t i o n sv i a t h e g u t-b r a i na x i s[J].JE x p M e d,2019,216(1):41-59.[15] N i s h i w a k iH,H a m a g u c h iT,I t o M,e ta l.S h o r t-c h a i nf a t t ya c i d-p r o d u c i n g g u t m i c r ob i o t ai s d ec r e a s ed i n p a r k i n s o n'sd i se a s eb u t n o t i nr a p i d-e y e-m o v e m e n t s l e e p b e h a v i o r d i s o r d e r[J].m S y s t e m s,2020,5(6):e00797-e007920.[16]S i l v aY P,B e r n a r d i A,F r o z z aR L.T h e r o l e o f s h o r t-c h a i n f a t t ya c i d sf r o m g u t m i c r ob i o t ai n g u t-b r a i nc o mm u n i c a t i o n[J].F r o n tE n d o c r i n o l(L a u s a n n e),2020,31(11):25.[17] D u c a s t e lS,T o u c h e V,T r a b e l s i M S,e t a l.T h e n u c l e a rr e c e p t o r F X R i n h i b i t s g l u c a g o n-l i k e p e p t i d e-1s e c r e t i o n i n r e s p o n s e t o m i c r o b i o t a-d e r i v e ds h o r t-c h a i nf a t t y a c i d s[J].S c iR e p,2020,10(1):174.[18] U y a r M,L e z i u s S,B u h m a n n C,e ta l.D i a b e t e s,g l y c a t e dh e m o g l o b i n(h b a1c),a n dn e u r o a x o n a l d a m a g e i n p a r k i n s o n'sd i se a s e(MA R K-P D s t u d y)[J].M o v D i s o r d,2022,37(6):1299-1304.[19] D r u c k e rD J.M e c h a n i s m s o f a c t i o na n d t h e r a p e u t i c a p p l i c a t i o no f g l u c a g o n-l i k e p e p t i d e-1[J].C e l lM e t a b,2018,27(4):740-756.[20] E l a b iO F,D a v i e sJ S,L a n eE L.L-d o p a-d e p e n d e n te f f e c t so fG L P-1R a g o n i s t s o n t h e s u r v i v a l o f d o p a m i n e r g i c c e l l st r a n s p l a n t e d i n t o a r a tm o d e l o f p a r k i n s o n d i s e a s e[J].I n t JM o l S c i,2021,22(22):12346.[21] C u iQ N,S t e i nL M,F o r t i nS M,e t a l.T h e r o l eo f g l i a i nt h ep h y s i o l o g y a n d p h a r m a c o l o g y o f g l u c a g o n-l i k e p e p t i d e-1:I m p l i c a t i o n s f o r o b e s i t y,d i a b e t e s,n e u r o d e g e n e r a t i o n a n dg l a u c o m a[J].B r JP h a r m a c o l,2022,179(4):715-726.㊃758㊃‘临床荟萃“2023年9月20日第38卷第9期 C l i n i c a l F o c u s,S e p t e m b e r20,2023,V o l38,N o.9[22] M a n f r e a d y R A,E n g e nP A,V e r h a g e n M L,e t a l.A t t e n u a t e dp o s t p r a n d i a lG L P-1r e s p o n s e i n p a r k i n s o n'sd i s e a s e[J].F r o n tN e u r o s c i,2021,2(15):660942.[23]郑鑫,朱育刚,王德峰.G L P-1受体激动剂对超重及肥胖2型糖尿病患者胰岛细胞功能影响的系统评价[J].临床荟萃, 2019,34(12):1102-1107.[24] Z h a n g Z Q,Höl s c h e r C.G I P h a sn e u r o p r o t e c t i v ee f f e c t si nA l z h e i m e r a n dP a r k i n s o n's d i s e a s em o d e l s[J].P e p t i d e s,2020,125:170184.[25] L vM,X u eG,C h e n g H,e t a l.T h eG L P-1/G I Pd u a l-r e c e p t o ra g o n i s tD A5-C Hi n h ib i t s t h eN F-κB i n f l a mm a t o r yp a t h w a y i nt h eM P T P m o u s em o d e l o f p a r k i n s o n's d i s e a s em o r e e f f e c t i v e l y t h a n t h e G L P-1s i n g l e-r e c e p t o r a g o n i s t N L Y01[J].B r a i nB e h a v,2021,11(8):e2231.[26] C h e nX,H u a n g Q,F e n g J,e ta l.G L P-1a l l e v i a t e s N L R P3i n f l a mm a s o m e-d e p e n d e n t i n f l a mm a t i o n i n p e r i v a s c u l a r a d i p o s et i s s u e b y i n h i b i t i n g t h e N F-κBs i g n a l l i n gp a t h w a y[J].JI n tM e dR e s,2021,49(2):300060521992981.[27]J a l e w a J,S h a r m aMK,G e n g l e r S,e t a l.An o v e lG L P-1/G I Pd u a l re c e p t o ra g o n i s t p r o t e c t sf r o m6-O H D Al e s i o ni nar a tm o d e l o f p a r k i n s o n's d i s e a s e[J].N e u r o p h a r m a c o l o g y,2017,1(117):238-248.[28] L iT,T u L,G u R,e ta l.N e u r o p r o t e c t i o no f G L P-1/G I Pr e c e p t o ra g o n i s t v i a i n h i b i t i o n㊁o f m i t o c h o n d r i a l s t r e s s b yA K T/J N K p a t h w a y i naP a r k i n s o n'sd i s e a s e m o d e l[J].L i f eS c i,2020,1(256):117824.[29] B r a u e rR,W e i L,M aT,e t a l.D i a b e t e sm e d i c a t i o n s a n d r i s ko f p a r k i n s o n's d i s e a s e:Ac o h o r t s t u d y o f p a t i e n t sw i t h d i a b e t e s[J].B r a i n,2020,143(10):3067-3076.收稿日期:2023-05-31编辑:张婷婷㊃858㊃‘临床荟萃“2023年9月20日第38卷第9期 C l i n i c a l F o c u s,S e p t e m b e r20,2023,V o l38,N o.9。

