Journal of Gene Medicine最新文献

Causal effects of female reproductive features on nonalcoholic fatty liver disease: A mendelian randomization study 女性生殖特征对非酒精性脂肪肝的因果效应：孟德尔随机化研究

IF 3.2 4区医学 Q2 BIOTECHNOLOGY & APPLIED MICROBIOLOGY

Journal of Gene Medicine

Pub Date : 2024-09-08 DOI: 10.1002/jgm.3738

Haoshuang Fu, Shuying Song, Bingying Du, Tianhui Zhou, Minghao Cai, Shaowen Jiang, Yaoxing Chen, Xinya Zang, Yan Huang, Weijing Wang, Qing Xie

Background and aims

Epidemiological evidence on the associations between female reproductive features and nonalcoholic fatty liver disease (NAFLD) is conflicting. To explore their causalities, we conducted a Mendelian randomization (MR) study.

Methods

Summary-level data were obtained, and univariable MR was performed to explore the causalities between female reproductive features and NAFLD. And we performed multivariable MR and MR mediation analysis to explore the mediation effects of educational attainment (EA) and body mass index (BMI) for these associations. Sensitivity analyses were performed to evaluate pleiotropy and heterogeneity.

Results

There were causal effects of age at menarche (AAMA) (odds ratio [OR]: 0.817, 95% confidence interval [CI]: 0.736–0.907, per year-increase), age at first birth (AFB) (OR: 0.851, 95%CI: 0.791–0.926, per year-increase) and age at first sexual intercourse (AFS) (OR: 0.676, 95%CI: 0.511–0.896, per standard deviation-increase) on NAFLD risk. Besides, the causal effects were also observed on NAFLD phenotypes including liver fat content (LFC) and alanine aminotransferase (ALT). Further mediation analysis showed that BMI mediated partial proportion of effects of AAMA and AFS on NAFLD/ALT, AFB on NAFLD/LFC/ALT, while EA mediated partial proportion of effects of AFB on NAFLD/LFC/ALT, and AFS on NAFLD/ALT.

Conclusions

This study provided convincing evidence that early AAMA, AFB, and AFS were risk factors for NAFLD. Reproductive health education, obesity management, and education spread might be the beneficial strategies for NAFLD prevention.

背景和目的：关于女性生殖特征与非酒精性脂肪肝（NAFLD）之间关系的流行病学证据相互矛盾。为了探究其因果关系，我们进行了一项孟德尔随机化（MR）研究：方法：我们获得了汇总数据，并进行了单变量 MR，以探讨女性生殖特征与非酒精性脂肪肝之间的因果关系。我们还进行了多变量 MR 和 MR 中介分析，以探讨教育程度（EA）和体重指数（BMI）对这些关联的中介效应。我们还进行了敏感性分析，以评估多义性和异质性：结果：初潮年龄（AAMA）有因果效应（几率比 [OR]：0.817，95% 置信区间 [CI]：初潮年龄（AAMA）（几率比[OR]：0.817，95%置信区间[CI]：0.736-0.907，每增加一年）、初产年龄（AFB）（OR：0.851，95%置信区间：0.791-0.926，每增加一年）和初次性交年龄（AFS）（OR：0.676，95%置信区间：0.511-0.896，每增加一个标准差）对非酒精性脂肪肝风险有因果效应。此外，非酒精性脂肪肝表型（包括肝脏脂肪含量（LFC）和丙氨酸氨基转移酶（ALT））也受到因果效应的影响。进一步的中介分析表明，BMI中介了AAMA和AFS对NAFLD/ALT、AFB对NAFLD/LFC/ALT的部分影响，而EA中介了AFB对NAFLD/LFC/ALT、AFS对NAFLD/ALT的部分影响：该研究提供了令人信服的证据，证明早期AAMA、AFB和AFS是非酒精性脂肪肝的危险因素。生殖健康教育、肥胖管理和教育传播可能是预防非酒精性脂肪肝的有益策略。

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引用次数: 0

Exploring the interplay between bisphenol A exposure, the immune microenvironment and hepatocellular carcinoma progression 探索双酚 A 暴露、免疫微环境与肝细胞癌进展之间的相互作用。

IF 3.2 4区医学 Q2 BIOTECHNOLOGY & APPLIED MICROBIOLOGY

Journal of Gene Medicine

Pub Date : 2024-09-03 DOI: 10.1002/jgm.3723

Qi Liu, Ruishu Niu, Yi Ye, Jie Li

Background

Hepatocellular carcinoma (HCC) remains a formidable challenge in oncology, with its pathogenesis and progression influenced by myriad factors. Among them, the pervasive organic synthetic compound, bisphenol A (BPA), previously linked with various adverse health effects, has been speculated to play a role. This study endeavors to elucidate the complex interplay between BPA, the immune microenvironment of HCC, and the broader molecular landscape of this malignancy.

