BACKGROUND:Lung adenocarcinoma (LUAD) remains a leading cause of cancer mortality due to resistance, metastasis, and recurrence. Unlike conventional cytotoxic therapies, Xingxiao Pills (XXP), a classic traditional Chinese medicine formula, offers a complementary approach to treating LUAD, while its non-cytotoxic anti-cancer mechanisms remain unclear. PURPOSE:To investigate the effect and mechanism of XXP on LUAD progression and stemness via lipid metabolism regulation. METHOD:UHPLC-MS/MS was used to analyze the chemical constituents of XXP. The effects of XXP on LUAD cell proliferation, migration, invasion, and stemness were evaluated using CCK-8, Transwell, and tumor sphere assays. A LUAD xenograft model confirmed XXP's anti-tumor effects. Transcriptomics, metabolomics, ELISA, qRT-PCR, and Western blot were used to investigate the underlying mechanisms. Kaplan-Meier (KM) survival analysis and stemness index scores were performed for LUAD patients based on the TCGA dataset. Statistical analyses were performed using Student's t-test, ANOVA, and KM survival analysis (p< 0.05 considered significant). RESULTS:XXP inhibits LUAD progression in mouse and cell models by targeting lipid metabolism reprogramming. It suppresses FA synthesis, elongation, oxidation, and glycerophospholipid (GPL) metabolism while upregulating arachidonic acid (AA) metabolism. Mechanistic studies revealed that XXP attenuates tumor stemness by inhibiting PLA2G4A (cPLA2), lowering AA release, and disrupting SMO/GLI1/SOX2 signaling, an effect also observed with the cPLA2 inhibitor AACOCF3. KM analysis showed that higher PLA2G4A expression correlated with a worse 5-year prognosis in LUAD (p = 0.0047). The low GPL/high AA group (consistent with XXP's metabolic pattern) had better survival (p = 0.0028) and a lower stemness index (p< 0.0001) than the high GPL/low AA unrelated group. CONCLUSION:Xingxiao Pill modulates GPL and AA metabolism and downregulates the PLA2G4A (cPLA2)-AA/SMO/GLI1/SOX2 axis. Through this mechanism, XXP effectively inhibits tumor growth and stemness by targeting lipid metabolism.

The aim of this study was to investigate the therapeutic effect of cryoablation treatment in advanced NSCLC patients who had failed first-line chemotherapy. Eighty-seven patients from ten hospitals in China were enrolled into the study, forty-four patients received cryoablation treatment plus basic treatment (experimental group), and forty-three patients had basic treatment alone (control group). Follow-up was performed once every three months until the end of the study or the death of the patient. The primary endpoints were overall and post-intervention survival; secondary endpoints included tumor markers, solid tumor efficacy, and symptom changes before and after treatment. There was no significant difference in median OS between the two groups of patients (9.0 months vs 11.2 months, P = 0.583). The disease control rate (DCR) and living quality of the experimental group was higher than that of the control group. In terms of OS, indiscriminate use of cryoablation for such patients was not beneficial, though it could improve symptoms of patients. Cryoablation had a significant effect on selected advanced NSCLC patients after the failure of first-line chemotherapy.

肺癌发病率和死亡率在我国及全球范围内均居前列,且发病率仍在逐年升高,发病年龄亦呈持续升高趋势.老年肺癌患者多久病体虚,较难承受杀伐有力的现代治疗方案,故多寻求较为和缓的中医治疗."命门学说"是张景岳的重要学术思想,命门、水火阴阳和五脏六腑相互协调,共同维持人体各项生理功能.我们认为,老年肺癌多因命门火衰、阳虚寒凝所致,临床治疗应从温阳散寒、补肾固本出发,多采用阳和汤加减温阳散寒,收效甚佳.

目的 观察接种不同细胞数量下C57BL/6小鼠Lewis肺癌(LLC)皮下移植瘤瘤体变化,选择适合冷冻消融实验的种子细胞数量.方法 将18只6～8周龄的C57BL/6小鼠随机分为三组,每组6只,在右上肢腋窝皮下接种LLC细胞,数量分别为1×106个(A组)、2×106个(B组)和5×106个(C组).比较三组移植瘤成瘤时间、肿瘤破溃时间和肿瘤破溃时瘤体最大径及体积.结果 C组小鼠成瘤时间短于A组(P<0.01),而小鼠肿瘤破溃时间、肿瘤破溃时瘤体最大径及体积均少于A、B组(P<0.05).B组小鼠肿瘤破溃时瘤体最大径亦小于A组(P<0.05).A、B组小鼠成瘤时间、肿瘤破溃时间和肿瘤破溃时瘤体体积比较均无统计学差异(P>0.05).结论 C57BL/6小鼠皮下接种1×106个或2×106个LLC细胞能够建立满足冷冻消融术实验的移植瘤动物模型.

