Objective:By integrating whole-genome resequencing (WGR) with longitudinal transcriptomic profiling, this study aimed to unravel the genetic-transcriptional regulatory network underlying thyroid immune-related adverse events (irAEs) in non-small cell lung cancer (NSCLC) patients treated with sintilimab. A key objective was to identify molecular biomarkers with predictive and therapeutic relevance. Methods:This prospective study included NSCLC patients receiving sintilimab, from whom peripheral blood samples were collected at three time points: baseline, post-first treatment, and post-second treatment. RNA sequencing (RNA-seq) and 30× WGR were performed. Differential gene expression analysis was conducted on the RNA-seq data, followed by longitudinal consistency filtering using the Longitudinal Concordant Gene Intersection (LCGI) algorithm to identify robust differentially expressed genes (DEGs). These DEGs underwent downstream integration with protein-protein interaction (PPI) network analysis and cis-expression quantitative trait loci (cis-eQTL) mapping to pinpoint key genes and regulatory single-nucleotide polymorphisms (SNPs) associated with thyroid irAEs. Results:The LCGI algorithm identified 13 DEGs exhibiting sustained directional shifts across treatment timepoints. Integration with conventional DEG signatures revealed a functionally cohesive module, with C1QA/B/C, FLT1, TEK, PDGFRB, SPP1, and HLA-DPB1 emerging as central regulators of thyroid irAEs. Cis-eQTL mapping identified 500 SNPs with significant cis-regulatory effects on 153 genes. A "C3 complement-matrix axis" was uncovered as a pivotal node, promoting macrophage polarization toward a pro-inflammatory phenotype. Based on the refined PPI network, we proposed a cascading pathological model in which a self-sustaining feedback loop drove progressive and irreversible thyroid autoimmunity. Conclusion:This study established a genetic-transcriptional regulatory framework for sintilimab-induced thyroid irAEs and identified a candidate gene set with biomarker potential. Our findings highlighted the central role of complement-driven mechanisms, providing a foundation for precision risk prediction and targeted intervention strategies that preserve antitumor efficacy while mitigating autoimmune toxicity.

目的 探讨贝伐珠单抗联合化疗治疗非小细胞肺癌(NSCLC)患者的疗效及不良反应,并分析可能影响贝伐珠单抗治疗效果的影响因素.方法 选取2017年1月至2019年12月中国医学科学院北京协和医学院肿瘤医院接受贝伐珠单抗联合化疗治疗的晚期NSCLC患者为研究对象.采用SPSS 22.0软件进行统计学分析,采用log-rank检验进行单因素分析,Cox回归模型进行多因素分析.结果 共纳入77例贝伐珠单抗联合化疗治疗的NSCLC患者,客观缓解率为27.3%,疾病控制率为67.5%,中位无进展生存期(PFS)为7.0个月;使用前T分期为T1～T2(HR=2.627,P=0.048)、贝伐珠单抗使用时机为化疗第1个周期后(HR=0.214,P=0.018)、贝伐珠单抗使用周期＞4个周期(HR=0.219,P=0.001)是影响患者PFS的独立预后因素.与同期行常规化疗未使用贝伐珠单抗治疗的患者匹配后相比,接受贝伐珠单抗联合化疗治疗的患者出现高血压、出血、蛋白尿及尿素氮的风险增高,但未发生严重的不良反应.结论 贝伐珠单抗联合化疗治疗NSCLC患者疗效确切,安全可控,尤其对于第1个周期化疗后使用贝伐珠单抗、使用周期＞4个周期、T分期越早(T1～T2)的患者使用贝伐珠单抗治疗的效果越好.