Methods

A comprehensive analysis was undertaken using data procured from both The Cancer Genome Atlas and the Comparative Toxicogenomics Database. Rigorous differential expression analyses were executed, supplemented by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses. In addition, single-sample gene set enrichment analysis, gene set enrichment analysis and gene set variation analysis were employed to reveal potential molecular links and insights. Immune infiltration patterns were delineated, and a series of in vitro experiments on HCC cells were conducted to directly assess the impact of BPA exposure.

Results

Our findings unveiled a diverse array of active immune cells and functions within HCC. Distinct correlations emerged between high-immune-related scores, established markers of the tumor microenvironment and the expression of immune checkpoint genes. A significant discovery was the identification of key genes simultaneously associated with immune-related pathways and BPA exposure. Leveraging these genes, a prognostic model was crafted, offering predictive insights into HCC patient outcomes. Intriguingly, in vitro studies suggested that BPA exposure could promote proliferation in HCC cells.

Conclusion

This research underscores the multifaceted nature of HCC’s immune microenvironment and sheds light on BPA’s potential modulatory effects therein. The constructed prognostic model, if validated further, could serve as a robust tool for risk stratification in HCC, potentially guiding therapeutic strategies. Furthermore, the implications of the findings for immunotherapy are profound, suggesting new avenues for enhancing treatment efficacy. As the battle against HCC continues, understanding of environmental modulators like BPA becomes increasingly pivotal.

背景：肝细胞癌（HCC）仍然是肿瘤学中的一项艰巨挑战，其发病机制和进展受多种因素的影响。其中，普遍存在的有机合成化合物双酚 A（BPA）曾与各种不良健康影响有关，人们推测它在其中发挥了作用。本研究试图阐明双酚 A、HCC 的免疫微环境以及这种恶性肿瘤更广泛的分子环境之间复杂的相互作用：利用从癌症基因组图谱（The Cancer Genome Atlas）和比较毒物基因组学数据库（Comparative Toxicogenomics Database）获得的数据进行了全面分析。进行了严格的差异表达分析，并辅以基因本体和京都基因和基因组百科全书的富集分析。此外，还采用了单样本基因组富集分析、基因组富集分析和基因组变异分析，以揭示潜在的分子联系和见解。对免疫浸润模式进行了描述，并对 HCC 细胞进行了一系列体外实验，以直接评估双酚 A 暴露的影响：结果：我们的研究结果揭示了 HCC 中活跃的免疫细胞和功能的多样性。高免疫相关评分、肿瘤微环境的既定标记物和免疫检查点基因的表达之间存在明显的相关性。一项重大发现是确定了与免疫相关途径和双酚 A 暴露同时相关的关键基因。利用这些基因建立了一个预后模型，为预测 HCC 患者的预后提供了洞察力。有趣的是，体外研究表明，暴露于双酚 A 可促进 HCC 细胞的增殖：这项研究强调了 HCC 免疫微环境的多面性，并揭示了双酚 A 在其中的潜在调节作用。所构建的预后模型如能得到进一步验证，将成为对 HCC 进行风险分层的有力工具，并有可能为治疗策略提供指导。此外，这些发现对免疫疗法也有深远的影响，为提高疗效提供了新的途径。随着与 HCC 斗争的继续，对双酚 A 等环境调节剂的了解变得越来越重要。

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引用次数: 0

Single-cell RNA sequencing reveals microenvironmental infiltration in non-small cell lung cancer with different responses to immunotherapy 单细胞 RNA 测序揭示了非小细胞肺癌微环境浸润对免疫疗法的不同反应。

IF 3.2 4区医学 Q2 BIOTECHNOLOGY & APPLIED MICROBIOLOGY

Journal of Gene Medicine

Pub Date : 2024-09-03 DOI: 10.1002/jgm.3736

Xinnan Hu, Yonghui Wu, Lixin Wang, Fujun Yang, Lingyun Ye, Xiaoxia Chen, Xiao Song, Ping Wei

Background

Immunotherapy represents a groundbreaking and monumental achievement in the field of cancer therapy, marking a significant advancement in fighting against this devastating disease. Lung cancer has showed consistent clinical improvements in response to immunotherapy treatments, yet, it is undeniable that challenges such as limited response rates acquire resistance, and the unclear fundamental mechanisms were inevitable problems.

Methods

The cellular composition was defined and distinguished through single-cell RNA sequencing (scRNA-seq) analysis of MPR (major pathologic response) and NMPR (non-major pathologic response) samples in GSE207422, including four primary MPR samples and eight primary NMPR samples.

