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Abstract: In recent years, new anticancer drugs have been investigated and approved for the treatment of breast cancer based on improved survival outcomes. However, these new treatments have specific class-related side effects. Pulmonary toxicity has been identified as an adverse event of special interest with everolimus, and is becoming an increasingly significant clinical challenge with the recent approval of trastuzumab deruxtecan. Overall, the risk of pulmonary toxicity is quite low but in some cases lung damage can be fatal. We conducted an update including the available published data regarding the incidence, mechanisms of pathogenesis, clinical presentations, and treatment of lung toxicity induced by new anticancer drugs. A literature search was performed between January and June 2024, considering papers, clinical trials, case reports, case series, meta-analyses, and systematic reviews published from January 2014 to June 2024. We also provide an algorithm for diagnosis and treatment, along with real-life cases managed at the Modena Cancer Center. Data provided here show that pulmonary toxicity is a quite frequent side effect and underline that early recognition and prompt treatment are crucial for the best outcome of patients, whose overall prognosis is being improved by the availability of these new anticancer agents.

Keywords: breast cancer, lung toxicity, Pulmonary toxicity, interstitial lung disease, pneumonia, trastuzumab deruxtecan, CDK4/6i

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背景：乳腺癌已成为威胁全球妇女健康的主要恶性肿瘤。研究表明，乳酸脱氢酶A（LDHA）在癌症的发生和开展中起着关键作用。我们旨在探讨LDHA和LDH5同工酶作为乳腺癌治疗靶点的可行性。

方法: 从TCGA、HPA、bc-GenExMiner v5.1、TNMplot和UALCAN等数据库中获取癌症组织中LDHA的表达数据，并分析LDHA表达与乳腺癌临床病理特征的关系。应用Kaplan-Meier法绘制LDHA生存曲线，Western blot检测LDHA蛋白表达。顺利获得MTT法、平板克隆形成实验、划痕实验、基质金属蛋白酶法和Transwell实验，检测过表达和敲低LDHA对乳腺癌BT549细胞增殖、迁移和侵袭能力的影响。顺利获得琼脂糖凝胶电泳检测乳腺癌细胞系、乳腺癌患者和健康对照者组织和血清中LDH同工酶的活性。

结果: 与正常组织相比，乳腺癌组织中LDHA的表达显著升高。患者的淋巴结转移情况、组织学类型、TP53突变状态和PAM50分型是影响LDHA表达的重要因素。LDHA过表达可促进BT549细胞增殖、迁移和侵袭，相反，敲低LDHA会抑制细胞增殖、迁移和侵袭。同时，琼脂糖凝胶电泳结果显示，LDHA的过表达和敲减分别增加和降低LDH5同工酶活性。１２位乳腺癌患者乳腺癌组织与癌旁正常组织相比，LDH5同工酶活性在乳腺癌组织显著增加。６９位乳腺癌患者和６９位健康对照者血清相比，LDH5同工酶活性在乳腺癌患者显著增加。Kaplan-Meier生存曲线结果显示，LDHA高表达的患者总生存期显著降低。

结论: LDHA顺利获得调节LDH5同工酶的活性，促进乳腺癌细胞的增殖、迁移和侵袭，是乳腺癌的潜在预后标志物和治疗靶点。

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摘要: 三阴性乳腺癌（triple-negative breast cancer, TNBC）因缺乏雌激素受体、孕激素受体及HER2表达，已成为侵袭性最强且预后最差的乳腺癌亚型。本文系统综述TNBC诊断、预后及治疗的研究进展。在诊断方面，影像技术（如动态对比增强磁共振成像、多模态超声）联合组织学与免疫组化检测（如Ki-67、PD-L1表达）可提高早期诊断率；分子标志物（PIM-1、miR-522）及亚型分类（LAR、IM、BLIS、MES）为精准分型给予依据。预后评估需结合临床病理特征（肿瘤大小、淋巴结转移、肿瘤间质比）、分子特征（BRCA突变、PD-L1表达）及预后评分系统。在治疗策略中，化疗仍是基础，但需平衡疗效与副作用；新辅助化疗可提高病理完全缓解率，而分子标志物（如循环肿瘤细胞）有助于预测疗效。靶向治疗方面，PARP抑制剂对BRCA突变患者疗效显著，抗体药物偶联物（如戈沙妥珠单抗）为化疗耐药患者给予新选择。免疫治疗中，PD-1/PD-L1抑制剂联合化疗显著改善无进展生存期，尤其对PD-L1阳性患者。未来需进一步探索联合治疗、代谢重编程及个体化治疗策略，以克服TNBC异质性及治疗耐药性。本文强调多学科协作与精准医学在优化TNBC管理中的关键作用，为临床实践及科研方向给予重要参考。