目的 挖掘并分析培唑帕尼上市后的药物不良事件(ADE)信号,为临床安全用药提供参考.方法 通过OpenVigil 2.1数据平台对美国FDA药物不良事件报告系统(FAERS)数据库进行信号挖掘,收集培唑帕尼2009年10月-2022年6月的ADE报告,采用比例失衡法中的比例报告比值(PRR)法和报告比值比(ROR)法检测该药的ADE信号并进行分析.结果 共筛选出以培唑帕尼为首要怀疑药物的ADE报告16 655份,经ROR法、PRR法挖掘出ADE信号220个,涉及19个系统器官分类.信号频度排前10位的ADE信号在该药的药品说明书中均有记载;发现了88个新的ADE信号,主要分布在胃肠系统、各种检查、肾脏和泌尿系统.嗜碱细胞数减少、甲床出血、肿瘤破裂、阴道瘘既是新的ADE信号,也是信号强度排前10位的ADE信号.结论 培唑帕尼在上市后应用中常见ADE(腹泻、毛发颜色改变、高血压等)的发生情况与其药品说明书基本一致;新的可疑风险信号(嗜碱细胞数减少、甲床出血、肿瘤破裂、阴道瘘等)报道例数较少,还需持续关注.

目的:探讨醋酸阿比特龙仿制药与原研药治疗转移性去势抵抗前列腺癌(mCRPC)的疗效与安全性,为临床提供参考依据.方法:以 2017 年 4 月至 2022 年 6 月在中国医学科学院肿瘤医院使用醋酸阿比特龙仿制药与原研药治疗的mCRPC患者为研究对象,分为仿制药组和原研药组,各 114 例.收集并比较两组患者的人口学特征(年龄、既往史等)、治疗相关信息(转移部位、基线检验值、治疗方案和合并疾病等)、不良事件发生情况及疗效评价等信息.对两组患者的年龄、体重指数(BMI)、美国东部肿瘤协作组(ECOG)评分、Gleason评分、血红蛋白和基线前列腺特异性抗原(PSA)等 7 个指标进行倾向性评分匹配后,比较两组患者的PSA50 缓解率、PSA50 缓解中位时间以及安全性.结果:两组患者在BMI、ECOG评分、转移部位、基线血红蛋白、肝肾指标及合并慢性疾病方面的差异均无统计学意义(P＞0.05).仿制药组与原研药组患者的PSA50 缓解率[55.26%(63/114)vs.59.64%(68/114),P=0.592]、PSA50缓解中位时间[1.90(1.10,3.00)个月 vs.2.50(1.00,4.00)个月,P=0.120]比较,差异均无统计学意义.仿制药组与原研药组患者的常见不良反应如肝功能损伤、三酰甘油升高、低钾、乏力、肌酐升高、高血压和体液潴留的发生率比较,差异均无统计学意义(P分别为0.086、0.682、0.568、0.437、1.000、1.000 和 0.119).进行倾向性评分匹配后,仿制药组和原研药组患者均为37例,PSA50缓解率[45.95%(17/37)vs.64.86%(24/37),P=0.161]、PSA50 缓解中位时间[2.01(1.24,3.11)个月 vs.2.00(1.00,4.00)个月,P=0.894]和常见不良事件发生率(P分别为1.00、1.00、0.24、1.00、1.00、1.00和1.00)比较,差异均无统计学意义.结论:采用倾向性评分匹配后,醋酸阿比特龙仿制药与原研药治疗mCRPC患者的疗效和安全性无显著性差异.

目的:探讨甲磺酸达拉非尼联合曲美替尼上市后的药品不良事件信号,为临床安全用药提供参考.方法:利用OpenVigil 2.1-MedDRA平台,收集美国食品药品监督管理局不良事件报告系统(FAERS)数据库中有关甲磺酸达拉非尼与曲美替尼联合应用的不良事件数据,截至2022年第2季度.采用比例失衡算法分析不良事件信号,分析不良事件上报的人群特征以及频数较高和新发的不良事件信息.结果:共获取甲磺酸达拉非尼与曲美替尼联合应用的不良事件报告9712例,涉及男性患者4555例(占46.90％),女性患者3921例(占40.37％);18～<65岁患者较多(2503例,占25.77％);上报数据主要源于美国(4287例,占44.14％);严重的不良事件主要包括死亡(2100例,占21.62％)、导致住院或住院时间延长(1889例,占19.45％).发生频数较高的不良事件主要有恶性肿瘤转移,发热和皮肤毒性等;新发的不良事件主要有吞咽困难、惊厥和脂膜炎等.结论:临床联合应用甲磺酸达拉非尼与曲美替尼时,应对发生频数较高以及新发的不良事件予以重视.在使用药物治疗前、治疗中及随访阶段,均应做好相关监测工作,有效保障患者用药安全.

