Background: Breast cancer predominantly affects women and poses challenges in the treatment of both local and advanced diseases. In a previous study, we reported the effectiveness of ER121, a structurally resolved small compound specifically designed to target human cancers expressing or overexpressing mutant EGFR and HER2.

Purpose: The objective of this study is to assess the efficacy and toxicity of ER121 in metastatic and triple negative breast cancer (TNBC, HER2+) cells and tumor models. The Herceptin-resistant breast cancer cell line JIMT-1 was used in an in vivo tumor model, and MMTV-erbB2 (Fo5) transgenic mice models were used to evaluate the efficacy and safety of ER121 as neoadjuvant.

Methods: ER121 treatment focusing on experimental brain metastasis in TNBC, HER2+ model, was quantified by total flux employing the In Vivo Imaging System (IVIS). We also compared the brain tissue from the treated and the controls groups. Additionally, ER121 was evaluated in JIMT-1, a Herceptin-resistant breast cancer cell line, both in vitro and in vivo tumor model. We also administered ER121 orally in neoadjuvant model with the MMTV-erbB2 (Fo5) transgenic mice, the survival rates were compared with the control group. Tumor-free survival of multiple treated groups were analyzed by Kaplan-Meier analysis employing the log-rank test with the Bonferroni correction using R Statistical Software.

Results: In this study, we present findings indicating that ER121 treatment significantly attenuated breast tumor growth using a TNBC, HER2+ model, focusing on experimental brain metastasis, as quantified by total flux employing IVIS. These observations were further corroborated by analysis of brain tissue from the treatment group compared to controls. Data is presented as Mean ± S.D. statistical significance was calculated using Student t test (*p <  0.05). Additionally, ER121 significantly inhibited JIMT-1, a Herceptin-resistant breast cancer cell line was used in vivo xenograft model. Additionally, we used a neoadjuvant model with the MMTV-erbB2 (Fo5) transgenics and the tumor-free survival rates exhibited a remarkable difference between the control and treated groups when ER121 was administered orally. We found statistically significant p values of 0.048 employing log-rank test with Bonferroni Correction for comparing ER121 high, ER121 Low, Herceptin and PBS groups. All analyses were performed using R Statistical Software.

Conclusion: ER121 is a non-toxic small-molecule erbB kinase inhibitor and holds promise as an oral and systemic therapeutic agent for treating progressive erbB-driven tumors in therapeutic settings. Moreover, ER121 shows potential as a preventive therapy in neoadjuvant settings for erbB2-associated tumors and when administered systemically can dramatically limit erbB2 brain metastases in animal models.

Keywords: breast cancer, ER121, kinase inhibitor, neoadjuvant model, TNBC, brain metastasis

Download Article

常悦1，杜瑞2，夏凡1，徐秀理1，王宏志1,*，陈学冉1,*

1中国科学院合肥肿瘤医院，肿瘤综合治疗中心，中国，合肥230031

2安徽医科大学第三附属医院，合肥市第一人民医院，肛肠外科，中国，合肥 230001

*通讯作者: 陈学冉，E-mail:xueranchen@cmpt.ac.cn
王宏志，E-mail:wanghz@hfcas.ac.cn

摘要: 乳腺癌已成为全球第一大癌症，其预防、诊断和治疗都面临挑战，尤其是三阴性乳腺癌的发病机制尚未明确，转移性乳腺癌的治疗陷入困境。目前，代谢重编程被认为是癌症的标志之一。乳腺癌的代谢改变，包括糖酵解、三羧酸循环活性、谷氨酰胺分解和脂肪酸生物合成的增强，在不同的乳腺癌亚型中有不同的表现，与肿瘤的生长、转移、死亡和耐药性有着复杂的关系。尤其是，脂肪酸合成和氧化相关酶的抑制剂在乳腺癌的治疗中具有一定的效果。本文综述了有关乳腺癌脂肪酸代谢的研究，以期更好地了解脂肪酸代谢在乳腺癌发病中的作用机制，并希望为靶向脂肪酸代谢治疗乳腺癌提供新思路。

关键词: 乳腺癌，脂肪酸代谢，代谢重编程，靶向治疗

Download Article

背景: 免疫系统在乳腺癌对化疗的反应过程中起着重要的作用。在本文中，我们研究了免疫及炎症的外周标志物中性粒细胞与白蛋白比值(NAR)，以探讨其与局部晚期乳腺癌患者接受新辅助化疗后出现病理完全缓解(pCR)的潜在关系。