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Abstract: Lung cancer is a leading cause of cancer-related mortality worldwide and in the People’s Republic of China. Recently, the pathological proportions of the various forms of lung cancer have changed. A shift to a preponderance of adenocarcinoma at the expense of squamous cell carcinoma is observable. Treatment decisions have historically been based on tumor histology, and evolution of our molecular understanding of cancer has led to development of targeted therapeutic agents. It is essential to further understand mutations that drive cancer development (driver mutations) in relevant genes and their effects on cancer cell proliferation and survival. The epidemiology of lung cancer in the People’s Republic of China has been extensively reviewed elsewhere. However, molecular epidemiological data from mainland China are scarce. Consequently, we herein review the prevalence of driver mutations in Chinese patients.

Keywords: lung cancer, driver mutation, prevalence, EGFR, EML4-ALK, KRAS, ROS1, PIK3CA, BRAF, RET, HER2

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Objective: Extensive stage Small-Cell Lung Cancer (ES-SCLC) is the most lethal lung cancer, and the addition of immunotherapy conferred a slight survival benefit for patients. Extensive molecular profiling of patients treated with chemotherapy (CT) or chemotherapy plus immunotherapy (CT+IO) would be able to identify molecular factors associated with patients' survival.

Material and Methods: In this retrospective study, 99 ES-SCLC patients were considered. Of the 79 includible patients, 42 received CT (median age 71 y/o, I–IIIQ: 65– 76), and 37 received CT+IO (median age 71 y/o, I–IIIQ 66– 75). The FoundationOne CDx assay was performed on patients' tumor tissues.

Results: The most mutated genes were TP53 (99%), RB1 (78%), PTEN (23%) and MLL2 (20%), with no significant differences between the treatment groups. As a continuous variable, Tumor Mutation Burden (TMB) had an effect on patients' progression-free survival (PFS) by type of treatment (HR 1.81 (95%, CI: 0.99– 3.31) and HR 0.84 (95%, CI: 0.56– 1.26) for patients treated with CT and CT+IO, respectively). TMB was also computed and dichotomized using two different cut-offs: considering cut-offs of 10 mut/Mb and > 16 mut/Mb, 45 patients (57%) and 68 patients (86.1%) had a low TMB, respectively. A high TMB (cut-off 10 mut/Mb) predicted worse PFS in patients treated with CT (p=0.046); even though not statistically significant, a high TMB (cut-off 16 mut/Mb) predicted a better survival in patients treated with CT+IO. Moreover, at univariate analysis, MLL2 mutations were associated with better prognosis in the overall case series (HR_PFS = 0.51, 95% CI: 0.28– 0.94), and overall survival (HR_OS = 0.52, 95% CI: 0.28– 0.97).

Conclusion: In ES-SCLC, TMB is associated with worse survival in patients treated with CT alone, and with better survival in patients treated with CT+IO, whether considered as a continuous or a dichotomized variable, at different cut-offs. Alterations in epigenetic factors are also associated to better patient prognosis.

Keywords: small-cell lung cancer, predictive biomarkers, immunotherapy, patients prognosis, tumor mutation burden

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Purpose: In epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) patients treated with EGFR-tyrosine kinase inhibitors (TKIs), transformation to small-cell lung cancer (SCLC) is associated with poor outcomes, and the optimal treatment strategy is unclear. This study aimed to investigate the clinical factors and treatments associated with outcomes in this group.

Patients and Methods: This retrospective multicenter study enrolled patients with SCLC transformed from advanced NSCLC after progression on EGFR-TKI treatment. We analyzed clinical and demographic characteristics, first-line EGFR-TKI treatments, and subsequent regimens to identify factors associated with clinical outcomes.