目的:比较第三批国家药品集中带量采购中标的卡培他滨仿制药与卡培他滨原研药在真实世界中的安全性与有效性.方法:以 2020 年 11 月至 2021 年 11 月中国医学科学院肿瘤医院使用仿制与原研卡培他滨治疗的患者为研究对象,收集患者人口学特征、治疗相关信息、不良事件发生情况及疗效评价等信息.将患者分为仿制药组和原研药组,进行安全性和有效性评价.结果:纳入研究的患者共 254 例,经倾向性评分匹配后,仿制药组和原研药组各 118 例,两组患者在基本特征及不良反应方面的差异均无统计学意义(P≥0.05).利用一线治疗的病例进行有效性评价,两组患者客观缓解率、疾病控制率的差异均无统计学意义(P=0.05;P=0.196).结论:仿制与原研卡培他滨在有效性和安全性方面的差异无统计学意义.

Introduction: Head and neck tumors account for more than 6% of all cancers. The primary treatment for tumors of the head and neck is radiation therapy, which can induce oropharyngeal mucositis as a side effect. At present, there is no widely available therapeutic for the treatment of oropharyngeal mucositis in clinical practice. Based on the traditional prescription Liushen Wan, the pathogenesis and pathology, we developed a new Chinese medicine prescription and made Zhenhuang submicron emulsion (ZHSE) spray, which has an effi cacious therapeutic effect for oropharyngeal mucositis. However, its mechanism is unclear.Methods: This research explored the mechanism behind the modulatory effects of ZHSE by a strategy of metabolomics and network pharmacology. Multivariate data analyses, including unsupervised principal component analysis (PCA) and supervised orthogonal partial least squares discriminant analysis (OPLS-DA), were performed. Potential biomarkers were identified depending on the mass-charge ratio of the selected compound. Statistical and pathway enrichment analysis was performed in the KEGG pathway database. Network pharmacology combining metabolomic analyses was conducted to illustrate the key targets and pathways.Results: Critical metabolic pathways were investigated, 56f biomarkers were enriched and key metabolites such as linoleic acid, 9, 10-epoxyoctadecenoic acid, acetoacetic acid and citric acid were identified. A complex network of "compound-target-potential metabolite" interactions was drawn to illuminate the regulation of chemical constituents on key metabolites. These findings manifest that ZHSE regulates endogenous metabolite disorders during the treatment of oropharyngeal mucositis by various constituents, interacting with multiple targets associated with inflammation and pain.Conclusion: In this work, we determined several critical biomarkers and metabolic pathways and identified the possible regulatory mechanism by which ZHSE functions in the treatment of oropharyngeal mucositis. This study provides a new perspective on integrating metabolomics and network pharmacology for exploring improved therapy for head and neck tumors based on the traditional classic prescription of LSW.

目的 基于文献计量学方法研究中成药不良反应发生特点及其影响因素,探讨中成药药学监护路径建立中的关键步骤.方法 检索2011年1月1日—2020年12月31日期间知网(China National Knowledge In-frastructure,CNKI)数据库中与中成药的不良反应、不合理应用相关的文献报道,利用SPSS 19.0和VOS viewer软件对文献基本信息、中成药不良反应发生特点及不合理使用情况等信息进行统计、分析.结果 共计纳入111篇文献,发布单位主要为医疗机构(108篇);中成药不良反应数据中女性(54.69％)多于男性,临床表现多以用药24 h内出现(62.31％)的程度一般的过敏反应(38.97％)和消化道反应(21.19％)为主;常见不合理使用情况为用药不适宜(32.7％)及用法用量不适宜(21.79％).结论 中成药不良反应研究多集中在临床表现的描述性分析,缺乏对影响不良反应发生因素的关联性分析;现有数据提示建立中成药药学监护路径时应尽量全程化、分阶段、针对性管理.

