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MOGAN for LUAD Subtype Classification by Integrating Three Omics Data Types 整合三组学数据类型的LUAD亚型分类MOGAN
Pub Date : 2025-02-28 DOI: 10.1002/cai2.160
Haibin He, Longxing Wang, Mingyue Ma

Background

Lung adenocarcinoma (LUAD) is a highly heterogeneous cancer type with a poor prognosis. Accurate subtype identification can help guide its treatment. The traditional subtype identification methods using a single-omics approach make it difficult to comprehensively characterize the molecular features of LUAD. Identification of subtypes through multi-omics association strategies can effectively supplement the shortcomings of single-omics information.

Methods

In this study, we used the Generative Adversarial Network (GAN) to mine transcriptomic, proteomic, and epigenomic information and generate an integrated data set. The newly integrated data were then used to identify LUAD immune subtypes. In the improved GAN (MOGAN) method, we not only integrated multiple omics datasets but also included the interactions between proteins and genes and between methylation and genes. Thus, we achieved effective complementarity of multi-omics information.

Results

Two subtypes, MOGANTPM_S1 and MOGANTPM_S2, were identified using immune cell infiltration analysis and the integrated multi-omics data. MOGANTPM_S1 patients displayed higher immune cell infiltration, better prognosis, and sensitivity to immune checkpoint inhibitors (ICIs), while MOGANTPM_S2 had lower immune cell infiltration, poorer prognosis, and were insensitive to ICIs. Therefore, immunotherapy was more suitable for MOGANTPM_S1 patients in clinical practice. In addition, this study developed a LUAD subtype diagnostic model using the transcriptomic and proteomic features of five genes, which can be used to guide clinical subtype diagnosis.

Conclusions

In summary, the MOGAN method was applied to integrate three omics data types and successfully identify two LUAD immune subtypes with significant survival differences. This classification method may be useful for LUAD treatment decisions.

肺腺癌(LUAD)是一种高度异质性的癌症类型,预后较差。准确的亚型识别有助于指导其治疗。传统的单组学亚型鉴定方法难以全面表征LUAD的分子特征。通过多组学关联策略识别亚型可以有效地弥补单组学信息的不足。方法在本研究中,我们使用生成对抗网络(GAN)来挖掘转录组学、蛋白质组学和表观基因组学信息,并生成一个集成的数据集。然后使用新整合的数据来识别LUAD免疫亚型。在改进的GAN (MOGAN)方法中,我们不仅集成了多个组学数据集,而且还包括了蛋白质与基因之间以及甲基化与基因之间的相互作用。从而实现了多组学信息的有效互补。结果利用免疫细胞浸润分析和综合多组学数据鉴定出MOGANTPM_S1和MOGANTPM_S2两个亚型。MOGANTPM_S1患者免疫细胞浸润较高,预后较好,对免疫检查点抑制剂(ici)敏感,而MOGANTPM_S2患者免疫细胞浸润较低,预后较差,对ici不敏感。因此,在临床实践中,免疫治疗更适合MOGANTPM_S1患者。此外,本研究利用5个基因的转录组学和蛋白质组学特征建立了LUAD亚型诊断模型,可用于指导临床亚型诊断。综上所述,采用MOGAN方法整合三种组学数据类型,成功鉴定出两种存在显著生存差异的LUAD免疫亚型。这种分类方法可能对LUAD的治疗决策有用。
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引用次数: 0
The Efficacy and Safety of Pegylated Liposomal Doxorubicin-Based Neoadjuvant Chemotherapy in Children With Osteosarcoma: A Retrospective Real-World Study 聚乙二醇脂质体多柔比星为基础的儿童骨肉瘤新辅助化疗的有效性和安全性:一项回顾性现实世界研究
Pub Date : 2025-02-28 DOI: 10.1002/cai2.162
Guoqi Wang, Suoqin Tang, Lina Chai, Yan Liang, Tongtong Li, Wenzhi Bi, Chen Feng

Background

Treatment of osteosarcoma in children remains difficult. The combination of chemotherapy and surgery is the classic treatment for osteosarcoma. With the development of medicine, chemotherapy has also improved greatly. This study aimed to explore the short-term efficacy and safety of neoadjuvant chemotherapy (NAC) with a protocol of pegylated liposomal doxorubicin (PLD), high-dose methotrexate, and ifosfamide (PLDMI) in pediatric patients with osteosarcoma.