Result: Twenty-seven patients diagnosed with SCLC transformation after EGFR-TKI therapy between 2018 and 2023 were enrolled, most of whom had an EGFR exon 19 deletion (67%). The subsequent treatment regimens included traditional chemotherapy (CT) in 12 patients (44%), combined CT/EGFR-TKI in 10 patients (37%), and combined CT/immunotherapy in 5 patients (19%). The median progression-free survival (PFS) with first-line EGFR-TKI treatment, subsequent SCLC treatment, and overall survival (OS) were 16.1 months, 6.4 months, and 39.5 months, respectively. The overall response rate (ORR), disease control rate (DCR), and median PFS for subsequent treatments were 38.5%, 69.2%, and 6.4 months, respectively. The DCRs for subsequent CT, CT/TKI, and CT/immunotherapy were 41.7%, 88.9%, and 100%, respectively. ORR and PFS were higher in the CT/TKI (44.4% and 7.2 months) and CT/immunotherapy (80.0% and 11.3 months) groups compared to CT (16.7% and 3.7 months), but these differences were not statistically significant. Univariate and multivariate analyses showed no significant differences in PFS and OS among treatments.

Conclusion: In patients with SCLC transformed from advanced NSCLC after EGFR-TKI treatment, adding immunotherapy and EGFR-TKI to CT improved DCR and showed trends in ORR and PFS, but did not provide an OS benefit. More prospective studies with varied therapeutic approaches are needed to confirm these findings.

Keywords: EGFR-mutant NSCLC, SCLC transformation, EGFR-TKI, chemotherapy, immunotherapy, clinical outcomes

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Background: Multiple myeloma (MM), an incurable plasma cell malignancy. The significance of the relationship between natural killer (NK) cell-related genes and clinical factors in MM remains unclear.

Methods: Initially, we extracted NK cell-related genes from peripheral blood mononuclear cells (PBMC) of healthy donors and MM samples by employing single-cell transcriptome data analysis in TISCH2. Subsequently, we screened NK cell-related genes with prognostic significance through univariate Cox regression analysis and protein-protein interaction (PPI) network analysis. Following the initial analyses, we developed potential subtypes and prognostic models for MM using consensus clustering and lasso regression analysis. Additionally, we conducted a correlation analysis to explore the relationship between clinical features and risk scores. Finally, we constructed a weighted gene co-expression network analysis (WGCNA) and identified differentially expressed genes (DEGs) within the MM cohort.

Results: We discovered that 153 NK cell-related genes were significantly associated with the prognosisof MM patients (P < 0.05). Patients in NK cluster A exhibited poorer survival outcomes compared to those in cluster B. Furthermore, our NK cell-related genes risk model revealed that patients with a high risk score had significantly worse prognoses (P < 0.05). Patients with a high risk score were more likely to exhibit adverse clinical markers. Additionally, the nomogram based on NK cell-related genes demonstrated strong prognostic performance. The enrichment analysis indicated that immune-related pathways were significantly correlated with both the NK subtypes and the NK cell-related genes risk model. Ultimately, through the combined use of WGCNA and DEGs analysis, and by employing Venn diagrams, we determined that ITM2C is an independent prognostic marker for MM patients.

Conclusion: In this study, we developed a novel model based on NK cell-related genes to stratify the prognosis of MM patients. Notably, higher expression levels of ITM2C were associated with more favorable survival outcomes in these patients.

Keywords: multiple myeloma, NK cell-related genes, NK subtypes, prognostic model, ITM2C

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Abstract: Despite recent advancements in treatments, including proteasome inhibitors, immunomodulators, and anti-CD38 monoclonal antibodies, multiple myeloma (MM) remains mostly incurable with patients frequently experiencing disease relapses due to therapy resistance. Hence there is an urgent need for innovative treatments for patients with relapsed and/or refractory MM (RRMM). This review examines Belantamab mafodotin, the first antibody-drug conjugate (ADC) targeting B-cell maturation antigen (BCMA), which has shown efficacy in pre-clinical and clinical settings for RRMM. BCMA, a type III transmembrane glycoprotein critical for B cell functions, is predominantly expressed in malignant plasma cells making it a promising therapeutic target. ADCs, comprising a monoclonal antibody, a cytotoxic payload, and a linker, offer a targeted and potent therapeutic approach to cancer treatment. Belantamab mafodotin integrates an afucosylated monoclonal antibody and monomethyl auristatin F (MMAF) as its cytotoxic agent. It induces apoptosis in MM cells by disrupting microtubule formation and interfering with important signaling pathways. The series of DREAMM (Driving Excellence in Approaches to MM) studies have extensively evaluated Belantamab mafodotin in various clinical settings. This review provides a comprehensive overview of pre-clinical and clinical data supporting Belantamab mafodotin as a future therapeutic option for RRMM.