方法: 我们对212例接受新辅助化疗的乳腺癌患者进行回顾性分析。新辅助化疗开始前通过检测外周血全血细胞计数和白蛋白水平来计算NAR。通过ROC曲线分析，我们确定NAR的最佳截断值为0.0877。我们使用Pearson卡方检验或Fisher精确检验来评估NAR与pCR及其他临床和病理特征之间的关系，采用Logistic回归模型进行单因素和多因素分析。

结果: 单因素和多因素logistic回归分析均显示NAR与肿瘤病理消退相关。高NAR组的pCR率高于低NAR组(OR 3.127 [95% CI 1.545-6.328];P = 0.002)。

结论: 本研究发现，具有高NAR水平的乳腺癌患者在新辅助化疗时更容易实现pCR。

关键词: 乳腺癌;新辅助化疗;病理完全缓解;中性粒细胞与白蛋白比值;预测因子

Download Article

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

Download Article

Abstract: Osimertinib is the current first-line treatment for EGFR-mutated NSCLC, however, patients frequently relapse due to acquired resistance mutations. Amivantamab is a bispecific antibody against EGFR and MET alterations. Lazertinib is a tyrosine kinase inhibitor active against EGFR mutations including common resistance mutations. The MARIPOSA trial was designed to study if the combination of amivantamab plus lazertinib in untreated epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) patients would provide improved progression-free survival. Here, we discuss the rationale for the study and the early results of MARIPOSA.

Keywords: epidermal growth factor receptor (EGFR) mutations, first line treatment, bispecific antibody

Download Article

Abstract: On December 22, 2023, the US Food and Drug Administration (FDA) approved the biologics license application for patritumab deruxtecan (HER3-DXd) for priority review. This treatment is aimed at adult patients with locally advanced or metastatic NSCLC with EGFR mutations, who have received at least two prior systemic therapies. Approval of patritumab deruxtecan would mark it as the first HER3 targeted therapy in the United States. This prioritization by the FDA is grounded in compelling results from the global Phase II HERTHENA-Lung01 trial, wherein HER3-DXd exhibited clinically meaningful efficacy, achieving a median progression-free survival (mPFS) of 5.5 months in patients with heavily treated EGFR-mutated NSCLC. A pivotal question remains: Is a mPFS of 5.5 months sufficient in the context of the evolving first-line landscape observed in the FLAURA-2 and MARIPOSA trials?

Keywords: EGFR, NSCLC, post-osimertinib, targeted therapy

Download Article

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

Download Article

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

Download Article

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

Download Article

背景: 动脉供血为主是肝细胞癌（hepatocellular carcinoma，HCC）的特征。然而，血供能否预测HCC病人肝切除术后的预后尚不清楚。这项回顾性研究调查了HCC病人术前三期肝脏CT计算的门静脉和动脉血供，分别为门静脉系数（portal venous coefficient，PVC）和肝动脉系数（hepatic arterial coefficient，HAC），对根治性手术预后预测的价值。

方法: 回顾性筛选在肝切除术前2周内进行了三期肝脏CT检查，且在2016年1月1日至2020年12月31日在昆明医科大学第二附属医院接受R0肝切除术的HCC病人。病人的PVC和HAC及其他变量被收集，采用最小绝对收缩和选择算子回归模型及Cox比例风险回归模型，预测总生存期（overall survival，OS）和无复发生存期（recurrence-free survival，RFS）。

结果: 共纳入419名病人（平均年龄53.2 ± 10.6岁，370名男性）。较短的OS与较高的血白蛋白和总胆红素等级[危险比（HR）2.020，95% 置信区间（CI）1.534-2.660]、较高的巴塞罗那临床肝癌（Barcelona Clinic Liver Cancer，BCLC）分期（HR 1.514，95% CI 1.290-1.777）、肿瘤PVC≤0.386（HR 1.628，95% CI 1.149-2.305）和肿瘤HAC>0.029（HR 1.969，95% CI 1.380-2.809）独立相关。较短的RFS与男性（HR 1.652，95% CI 1.005-2.716）、血清甲胎蛋白≥400 ng/mL（HR 1.672，95% CI 1.236-2.263）、较高的BCLC分期（HR 1.516，95% CI 1.300-1.768）、肿瘤PVC≤0.386（HR 1.641，95% CI 1.198-2.249）和肿瘤HAC>0.029（HR 1.455，95% CI 1.060-1.997）独立相关。

结论: 肝切除术前的肿瘤PVC或HAC对独立预测HCC病人的术后生存率很有价值。

关键词: 血液供应、计算机断层扫描、肝切除术、肝细胞癌、复发、生存率

Download Article

陈田1，向伦建2，章文锦3，夏祯祎4*，陈维贤1*

1. 重庆医科大学附属第二医院检验科；
2. 重庆大学附属三峡医院肝胆外科；
3. 重庆大学附属三峡医院重庆市内分泌代谢病临床研究中心；
4. 重庆大学附属三峡医院胸外科；