Results

We found obvious difference in CD8+ T cell population between MPR and NMPR samples, with high expression of TYMS, RRM2, and BIRC5 in NPMR samples. Meanwhile, the proportion of macrophages and tumor epithelial cells infiltration increased in the NMPR samples. We discovered biomarkers (ACTN4, ATF3, BRD2, CDKN1A, and CHMP4B) in epithelial cells which were potentially represented worse outcomes.

Conclusions

By exploring the difference of tumor microenvironment (TME) in samples with different corresponding degrees of neoadjuvant immunotherapy, this research introduces a number of novel biomarkers for predicting the response of treatment and a theoretical basis for overcoming immunotherapy resistance.

背景：免疫疗法是癌症治疗领域的一项开创性的巨大成就，标志着抗击这一毁灭性疾病的重大进展。肺癌对免疫疗法的临床反应持续改善，但不可否认的是，有限的反应率和耐药性以及基本机制不明等挑战是不可避免的问题：方法：通过单细胞RNA测序（scRNA-seq）分析GSE207422中的MPR（主要病理反应）和NMPR（非主要病理反应）样本，包括4个原发MPR样本和8个原发NMPR样本，确定并区分细胞组成：结果：我们发现MPR和NMPR样本的CD8+T细胞群存在明显差异，NMPR样本中TYMS、RRM2和BIRC5表达量较高。同时，NMPR样本中巨噬细胞和肿瘤上皮细胞浸润比例增加。我们在上皮细胞中发现了生物标记物（ACTN4、ATF3、BRD2、CDKN1A和CHMP4B），这些标记物可能代表着更差的预后：本研究通过探讨新辅助免疫治疗相应程度不同的样本中肿瘤微环境（TME）的差异，提出了一些预测治疗反应的新型生物标志物，为克服免疫治疗耐药性提供了理论依据。

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引用次数: 0

Oncogenic tRNA-derived fragment tRF-Leu-CAG promotes tumorigenesis of lung cancer via targeting TCEA3 and increasing autophagy 致癌 tRNA 衍生片段 tRF-Leu-CAG 通过靶向 TCEA3 和增加自噬促进肺癌的肿瘤发生

IF 3.2 4区医学 Q2 BIOTECHNOLOGY & APPLIED MICROBIOLOGY

Journal of Gene Medicine

Pub Date : 2024-08-28 DOI: 10.1002/jgm.3737

Fan Wu, Binshu Chai, Pengfei Qi, Yaqi Han, Zhitao Gu, Wei Pan, Hui Zhang, Xianyi Wang, Xiaomin Liu, Heng Zou, Chen Liang, YanLi Li, Wentao Fang, Zhongliang Ma

Background

Lung cancer is a prevalent and severe form of malignant tumors worldwide. tRF-Leu-CAG, a recently discovered non-coding single-stranded small RNA derived from transfer RNA, has sparked interest in exploring its biological functions and potential molecular mechanisms in lung cancer.

Methods

The abundance of tRF-Leu-CAG was measured via quantitative real-time polymerase chain reaction (qRT-PCR) in 96 sets of lung cancer tissue samples obtained from clinical patients. Subsequently, both in vivo and in vitro experiments were conducted to validate the biological functions of tRF-Leu-CAG in lung cancer. Furthermore, an exploration of the potential target genes of tRF-Leu-CAG and its association with autophagy and drug resistance in lung cancer was undertaken.

Results

Our analysis revealed a significant upregulation of tRF-Leu-CAG in non-small cell lung cancer (NSCLC) tissues. Additionally, we observed that heightened expression of tRF-Leu-CAG significantly augmented the proliferation and migration of NSCLC cells, facilitated cell cycle progression, and suppressed apoptosis. Furthermore, we identified transcription elongation factor A3 (TCEA3) as a direct target gene of tRF-Leu-CAG. TCEA3 inhibited the proliferation and migration of NSCLC, and tRF-Leu-CAG promoted the proliferation and migration of NSCLC by mediating the silencing of TCEA3. Moreover, we demonstrated that the augmentation of paclitaxel resistance by tRF-Leu-CAG was contingent on autophagy. Finally, tRF-Leu-CAG notably accelerated tumor growth and promoted the process of epithelial-mesenchymal transition (EMT) in vivo.