Keywords: belantamab mafodotin, multiple myeloma, antibody-drug conjugate

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Abstract: Despite excellent results in frontline therapy, particularly in pediatric age, refractory Burkitt lymphoma still remains a therapeutic challenge, with dismal outcome. The prognosis is very poor, ranging from less than 10% to 30– 40%, with longer survival only in transplanted patients. On account of the paucity of data, mostly reporting on small series of patients, with heterogeneous characteristics and salvage treatments, at present it is impossible to draw definitive conclusions on the treatment of choice for this difficult to treat subset of patients. New insights into Burkitt lymphoma/leukemia cell biology have led to the development of new drugs, currently being tested, directed at different specific targets. Herein, we describe the results so far reported in refractory Burkitt lymphoma/leukemia, with standard treatments and hematopoietic stem cell transplant, and we review the new targeted drugs currently under evaluation.

Keywords: Burkitt lymphoma, target therapy, relapse, refractory, outcome

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摘要

目的: 载脂蛋白 E（APOE）基因是导致迟发性阿尔茨海默病（AD）发病风险的最强遗传因素之一，而且可能还会增加患癌的风险。然而，其重要性远不止于此。本研究旨在利用生物信息学和多重荧光免疫组织化学（mIHC）技术，全面分析 APOE 在肝细胞癌（HCC）中的潜在作用及预后价值。

方法: 本研究纳入了 2007 年 4 月至 2012 年 6 月期间 90 例肝细胞癌（HCC）患者的临床病理样本。我们利用组织微阵列（HLiv180Su09）和多重荧光免疫组织化学分析来验证 APOE 蛋白表达情况以及患者的预后情况。同时还利用多个在线数据库来研究 APOE 在 HCC 中的表达情况和预后情况，并对 APOE 与临床病理特征、免疫细胞浸润水平、免疫检查点基因、突变以及功能富集分析之间的相关性进行了综合分析。此外，还利用单细胞数据库确定了免疫细胞群体中 APOE 的分布情况。

结果: APOE mRNA 在 HCC 中的转录和翻译水平均明显过表达。生存期分析表明，APOE可能是HCC患者的一个有利预后指标。除了参与 HCC 中的免疫细胞浸润、免疫检查点基因表达、基因变异、免疫调节基因和甲基化改变外，富集分析表明 APOE 还参与了多种癌症相关信号通路。

结论: 本研究全面探讨了 APOE 在 HCC 中的关键作用，并强调了其作为生物标记物和治疗靶点的巨大潜力。这一发现不仅为 HCC 的研究开辟了新途径，还为临床诊断和治疗策略给予了宝贵的见解。

关键词: 肝细胞癌 APOE 生存预后 肿瘤免疫 生物标志物

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背景： 伊匹木单抗和纳武单抗的联合治疗在肝细胞癌（HCC）的一线治疗中已显示出显著的抗肿瘤活性，并且在索拉非尼治疗后进展的二线治疗中也取得了一定疗效。然而，伊匹单抗联合抗PD-1/PD-L1抗体治疗在经历多线治疗后进展的晚期HCC患者中的疗效和安全性尚未报道。

材料与方法： 我们召开了一项多中心回顾性研究，纳入了33名经过多线靶向免疫治疗后进展并接受伊匹木单抗联合治疗的HCC患者。所有患者均接受过至少一线免疫治疗联合疗法（排除接受抗CTLA-4抑制剂治疗的患者）。主要终点为总生存期（OS）和无进展生存期（PFS）。疗效评估采用RECIST 1.1标准，而不良事件按照CTCAE 5.0进行评估。

结果： 在这些患者中，29例（87.9%）接受了伊匹木单抗联合治疗作为三线或更晚的治疗。整个队列的中位OS为14.07个月（95% CI：5.57个月 - 未达到），中位PFS为2.36个月（95% CI：1.97-5.64个月）。单因素生存分析表明，NLR ≥ 3.1和肿瘤大小 ≥ 63 mm是总生存期的预后危险因素（P=0.03 和 P=0.027）。多因素生存分析发现，NLR ≥ 3.1是总生存期的唯一独立预后危险因素（P=0.048）。总体反应率（ORR）为12.1%，疾病控制率（DCR）为48.5%。1例患者出现与治疗相关的死亡（3%），2例出现肿瘤超进展（6.1%），3例因不良事件中断治疗（9.1%）。