Thermal ablation is widely used in the treatment of lung cancer and is beneficial for the overall survival of patients in clinic. However, there is barely a priority in which ablation system should be chosen under different periods of tumor progression in lung cancer. The present study investigated different modes of thermal ablation systems in mice with transplanted Lewis lung carcinoma tumors and their various biological effects in local regions using untargeted metabolomics. The results showed that thermal ablation could significantly suppress tumor growth and the differentially expressed metabolites of tumors after ablation relative to untreated tumors concentrated on organic compounds, organic acids and derivatives, nucleosides, nucleotides, and lipids. The upregulated metabolites indicated an inflammatory reaction in the ablation groups at an early stage after ablation. Steroid hormone and tryptophan metabolism, which are associated with immune responses, were modulated after both cryoablation and hyperthermal ablation. Characteristically, the results also indicated that cryoablation suppressed glucose oxidation and carbohydrate metabolism of tumor, while hyperthermal ablation suppressed lipid metabolism of tumor. In conclusion, thermal ablation could inhibit tumor growth under either freezing or heating modes with characteristic different biological effects on tumors.

近年来研究发现恶性肿瘤与人体的关系相对独立,既自成一体又与人体有着密切的联系.经过近20年临床考证,胡凯文教授在传统中医肿瘤思想的基础上提出恶性肿瘤是阴阳俱盛的独立产物,于形成期窃取人体阴阳而生,形成后与人体阴阳相对独立的现代中医肿瘤观.故此提出"离决肿瘤阴阳法",即借助现代中医内治、外科手段,只针对恶性肿瘤进行单阴或单阳属性的干预,使肿瘤阴阳失和,阴阳离决而亡.基于此法,在内治用药方面,胡教授提出"引经-入瘤-离决"组方理念;在现代中医外科方面,胡教授提出冷消融"决阳"和热消融"离阴"的治疗理念.经过前期研究与临床验证,"离决肿瘤阴阳法"疗效显著.

Background: Lung adenocarcinoma (LUAD) is the most common subtype of non-small-cell lung cancer (NSCLC). The aim of our study was to determine prognostic risk factors and establish a novel nomogram for lung adenocarcinoma patients. Methods: This retrospective cohort study is based on the Surveillance, Epidemiology, and End Results (SEER) database and the Chinese multicenter lung cancer database. We selected 22,368 eligible LUAD patients diagnosed between 2010 and 2015 from the SEER database and screened them based on the inclusion and exclusion criteria. Subsequently, the patients were randomly divided into the training cohort (n = 15,657) and the testing cohort (n = 6711), with a ratio of 7:3. Meanwhile, 736 eligible LUAD patients from the Chinese multicenter lung cancer database diagnosed between 2011 and 2021 were considered as the validation cohort. Results: We established a nomogram based on each independent prognostic factor analysis for 1-, 3-, and 5-year overall survival (OS) . For the training cohort, the area under the curves (AUCs) for predicting the 1-, 3-, and 5-year OS were 0.806, 0.856, and 0.886. For the testing cohort, AUCs for predicting the 1-, 3-, and 5-year OS were 0.804, 0.849, and 0.873. For the validation cohort, AUCs for predicting the 1-, 3-, and 5-year OS were 0.86, 0.874, and 0.861. The calibration curves were observed to be closer to the ideal 45° dotted line with regard to 1-, 3-, and 5-year OS in the training cohort, the testing cohort, and the validation cohort. The decision curve analysis (DCA) plots indicated that the established nomogram had greater net benefits in comparison with the Tumor-Node-Metastasis (TNM) staging system for predicting 1-, 3-, and 5-year OS of lung adenocarcinoma patients. The Kaplan–Meier curves indicated that patients’ survival in the low-risk group was better than that in the high-risk group ( P < .001). Conclusion: The nomogram performed very well with excellent predictive ability in both the US population and the Chinese population.