Conclusions

tRF-Leu-CAG promotes NSCLC tumor growth and metastasis by targeting TCEA3 and promotes paclitaxel resistance by enhancing cellular autophagy. These results provide potentially effective targets and therapeutic options for the clinical treatment of NSCLC.

tRF-Leu-CAG 是最近发现的一种源自转移 RNA 的非编码单链小 RNA，它引发了人们对其在肺癌中的生物学功能和潜在分子机制的兴趣。方法通过实时定量聚合酶链反应（qRT-PCR）测定了 96 组临床患者肺癌组织样本中 tRF-Leu-CAG 的丰度。随后，通过体内和体外实验验证了 tRF-Leu-CAG 在肺癌中的生物学功能。此外，研究人员还探讨了 tRF-Leu-CAG 的潜在靶基因及其与肺癌自噬和耐药性的关系。结果我们的分析发现，tRF-Leu-CAG 在非小细胞肺癌（NSCLC）组织中明显上调。此外，我们还观察到，tRF-Leu-CAG 的高表达明显增加了 NSCLC 细胞的增殖和迁移，促进了细胞周期的进展，并抑制了细胞凋亡。此外，我们还发现转录延伸因子 A3（TCEA3）是 tRF-Leu-CAG 的直接靶基因。TCEA3抑制NSCLC的增殖和迁移，而tRF-Leu-CAG通过介导TCEA3的沉默促进NSCLC的增殖和迁移。此外，我们还证明了tRF-Leu-CAG对紫杉醇耐药性的增强取决于自噬作用。最后，tRF-Leu-CAG 明显加速了肿瘤的生长，并促进了体内上皮-间质转化（EMT）过程。结论 tRF-Leu-CAG 通过靶向 TCEA3 促进 NSCLC 肿瘤生长和转移，并通过增强细胞自噬促进紫杉醇抗性。这些结果为临床治疗 NSCLC 提供了潜在的有效靶点和治疗方案。

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引用次数: 0

Integrative in silico approaches to analyse microRNA-mediated responses in human diseases 分析人类疾病中 microRNA 介导的反应的整合性硅学方法

IF 3.2 4区医学 Q2 BIOTECHNOLOGY & APPLIED MICROBIOLOGY

Journal of Gene Medicine

Pub Date : 2024-08-28 DOI: 10.1002/jgm.3734

Meghna Agrawal, Ashutosh Mani

Advancements in sequencing technologies have facilitated omics level information generation for various diseases in human. High-throughput technologies have become a powerful tool to understand differential expression studies and transcriptional network analysis. An understanding of complex transcriptional networks in human diseases requires integration of datasets representing different RNA species including microRNA (miRNA) and messenger RNA (mRNA). This review emphasises on conceptual explanation of generalized workflow and methodologies to the miRNA mediated responses in human diseases by using different in silico analysis. Although, there have been many prior explorations in miRNA-mediated responses in human diseases, the advantages, limitations and overcoming the limitation through different statistical techniques have not yet been discussed. This review focuses on miRNAs as important gene regulators in human diseases, methodologies for miRNA-target gene prediction and data driven methods for enrichment and network analysis for miRnome–targetome interactions. Additionally, it proposes an integrative workflow to analyse structural components of networks obtained from high-throughput data. This review explains how to apply the existing methods to analyse miRNA-mediated responses in human diseases. It addresses unique characteristics of different analysis, its limitations and its statistical solutions influencing the choice of methods for the analysis through a workflow. Moreover, it provides an overview of promising common integrative approaches to comprehend miRNA-mediated gene regulatory events in biological processes in humans. The proposed methodologies and workflow shall help in the analysis of multi-source data to identify molecular signatures of various human diseases.

测序技术的进步促进了人类各种疾病的omics级信息生成。高通量技术已成为了解差异表达研究和转录网络分析的有力工具。要了解人类疾病中复杂的转录网络，需要整合代表不同 RNA 物种的数据集，包括微 RNA (miRNA) 和信使 RNA (mRNA)。这篇综述着重从概念上解释了通过使用不同的硅学分析来研究人类疾病中 miRNA 介导的反应的一般工作流程和方法。虽然此前已有许多关于 miRNA 介导的人类疾病反应的探索，但尚未讨论其优势、局限性以及通过不同统计技术克服局限性的问题。本综述重点讨论了作为人类疾病重要基因调控因子的 miRNA、miRNA-靶基因预测方法以及数据驱动的 miRnome-靶基因组相互作用富集和网络分析方法。此外，它还提出了一种综合工作流程，用于分析从高通量数据中获得的网络结构成分。本综述解释了如何应用现有方法分析 miRNA 介导的人类疾病反应。它探讨了不同分析方法的独特性、局限性以及影响通过工作流程选择分析方法的统计解决方案。此外，它还概述了有前景的常用综合方法，以理解人类生物过程中 miRNA 介导的基因调控事件。所提出的方法和工作流程将有助于分析多源数据，以确定各种人类疾病的分子特征。

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引用次数: 0

Strategic deactivation of mRNA COVID-19 vaccines: New applications for siRNA therapy and RIBOTACs mRNA COVID-19 疫苗的战略性失活：siRNA 疗法和 RIBOTAC 的新应用。