*上述作者对本研究的贡献相等。

通讯作者：陈维贤（300801@cqmu.edu.cn）和夏祯祎（treezhenyi@163.com）。

通讯地址：中国重庆市渝中区临江路74号，邮编400010。

电话：+86-13527526490

传真：+86-23-581045783

摘要

目的： 丙氨酸乙醛酸氨基转移酶(AGXT)家族成员在癌症过程中起着关键作用，但在肝细胞癌代谢中的作用尚不明确。本研究旨在研究AGXT2在肝细胞癌中的功能作用。

方法： 采用生物信息学、定量即时聚合酶链锁反应法(RT-qPCR)、免疫印迹法（WB）和酶联免疫吸附剂测定法(ELISA)研究AGXT2在肝细胞癌患者中的差异表达。构建慢病毒诱导AGXT2过表达的细胞模型，通过RNA测序(RNA-seq)和液相色谱-质谱法(LC-MS)进行检测分析，通过油红O染色确认细胞内胆固醇水平。通过细胞周期分析、细胞划痕实验和细胞体外侵袭实验（Transwell）评估AGXT2对细胞的影响。在重度联合免疫缺陷小鼠（NTG）皮下成瘤实验中观察肿瘤生成效应。通过共免疫沉淀方法研究蛋白质相互作用。

结果： 我们观察到在肝癌患者肿瘤组织和血清样本中AGXT2 mRNA和蛋白水平显著降低，这与患者的不良预后相关。AGXT2的激活可以有效降低肝癌细胞中的胆固醇水平，作为胆固醇代谢途径的拮抗剂。 在过表达AGXT2的细胞中，低密度脂蛋白受体(LDLR) mRNA水平增加，伴有LDLR蛋白水平降低，蛋白转化酶枯草菌素/kexin 9型(PCSK9)基因的 mRNA和蛋白水平升高。分子对接和共免疫沉淀实验进一步阐明了AGXT2与LDLR蛋白之间有相互作用。 激活AGXT2被观察到抑制HCC细胞的迁移和侵袭能力，并诱导细胞在G2/M期停滞。在NTG小鼠的皮下成瘤模型中，激活AGXT2抑制了肿瘤生长。

结论： AGXT2在肝癌中含量显著降低，可作为肝癌的诊断标志物。激活AGXT2可降低肝癌细胞中的胆固醇水平，可能通过与LDLR蛋白的相互作用和调节PCSK9介导的LDLR降解来实现。这种机制可能会阻碍胆固醇向肝癌细胞的运输，从而抑制其生长和转移。

关键词： LDLR、PCSK9、胆固醇代谢、生物标志物

Download Article

房杨 金秀颖 崔慧莹 韩哲洙 许强 张松男*

作者单位：延边大学附属医院 肿瘤科 （吉林 延吉 133000）

* 通信作者：张松男 zhangsn21@163.com

摘要

背景: 原发性肝神经内分泌癌（PHNEC）十分罕见，不可切除的局部晚期PHNEC 以全身综合治疗为主，但治疗效果欠佳。目前最佳治疗方法还存在一定的争议。

病例介绍: 我们报道一例通过病理学确诊、不可手术切除的女性PHNEC 患者。该病例接受4周期标准一线全身化疗方案后，复查影像学提示局部病灶控制欠佳，予以介入联合微波消融局部治疗，术后根据mRECIST评价标准，评估病情达到完全缓解。继续予以免疫检查点抑制剂14周期维持治疗，随访14个月过程中未见局部复发或远处转移，并且无相关并发症。

结论： 本病例对不可手术且全身化疗失败的患者提供了一种新的治疗方案。结合本病例对PHNEC的诊断和治疗进行探讨。

关键词： 原发性肝脏神经内分泌癌；大细胞型；神经内分泌癌；肝脏；介入

Download Article

Purpose: Our previous study has demonstrated that high expression of immune checkpoints (ICs) was significantly associated with adverse clinical outcomes in patients with acute myeloid leukemia (AML). This study aims to investigate the significance of the alteration of IC co-expression for evaluating the prognosis of AML patients following allogeneic hematopoietic stem cell transplantation (allo-HSCT).

Patients and Methods: Quantitative real-time PCR (qRT-PCR) data of bone marrow (BM) samples from 62 de novo AML patients, including 37 patients who received allo-HSCT and 25 patients who received chemotherapy only, were used for prognostic analysis.