Lung cancer ranks as a leading cause of death. Although targeted therapies usually trigger profound initial patient responses, these effects are transient due to drug resistance and severe side effects. Xihuang Pill (XHW) is a popular Chinese medicine formula that might benefit cancer patients when used as a complementary therapy. However, its underlying mechanism when combined with anticancer drugs is not clearly understood. Here, we used an integrated strategy to reveal the regulatory properties of XHW in increasing the antitumor activity of anlotinib in lung cancer. We evaluated the anti-lung cancer effect of XHW combined with anlotinib in mice bearing Lewis lung carcinoma (LLC). We applied untargeted metabolomics to identify the differences metabolism and found that XHW improved the effects of anlotinib on lung cancer. The components and targets related to the effects of XHW treatment on lung cancer were obtained through network pharmacology. Then, by integrating the biologically active components of XHW and anlotinib as well as the treatment-responsive metabolites and their related targets, an interaction network was constructed to evaluate the combination therapy. Finally, important protein candidates for this response were verified by immunohistochemistry of tumor tissues. The results showed that XHW significantly improved the inhibitory effect of anlotinib on tumor growth in LLC-bearing mice. Additionally, 12 differentially-abundant metabolites were identified by untargeted metabolomics in the XHW/anlotinib group compared with the XHW or anlotinib groups, and they were mainly enriched in fatty acid metabolism, lipid metabolism and amino acid metabolism pathways. Anlotinib, 23 components in Shexiang, 2 components in Niuhuang, 30 components in Ruxiang and 60 components in Moyao work together to act on 30 targets to regulate hexadecanoic acid (also named palmitic acid), linoleic acid, lactosylceramide, adrenaline, arachidonic acid and lysoPC(18:1(9Z)). The results of immunohistochemistry showed that XHW combined with anlotinib reduced the expression of PDGFRA in tumors. Overall, the key metabolites of XHW that enhances the efficacy of anlotinib were regulated by a multicomponent and multitarget interaction network. Our results suggested that anlotinib combined with XHW may be a promising strategy for the treatment of lung cancer.

Of late, lorlatinib has played an increasingly pivotal role in the treatment of brain metastasis from non-small cell lung cancer. However, its pharmacokinetics in the brain and the mechanism of entry are still controversial. The purpose of this study was to explore the mechanisms of brain penetration by lorlatinib and identify potential biomarkers for the prediction of lorlatinib concentration in the brain. Detection of lorlatinib in lorlatinib-administered mice and control mice was performed using liquid chromatography and mass spectrometry. Metabolomics and transcriptomics were combined to investigate the pathway and relationships between metabolites and genes. Multilayer perceptron was applied to construct an artificial neural network model for prediction of the distribution of lorlatinib in the brain. Nine biomarkers related to lorlatinib concentration in the brain were identified. A metabolite-reaction-enzyme-gene interaction network was built to reveal the mechanism of lorlatinib. A multilayer perceptron model based on the identified biomarkers provides a prediction accuracy rate of greater than 85%. The identified biomarkers and the neural network constructed with these metabolites will be valuable for predicting the concentration of drugs in the brain. The model provides a lorlatinib to treat tumor brain metastases in the clinic.

Background: Recently, several clinical studies have evaluated the first-line use of immune checkpoint inhibitors (ICIs) combined with platinum-doublet chemotherapy in patients with non-squamous non-small cell lung cancer (NSCLC), however, the differences in safety and efficacy between the various types of ICIs still require investigation.In this study, we evaluated the efficacy and safety of the first-line use of ICIs combined with platinum-doublet chemotherapy in patients with non-squamous NSCLC by meta-analysis and indirect comparison.Methods: Literature searches were performed using PubMed, the Cochrane Library, Embase, China Knowledge Resource Integrated Database, and Wanfang Data to identify all relevant randomized clinical trials for non-squamous NSCLC after 2010.Overall survival (OS), progression-free survival (PFS), and adverse effects (AEs) were pooled for meta-analysis and indirect comparison.Subgroup analyses were conducted to examine the factors associated with PFS. Results:The meta-analysis showed that the additional use of ICIs could significantly improve PFS and OS.The indirect comparison showed no significant difference in pembrolizumab + chemotherapy and atezolizumab + chemotherapy in the reducing of disease progression, while a significant difference in restricted mean survival time (RMST) was found between pembrolizumab + chemotherapy compared with atezolizumab + chemotherapy.A significant increase in grade ≥3 AEs was observed with the additional use of atezolizumab combined with chemotherapy.Subgroups including PD-1 status [high (>50%), intermediate (1-49%), and negative (<1%) expression], sex (male and female), smoking status (current or former smoker, and never smoked), liver metastases (with and without), age (>65 and ≤65) and Eastern Cooperative Oncology Group (ECOG) score (ECOG=0 and ECOG=1) were all associated with better PFS.Conclusions: This meta-analysis confirmed the treatment effects of ICIs combined with chemotherapy for non-squamous NSCLC.The pembrolizumab combination group had a greater RMST benefit compared with the atezolizumab combination group.Furthermore, our study also demonstrated a PFS advantage for non-squamous NSCLC using ICIs combined with chemotherapy irrespective of programmed death-ligand 1 (PD-L1) expression level, smoking status, liver metastasis status, sex, age and ECOG score.Due to the significant increase in AEs (> grade 3), more attention should be paid to the additional use of atezolizumab.