IF 3.2 4区医学 Q2 BIOTECHNOLOGY & APPLIED MICROBIOLOGY

Journal of Gene Medicine

Pub Date : 2024-08-26 DOI: 10.1002/jgm.3733

Nicolas Hulscher, Peter A. McCullough, Diane E. Marotta

The rapid development and authorization of messenger ribonucleic acid (mRNA) vaccines by Pfizer-BioNTech (BNT162b2) and Moderna (mRNA-1273) in 2020 marked a significant milestone in human mRNA product application, overcoming previous obstacles such as mRNA instability and immunogenicity. This paper reviews the strategic modifications incorporated into these vaccines to enhance mRNA stability and translation efficiency, such as the inclusion of nucleoside modifications and optimized mRNA design elements including the 5′ cap and poly(A) tail. We highlight emerging concerns regarding the wide systemic biodistribution of these mRNA vaccines leading to prolonged inflammatory responses and other safety concerns. The regulatory framework guiding the biodistribution studies is pivotal in assessing the safety profiles of new mRNA formulations in use today. The stability of mRNA vaccines, their pervasive distribution, and the longevity of the encapsulated mRNA along with unlimited production of the damaging and potentially lethal spike (S) protein call for strategies to mitigate potential adverse effects. Here, we explore the potential of small interfering RNA (siRNA) and ribonuclease targeting chimeras (RIBOTACs) as promising solutions to target, inactivate, and degrade residual and persistent vaccine mRNA, thereby potentially preventing uncontrolled S protein production and reducing toxicity. The targeted nature of siRNA and RIBOTACs allows for precise intervention, offering a path to prevent and mitigate adverse events of mRNA-based therapies. This review calls for further research into siRNA and RIBOTAC applications as antidotes and detoxication products for mRNA vaccine technology.

辉瑞-生物技术公司（BNT162b2）和Moderna公司（mRNA-1273）于2020年迅速开发出信使核糖核酸（mRNA）疫苗并获得授权，标志着人类mRNA产品应用领域的一个重要里程碑，克服了以往mRNA不稳定性和免疫原性等障碍。本文回顾了这些疫苗为提高 mRNA 稳定性和翻译效率而进行的战略性修改，如加入核苷修饰和优化的 mRNA 设计元素，包括 5' 帽和 poly(A) 尾。我们强调了新出现的问题，即这些 mRNA 疫苗的广泛全身生物分布会导致长时间的炎症反应和其他安全问题。指导生物分布研究的监管框架对于评估目前使用的新型 mRNA 制剂的安全性至关重要。mRNA 疫苗的稳定性、广泛分布、封装 mRNA 的寿命以及破坏性和潜在致命性尖峰 (S) 蛋白的无限生产，都要求采取策略来减轻潜在的不良影响。在此，我们探讨了小干扰 RNA（siRNA）和核糖核酸酶靶向嵌合体（RIBOTACs）作为靶向、灭活和降解残留和持久性疫苗 mRNA 的潜在解决方案的潜力，从而有可能防止不受控制的 S 蛋白生成并降低毒性。siRNA 和 RIBOTACs 的靶向性允许精确干预，为预防和减轻基于 mRNA 治疗的不良反应提供了途径。本综述呼吁进一步研究 siRNA 和 RIBOTAC 在 mRNA 疫苗技术中作为解毒剂和解毒产品的应用。

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引用次数: 0

Leveraging SEER data through machine learning to predict distant lymph node metastasis and prognosticate outcomes in hepatocellular carcinoma patients 通过机器学习利用 SEER 数据预测肝癌患者的远处淋巴结转移和预后。

IF 3.2 4区医学 Q2 BIOTECHNOLOGY & APPLIED MICROBIOLOGY

Journal of Gene Medicine

Pub Date : 2024-08-26 DOI: 10.1002/jgm.3732

Jiaxuan Sun, Lei Huang, Yahui Liu

Objectives

This study aims to develop and validate machine learning–based diagnostic and prognostic models to predict the risk of distant lymph node metastases (DLNM) in patients with hepatocellular carcinoma (HCC) and to evaluate the prognosis for this cohort.

Design

Utilizing a retrospective design, this investigation leverages data extracted from the Surveillance, Epidemiology, and End Results (SEER) database, specifically the January 2024 subset, to conduct the analysis.

Participants

The study cohort consists of 15,775 patients diagnosed with HCC as identified within the SEER database, spanning 2016 to 2020.

Method

In the construction of the diagnostic model, recursive feature elimination (RFE) is employed for variable selection, incorporating five critical predictors: age, tumor size, radiation therapy, T-stage, and serum alpha-fetoprotein (AFP) levels. These variables are the foundation for a stacking ensemble model, which is further elucidated through Shapley Additive Explanations (SHAP). Conversely, the prognostic model is crafted utilizing stepwise backward regression to select pertinent variables, including chemotherapy, radiation therapy, tumor size, and age. This model culminates in the development of a prognostic nomogram, underpinned by the Cox proportional hazards model.