Methods

Between May 1, 2018 and May 1, 2021, 25 pediatric patients with osteosarcoma were included in this retrospective, observational study. All patients received PLDMI including PLD, high-dose methotrexate, and ifosfamide, followed by surgery and postoperative chemotherapy. Tumor parameters at the time of preoperative chemotherapy were evaluated by the investigator using MRI, and the response to preoperative chemotherapy was scored according to the Huvos grading system. Short-term survival was analyzed by a Cox proportional hazard model. Safety was assessed as adverse events (AEs) by the Common Terminology Criteria for AEs version 5.0.

Results

MRI showed that preoperative chemotherapy significantly decreased the coronal tumor width, sagittal anteroposterior diameter, and tumor volume (all p < 0.05), while no significant change was found in tumor length (p > 0.05). More than 90% of tumor necrosis was achieved in 13 (61.9%, 13/21) patients. The 2-year overall survival and disease-free survival rates were 92% and 76%, respectively. Cox regression analysis identified pathological type and imaging at the time of completion of treatment as independent prognostic factors for children with osteosarcoma. Grade 3–4 AEs included febrile neutropenia (25/25, 100%), secondary anemia (18/25, 72%), secondary thrombocytopenia (20/25, 80%), and mucositis with local infection (3/25, 12%), which were resolved with symptomatic treatment.

Conclusions

PLDMI was an effective protocol for children with osteosarcoma and could effectively reduce the tumor burden in the primary site and augment surgical treatment, although with a high incidence of AEs.

背景:儿童骨肉瘤的治疗仍然很困难。化疗和手术相结合是骨肉瘤的经典治疗方法。随着医学的发展,化疗也有了很大的进步。本研究旨在探讨聚乙二醇化脂质体多柔比星(PLD)、大剂量甲氨蝶呤和异环磷酰胺(PLDMI)联合新辅助化疗(NAC)治疗小儿骨肉瘤患者的短期疗效和安全性。方法2018年5月1日至2021年5月1日,25例小儿骨肉瘤患者纳入本回顾性观察性研究。所有患者均接受PLDMI治疗,包括PLD、大剂量甲氨蝶呤和异环磷酰胺,术后行手术和化疗。研究者使用MRI评估术前化疗时的肿瘤参数,并根据Huvos分级系统对术前化疗反应进行评分。采用Cox比例风险模型分析短期生存率。安全性按照不良事件(ae)通用术语标准5.0版进行评估。结果MRI显示术前化疗可显著降低冠状面肿瘤宽度、矢状面前后径及肿瘤体积(p < 0.05),而对肿瘤长度无显著影响(p < 0.05)。13例(61.9%,13/21)患者肿瘤坏死达到90%以上。2年总生存率和无病生存率分别为92%和76%。Cox回归分析确定治疗完成时的病理类型和影像学是骨肉瘤儿童的独立预后因素。3-4级ae包括发热性中性粒细胞减少症(25/ 25,100%)、继发性贫血(18/ 25,72%)、继发性血小板减少症(20/ 25,80%)和粘膜炎合并局部感染(3/ 25,12%),均经对症治疗解决。结论PLDMI是治疗儿童骨肉瘤的有效方案,可有效减轻原发部位的肿瘤负担,增加手术治疗,但ae发生率较高。
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引用次数: 0
Predictive Value of Neutrophil-to-Lymphocyte Ratio for Immune Checkpoint Inhibitor-Related Myocarditis Among Patients Treated for Non-Small-Cell Lung Cancer 中性粒细胞与淋巴细胞比值对非小细胞肺癌患者免疫检查点抑制剂相关心肌炎的预测价值
Pub Date : 2025-02-20 DOI: 10.1002/cai2.163
Jian Xue, Chuanbin Liu, Jun Shao, Li Wang, Yating Han, Jing Wang, Jinda Wang

Background

The predictive value of the neutrophil-to-lymphocyte ratio (NLR) for immune checkpoint inhibitors (ICIs) in various tumors remains uncertain despite its use in forecasting the effectiveness of immunotherapy. The purpose of our research was to determine the prognostic significance of NLR for immune checkpoint inhibitor-related myocarditis in non-small-cell lung cancer (NSCLC) patients.