Results: High expression of PD-1, PD-L1, PD-L2, CTLA-4, and LAG-3 was associated with poor overall survival (OS) in AML patients receiving allo-HSCT, while the expression levels of PD-1, PD-L2, CTLA-4, and LAG-3, other than PD-L1, were not significantly correlated with OS in AML patients receiving chemotherapy. Importantly, PD-L1/CTLA-4 was the best combination model for predicting poor OS in AML patients following allo-HSCT, especially combined with minimal residual disease (MRD).

Conclusion: High expression of ICs in BM of AML patients following allo-HSCT was related to poor outcomes, and increasing co-expression of PD-L1 and CTLA-4 might be one of the best immune biomarkers to predict outcomes in patients with AML.

Keywords: acute myeloid leukemia, allo-HSCT, immune checkpoint, biomarker, prognosis

Download Article

Background: Colorectal cancer (CRC) is the third most prevalent cancer worldwide, with numerous risk factors contributing to its development. Recent research has illuminated the significant role of the gut microbiota in CRC pathogenesis, identifying various microbial antigens as potential targets for vaccine development.

Aim: This review aimed at exploring the potential sources of microbial antigens that could be harnessed to create effective CRC vaccines and understand the role of microbiome-CRC interactions in carcinogenesis.

Methods: A comprehensive search of original research and review articles on the pathological links between key microbial candidates, particularly those more prevalent in CRC tissues, was conducted. This involved extensive use of the PubMed and Medline databases, as well as the Google Scholar search engine, utilizing pertinent keywords. A total of one hundred and forty-three relevant articles in English, mostly published between 2018 and 2024, were selected.

Results: Numerous microbes, particularly bacteria and viruses, are significantly overrepresented in CRC tissues and have been shown to promote tumorigenesis by inducing inflammation and modulating the immune system. This makes them promising candidates for antigens in the development of CRC vaccines.

Conclusion: The selection of microbial antigens focuses on their capacity to trigger a strong immune response and their link to tumor presence and progression. Identifying and validating these antigens through preclinical testing is essential in developing a CRC vaccine.

Plain Language Summary: Colorectal cancer (CRC) is a common and serious disease that affects many people worldwide. Research has shown that the bacteria and other microorganisms in our gut play a significant role in the development of CRC. This review aimed to identify specific microbial targets that could be used to develop effective vaccines against CRC.

The researchers searched through numerous scientific articles and found that certain bacteria and viruses are more commonly found in CRC tissues and promote tumor growth by causing inflammation and affecting the immune system. These microbes have the potential to be used as antigens in CRC vaccines.

The identification of these antigens is a crucial step towards developing a vaccine that can prevent or treat CRC. Further research is needed to validate these findings and move closer to creating an effective vaccine against this disease.

In simpler terms, this research is exploring how the gut microbiome contributes to colorectal cancer and searching for specific targets to develop a vaccine that can help prevent or treat the disease.

Keywords: colorectal cancer, microbe, antigen, vaccine, tumor

Download Article

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

Download Article

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提供了新的方向。

Download Article

Introduction: Nasopharyngeal cancer (NPC) is a multifaceted disease characterized by genetic and epigenetic modifications. While Epstein–Barr virus (EBV) infection is a known risk factor, recent studies highlight the significant role of DNA methylation in NPC pathogenesis. Aberrant methylation, particularly at CpG sites, can silence tumour suppressor genes, promoting uncontrolled cell growth. This study aims to analyse the methylation patterns in Indonesian NPC patients through whole-epigenome sequencing.

Methods: Seven clinical nasopharyngeal cancer samples were collected and confirmed histopathologically. DNA was extracted, sequenced using Oxford Nanopore technology, and aligned to the GRCh38 human reference genome. Methylation analysis was performed using modkit and statistical analysis with R software. Enriched pathways and processes were identified using ClusterProfiler in R, and gene overlap analysis was conducted.

Results: The analysis identified both globally hypermethylated and hypomethylated NPC samples. Key tumour suppressor genes, such as PRKCB, PLCB3, ITGB3, EPHA2, PLCE1, PRKCD, CDKN2A, CDKN2B, RPS6KA2, ERBB4, LRRC4, AKT1, PPP2R5C, and STK11 were frequently hypermethylated and confirmed to have lower expression in an independent NPC transcriptome cohort, suggesting their role in NPC carcinogenesis. Enriched KEGG pathways included PI3K-Akt signalling, ECM–receptor interaction, and focal adhesion. The presence of EBV DNA was confirmed in all samples, implicating its role in influencing methylation patterns.

Discussion: This study provides comprehensive insights into the epigenetic landscape of NPC, underscoring the role of CpG methylation in tumour suppressor gene silencing. These findings pave the way for targeted therapies and highlight the need for region-specific approaches in NPC management.

Keywords: nasopharyngeal cancer, epigenome, methylation, Epstein–Barr virus, whole-genome sequencing

Download Article

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

Download Article