Main outcome measures

The outcome of the diagnostic model is the occurrence of DLNM in patients. The outcome of the prognosis model is determined by survival time and survival status.

Results

The integrated model developed based on stacking demonstrates good predictive performance and high interpretative variability and differentiation. The area under the curve (AUC) in the training set is 0.767, while the AUC in the validation set is 0.768. The nomogram, constructed using the Cox model, also demonstrates consistent and strong predictive capabilities. At the same time, we recognized elements that have a substantial impact on DLNM and the prognosis and extensively discussed their significance in the model and clinical practice.

Conclusion

Our study identified key predictive factors for DLNM and elucidated significant prognostic indicators for HCC patients with

研究目的本研究旨在开发和验证基于机器学习的诊断和预后模型，以预测肝细胞癌（HCC）患者发生远处淋巴结转移（DLNM）的风险，并评估该人群的预后：本研究采用回顾性设计，利用从监测、流行病学和最终结果（SEER）数据库（特别是 2024 年 1 月的子集）中提取的数据进行分析：研究队列由 SEER 数据库中确定的 15,775 名确诊为 HCC 的患者组成，时间跨度为 2016 年至 2020 年：在构建诊断模型时，采用递归特征消除法（RFE）进行变量选择，其中包含五个关键预测因素：年龄、肿瘤大小、放射治疗、T期和血清甲胎蛋白（AFP）水平。这些变量是堆叠集合模型的基础，该模型通过夏普利相加解释（SHAP）得到进一步阐明。相反，预后模型则是利用逐步回归法来选择相关变量，包括化疗、放疗、肿瘤大小和年龄。该模型的最终结果是建立一个预后提名图，并以 Cox 比例危险模型为基础：诊断模型的结果是患者出现 DLNM。预后模型的结果由生存时间和生存状态决定：结果：基于堆叠法开发的综合模型显示出良好的预测性能、较高的解释变异性和区分度。训练集的曲线下面积（AUC）为 0.767，验证集的 AUC 为 0.768。使用 Cox 模型构建的提名图也显示出一致而强大的预测能力。同时，我们发现了对 DLNM 和预后有重大影响的因素，并广泛讨论了这些因素在模型和临床实践中的意义：我们的研究确定了 DLNM 的关键预测因素，并阐明了患有 DLNM 的 HCC 患者的重要预后指标。这些发现为临床医生准确识别 DLNM 的高危人群并对这一患者亚群进行更精确的风险分层提供了宝贵的工具，从而有可能改善管理策略和患者预后。

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引用次数: 0

mRNA expression insights: Unraveling the relationship between COPD and lung cancer mRNA 表达见解：揭示慢性阻塞性肺病与肺癌之间的关系

IF 3.2 4区医学 Q2 BIOTECHNOLOGY & APPLIED MICROBIOLOGY

Journal of Gene Medicine

Pub Date : 2024-08-25 DOI: 10.1002/jgm.3728

Zhan Gu, Jijia Sun, Lixin Wang

Background

Lung cancer is a prevalent form of cancer worldwide. A possible link between lung cancer and chronic obstructive pulmonary disease (COPD) has been suggested by recent studies. The objective of our research was to analyze the mRNA expression patterns in both situations, with a specific emphasis on their biological functions and the pathways they are linked to.

Method

Data on COPD mRNA expression was collected from the NCBI-GEO database, while information regarding lung cancer mRNA was acquired from The Cancer Genome Atlas database. To examine the association of COPD-related scores in lung cancer patients, we utilized the ssGSEA algorithm for single sample gene set enrichment analysis. The possible routes were examined through the utilization of Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis. Risk models were developed using Cox and least absolute shrinkage and selection operator (LASSO) regression analyses. Moreover, a GSEA was performed to investigate significant pathways among various risk groups.

Result

After identifying 17 genes that were differentially expressed and linked to COPD, we found that they met the criteria of having a false discovery rate < 0.05 and an absolute log₂ fold change > 0.585. By utilizing the ssGSEA algorithm, it became possible to classify individuals with lung cancer into two distinct groups based on their COPD status. Consequently, a seven-gene risk model was developed specifically for these patients. The risk score was determined by applying the given formula: risk score = AC022784.1 × 0.0423737993775888 + CRISP3 × 0.0415322046890524 + MELTF × 0.0661848418476596 + MT2P1 × 0.111843227536117 + FAM83A-AS1 × 0.045295939710361 + ZNF506 × −0.309489953363417 + ITGA6 × 0.01813978449589. The risk model associated with COPD showed a notable connection with different immune cells found in the lung cancer sample, including macrophages of M0/M1/M2 types, hematopoietic stem cells, mast cells, NK T cells and regulatory T cells. Overexpression of crucial genes was seen to enhance cell proliferation and invasive potential in the lung cancer sample. In the lung cancer sample, it was observed that an increase in ZNF506 expression enhanced both cell proliferation and invasion.