Background Numerous studies have revealed that the abnormal expression of pyroptosis-related genes is closely related to the prognosis of lung adenocarcinoma (LUAD); however, a comprehensive analysis has yet to be conducted. This study aimed to reveal the influence of pyroptosis-related genes on the prognosis of LUAD and establish a prognostic model based on those genes, in order to evaluate the prognosis of LUAD. Methods The data of tumor and normal samples were downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Differential analysis was used to identify pyroptosis-related genes (obtained from the GeneCards database) that were differentially expressed (DE) in TCGA database. Univariate and stepwise multivariate Cox proportional hazards regression analyses were used to screen feature genes related to LUAD overall survival (OS) and construct gene signature. Gene set enrichment analysis (GSEA) was then performed to reveal potential functions related to gene signature. Finally, the Cell-type Identification by Estimating Relative Subsets of RNA Transcripts (CIBERSORT) algorithm was used to reveal distinctions in each cell-subtype groups in the immune landscape of LUAD. Results Overall, 26 DE genes (DEGs) associated with pyroptosis were obtained. Among them, 4 (MKI67, BTK, MST1, and TUBB6) were selected as prognostic genes and a 4-gene signature with a good prognostic performance in the TCGA and GEO was constructed. The gene signature was shown to be an independent prognostic factor of LUAD in subsequent analysis. Functional enrichment indicated that the 4-gene signature may participate in the tumorigenesis and development of LUAD through various pathways related to tumor progression to play a prognostic role in LUAD. Additionally, the results of the immune landscape indicated that the 4-gene signature may affect the prognosis of LUAD via cooperating with changes in the immune microenvironment. Conclusions The key biomarkers and pathways identified in this study would deepen the comprehension of the molecular mechanism of pyroptosis in LUAD. More importantly, the 4-gene signature may serve as a novel potential prognostic model for LUAD.

肺结节是指直径≤3 cm的局灶性、类圆形、密度增高的实性或亚实性肺部阴影,可单发或多发,边界清晰或不清晰的病灶,其作为肺癌的癌前病变,近年来随着癌症早筛的普及和检测技术的升级逐渐走进大众的视野[1-3].因肺癌的发病率及致死率在所有恶性肿瘤中均较高,导致大多数患者在筛查发现肺结节时常怀有巨大健康焦虑[4].现代医学对肺结节的治疗方案常根据结节影像的大小、边缘、血管走行等因素进行评估,分别予以手术切除或随访观察[1,5].大多数西医未予手术切除的肺结节患者心理压力较大,多寻求中医药治疗.临床观察发现,中医药治疗肺结节疗效满意.通过中医药治疗,大量肺结节患者结节体积缩小、随访周期延长甚至手术指征消失,实现手术创伤与健康焦虑双避免[6-8].因此,有必要对肺结节的中医治疗及临床研究进行深入了解,现就肺结节的中医药治疗及临床研究予以综述.

中医早期常用疮疡代指肿瘤,经过后世的医家不断补充与完善逐渐形成了肿瘤疮疡理论,在很长一段时间内指导中医肿瘤的治疗.随着现代科技的进步,越来越多的肿瘤新特性理论被发现,其中慢性炎症理论及肿瘤内微生物理论为中医肿瘤疮疡理论提供了新的证据.文章旨在基于肿瘤内微生物及肿瘤慢性炎症理论对中医肿瘤疮疡理论的现代化内容进行浅析.

能量代谢异常在肿瘤发生发展的过程中发挥了重要作用.现代研究发现,不同于以往被认为是肿瘤细胞代谢途径受损的结果,这种异常代谢的方式是肿瘤细胞自主选择的基因重编程.目前,针对肿瘤能量代谢异常有效靶点的个体化治疗成为了新的研究热点.本文将综述肿瘤细胞能量代谢重编程特点,并探讨中医药或可从能量代谢途径治疗肿瘤的作用机制,从而使中药抗癌更好地指导临床应用.

Background/Aim: Xihuang Wan (XHW), a traditional Chinese medicine (TCM), has been used in China for a variety of cancers including lung cancer. The present study evaluated the efficacy of XHW on a Lewis lung mouse model and explored the potential mechanism via transcriptomics. Materials and Methods: The mice were randomized into 6 groups: 1) untreated control (n=10); 2) low-dose XHW; 3) medium-dose XHW; 4) high-dose XHW; 5) cisplatin; and 6) untreated blank (n=4). Lewis lung carcinoma (LLC) cells were injected subcutaneously except for the 4 mice in the blank group. The body weight and tumor length and width were measured every 3 days. RNA-sequencing was performed on tumors in the high-dose XHW group and the control group. Results: XHW inhibited the growth of LLC in a syngeneic mouse model, without toxicity, with equivalent efficacy to cisplatin. RNA-sequencing demonstrated that many signaling pathways were involved in XHW-mediated inhibition of LLC, including tumor necrosis factor, estrogen, cyclic guanosine 3', 5'-monophosphate-protein kinase G, apelin and the peroxisome proliferator-activated receptor signaling pathways. Conclusion: XHW inhibited LLC carcinoma through different pathways and shows clinical promise for patients who cannot tolerate platinum-based drugs.