结论： 伊匹木单抗联合治疗在极后线治疗中是一种可行的选择，但需要密切监测治疗相关不良反应。更早期应用这一联合疗法可能会使患者取得更好的获益。

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摘要

背景: 随着肥胖与糖尿病的全球流行，非酒精性脂肪性肝病（NAFLD）正成为最常见的慢性肝病，而非酒精性脂肪性肝炎（NASH）日益成为肝细胞癌（HCC）的主要风险因素。因此，探索NASH相关HCC的新型生物标志物具有重要意义。

方法: 深度学习（DL）顺利获得自动构建神经网络（NNs）成为基因组学研究中极具潜力的工具。本研究整合DL算法、"limma"差异分析、加权基因共表达网络分析（WGCNA）及蛋白质互作网络（PPI）筛选特征基因，顺利获得实时荧光定量PCR验证特征基因在NAFLD小鼠模型中的表达，并利用富集分析与单细胞测序技术探究特征基因在NASH相关HCC中的作用机制。

结果： 顺利获得DL筛选的NAFLD核心基因与代谢综合征关键基因交叉验证，最终取得6个特征基因（FDFT1、TNFSF10、DNAJC16、RDH11、PGRMC1和MYC）。ROC曲线分析显示模型预测效能优异（AUC=0.983，95%CI:0.9241-0.98885）。基于NAFLD小鼠模型的动物实验证实FDFT1、TNFSF10、DNAJC16、RDH11和PGRMC1在NAFLD肝脏中显著高表达。其中，FDFT1与PGRMC1在NASH-HCC中呈现显著表达趋势及突出的诊断价值。

结论： FDFT1和PGRMC1作为胆固醇合成通路的关键酶，本研究从新视角验证胆固醇代谢在NAFLD中的重要作用，提示二者可能成为NASH-HCC的新型预后与诊断标志物。

关键词： 非酒精性脂肪性肝病；NASH相关肝细胞癌；深度学习；生物标志物；代谢综合征；胆固醇代谢

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柯晨昕¹，俞越峰¹，李江¹，余悦田¹，孙颖¹，王禹盈¹，王斌¹，陆颖理¹，唐孟军²，王宁荐¹，陈奕¹
(1. 上海交通大学医学院附属第九人民医院内分泌科，上海 200011；2. 浙江省台州医院，浙江 台州 318000）

【摘要】背景: 血液蛋白质组是生物标志物和治疗靶点的主要来源。我们的目的是顺利获得系统性的遗传分析，探索Graves病（GD）和Graves眼病（GO）的致病蛋白和潜在治疗靶点。方法 英国生物样本库制药蛋白组学项目（UK Biobank Pharma Proteomics Project, UKB-PPP）的全基因组关联研究（Genome-Wide Association Studies，GWAS）从54219名参与者中收集了2923个Olink蛋白质。我们利用顺式-pQTLs进行了孟德尔随机化（Mendelian Randomization, MR）研究，以筛选与GD和GO风险相关的候选蛋白质。我们采用共定位分析和海蒂检验评估已确定的蛋白质和疾病是否共享相同的遗传变异。在基于摘要数据的孟德尔随机化（Summary-data-based MR, SMR）分析中，利用反式-pQTLs识别出更多具有潜在因果关系的蛋白质。随后，我们进行了下游分析，包括蛋白质相互作用、基因功能、细胞类型特异性表达以及可药用性评估。

结果: 本研究从基因角度预测了 62 种血浆蛋白的水平与 GD 风险相关。研究表明，CD40、TINAGL1、GMPR 和 CXCL10 四种蛋白质均存在与 GD 相关的相同变异，因此被优先考虑。具体来说，一些蛋白质与 CD40 中映射的反式-pQTLs 可能与GD 存在潜在关联。这四种优先考虑的蛋白编码基因主要富集于细胞凋亡和死亡过程的调控中。此外，GMPR 与 GO 和 GD 的关联方向一致。BTN1A1 和 FCRL1 被优先列为 GO 发生的因果蛋白，但与 GD 无关。