Methods

We enrolled and monitored patients with NSCLC who received ICI therapy at the Fifth Medical Center of Chinese PLA General Hospital between January 1, 2018, and February 20, 2021. NLR was determined before and soon after each cycle of ICIs. All participants in this study were periodically examined for troponin and brain natriuretic peptide (BNP), and an electrocardiogram (ECG) and echocardiography were done. Cox's proportional hazards regression model and receiver operating characteristic (ROC) were used to assess the predictive value for ICI-related myocarditis.

Results

A total of 146 patients received ICI treatment and completed a follow-up. Of these, 17 patients (11.64%) developed ICI-related myocarditis that met the diagnostic criteria. The initial cycle revealed that the NLR was a reliable predictor of potential myocarditis related to ICIs, with an area under the curve (AUC) of 0.833 and a 95% confidence interval (CI) of 0.721–0.945. Following the initial round of ICI treatment, an NLR elevation (NLR ≥ 3.25) appeared to be the most significant standalone indicator of ICI-related myocarditis (HR: 11.094; 95% CI: 3.186–38.631; p < 0.001).

Conclusions

Our study confirmed that NLR elevation in the early phase after ICI treatment of NSCLC is a reliable predictive factor of ICI-related myocarditis. Regular and frequent cardiac monitoring may help to avoid the occurrence of severe and fatal cases.

中性粒细胞与淋巴细胞比率(NLR)在各种肿瘤中对免疫检查点抑制剂(ICIs)的预测价值仍然不确定,尽管它用于预测免疫治疗的有效性。我们研究的目的是确定NLR对非小细胞肺癌(NSCLC)患者免疫检查点抑制剂相关性心肌炎的预后意义。方法纳入2018年1月1日至2021年2月20日在中国人民解放军总医院第五医学中心接受ICI治疗的非小细胞肺癌患者并进行监测。NLR在每个周期的ici之前和之后测定。本研究所有参与者均定期检查肌钙蛋白和脑钠肽(BNP),并进行心电图和超声心动图检查。采用Cox比例风险回归模型和受试者工作特征(ROC)评估ci相关性心肌炎的预测价值。结果146例患者接受了ICI治疗并完成了随访。其中17例(11.64%)发展为符合诊断标准的ici相关性心肌炎。初始周期显示NLR是与ICIs相关的潜在心肌炎的可靠预测因子,曲线下面积(AUC)为0.833,95%可信区间(CI)为0.721-0.945。在第一轮ICI治疗后,NLR升高(NLR≥3.25)似乎是ICI相关性心肌炎最重要的独立指标(HR: 11.094;95% ci: 3.186-38.631;p < 0.001)。结论本研究证实,非小细胞肺癌ICI治疗后早期NLR升高是ICI相关性心肌炎的可靠预测因素。定期和频繁的心脏监测可能有助于避免严重和致命病例的发生。
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引用次数: 0
Artificial Intelligence and Breast Cancer Management: From Data to the Clinic 人工智能与乳腺癌管理:从数据到临床
Pub Date : 2025-02-20 DOI: 10.1002/cai2.159
Kaixiang Feng, Zongbi Yi, Binghe Xu

Breast cancer (BC) remains a significant threat to women's health worldwide. The oncology field had an exponential growth in the abundance of medical images, clinical information, and genomic data. With its continuous advancement and refinement, artificial intelligence (AI) has demonstrated exceptional capabilities in processing intricate multidimensional BC-related data. AI has proven advantageous in various facets of BC management, encompassing efficient screening and diagnosis, precise prognosis assessment, and personalized treatment planning. However, the implementation of AI into precision medicine and clinical practice presents ongoing challenges that necessitate enhanced regulation, transparency, fairness, and integration of multiple clinical pathways. In this review, we provide a comprehensive overview of the current research related to AI in BC, highlighting its extensive applications throughout the whole BC cycle management and its potential for innovative impact. Furthermore, this article emphasizes the significance of constructing patient-oriented AI algorithms. Additionally, we explore the opportunities and potential research directions within this burgeoning field.

