Journal of Gene Medicine最新文献

英文中文

Identification of prognostic biomarkers for cervical cancer based on programmed cell death-related genes and assessment of their immune profile and response to drug therapy 基于程序性细胞死亡相关基因的宫颈癌预后生物标志物鉴定及其免疫特征和对药物治疗反应的评估

IF 3.5 4区医学 Q2 Biochemistry, Genetics and Molecular Biology

Journal of Gene Medicine

Pub Date : 2023-12-04 DOI: 10.1002/jgm.3643

Sijie Feng, Zhenhui Wang, Huizhen Zhang, Baohua Hou, Yanjun Xu, Shuangying Hao, Yunkun Lu

Background

Programmed cell death (PCD) has been widely investigated in various human diseases. The present study aimed to identify a novel PCD-related genetic signature in cervical squamous cell carcinoma (CESC) to provide clues for survival, immunotherapy and drug sensitization prediction.

Methods

Single-sample gene set enrichment analysis (ssGSEA) was used to quantify the PCD score and assess the distribution of PCD in clinicopathological characteristics in The Cancer Genome Atlas (TCGA)-CESC samples. Then, the ConsensusClusterPlus method was used to identify molecular subtypes in the TCGA-CESC database. Genomic mutation analysis, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes functional enrichment, as well as tumor microenvironment (TME) infiltration analysis, were performed for each molecular subtype group. Finally, a prognostic model by Uni-Cox and least absolute shrinkage and selection operator-Cox analysis was established based on differentially expressed genes from molecular subtypes. ESTIMATE (i.e. Estimation of STromal and Immune cells in MAlignantTumours using Expression data) and ssGSEA were performed to assess the correlation between the model and TME. Drug sensitization prediction was carried out with the oncoPredict package.

Results

Preliminary analysis indicated that PCD had a potential association clinical characteristics of the TCGA-CESC cohort, and PCD-related genes mutated in 289 (70.59%) CESC patients. Next, four groups of CESC molecular typing were clustered based on 63 significantly prognostic PCD-related genes. Among four subtypes, C1 group displayed the worst prognosis combined with over expressed PCD genes and enriched cell cycle-related pathways. C4 group exhibited the best prognosis accompanied with high degree of immune infiltration. Finally, a five-gene (SERPINE1, TNF, CA9, CX3CL1 and JAK3) prognostic model was constructed. Patients in the high-risk group displayed unfavorable survival. Immune infiltration analysis found that the low-risk group had significantly higher levels of immune cell infiltration such as T cells, Macrophages_M1, relative to the high-risk group, and were significantly enriched in apoptosis-associated pathways, which predicted a higher level of immunity. Drug sensitivity correlation analysis revealed that the high-risk group was resistant to conventional chemotherapeutic drugs and sensitive to the Food and Drug Administration-approved drugs BI.2536_1086 and SCH772984_1564.

Conclusions

In the present study, we first found that PC

背景:程序性细胞死亡(PCD)在各种人类疾病中得到了广泛的研究。本研究旨在发现宫颈鳞状细胞癌(CESC)中一个新的与pcd相关的遗传特征，为生存、免疫治疗和药物致敏预测提供线索。方法:采用单样本基因集富集分析(ssGSEA)定量PCD评分，评估PCD在the Cancer Genome Atlas (TCGA)-CESC样本临床病理特征中的分布。然后，使用ConsensusClusterPlus方法在TCGA-CESC数据库中识别分子亚型。对每个分子亚型组进行基因组突变分析、基因本体和京都基因与基因组百科全书功能富集分析以及肿瘤微环境(TME)浸润分析。最后，基于分子亚型差异表达基因，通过Uni-Cox、最小绝对收缩和选择算子- cox分析建立预后模型。通过ESTIMATE(即利用表达数据估计恶性肿瘤中的基质细胞和免疫细胞)和ssGSEA来评估模型与TME之间的相关性。使用oncoppredict包进行药物致敏预测。结果:初步分析显示PCD与TCGA-CESC队列有潜在的关联临床特征，289例(70.59%)CESC患者出现PCD相关基因突变。接下来，根据63个与pcd预后相关的基因对四组CESC分子分型进行聚类。4种亚型中，C1组预后最差，PCD基因过表达，细胞周期相关通路富集。C4组预后最好，且免疫浸润程度高。最后，构建五基因(SERPINE1、TNF、CA9、CX3CL1和JAK3)预后模型。高危组患者生存率较低。免疫浸润分析发现，与高危组相比，低危组T细胞、巨噬ges_m1等免疫细胞浸润水平显著升高，凋亡相关通路显著富集，预示着较高的免疫水平。药物敏感性相关分析显示，高危组对常规化疗药物耐药，对fda批准的药物BI.2536_1086和SCH772984_1564敏感。结论:在本研究中，我们首次发现pcd相关基因表达模式与CESC患者的临床特征相关，这预示了后续基于这些基因挖掘预后特征的可行性。PCD- 5相关基因预后模型在预测患者预后、免疫反应和药物敏感反应方面具有较好的评估能力，为阐明PCD影响CESC的机制及临床药物靶向治疗提供指导。