Objective:To compare the efficacy and safety between the generic pemetrexed produced by Sichuan Huiyu Pharmaceutical Co., LTD and the original pemetrexed produced by Eli Lilly Nederland B.V. in the treatment for patients with non-small cell lung cancer (NSCLC).Methods:The subjects were patients who received generic and original pemetrexed from March 2019 to December 2019 in Cancer Hospital of Chinese Academy of Medical Sciences. Demographic characteristics (age, gender, past history, etc.), treatment-related information (NSCLC stage, treatment regimen, underlying diseases, etc.), occurrence of adverse events, and efficacy evaluation in patients were collected. Patients were divided into the generic group and the original group, and the general situation, clinical use of pemetrexed, and adverse events in patients in the 2 groups were compared. After propensity score matching for 7 variables such as gender, age, body weight, body surface area, Eastern Cooperative Oncology Group (ECOG) score, tumor stage, and standardized chemotherapy dose, the efficacy and safety in patients between the 2 groups after 2 cycles of treatment with generic and original pemetrexed were compared.Results:A total of 182 patients were enrolled in the study, including 85 patients in the generic group and 97 patients in the original group. The differences in age, gender, ECOG score, body weight and body surface area, and underlying chronic diseases between the 2 groups were not statistically significant (all P>0.05). The patients with advanced stage Ⅲ and Ⅳ cancer in the generic group were significantly more than those in the original group [92%(78/85) vs. 79% (77/97), P=0.032]. The proportion of palliative chemotherapy and maintenance chemotherapy in the generic group was higher than that in the original group ( P<0.001). The difference in median dosage between the generic group and the original group was statistically significant [900 (800, 1 000) mg/m 2vs. 800 (800, 900) mg/m 2, P=0.019]. The difference in chemotherapy cycles between the 2 groups was statistically significant [5 (4, 10) vs. 4 (2, 4), P<0.001]. The overall incidence of adverse events and the incidences of bone marrow toxicity and liver toxicity in the generic group were higher than those in the original group ( P=0.018, P=0.037, P=0.018). After propensity score matching, there were 38 patients in both groups, and the differences in the objective response rate, disease control rate and the incidence of adverse events between the 2 groups were not statistically significant [26% (10/38) vs. 32%(12/38), P=0.723; 89% (34/38) vs. 96% (36/38), P=0.674; 47% (18/38) vs. 24%(9/38), P=0.055]. Conclusion:After propensity score matching, the difference in the efficacy and safety between the generic and the original pemetrexed was not significant.