乳腺癌(BC)仍然是全世界妇女健康的一个重大威胁。肿瘤学领域在丰富的医学图像、临床信息和基因组数据方面呈指数级增长。随着人工智能(AI)的不断进步和完善,人工智能在处理复杂的多维bc相关数据方面表现出了卓越的能力。人工智能已被证明在BC管理的各个方面具有优势,包括有效的筛查和诊断,精确的预后评估和个性化的治疗计划。然而,在精准医疗和临床实践中实施人工智能带来了持续的挑战,需要加强监管、透明度、公平性和多种临床途径的整合。在这篇综述中,我们全面概述了目前与BC中人工智能相关的研究,强调了其在整个BC周期管理中的广泛应用及其创新影响的潜力。此外,本文还强调了构建面向患者的人工智能算法的重要性。此外,我们还探索了这个新兴领域的机会和潜在的研究方向。
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引用次数: 0
Biological function and mechanism of NAT10 in cancer NAT10在肿瘤中的生物学功能及机制。
Pub Date : 2025-01-14 DOI: 10.1002/cai2.154
Yufeng Han, Xinxin Zhang, Lei Miao, Huiran Lin, Zhenjian Zhuo, Jing He, Wen Fu

N-acetyltransferase 10 (NAT10) is a nucleolar acetyltransferase with an acetylation catalytic function and can bind various protein and RNA molecules. As the N4-acetylcytidine (ac4C) “writer” enzyme, NAT10 is reportedly involved in a variety of physiological and pathological activities. Currently, the NAT10-related molecular mechanisms in various cancers are not fully understood. In this review, we first describe the cellular localization of NAT10 and then summarize its numerous biological functions. NAT10 is involved in various biological processes by mediating the acetylation of different proteins and RNAs. These biological functions are also associated with cancer progression and patient prognosis. We also review the mechanisms by which NAT10 plays roles in various cancer types. NAT10 can affect tumor cell proliferation, metastasis, and stress tolerance through its acetyltransferase properties. Further research into NAT10 functions and expression regulation in tumors will help explore its future potential in cancer diagnosis, treatment, and prognosis.

n -乙酰基转移酶10 (NAT10)是一种具有乙酰化催化功能的核仁乙酰基转移酶,可结合多种蛋白质和RNA分子。作为n4 -乙酰胞苷(ac4C)据报道,“writer”酶NAT10参与多种生理和病理活动。目前,nat10在各种癌症中的相关分子机制尚不完全清楚。在这篇综述中,我们首先描述了NAT10的细胞定位,然后总结了其众多的生物学功能。NAT10通过介导不同蛋白质和rna的乙酰化参与多种生物过程。这些生物学功能也与癌症进展和患者预后有关。我们还回顾了NAT10在各种癌症类型中发挥作用的机制。NAT10可以通过其乙酰转移酶特性影响肿瘤细胞的增殖、转移和应激耐受。进一步研究NAT10在肿瘤中的功能和表达调控,将有助于挖掘其在癌症诊断、治疗和预后方面的潜力。
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引用次数: 0
Identification of significant single-nucleotide polymorphisms associated with breast cancer recurrence and metastasis using GWAS 使用GWAS鉴定与乳腺癌复发和转移相关的显著单核苷酸多态性。
Pub Date : 2025-01-07 DOI: 10.1002/cai2.142
Shujuan Sun, Sha Yin, Jie Huang, Dongdong Zhou, Qiaorui Tan, Xiaochu Man, Wen Wang, Jiale Zhang, Huihui Li

Background

Identification of risk genes and loci associated with the recurrence and metastasis of breast cancer (BC) is of utmost importance. Genome-wide association studies (GWASs) represent valuable tools for identifying the disease risk associated with a given single-nucleotide polymorphism (SNP); they offer significant insights into the disease progression mechanism by analyzing SNP information of the entire genome. Though GWAS has already identified several genetic susceptibility SNPs for BC, their significance in the recurrence and metastasis of this cancer remains unclear. Here, we used a GWAS approach to identify SNPs specifically associated with the risk of BC recurrence and metastasis.