前列腺癌新辅助化疗进展发布时间：2021-09-07T05:44:11.471Z 来源：《科学与技术》2021年5月第13期作者：梁鹏陈飞飞田志崇胡俊超[导读] 根治性前列腺切除术（RP）是前列腺癌患者的重要治疗手段，梁鹏陈飞飞田志崇胡俊超华北理工大学附属医院河北省唐山市 063000摘要：根治性前列腺切除术（RP）是前列腺癌患者的重要治疗手段，但是前列腺患者术前分期困难重重，为了使得更多病人能在RP中获益，新辅助治疗的地位也在越来越高。

其中，以多西他赛为基础的新辅助化疗手段值得我们关注。

关键词：前列腺癌；根治性前列腺切除术（RP）；新辅助治疗；新辅助化疗；多西他赛前列腺癌是最常被诊断出的癌症之一，由于与发达国家相比，我国早期发现和筛查相关的诊断活动较差，故前列腺癌并不是我们诊断最常见的癌症类型，但可能包括逐步实施前列腺特异性抗原筛查和改进的活检技术又或日益西化的生活方式的影响，前列腺癌在我国的发病率及病死率正逐步上升【1】。

总体而言，高危和局部进展期的前列腺癌是威胁患者生命的主要原因，这部分患者在初诊时比例可达20%-30%【2】。

前列腺癌根治性切除术是低危局限性前列腺癌患者的最佳治疗方式，随着近些年来的研究，指南逐渐将手术适应症放宽到中-低危前列腺癌，甚至于已有研究者在转移性前列腺癌中实施包括手术在内的综合性治疗。

但随之而来的，是手术失败、放疗失败、生化复发率高等问题【3，4】，故许多学者开始对前列腺癌的新辅助治疗进行了探索。

前列腺癌新辅助包括辅助内分泌治疗（neoad-juvanthormonaltherapy，NHT）、新辅助化疗（neoadjuvantchemotherapy，NCT）以及两者的结合，其中NHT研究占了大多数。

然而，目前欧洲泌尿外科学会的指南不推荐在根治性切除术前进行新辅助内分泌治疗(证据等级别strong)，美国国家综合癌症网络也不建议患者接受除临床试验以外的新辅助内分泌治疗。

网络出版时间：２０２３－０３－１００９：１０：２９　网络出版地址：ｈｔｔｐｓ：／／ｋｎｓ．ｃｎｋｉ．ｎｅｔ／ｋｃｍｓ／ｄｅｔａｉｌ／３４．１０８６．Ｒ．２０２３０３０８．１８１０．０５４．ｈｔｍｌ桃红四物汤增强顺铂化疗对肺腺癌小鼠的抑瘤作用李白坤１，２，陈诗雨１，２，吴晓红１，２，叶明君２，３，朱　婷２，３，朱继民２，４，李庆林２，３（１．安徽中医药大学中医学院，安徽合肥　２３００１２；２．安徽中医药大学新安医学教育部重点实验室，安徽合肥　２３００３８；安徽中医药大学３．药学院、４．生命科学学院，安徽合肥　２３００１２）收稿日期：２０２２－１０－１０，修回日期：２０２２－１２－１５基金项目：安徽省自然科学基金项目（Ｎｏ２２０８０８５ＭＨ２７９）；安徽中医药大学自然科学研究重点项目（Ｎｏ２０２１ｚｒｚｄ０６）；安徽中医药大学人才支持计划项目（Ｎｏ２０２２ｒｃｙｂ０２７）；安徽高校自然科学研究重点项目（ＮｏＫＪ２０１９Ａ０４６０，２０２２ＡＨ０５０５１９）；新安医学教育部重点实验室开放课题（Ｎｏ２０２０ｘａｙｘ０５）作者简介：李白坤（１９７９－），女，博士，研究方向：中药复方药理学，Ｅ ｍａｉｌ：ｌｉｂａｉ５２６＠ａｈｔｃｍ．ｅｄｕ．ｃｎ；李庆林（１９６８－），男，博士，教授，博士生导师，研究方向：肿瘤药理学，通信作者，Ｅ ｍａｉｌ：ｌｉｑｉｎｇｌｉｎ＠ａｈｔｃｍ．ｅｄｕ．ｃｎｄｏｉ：１０．１２３６０／ＣＰＢ２０２２０８０６４文献标志码：Ａ文章编号：１００１－１９７８（２０２３）０３－０５８８－０６中国图书分类号：Ｒ ３３２；Ｒ２８９ ５；Ｒ７３４ ２；Ｒ９７９ １摘要：目的　研究桃红四物汤（ＴａｏｈｏｎｇＳｉｗｕＤｅｃｏｃｔｉｏｎ，ＴＳＤ）增强顺铂（ｃｉｓｐｌａｔｉｎ，ＤＤＰ）化疗对肺腺癌移植小鼠的抑瘤作用。