Conclusion

In conclusion, this study effectively examines the potential correlation between COPD and lung cancer. A prognostic model based on seven COPD-associated genes demonstrated robust predictive potential in the lung cancer sample. Our analysis

背景：肺癌是全球流行的一种癌症。最近的研究表明，肺癌与慢性阻塞性肺病（COPD）之间可能存在联系。我们的研究目的是分析这两种情况下的 mRNA 表达模式，重点是它们的生物学功能及其相关途径：方法：慢性阻塞性肺病 mRNA 表达数据来自 NCBI-GEO 数据库，肺癌 mRNA 信息来自癌症基因组图谱数据库。为了研究肺癌患者 COPD 相关评分的关联性，我们使用了 ssGSEA 算法进行单样本基因组富集分析。通过基因本体和京都基因与基因组百科全书的富集分析，研究了可能的途径。利用 Cox 和最小绝对收缩和选择算子（LASSO）回归分析建立了风险模型。此外，还进行了GSEA分析，以研究不同风险组之间的重要通路：结果：在确定了 17 个与慢性阻塞性肺病相关的差异表达基因后，我们发现这些基因符合假发现率 2 折变化> 0.585 的标准。通过使用 ssGSEA 算法，我们可以根据慢性阻塞性肺病的状况将肺癌患者分为两个不同的组别。因此，专门为这些患者开发了一个七基因风险模型。风险分值通过以下公式确定：风险分值 = AC022784.1 × 0.0423737993775888 + CRISP3 × 0.0415322046890524 + MELTF × 0.0661848418476596 + MT2P1 × 0.111843227536117 + FAM83A-AS1 × 0.045295939710361 + ZNF506 × -0.309489953363417 + ITGA6 × 0.01813978449589。与慢性阻塞性肺病相关的风险模型显示，与肺癌样本中发现的不同免疫细胞，包括 M0/M1/M2 型巨噬细胞、造血干细胞、肥大细胞、NK T 细胞和调节性 T 细胞有显著联系。在肺癌样本中，关键基因的过度表达会增强细胞增殖和侵袭潜力。在肺癌样本中，观察到 ZNF506 表达的增加增强了细胞增殖和侵袭能力：总之，本研究有效地探讨了慢性阻塞性肺病与肺癌之间的潜在关联。基于七个慢性阻塞性肺病相关基因的预后模型在肺癌样本中显示出强大的预测潜力。我们的分析为肺癌患者提供了全面的见解。

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引用次数: 0

Expression and prognostic value of cell-cycle-associated genes in lung squamous cell carcinoma 肺鳞状细胞癌细胞周期相关基因的表达和预后价值。

IF 3.2 4区医学 Q2 BIOTECHNOLOGY & APPLIED MICROBIOLOGY

Journal of Gene Medicine

Pub Date : 2024-08-22 DOI: 10.1002/jgm.3735

Xinnan Xu, Kaiqi Jin, Xiaoxiong Xu, Yang Yang, Bin Zhou

Background

Lung cancer continues to be a prevalent cause of cancer-related deaths worldwide, with lung squamous carcinoma (LUSC) being a significant subtype characterized by comparatively low survival rates. Extensive molecular studies on LUSC have been conducted; however, the clinical importance of cell-cycle-associated genes has rarely been examined. This study aimed to investigate the relationship between these genes and LUSC.

Methods

The expression trends of genes related to the cell cycle in a group of patients with LUSC were analyzed. Clinical information and mRNA expression data were obtained from The Cancer Genome Atlas via cBioportal. Multiple analyses have been performed to investigate the association between these genes and LUSC.

Results

Three clusters were identified based on the mRNA expression of 124 cell cycle-associated genes. Cluster 3 exhibited the worst prognosis. A comparative analysis showed that nine expressed genes differed distinctly among all the clusters. Among these nine genes, elevated expression of CDK4 was strongly associated with positive prognosis. Furthermore, the expression of ANAPC11, ANAPC5, and ORC4 correlated with the advancement of LUSC pathological stages.

Conclusions

Gene expression profiles associated with the cell cycle across various LUSC subtypes were identified, highlighting that specific genes are related to prognosis and disease stages. Based on these results, new prognostic strategies, patient stratification, and targeted therapy trials have been conducted for LUSC.