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引用次数: 0

Surface modification of lipid nanoparticles for gene therapy 用于基因治疗的脂质纳米颗粒表面修饰。

IF 3.5 4区医学 Q2 Biochemistry, Genetics and Molecular Biology

Journal of Gene Medicine

Pub Date : 2023-12-03 DOI: 10.1002/jgm.3642

Belal Tafech, Fatemeh Mohabatpour, Sarah Hedtrich

Gene therapies have the potential to target and effectively treat a variety of diseases including cancer as well as genetic, neurological, and autoimmune disorders. Although we have made significant advances in identifying non-viral strategies to deliver genetic cargo, certain limitations remain. In general, gene delivery is challenging for several reasons including the instabilities of nucleic acids to enzymatic and chemical degradation and the presence of restrictive biological barriers such as cell, endosomal and nuclear membranes. The emergence of lipid nanoparticles (LNPs) helped overcome many of these challenges. Despite its success, further optimization is required for LNPs to yield efficient gene delivery to extrahepatic tissues, as LNPs favor accumulation in the liver after systemic administration. In this mini-review, we provide an overview of current preclinical approaches in that LNP surface modification was leveraged for cell and tissue targeting by conjugating aptamers, antibodies, and peptides among others. In addition to their cell uptake and efficiency-enhancing effects, we outline the (dis-)advantages of the different targeting moieties and commonly used conjugation strategies.

基因疗法具有靶向和有效治疗多种疾病的潜力，包括癌症以及遗传、神经和自身免疫性疾病。尽管我们在确定传递遗传货物的非病毒策略方面取得了重大进展，但仍存在某些局限性。一般来说，基因传递具有挑战性的原因有几个，包括核酸对酶和化学降解的不稳定性以及限制性生物屏障(如细胞、内体和核膜)的存在。脂质纳米颗粒(LNPs)的出现帮助克服了许多这些挑战。尽管取得了成功，但LNPs需要进一步优化才能有效地将基因传递到肝外组织，因为LNPs在全身给药后有利于在肝脏中积累。在这篇小型综述中，我们概述了目前的临床前方法，其中LNP表面修饰通过偶联适配体、抗体和肽等来利用细胞和组织靶向。除了它们的细胞摄取和提高效率的作用，我们概述了不同的靶向部分和常用的偶联策略的(缺点)优势。

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引用次数: 0

Novel molecular insights into pyroptosis in triple-negative breast cancer prognosis and immunotherapy 三阴性乳腺癌预后和免疫治疗中焦亡的新分子见解。

IF 3.5 4区医学 Q2 Biochemistry, Genetics and Molecular Biology

Journal of Gene Medicine

Pub Date : 2023-12-02 DOI: 10.1002/jgm.3645

Bin Yu, Junjie Luo, Yifei Yang, Ke Zhen, Binjie Shen

Background

Patients with triple-negative breast cancer (TNBC) often have a poor prognostic outcome. Current treatment strategies cannot benefit all TNBC patients. Previous findings suggested pyroptosis as a novel target for suppressing cancer development, although the relationship between TNBC and pyroptosis-related genes (PRGs) was still unclear.

Methods

Gene expression data and clinical follow-up of TNBC patients were collected from the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) and Gene Expression Omnibus (GEO). PRGs were screened using weighted gene co-expression network analysis. Cox regression analysis and the least absolute shrinkage and selection operator (i.e. LASSO) technique were applied to construct a pyroptosis-related prognostic risk score (PPRS) model, which was further combined with the clinicopathological characteristics of TNBC patients to develop a survival decision tree and a nomogram. The model was used to calculate the PPRS, and then the overall survival, immune infiltration, immunotherapy response and drug sensitivity of TNBC patients were analyzed based on the PPRS.