方法　以鼠源肺腺癌细胞系Ｌｅｗｉｓ制备鼠肺腺癌细胞移植瘤模型，设５组：正常对照、模型、ＴＳＤ、ＤＤＰ、ＴＳＤ＋ＤＤＰ。

doi:10.3971/j.issn.1000-8578.2023.22.1503α-常春藤皂苷调控SREBP1/FASN 通路抑制非小细胞肺癌的恶性表型常毓真1,2，杨浩1,2，黄钢1,2α-Hederin Regulates SREBP1/FASN Pathway and Inhibits Malignant Phenotype of Non-small Cell Lung CancerCHANG Yuzhen 1,2, YANG Hao 1,2, HUANG Gang 1,21. Shanghai University of Traditional Chinese Medicine, Shanghai 200120, China;2. Shanghai Key Laboratory of Molecular Imaging, Shanghai University of Medicine and Health Sciences, Shanghai 201318, ChinaCorrespondingAuthors:HUANGGang,E-mail:*******************.cn;YANGHao,E-mail:***************.cnAbstract: Objective To explore the regulative effect of α-Hederin on the proliferation and invasion of NSCLC and investigate its related molecular mechanism. Methods After A549 and HCC-1833 cells were treated with a concentration gradient of α-Hederin for 24 and 48 h, the OD 450nm was detected by using CCK8 assays, and the IC 50 was calculated. The A549 and HCC-1833 cells were divided into the blank control and α-Hederin groups in accordance with IC 50 values. Cell proliferation was detected by EdU assays, and cell cycle transformation and cell apoptosis were detected by flow cytometry. Cell mobility was detected by using Transwell and scratch assays. SREBP1 and FASN protein expression levels were detected through Western blot analysis, and cell lipid accumulation was detected via oil red O staining. Results The survival rate of lung cancer cells decreased significantly with the increase of α-Hederin concentration, and the IC 50 values of A549 and HCC-1833 cells at 48 h were 15 and 25 μg/ml, respectively. Compared with the blank control group, cells proliferation and migration were significantly inhibited, cells were blocked in the G 1/S phase, the apoptosis rate increased, and the protein expression and lipid accumulation of SREBP1/FASN significantly reduced after α-Hederin treatment. Conclusion α-Hederin can inhibit the proliferation and migration, G 1/S phase transition and induce the apoptosis of NSCLC cells and hinder the malignant progression of NSCLC by downregulating the expression of SREBP1 and FASN and reducing the accumulation of cell lipids. Key words: α-Hederin; NSCLC; SREBP1; FASN; Lipid accumulationFunding: The National Natural Science Foundation of China (No. 82127807); Shanghai Key Laboratory of Molecular Imaging (No. 18DZ2260400); The National Key Research and Development Pregram of China (No. 2020YFA0909000)Competing interests: The authors declare that they have no competing interests.摘 要：目的 探讨α-常春藤皂苷对非小细胞肺癌细胞增殖和侵袭的调控作用及其相关分子机制。

WHO Classification Of Tumours Of The Lung, Pleura, Thymus And Heart (IARC WHO Classification Of Tumours) By International Agency For Research On CancerIf you are searched for the ebook WHO Classification of Tumours of the Lung, Pleura, Thymus and Heart (IARC WHO Classification of Tumours) in pdf form, in that case you come on tothe correct website. We furnish utter version of this book in txt, PDF, DjVu, doc, ePub forms. You can readWHO Classification of Tumours of the Lung, Pleura, Thymus and Heart (IARC WHO Classification of Tumours) online or download. In addition, on our website you can read guides andanother art books online, or downloading their as well. We will to attract consideration what our website does notstore the book itself, but we grant link to website wherever you may downloading or reading online. 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