目的 观察自制珍黄亚微乳喷雾对急性咽炎模型大鼠的治疗作用.方法 将大鼠随机分为5组(模型组、空白组、空白亚微乳组、六神丸组、珍黄亚微乳组),每组6只,除空白组不进行处理外,其他各组通过15％氨水连续喷喉3 d的方法制备大鼠急性咽炎模型;造模成功后,模型组大鼠腹主动脉取血,处死,摘除咽壁组织,备用;空白亚微乳组、六神丸组、珍黄亚微乳组分别给予空白亚微乳、六神丸、珍黄亚微乳等药物治疗4 d,后腹主动脉取血,处死,摘除咽壁组织,备用.观察各组对模型动物病理状态和血清中白细胞介素-1(IL-1)、白细胞介素-6(IL-6)和肿瘤坏死因子-α(TNF-α)表达的影响.结果 与模型组相比,六神丸组、珍黄亚微乳组可明显改善大鼠急性咽炎的炎症病变、同时对模型动物血清中的IL-1、IL-6、TNF-α的表达有抑制作用.结论 珍黄亚微乳对大鼠的急性咽炎有治疗作用,但治疗效果与六神丸没有明显差异性.

Although increasing reports from the literature on herbal-related hepatotoxicity, the identification of susceptibility-related factors and biomarkers remains challenging due to idiosyncratic drug-induced liver injury (IDILI). As a well-known Chinese medicine prescription, Xianling Gubao Capsule (XLGB) has attracted great attention due to reports of potential liver toxicity. But the mechanism behind it is difficult to determine. In this paper, we found that XLGB-induced liver injury belongs to IDILI through the analysis of clinical liver injury cases. In toxicological experiment assessment, co-exposure to XLGB and non-toxic dose of lipopolysaccharide (LPS) could cause evident liver injury as manifested by significantly increased plasma alanine aminotransferase activity and obvious liver histological damage. However, it failed to induce observable liver injury in normal rats, suggesting that mild immune stress may be a susceptibility factor for XLGB-induced idiosyncratic liver injury. Furthermore, plasma cytokines were determined and 15 cytokines (such as IL-1β, IFN-γ, and MIP-2α etc) were acquired by receiver operating characteristic (ROC) curves analysis. The expression of these 15 cytokines in LPS group was significantly up-regulated in contrast to the normal group. Meanwhile, the metabolomics profile showed that mild immune stress caused metabolic reprogramming, including sphingolipid metabolism, phenylalanine metabolism, and glycerophospholipid metabolism. 8 potential biomarkers (such as sphinganine, glycerophosphoethanolamine, and phenylalanine etc.) were identified by correlation analysis. Therefore, these results suggested that intracellular metabolism and immune changes induced by mild immune stress may be important susceptibility mechanisms for XLGB IDILI.

Abstract Objective To clarify the distribution of lorlatinib in the brain and elucidate the molecular mechanisms of lorlatinib penetration across the blood‐brain barrier (BBB). Methods Cytological experiments were performed to investigate the growth inhibitory effect of lorlatinib on different cells (endothelial cells HUVEC, HMEC‐1, and HCMEC/D3) and to investigate the protective effect of lorlatinib on neuronal cells after SH‐SY5Y hypoxia/reoxygenation injury. Furthermore, rat brain tissue was sequenced, and the differentially expressed genes (secreted phosphoprotein 1 (SPP1), vascular endothelial growth factor (VEGF), transforming growth factor beta (TGF‐β), Claudin, ZO‐1 and P‐gp) in several different drug treatment groups were verified by Real‐Time PCR. Lorlatinib brain distribution was predicted by physiologically based pharmacokinetics (PBPK). Results Lorlatinib and crizotinib both had inhibitory effects on endothelial cells, however lorlatinib inhibited the growth of HCMEC/D3 more efficaciously than crizotinib. In the SH‐SY5Y hypoxia model, lorlatinib had a greater protective effect on nerve cell damage caused by hypoxia and reoxygenation than crizotinib. The expression of SPP1, VEGF, TGF‐β, and Claudin in brain tissue was significantly downregulated after lorlatinib administration, and the expression level of early growth transcription factor 1 (Egr‐1) was significantly increased. The PBPK model successfully described lorlatinib concentrations in blood and brain tissue in the mouse model and gave a brain tissue partition coefficient of 0.7. Conclusion Lorlatinib can increase the permeability of the blood‐brain barrier whereby we suggest its underlying working mechanism is related to downregulating SPP1, inhibiting VEGF, TGF‐β, and Claudin subsequently reducing the number of tight junctions between BBB cells. Lorlatinib plays a protective role on injured nerve cells and does not change the amount of P‐gp expression in brain tissue, which may be important for its ability to be efficacious across the BBB with a low incidence of resistance.