Results

The PPRS model was closely related to clinicopathological features and can independently and accurately predict the prognosis of TNBC. According to normalized PPRS, patients in different cohorts were divided into two groups. Compared with the high-PPRS group, the low-PPRS group had significantly higher ESTIMATE (i.e. Estimation of STromal and Immune cells in MAlignantTumours using Expression data) score, immune score and stromal score, and it also had overexpressed immune checkpoints and significantly reduced Tumor Immune Dysfunction and Exclusion (TIDE) score, as well as higher sensitivity to paclitaxel, veliparib, olaparib and talazoparib. A decision tree and nomogram based on PPRS and clinical characteristics can improve the prognosis stratification and survival prediction for TNBC patients.

Conclusions

A PPRS model was developed to predict TNBC patients' immune characteristics and response to immunotherapy, chemotherapy and targeted therapy, as well as their survival outcomes.

背景:三阴性乳腺癌(TNBC)患者通常预后较差。目前的治疗策略不能使所有TNBC患者受益。先前的研究结果表明，虽然TNBC与焦亡相关基因(PRGs)之间的关系尚不清楚，但焦亡是抑制癌症发展的新靶点。方法:从国际乳腺癌分子分类联盟(METABRIC)和基因表达综合数据库(GEO)收集TNBC患者的基因表达数据和临床随访。采用加权基因共表达网络分析筛选PRGs。采用Cox回归分析和最小绝对收缩和选择算子(LASSO)技术构建热休克相关预后风险评分(PPRS)模型，并结合TNBC患者的临床病理特征，形成生存决策树和nomogram。利用该模型计算PPRS，基于PPRS分析TNBC患者的总生存率、免疫浸润、免疫治疗反应和药物敏感性。结果:PPRS模型与临床病理特征密切相关，能独立准确预测TNBC的预后。根据标准化PPRS，将不同队列的患者分为两组。与高pprs组相比，低pprs组的ESTIMATE(利用表达数据估计恶性肿瘤基质和免疫细胞)评分、免疫评分和基质评分均显著升高，免疫检查点过表达，肿瘤免疫功能障碍和排斥(TIDE)评分显著降低，对紫杉醇、维利帕尼、奥拉帕尼和塔拉唑帕尼的敏感性更高。基于PPRS和临床特征的决策树和nomogram可以改善TNBC患者的预后分层和生存预测。结论:建立了PPRS模型，预测TNBC患者的免疫特征、免疫治疗、化疗和靶向治疗的反应以及生存结局。

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引用次数: 0

Shikonin potentiates skin wound healing in Sprague–Dawley rats by stimulating fibroblast and endothelial cell proliferation and angiogenesis 紫草素通过刺激成纤维细胞和内皮细胞的增殖和血管生成来促进Sprague-Dawley大鼠皮肤伤口愈合。

IF 3.5 4区医学 Q2 Biochemistry, Genetics and Molecular Biology

Journal of Gene Medicine

Pub Date : 2023-11-28 DOI: 10.1002/jgm.3633

Chenhong Xue, Jinfa Dou, Shuzhen Zhang, Huiqian Yu, Shoumin Zhang

Background

Shikonin, a major component of Lithospermum erythrorhizon, exerts anti-inflammatory and antibacterial effects and expedites wound healing. This study aims to evaluate the anti-inflammatory and antioxidant activities of shikonin in a Sprague–Dawley rat model and cell models using fibroblast and endothelial cells.

Methods

The impact of shikonin on the activity of endothelial cells and fibroblasts was examined by cell counting kit 8 and wound-healing assays. A diabetic rat model was constructed, followed by wound creation for treatment with shikonin. Hematoxylin–eosin staining was used to assess pathological changes, and Masson’s trichrome method to detect collagen deposition. Immunohistochemistry using antibodies against proliferating cell nuclear antigen and CD31 was conducted to detect proliferation and vascular density. Enzyme-linked immunosorbent assay and immunohistochemistry were carried out to assess pro-inflammatory and anti-inflammatory factor concentrations. Western blot and immunofluorescence were implemented to analyze oxidative stress-related protein expression.