肿瘤代谢以有氧糖酵解为主要特征,同时伴随氨基酸、脂质的代谢异常,是肿瘤发生、发展的基础.肿瘤特殊的代谢模式不仅能满足肿瘤细胞快速生长的物质能量需求,还使肿瘤在缺氧酸性微环境中获得生存优势,在诱导肿瘤基因突变、促进增殖转移、抑制周围免疫等方面发挥重要作用.这种代谢模式为肿瘤生长及侵袭提供了良好的条件,也成为近年来的研究热点.中医血瘀证是晚期肿瘤患者的主要证型,其病理机制与代谢障碍十分相似,因而活血药治疗肿瘤的作用机制被认为与调控肿瘤代谢有关.现代研究显示,活血药具有调节代谢酶及代谢通路相关蛋白的活性,影响线粒体功能,降低肿瘤细胞葡萄糖等营养物质的摄入,抑制有氧糖酵解,减少乳酸生成,改变肿瘤乏氧环境,抑制血管生成等作用,为活血药调控肿瘤代谢的作用提供了证据.本文通过探讨活血药对肿瘤代谢的调控作用,并阐述活血药的抗肿瘤作用机制,为后续研究提供思路,以期指导活血药的临床应用.

肺癌的发病率和死亡率较高,大多起病隐匿,大部分患者确诊时已为晚期,错失手术机会,因此化疗为晚期非小细胞肺癌(NSCLC)最主要的治疗手段.但晚期NSCLC的一线化疗效果并不理想,二线化疗应用率则明显降低,且不良反应进一步加重,靶向与免疫治疗也因其选择性而在临床应用受限.中医药治疗方案以辨证论治为理论指导,治疗晚期NSCLC的临床疗效显著.因此,将中医药与现代医学有机结合并形成综合诊疗方案,可为晚期NSCLC的临床治疗提供更为有效的方案选择.

目的:探讨川芎嗪联合顺铂对人肺癌A549细胞侵袭能力及线粒体功能的影响.方法:体外培养人肺癌A549细胞,采用CCK-8法检测川芎嗪干预后细胞增殖抑制率并确定川芎嗪高中低浓度,将细胞分为对照组,顺铂组及顺铂联合高、中、低浓度川芎嗪组,分别采用Transwell小室实验检测细胞侵袭能力,透射电镜观察线粒体超微结构,JC-1试剂盒检测线粒体膜电位变化,Western blot检测PI3K/AKT/mTOR通路相关蛋白表达.结果:与对照组相比,川芎嗪呈剂量依赖性抑制肺癌A549细胞增殖;经高、中、低剂量川芎嗪联合顺铂处理细胞24 h后,各组肺癌A549细胞侵袭能力下降,线粒体损伤减轻,膜电位升高,PI3K/AKT/mTOR通路蛋白表达降低,且其效果与剂量呈正相关.结论:川芎嗪联合顺铂可抑制人肺癌A549细胞增殖及侵袭能力,其可能与改善线粒体功能,影响癌细胞能量代谢有关.

目的:探讨川芎嗪(tetramethylpyrazine,TMP)对人肺癌A549细胞生长侵袭的干预作用与活性氧(re-active oxygen species,ROS)及其调控蛋白表达水平的相关性.方法:采用CCK-8法检测川芎嗪对A549细胞生长的影响,采用Transwell小室实验检测川芎嗪对A549细胞侵袭能力的影响,采用DCFH-DA荧光探针检测川芎嗪对A549细胞内ROS水平的影响,Western-blot法检测川芎嗪对HIF-1α、VEGF-C、MMP-9蛋白表达水平的影响.结果:川芎嗪呈浓度依赖性抑制肺癌A549细胞增殖和侵袭能力(P＜0.05),同时减少细胞内ROS生成(P＜0.05),抑制HIF-1α、VEGF-C、MMP-9蛋白表达(P＜0.05).结论:川芎嗪可降低人肺癌A549细胞ROS水平,减轻氧化应激损伤,从而抑制肿瘤细胞的增殖及侵袭.