Methods

This study adopted a two-stage GWAS approach. In the first stage, 97 pairs of BC patients with or without recurrence and metastasis, treated at the Shandong Cancer Hospital and Institute from November 2013 to April 2014, were identified using propensity score matching. DNA extracted from the patient peripheral blood was then subjected to Illumina ASA chip analysis for genome-wide SNP detection. In the second stage, the findings were verified in a validation set of 854 BC patients recruited at the same hospital from May 2014 to June 2015. SNP genotyping was performed using time-of-flight mass spectrometry. The SNP loci and their corresponding genes and pathways were analyzed using the DAVID (https://david.ncifcrf.gov/) online enrichment analysis tool.

Results

Based on the GWAS results, 191 SNP-related genes significantly associated with BC recurrence and metastasis were identified as expression quantitivative trait loci (p < 0.001). Functional and pathway enrichment analyses subsequently revealed the potential involvement of glutamatergic synaptic transmission, calcium signaling, and insulin secretion pathways in BC recurrence and metastasis. Based on genotype correlation and database expression levels, rs10108514, rs12920540, rs4273077, and rs4730155 were found to be significantly associated with the risk of BC recurrence and metastasis.

Conclusion

Our study suggests that the SNPs rs10108514, rs12920540, rs4273077, and rs4730155 are correlated with the risk of BC recurrence and metastasis, potentially by being implicated in glutamatergic synaptic transmission, calcium signaling, and insulin secretion pathways.

背景:确定与乳腺癌(BC)复发和转移相关的危险基因和基因座是至关重要的。全基因组关联研究(GWASs)是识别与给定单核苷酸多态性(SNP)相关的疾病风险的有价值的工具;它们通过分析整个基因组的SNP信息,为疾病进展机制提供了重要的见解。虽然GWAS已经确定了几个BC的遗传易感性snp,但它们在这种癌症的复发和转移中的意义尚不清楚。在这里,我们使用GWAS方法来鉴定与BC复发和转移风险特异性相关的snp。方法:本研究采用两阶段GWAS方法。第一阶段选取2013年11月至2014年4月在山东省肿瘤医院和肿瘤研究所治疗的97对有或无复发转移的BC患者,采用倾向评分匹配法进行鉴定。从患者外周血中提取DNA,然后进行Illumina ASA芯片分析,进行全基因组SNP检测。在第二阶段,研究结果在2014年5月至2015年6月在同一家医院招募的854名BC患者的验证集中得到验证。使用飞行时间质谱法进行SNP基因分型。使用DAVID (https://david.ncifcrf.gov/)在线富集分析工具分析SNP位点及其对应的基因和通路。结果:基于GWAS结果,191个与BC复发和转移相关的snp相关基因被确定为表达定量性状位点(p)。结论:我们的研究提示snp rs10108514、rs12920540、rs4273077和rs4730155与BC复发和转移风险相关,可能与谷氨酸能突触传递、钙信号传导和胰岛素分泌途径有关。
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引用次数: 0
lncRNA TCONS_00251376 promotes the proliferation and migration of gastric cancer cell through upregulating ETV1 lncRNA tcon_00251376通过上调ETV1促进胃癌细胞的增殖和迁移。
Pub Date : 2024-12-12 DOI: 10.1002/cai2.156
Dengfeng Ren, Fuxing Zhao, Jinming Li, Xinjian Guo, Xinfu Ma, Yonghui Zheng, Guoshuang Shen, Jiuda Zhao

Background

Although there have been significant advancements in the treatment modalities for gastric cancer (GC) in recent years, the overall prognosis remains poor, particularly for individuals in advanced stages. The absence of a sensitive tumor marker in GC is a crucial factor contributing to this challenge.

Methods

Our study focused on investigating a newly discovered long noncoding RNA (lncRNA) known as TCONS_00251376, which has been confirmed to exhibit differential expression in GC compared to adjacent tissues. To further validate these expression differences, we collected 22 pairs of GC and adjacent noncancerous tissues. Subsequent cell function experiments and animal studies were conducted to elucidate the role and underlying mechanisms of lncRNA TCONS_00251376 in the development of GC.