背景：肺癌仍然是全球癌症相关死亡的一个普遍原因，其中肺鳞状癌（LUSC）是一个重要的亚型，其特点是生存率相对较低。目前已对肺鳞癌进行了广泛的分子研究，但细胞周期相关基因的临床重要性却很少得到研究。本研究旨在探讨这些基因与 LUSC 之间的关系：方法：分析一组 LUSC 患者中细胞周期相关基因的表达趋势。临床信息和mRNA表达数据通过cBioportal从癌症基因组图谱中获取。为了研究这些基因与 LUSC 之间的关联，研究人员进行了多重分析：结果：根据 124 个细胞周期相关基因的 mRNA 表达，确定了三个群组。第 3 组的预后最差。对比分析表明，有九个表达基因在所有群组中存在明显差异。在这九个基因中，CDK4的表达升高与预后呈阳性密切相关。此外，ANAPC11、ANAPC5和ORC4的表达与LUSC病理分期的进展相关：结论：研究发现了不同LUSC亚型中与细胞周期相关的基因表达谱，突显出特定基因与预后和疾病分期相关。基于这些结果，我们已针对 LUSC 开展了新的预后策略、患者分层和靶向治疗试验。

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引用次数: 0

Stable transduction of the neonatal mouse liver using a hybrid rAAV/sleeping beauty transposon gene delivery system 使用混合 rAAV/睡美人转座子基因递送系统对新生小鼠肝脏进行稳定转导。

IF 3.2 4区医学 Q2 BIOTECHNOLOGY & APPLIED MICROBIOLOGY

Journal of Gene Medicine

Pub Date : 2024-08-19 DOI: 10.1002/jgm.3726

Sharon C. Cunningham, Philip M. Zakas, Natsuki Sasaki, Eva B. van Dijk, Erhua Zhu, Yanfang Fu, William E. Salomon, Robert J. Citorik, Jacob R. Rubens, Cecilia Cotta-Ramusino, William Querbes, Ian E. Alexander

Background

Conventional adeno-associated viral (AAV) vectors, while highly effective in quiescent cells such as hepatocytes in the adult liver, confer less durable transgene expression in proliferating cells owing to episome loss. Sustained therapeutic success is therefore less likely in liver disorders requiring early intervention. We have previously developed a hybrid, dual virion approach, recombinant AAV (rAAV)/piggyBac transposon system capable of achieving stable gene transfer in proliferating hepatocytes at levels many fold above conventional AAV vectors. An alternative transposon system, Sleeping Beauty, has been widely used for ex vivo gene delivery; however liver-targeted delivery using a hybrid rAAV/Sleeping Beauty approach remains relatively unexplored.

Methods

We investigated the capacity of a Sleeping Beauty (SB)-based dual rAAV virion approach to achieve stable and efficient gene transfer to the newborn murine liver using transposable therapeutic cassettes encoding coagulation factor IX or ornithine transcarbamylase (OTC).

Results

At equivalent doses, rAAV/SB100X transduced hepatocytes with high efficiency, achieving stable expression into adulthood. Compared with conventional AAV, the proportion of hepatocytes transduced, and factor IX and OTC activity levels, were both markedly increased. The proportion of hepatocytes stably transduced increased 4- to 8-fold from <5%, and activity levels increased correspondingly, with markedly increased survival and stable urinary orotate levels in the OTC-deficient Spf^ash mouse following elimination of residual endogenous murine OTC.

Conclusions

The present study demonstrates the first in vivo utility of a hybrid rAAV/SB100X transposon system to achieve stable long-term therapeutic gene expression following delivery to the highly proliferative newborn mouse liver. These results have relevance to the treatment of genetic metabolic liver diseases with neonatal onset.

背景：传统的腺相关病毒（AAV）载体虽然对静止细胞（如成人肝脏中的肝细胞）非常有效，但由于外显子丢失，在增殖细胞中转基因表达的持久性较差。因此，在需要早期干预的肝脏疾病中，持续治疗成功的可能性较小。我们之前开发了一种混合双病毒方法，即重组 AAV（rAAV）/piggyBac 转座子系统，能够在增殖肝细胞中实现稳定的基因转移，其水平比传统 AAV 载体高出许多倍。另一种转座子系统 "睡美人 "已被广泛用于体内外基因递送，但使用rAAV/"睡美人 "混合方法进行肝脏靶向递送的研究相对较少：我们研究了基于睡美人（SB）的双 rAAV 病毒方法，利用编码凝血因子 IX 或鸟氨酸转氨酶（OTC）的可转座治疗盒实现稳定、高效的基因转移到新生小鼠肝脏的能力：结果：在同等剂量下，rAAV/SB100X 转导肝细胞的效率很高，可稳定表达至成年。与传统 AAV 相比，转导的肝细胞比例、因子 IX 和 OTC 活性水平均显著提高。在消除残留的内源性小鼠 OTC 后，稳定转导的肝细胞比例比灰鼠增加了 4 到 8 倍：本研究首次证明了混合 rAAV/SB100X 转座子系统在体内的实用性，该系统可在向高度增殖的新生小鼠肝脏输送基因后实现长期稳定的治疗基因表达。这些结果对治疗新生儿发病的遗传代谢性肝病具有重要意义。

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引用次数: 0

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