结论: 顺利获得整合蛋白质组学和遗传学数据，我们发现了多种 GD 的蛋白质生物标志物，其中一种与 GD 和 GO均相关，另外两种则是 GO 发病的特异性标志物。这一发现为两种疾病的病因学研究和潜在治疗靶点给予了重要见解。

关键词: 血浆蛋白质组学；Graves病；Olink；孟德尔研究

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作者: 陈淼，田娜，崔然，张华，王倩，童强，陈智勇，王煜勛，魏正宗

摘要

目的: 旨在顺利获得大样本人群分析银屑病患者并发皮肌炎的风险。

方法: 基于TriNetX数据库（2002年1月1日至2022年12月31日），纳入年龄≥20岁的银屑病患者及非银屑病对照人群。顺利获得国际疾病分类第十版（ICD-10-CM）诊断编码定义银屑病、皮肌炎及相关合并症。采用1:1倾向评分匹配（PSM）平衡两组基线特征，并顺利获得Kaplan-Meier曲线和Cox比例风险模型评估风险比（HR）。

结果: 匹配后，银屑病组与非银屑病组各纳入301,018例患者。银屑病组患皮肌炎的风险显著高于对照组（HR: 2.41, 95% CI: 2.01–2.89）。亚组分析显示，银屑病关节炎（PsA）患者的皮肌炎风险进一步升高（HR: 1.73, 95% CI: 1.32–2.28）。接受白细胞介素-17抑制剂（IL-17i）治疗的银屑病患者，其皮肌炎风险较未使用生物制剂者显著增加（HR: 5.79, 95% CI: 1.57–21.31）。在欧洲、中东、非洲（EMEA）和亚太（APAC）人群中，银屑病患者的皮肌炎风险亦显著升高（HR分别为4.77和2.50）。

结论: 本研究首次证实银屑病患者患皮肌炎的风险显著增加，尤其见于合并PsA或接受IL-17i治疗的患者。提示临床需对银屑病患者进行皮肌炎筛查，特别是出现非典型皮疹时。未来需进一步探索两者关联的机制。

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Purpose: Medulloblastoma (MB) is the most prevalent paediatric brain tumour. Despite improvements in patient survival with current treatment strategies, the quality of life of these patients remains poor owing to the sequelae and relapse risk. An alternative, or, in addition to the current standard treatment, could be considered immunotherapy, such as Natural Killer cells (NK). NK cells are cytotoxic innate lymphoid cells that play a major role in cancer immunosurveillance. To date, the mechanism of cytotoxicity of NK cells, especially regarding the steps of adhesion, conjugation, cytotoxic granule polarisation in the cell contact area, perforin and granzyme release in two and three dimensions, and therapeutic efficacy in vivo have not been precisely described.

Materials and Methods: Each step of NK cytotoxicity against the three MB cell lines was explored using confocal microscopy for conjugation, Elispot for degranulation, flow cytometry, and luminescence assays for target cell necrosis and lysis and mediators released by cytokine array, and then confirmed in a 3D spheroid model. Medulloblastoma-xenografted mice were treated with NK cells. Their persistence was evaluated by flow cytometry, and their efficacy in tumour growth and survival was determined. In addition, their effects on the tumour transcriptome were evaluated.

Results: NK cells showed variable affinities for conjugation with MB target cells depending on their subgroup and cytokine activation. Chemokines secreted during NK and MB cell co-culture are mainly associated with angiogenesis and immune cell recruitment. NK cell cytotoxicity induces MB cell death in both 2D and 3D co-culture models. NK cells initiated an inflammatory response in a human MB murine model by modulating the MB cell transcriptome.

Conclusion: Our study confirmed that NK cells possess both in vitro and in vivo cytotoxic activity against MB cells and are of interest for the development of immunotherapy.