Results

The study revealed a significant upregulation of lncRNA TCONS_00251376 in cancer tissues (p < 0.01) and a consistent upregulation in GC cell lines (AGS, MKN45, BGC-823, and MGC-803). Furthermore, it was observed that lncRNA TCONS_00251376 played a promotive role in the proliferation, migration, and invasion of GC cells. Subsequent analysis indicated that lncRNA TCONS_00251376 could upregulate the expression of ETV1, a factor associated with the prognosis of GC.

Conclusions

Therefore, our findings suggest that lncRNA TCONS_00251376 functions as an oncogenic lncRNA, promoting tumorigenesis and progression by regulating the expression of ETV1 gene. This highlights its potential as an effective target for treating GC.

背景:尽管近年来胃癌(GC)的治疗方法取得了重大进展,但总体预后仍然不佳,尤其是晚期患者。胃癌缺乏敏感的肿瘤标志物是导致这一挑战的关键因素:我们的研究重点是调查一种新发现的长非编码 RNA(lncRNA),即 TCONS_00251376。为了进一步验证这些表达差异,我们收集了 22 对 GC 和邻近非癌组织。随后进行了细胞功能实验和动物实验,以阐明 lncRNA TCONS_00251376 在 GC 发病过程中的作用和内在机制:研究发现,lncRNA TCONS_00251376在癌组织中明显上调(p 结论:lncRNA TCONS_00251376在癌组织中明显上调:因此,我们的研究结果表明,lncRNA TCONS_00251376作为一种致癌lncRNA,通过调节ETV1基因的表达促进肿瘤的发生和发展。这凸显了其作为治疗 GC 的有效靶点的潜力。
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引用次数: 0
Expression pattern and prognostic significance of aldehyde dehydrogenase 2 in lung adenocarcinoma as a potential predictor of immunotherapy efficacy 醛脱氢酶2在肺腺癌中的表达模式及其预后意义作为免疫治疗疗效的潜在预测因子。
Pub Date : 2024-12-05 DOI: 10.1002/cai2.149
Silvia Baldari, Annalisa Antonini, Giuliana Di Rocco, Gabriele Toietta

Background

The incidence of alcohol-associated cancers is higher within Asian populations having an increased prevalence of an inactivating mutation in aldehyde dehydrogenase 2 (ALDH2), a mitochondrial enzyme required for the clearance of acetaldehyde, a cytotoxic metabolite of ethanol. The role of alcohol consumption in promoting lung cancer is controversial, and little attention has been paid to the association between alcohol drinking and pulmonary ALDH2 expression.

Methods

We performed a comprehensive bioinformatic analysis of multi-omics data available in public databases to elucidate the role of ALDH2 in lung adenocarcinoma (LUAD).

Results

Transcriptional and proteomic data indicate a substantial pulmonary expression of ALDH2, which is functional for the metabolism of alcohol diffused from the bronchial circulation. ALDH2 expression is higher in healthy lung tissue than in LUAD and inhibits cell cycle, apoptosis, and epithelial–mesenchymal transition pathways. Moreover, low ALDH2 mRNA levels predict poor prognosis and low overall survival in LUAD patients. Interestingly, ALDH2 expression correlates with immune infiltration in LUAD.

Conclusions

A better understanding of the role of ALDH2 in lung tumor progression and immune infiltration might support its potential use as a prognostic marker and therapeutic target for improving immunotherapeutic response.

背景:在醛脱氢酶2 (ALDH2)失活突变的患病率增加的亚洲人群中,酒精相关癌症的发病率更高,醛脱氢酶2是清除乙醛(乙醇的细胞毒性代谢物)所需的线粒体酶。饮酒对肺癌的促进作用存在争议,饮酒与肺ALDH2表达之间的关系很少受到关注。方法:我们对公共数据库中的多组学数据进行了全面的生物信息学分析,以阐明ALDH2在肺腺癌(LUAD)中的作用。结果:转录和蛋白质组学数据表明ALDH2在肺中大量表达,这对支气管循环弥散的酒精代谢起作用。ALDH2在健康肺组织中的表达高于LUAD,并抑制细胞周期、凋亡和上皮-间质转化途径。此外,低ALDH2 mRNA水平预示着LUAD患者预后差和总生存率低。有趣的是,ALDH2的表达与LUAD的免疫浸润相关。结论:更好地了解ALDH2在肺肿瘤进展和免疫浸润中的作用可能支持其作为预后标志物和改善免疫治疗反应的治疗靶点的潜在应用。
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引用次数: 0
Subtype-specific transcription factors affect polyamine metabolism and the tumor microenvironment in breast cancer 亚型特异性转录因子影响乳腺癌多胺代谢和肿瘤微环境
Pub Date : 2024-12-02 DOI: 10.1002/cai2.138
Qi Song, Yixuan Wang, Sen Liu