Background:The features and survival outcome large cell lung cancer(LCLC) are scarce reported due to its low incidence,as a result, the prognoses of LCLC remain unclear.The aim of this study was to describe the demographic and clinical characteristics of large cell lung cancer with a population-base database and find the prognosis factors for cancer-specific survival(CSS) of the LCLC patients.Besides,a nomogram would be developed and independently validated to predict the CSS for LCLC based on the found prognosis factors. Methods: We extracted LCLC patients information from the Surveillance, Epidemiology, and End Results(SEER) database(2005-2014) and summarized the characteristic of the extracted factors.We used the Cox proportional hazards regression to find the prognosis factors for LCLC patients and develop the nomogram based on these in a splitted train cohort from the extracted data.The validation of the developed nomogram would be performed in an independent validation cohort from the extracted data, in which the C-index and the average of the time-dependent area under the receiver operating characteristic curve(time-dependent AUC) for CSS in 1-year, 3-year and 5-year would be calculated.The calibration curves would be drawn to visualize the performance of the established nomogram. Results: In result,4936 patients with LCLC were identified from the SEER database. Nearly half of LCLC patients were diagnosis with stage IV,only approximately 20% of patients was performed surgery.The prognosis factors influence the LCLC patients included age, sex,American Joint Committee on Cancer (AJCC) stage,race,surgery, tumour size and marital status.The calculated C-index was 0.701±0.01,mean time-dependent AUC for CSS in 1-year, 3-year and 5-year was 0.88.The calibrate curve showed that the gap between the predicted and observed CSS for 1-year, 3-year and 5-year was small. Conclusions:Sex,age,race,marital status,AJCC stage, surgery and tumour size are all the independent prognostic factors for CSS of the LCLC.The established nomogram can provide more precise evaluation for the survival of LCLC patients,and help the clinicians to make individual management.

Lung cancer remains the leading cause of cancer death worldwide, and the current therapy seems to have reached a plateau due to toxicities and acquired resistance. Therefore, exploration of novel therapeutic avenues may be useful. Si Jun Zi Tang (SJZ), a four-herb Chinese medicine formula first described approximately one thousand years, is often prescribed for cancer patients as a complementary therapy. However, whether SJZ benefits cancer patients as well as the main active constituents and its regulatory mechanism in combination with anticancer drugs remains unknown. Here, we investigated the anti-lung cancer potency and underlying mechanisms of the combination of gefitinib plus SJZ in mice with Lewis lung carcinoma (LLC), using histopathology and an integrated strategy of metabolomics and network pharmacology. The results showed that SJZ significantly enhanced gefitinib suppressing tumor growth and inhibiting LLC metastasis in LLC-bearing mice. Furthermore, 9 potential metabolomics biomarkers that differentially expressed in the SJZ/gefitinib group compared to the SJZ group or gefitinib group were identified by untargeted metabolomics, mainly involved three pathways: tricarboxylic acid cycle, tyrosine and tryptophan biosynthesis metabolism and linoleic acid metabolism. Five active ingredients, kaempferol, ginsenoside Rf, caprylic acid, lauric acid and naringenin, acted directly on 9 targets and regulated 4 out of 9 metabolites. Our results indicated that SJZ enhanced the anti-lung cancer effects of gefitinib via the key targets ABCG2, ABCC1, ABAT, GSR, CYP1A2, ALOX5, CYP3A4, PLA2G1B and PLA2G2A and the key metabolites 2-oxoglutarate, taurocholic acid, oxidized glutathione and linoleic acid. This work illustrated the modulatory properties of SJZ, which enhanced the anticancer effects of gefitinib, using metabolomics and network pharmacology analyses, and provided insights into underlying the mechanism the active ingredients of SJZfor the treatment of lung cancer in combination with gefitinib.