Keywords: cancer, medulloblastoma, immune cells, adoptive transfer

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摘要: 鼻眶血管瘤是一种常见的成人良性眶内病变，复发性病例在传统手术治疗后仍面临较高的复发风险及并发症。本报告介绍了一例21岁男性患者，先后接受多次手术治疗后血管瘤复发，且伴随严重鼻出血，手术已无法进一步控制病情。采用抗血管生成药物贝伐单抗进行非手术治疗，显著缩小了肿瘤，并有效控制了症状。经过两年的随访观察，患者肿瘤未出现复发，且无严重不良反应。本案例表明，贝伐单抗可作为复发性鼻眶血管瘤的一种安全且有效的非手术治疗选择，为该类难治性血管瘤的治疗给予了新的方向。

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摘要

背景: 本研究旨在揭示DNA拓扑异构酶IIα（TOP2A）在视网膜母细胞瘤（RB）中的关键作用，重点关注其对上皮-间质转化（EMT）的调控机制，并探讨TOP2A抑制作为潜在治疗策略的临床应用价值。

方法: 顺利获得分析公共基因表达数据库（GSE97508、GSE110811和GSE172170）中的RB组织数据，我们评估了TOP2A的表达水平。随后，在人RB细胞系（Y79和WERI-Rb-1）中，顺利获得敲低或过表达TOP2A进行功能实验，检测其对细胞增殖、迁移、侵袭能力的影响，并利用RT-PCR和Western blot技术分析EMT标志物的表达变化。此外，我们在皮下移植瘤和肝转移小鼠模型中进一步验证了TOP2A调控对肿瘤生长和转移的抑制作用。

结果: RB组织中TOP2A的表达显著上调（p < 0.0001）。体外实验表明，敲低TOP2A可显著抑制RB细胞的增殖、迁移和侵袭能力，并逆转EMT标志物的表达（p < 0.05）；而TOP2A过表达则促进了这些致癌过程。在体内实验中，敲低或抑制TOP2A显著减缓了皮下移植瘤和肝转移模型的肿瘤生长及转移（p < 0.05）。值得注意的是，TOP2A抑制剂与EMT抑制剂的联合治疗表现出协同抗肿瘤效应，显著降低了肿瘤负荷和转移病灶的数量（p < 0.01）。

结论: TOP2A在RB的发病机制和进展中扮演了核心角色，其顺利获得调控EMT促进了肿瘤的恶性表型。抑制TOP2A不仅能够有效抑制RB细胞的增殖和转移，还可逆转EMT过程，从而为RB的治疗给予了新的靶点。本研究为开发靶向TOP2A的治疗策略奠定了重要理论基础，并为后续临床转化研究给予了科学依据。

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Purpose: Chronic suppurative otitis media (CSOM) is a prominent contributor to preventable hearing loss globally. Probiotic therapy has attracted research interest in human infectious and inflammatory disease. As the most prevalent probiotic, the role of Lactobacillus in CSOM remains poorly defined. This study aimed to investigate the antipathogenic effects and underlying mechanism of Lactobacillus on CSOM.

Methods: RNA sequencing of granulation of middle ear cavity from CSOM patients and lavage fluid of middle ear from normal volunteer was conducted. Human middle ear epithelial cells (HMEEC) and rats infected with Bacillus cereus (B. cereus) and Staphylococcus aureus (S. aureus) were used for CSOM constructing. Western blot, qPCR and Vybrant™ Alexa Fluor™ 488 lipid raft labeling were performed to explore the possible molecular mechanism by which lipid raft linker (RFTN1) regulates lipid raft/toll-like receptor 4 (TLR4). ELISA and HE staining was utilized to evaluate the effect of Lactobacillus on the progression of CSOM in vivo.

Results: Based on RNA Sequence analysis, a total of 3646 differentially expressed genes (1620 up-regulated and 2026 down-regulated) were identified in CSOM. RFTN1 was highly expressed in CSOM. Inhibition of RFTN1 not only reduced the inflammatory response of CSOM but also suppressed the formation of lipid rafts. Further investigation revealed that RFTN1 inhibition could reduce the expression of TLR4, which also localizes to the lipid rafts. TLR4 responds to RFTN1-mediated inflammatory responses in CSOM. We treated the CSOM model with Lactobacillus, which has great potential for alleviating the inflammatory response, and found that Lactobacillus attenuated the development of CSOM by reducing RFTN1 and TLR4 expression.

Conclusion: In conclusion, these findings suggest a crucial role for Lactobacillus in alleviating CSOM progression and uncovered the molecular mechanism involving Lactobacillus-regulated inhibition of the RFTN1-lipid raft-TLR4 signaling pathway under CSOM conditions.

Keywords: CSOM, Lactobacillus, RFTN1, TLR4, S. aureus, B. cereus

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