Background

Polyamines play important roles in cell growth and proliferation. Polyamine metabolism genes are dysregulated in various tumors. Some polyamine metabolism genes are regulated by transcription factors. However, the transcription factors that regulate polyamine metabolism genes have not been completely identified. Additionally, whether any of the transcriptional regulations depend on tumor heterogeneity and the tumor microenvironment has not been investigated.

Methods

We used bulk RNA-seq data to identify dysregulated polyamine metabolism genes and their transcription factors across breast cancer subtypes. Genes highly correlated with polyamine changes were obtained, and their subtype-specific expressions were checked in tumor microenvironment cells using single-cell RNA (scRNA)-seq data. Gene Ontology enrichment analysis was used to explore their molecular functions and biological processes, and survival analysis was used to examine the impact of these genes on therapeutic outcome.

Results

We first analyzed the dysregulation of polyamine synthesis, catabolism, and transport in four breast cancer subtypes. Genes such as AGMAT and CAV1 were dysregulated across all subtypes, while APRT, SAT1, and other genes were dysregulated in the more lethal subtypes. Among the dysregulated genes of polyamine metabolism, we focused on three genes (SRM, APRT, and SAT1) and identified their transcription factors (SPI1 and IRF1 correspond to SAT1, and IRF3 corresponds to SRM and APRT). With scRNA-seq data, we verified that these three transcription factors also regulated these three polyamine metabolism genes in the tumor microenvironment. Both bulk RNA-seq and scRNA-seq data indicated that these genes were specifically upregulated in high-risk breast cancer subtypes, such as the basal-like type. High expression of these genes corresponded to worse outcomes in the basal-like subtype under chemotherapy and radiation treatment.

Conclusion

Our work identified three subtype-specific transcription factors that regulate three polyamine metabolism genes in high-risk breast cancer subtypes and the tumor microenvironment. Our results deepen the understanding of the role of polyamine metabolism in breast cancer and may help the clinical therapy of advanced breast cancer subtypes.

多胺在细胞生长和增殖中起着重要作用。多胺代谢基因在多种肿瘤中失调。一些多胺代谢基因受转录因子调控。然而,调控多胺代谢基因的转录因子尚未完全确定。此外,是否有任何转录调控依赖于肿瘤异质性和肿瘤微环境尚未被研究。方法利用大量RNA-seq数据鉴定乳腺癌亚型中多胺代谢失调基因及其转录因子。获得与多胺变化高度相关的基因,并使用单细胞RNA (scRNA)-seq数据在肿瘤微环境细胞中检查其亚型特异性表达。利用基因本体富集分析探索其分子功能和生物学过程,利用生存分析研究这些基因对治疗结果的影响。我们首先分析了四种乳腺癌亚型中多胺合成、分解代谢和运输的失调。AGMAT和CAV1等基因在所有亚型中都出现了失调,而APRT、SAT1和其他基因在更致命的亚型中出现了失调。在多胺代谢失调基因中,我们重点研究了三个基因(SRM、APRT和SAT1),并鉴定了它们的转录因子(SPI1和IRF1对应SAT1, IRF3对应SRM和APRT)。通过scRNA-seq数据,我们验证了这三种转录因子在肿瘤微环境中也调节了这三种多胺代谢基因。大量RNA-seq和scRNA-seq数据均表明,这些基因在高危乳腺癌亚型(如基底样型)中特异性上调。这些基因的高表达与基底样亚型在化疗和放疗下的预后较差相对应。结论在乳腺癌高危亚型和肿瘤微环境中,我们发现了三种亚型特异性转录因子调控三种多胺代谢基因。我们的研究结果加深了对多胺代谢在乳腺癌中的作用的理解,并可能有助于晚期乳腺癌亚型的临床治疗。
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引用次数: 0
Mitigating ibrutinib-induced ventricular arrhythmia and cardiac dysfunction with metformin 用二甲双胍缓解伊布替尼诱发的室性心律失常和心功能障碍
Pub Date : 2024-11-13 DOI: 10.1002/cai2.151
Pengsha Li, Daiqi Liu, Pan Gao, Ming Yuan, Zhiqiang Zhao, Yue Zhang, Zandong Zhou, Qingling Zhang, Meng Yuan, Xing Liu, Gary Tse, Guangping Li, Qiankun Bao, Tong Liu