目的:探讨非小细胞肺癌化疗后骨髓抑制影响因素,为化疗前对患者进行评估提供参考依据.方法:回顾性分析2149例化疗后非小细胞肺癌患者信息,对骨髓抑制可能有关的因素进行单因素分析及多因素Logistic回归分析.结果:合并放疗、多周期化疗(化疗周期＞4周期)为血红蛋白(合并化疗:OR=1.452;多周期化疗:OR=1.884)、白细胞计数(合并化疗:OR =2.242;多周期化疗:OR=2.126)、粒细胞计数(合并化疗:OR=1.348;多周期化疗:OR=1.905)降低的危险因素;Karnofsky功能状态(KPS)评分≤80为血红蛋白(OR=1.770)、血小板计数(OR=1.407)降低发生的危险因素;应用长春瑞滨联合铂类为血红蛋白(OR=2.468)、白细胞计数(OR=4.827)降低的危险因素;应用依托泊苷联合铂类为白细胞计数(OR=2.455)、粒细胞计数(OR=2.855)降低的危险因素;年龄≥65岁,身体质量指数(BMI) ＜18.5,肿瘤分期(TNM分期)在Ⅲ～Ⅳ期,有骨转移为血红蛋白(OR依次为:1.619,2.021,1.388,1.447)降低的危险因素;应用培美曲塞联合铂类治疗可降低患者白细胞计数(OR=0.561)、血小板计数(OR=0.319)降低发生风险.结论:年龄、KPS评分、TNM分期、化疗方案,骨转移情况,放疗情况均为影响骨髓抑制发生的关键因素,密切关注这些相关因素可为降低非小细胞肺癌患者化疗相关性骨髓抑制风险提供参考.

In the present study, we developed and validated a rapid and simple liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the determination of lorlatinib in mouse serum and tissue samples, and such a method was successfully applied to investigate the pharmacokinetic study and tissue distribution of lorlatinib after oral administration. Samples were processed with methanol to precipitate protein and extract drugs, and Afatinib-d6 was used as the internal standard (IS). For LC-MS/MS analysis, compounds were separated on a C18 column by gradient elution (0.1% of formic acid and methanol) at 0.5 mL/min in the positive-ion mode with m/z 407.28 [M + H]+ for lorlatinib and m/z 492.10 [M + H]+ for IS. Good linearity was observed within the calibration ranges. Selectivity, accuracy (−6.42% to 8.84%), precision (1.69% to 10.98%), recoveries (91.4% to 115.0%), and matrix effect (84.2% to 110.6%) were all within the acceptable ranges. After oral administration, serum concentration of lorlatinib quickly achieved the maximal concentration (2,705.683 ± 539.779 μg/L) at 0.625 ± 0.231 h. The highest concentration was detected in the liver (3,153.93 ng/100 mg), followed by the stomach (2,159.92 ng/100 mg) and the kidney (548.83 ng/100 mg). In conclusion, a simple and rapid detection method was established and validated for determination of lorlatinib in blood and tissue samples of mouse. The pharmacokinetic study and tissue distribution of lorlatinib were successfully investigated using this method.

Currently, an increasing number of patients are seriously affected by acute thrombotic events. In China, Polygonum multiflorum (PM) is commonly used to treat diseases associated with thrombosis. Our previous work showed that PM could inhibit the platelet aggregation that plays a key role in the pathogenesis of thrombosis. However, the constituents of PM are complicated, and quality control methods cannot completely ensure the quality and clinical efficacy. In an attempts to explore this problem, we constructed a direct bioassay method to evaluate the antiplatelet aggregation effects of PM. To ensure the precision and reliability of this bioassay, we optimized and standardized the experimental conditions and then tested the standardized bioassay by analyzing 10 PM samples. Additionally, we combined chemical and biological evaluation methods to identify antiplatelet aggregation markers. The evaluation indicated that 10 samples of PM could inhibit platelet aggregation and there was a notable difference in biopotency between the different PM groups. Chemical fingerprints revealed variations in the contents of the 7 main peaks. Trans-2,3,5,4'-tetrahydroxy-stilbene-2-O-β-d-glucoside and catechin might be active constituents of antiplatelet aggregation as determined by spectrum-effect relationships. This work indicates that bioassay and spectrum-effect relationships are useful tools to associate sample quality with the potential chemical markers linked to the clinical effects of Traditional Chinese Medicines.