Abstract Background: Gastroparesis affects the quality of life of many patients, but there is no effective treatment. Now, complementary and alternative medicine originated from China is gradually accepted by the world because of its unique treatment principles and relatively safe treatment methods. However, at present, there is still a lack of more definitive clinical application evidence for the treatment of gastroparesis with complementary and alternative medicine to confirm the safety and efficacy of complementary and alternative medicine in the treatment of gastroparesis caused by various causes. More comprehensive and stronger evidence-based medicine evidence is needed. Methods: We will retrieve literatures using Medline, Embase, the Cochrane Library database, Web of science, CNKI, VIP, CBM, and WanFang. We will look for RCTs or CCTs on the use of complementary and alternative medicine in the treatment of gastroparesis, and extract relevant data into the excel sheet. The whole retrieval and data extraction process were carried out by 2 researchers independently. Then we will use meta-analysis to make statistical analysis of all the results and make a systematic review of all the included literatures. Results: All results and safety data were analyzed for a comprehensive evaluation and/or descriptive analysis of the efficacy and safety of complementary and alternative therapies for gastroparesis. Conclusion: This study will provide more comprehensive clinical evidence for the treatment of gastroparesis with complementary and alternative therapies. Registration: The research has been registered and approved on the INPLASY.COM website. The registration number is INPLASY2020100033.

微卫星不稳定是基因组不稳定的表现之一,其在结直肠癌、乳癌、肺癌以及淋巴瘤等多种恶性肿瘤中均有存在,并且对肿瘤的发生、发展以及预后转归起到关键作用.近年来,国内外学者对微卫星不稳定的相关研究取得了显著成果,尤其在结直肠癌领域,其对结直肠癌免疫治疗和化学治疗的指导性意见已被纳入诊疗指南,并且成为该病治疗以及预后指导上的重要分子指标.本文就此总结国内外相关研究进展,以期为后续研究工作提供指导.

Introduction National Comprehensive Cancer Network has recommended cryoablation to replace the resection in the treatment of medically operable non-small cell lung cancer (NSCLC). Cryoablation also has been used for the advanced NSCLC in randomised controlled trials. However, they have not been systematically reviewed. Here, we provide a protocol to evaluate the effectiveness and safety of cryoablation in the treatment of advanced NSCLC.Methods and analyses We will search PubMed, Embase, the Cochrane Library, Chinese Biomedical Database, China National Knowledge Infrastructure, Wanfang Database and Chinese Scientific Journal Database without language restrictions from inception until 1 February 2020. Trial registers (International Clinical Trials Registry platform, the US National Institutes of Health Ongoing Trials Register and the ISRCTN registry) and reference lists of retrieved articles will also be searched. Two reviewers will independently extract data on participants, interventions, comparisons, outcomes and assess the methodological quality by the Cochrane risk of bias tool. The strength of evidences will be evaluated according to the Grading of Recommendations Assessment, Development and Evaluation approach. Review Manager V.5.3 software will be used for data analyses. Meta-analyses will be performed if the data are sufficiently homogeneous. The primary outcomes will be objective response rate and overall survival. The secondary outcomes will be adverse effects, health-related quality of life, changes of immune indicators and surrogate outcomes (disease control rate, progression-free survival and survival rate).Ethics and dissemination Ethics approval is not required, as this study will not involve patients. The results of this study will be submitted to a peer-reviewed journal for publication, to inform both clinical practice and further research.PROSPERO registration number CRD42019138660.

Background: Chemotherapy is the main therapy for stage IIIB/IV non-small cell lung cancer (NSCLC). However, the 5-year survival rate is 6%. Cancer Green Therapy is a novel therapy in China, which refers to cryoablation combined with traditional Chinese medicine (TCM) formula. Our previous retrospective analysis showed that patients with NSCLC had longer survival time and better quality of life after receiving cryoablation combined with TCM formula, compared with patients who received chemotherapy alone. Methods: This study is a multicenter, randomized, controlled clinical study. The experiment will be carried out in 6 hospitals at the same time, and a total of 450 cases of participants will be randomly assigned to the experimental group and the control group (n = 225). The experimental group will be given cryoablation and 28-days TCM formula, and the control group will be given 4 cycles chemotherapy. After 30 months of follow-up, the efficacy and safety of cryoablation combines with TCM formula in patients with stage IIIB/IV NSCLC will be observed. The primary outcome is overall survival. The secondary outcomes include progression-free survival, objective response rate, and quality of life. We will also conduct a safety evaluation of the treatment at the end of the trial. Discussion: This multicenter, randomized, controlled clinical study not only provides data on the efficacy and safety of cryoablation combined with TCM formula, but also provides a novel treatment strategy for clinicians and advanced NSCLC patients.