Background

Ibrutinib is a first-line drug that targets Bruton's tyrosine kinase for the treatment of B cell cancer. However, cardiotoxicity induced by ibrutinib is a major side effect that limits its clinical use. This study aimed to investigate the mechanism of ibrutinib-induced cardiotoxicity and evaluate the protective role of metformin.

Methods

The study utilized male C57BL/6 J mice, which were administered ibrutinib at a dosage of 30 mg/kg/day via oral gavage for 4 weeks to induce cardiotoxicity. Metformin was administered orally at 200 mg/kg/day for 5 weeks, starting 1 week before ibrutinib treatment. Cardiac function was assessed using echocardiography and electrophysiological studies, including surface electrocardiography and epicardial electrical mapping. Blood pressure was measured using a tail-cuff system. Western blot analysis was conducted to evaluate the activity of the PI3K-AKT and AMPK pathways, along with apoptosis markers.

Results

C57BL/6 J mice were treated with ibrutinib for 4 weeks to assess its effect on cardiac function. We observed that ibrutinib induced ventricular arrhythmia and abnormal conduction while reducing the left ventricular ejection fraction. Furthermore, pretreatment with metformin reversed ibrutinib-induced cardiotoxicity. Mechanistically, ibrutinib decreased PI3K-AKT activity, resulting in apoptosis of cardiomyocytes. Administration of metformin upregulated AMPK and PI3K-AKT activity, which contributed to the improvement of cardiac function.

Conclusion

The study concludes that metformin effectively mitigates ibrutinib-induced cardiotoxicity, including ventricular arrhythmia and cardiac dysfunction, by enhancing AMPK and PI3K-AKT pathway activity. These findings suggest that metformin holds potential as a therapeutic strategy to protect against the adverse cardiac effects associated with ibrutinib treatment, offering a promising approach for improving the cardiovascular safety of patients undergoing therapy for B cell cancers.

背景介绍伊布替尼是一种靶向布鲁顿酪氨酸激酶的一线药物,用于治疗B细胞癌。然而,伊布替尼诱导的心脏毒性是限制其临床应用的主要副作用。本研究旨在探讨伊布替尼诱发心脏毒性的机制,并评估二甲双胍的保护作用:研究利用雄性C57BL/6 J小鼠,以30毫克/千克/天的剂量通过口服灌胃给药伊布替尼,连续4周诱导心脏毒性。二甲双胍的剂量为200毫克/千克/天,口服5周,在伊布替尼治疗前1周开始。使用超声心动图和电生理研究(包括表面心电图和心外膜电图)评估心脏功能。使用尾袖带系统测量血压。进行了 Western 印迹分析,以评估 PI3K-AKT 和 AMPK 通路以及细胞凋亡标记物的活性:C57BL/6 J小鼠接受伊布替尼治疗4周,以评估其对心脏功能的影响。我们观察到,伊布替尼会诱发室性心律失常和传导异常,同时降低左室射血分数。此外,二甲双胍可逆转伊布替尼诱导的心脏毒性。从机理上讲,伊布替尼降低了PI3K-AKT活性,导致心肌细胞凋亡。服用二甲双胍可上调AMPK和PI3K-AKT的活性,从而改善心脏功能:研究得出结论:二甲双胍通过增强AMPK和PI3K-AKT通路的活性,有效缓解了伊布替尼诱导的心脏毒性,包括室性心律失常和心功能不全。这些研究结果表明,二甲双胍有可能作为一种治疗策略,防止与伊布替尼治疗相关的心脏不良反应,为改善接受B细胞癌症治疗的患者的心血管安全性提供了一种前景广阔的方法。
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引用次数: 0
期刊
Cancer Innovation
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