Results

Shikonin induced the activity of both fibroblasts and endothelial cells. Shikonin treatment contributed to facilitated wound healing and higher healing rates in rats. It also resulted in faster lesion debulking in tissues, reduced inflammatory infiltration, increased collagen deposition, and enhanced angiogenesis. Detection of markers at the wounds showed that shikonin accelerated cell proliferation, enhanced tissue remodeling, and inhibited oxidative stress.

Conclusion

Shikonin stimulates the proliferation and migration of fibroblasts and endothelial cells to promote angiogenesis and tissue remodeling, resulting in faster wound healing.

背景:紫草素是紫草草的主要成分，具有抗炎、抗菌、促进伤口愈合的作用。本研究旨在评价紫草素在Sprague-Dawley大鼠模型和成纤维细胞和内皮细胞模型中的抗炎和抗氧化活性。方法:采用细胞计数试剂盒8和创面愈合实验检测紫草素对内皮细胞和成纤维细胞活性的影响。建立糖尿病大鼠模型，创面用紫草素治疗。采用苏木精-伊红染色评价病理变化，马松三色法检测胶原沉积。采用抗增殖细胞核抗原抗体和CD31免疫组化检测细胞增殖和血管密度。采用酶联免疫吸附试验和免疫组织化学评估促炎因子和抗炎因子浓度。Western blot和免疫荧光法检测氧化应激相关蛋白的表达。结果:紫草素对成纤维细胞和内皮细胞均有诱导作用。紫草素能促进大鼠伤口愈合，提高愈合率。它还导致组织中更快的病变缩小，减少炎症浸润，增加胶原沉积，增强血管生成。创面标记物检测显示，紫草素能促进细胞增殖，增强组织重塑，抑制氧化应激。结论:紫草素可刺激成纤维细胞和内皮细胞的增殖和迁移，促进血管生成和组织重塑，加快创面愈合。

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引用次数: 0

Prognostic evaluation of the novel blueprint of DNA methylation sites by integrating bulk RNA-sequencing and methylation modification data in endometrial cancer 通过整合大量rna测序和甲基化修饰数据对子宫内膜癌DNA甲基化位点新蓝图的预后评估。

IF 3.5 4区医学 Q2 Biochemistry, Genetics and Molecular Biology

Journal of Gene Medicine

Pub Date : 2023-11-27 DOI: 10.1002/jgm.3638

Huanzhen Zhou, Yingzhi Zhang, Jing Jin, Kewei Shen, Yang Yang, Peiwei Lao

Introduction

Endometrial cancer (EC) is a prevalent malignancy affecting the female population, with an increasing incidence among younger age groups. DNA methylation, a common epigenetic modification, is well-established to play a key role in cancer progression. We suspected whether DNA methylation could be used as biomarkers for EC prognosis.

Methods

In the present study, we analyzed bulk RNA-sequencing data from 544 EC patients and DNA methylation data from 430 EC patients in the TCGA-UCEC cohort. We applied weighted correlation network analysis to select a key gene set associated with panoptosis. We conducted correlation analysis between transcriptomic data of the selected key genes and DNA methylation data to identify valuable DNA methylation sites. These sites were further screened by Cox regression and least absolute shrinkage and selection operator analysis. Immune microenvironment differences between high-risk and low-risk groups were assessed using single-sample gene set enrichment analysi, xCell and MCPcounter algorithms.

Results

Our results identified five DNA methylation sites (cg03906681, cg04549977, cg06029846, cg10043253 and cg15658376) with significant prognostic value in EC. We constructed a prognostic model using these sites, demonstrating satisfactory predictive performance. The low-risk group showed higher immune cell infiltration. Notably, methylation of site cg03906681 was negatively related to CD8 T cell infiltration, whereas cg04549977 exhibited positive correlations with immune infiltration, particularly in macrophages, activated B cells, dendritic cells and myeloid-derived suppressor cells. PD0325901_1060 was strongly correlated with risk scores, indicating a potential therapeutic response for high-risk EC patients.

Conclusion

We have developed a robust DNA methylation-based prognostic model for EC, which holds promise for improving prognosis prediction and personalized treatment approaches. These findings may contribute to better management of EC patients, particularly in identifying those at higher risk who may benefit from tailored interventions.

子宫内膜癌(EC)是一种影响女性人群的普遍恶性肿瘤，在年轻人群中发病率越来越高。DNA甲基化是一种常见的表观遗传修饰，在癌症进展中起着关键作用。我们怀疑DNA甲基化是否可以作为EC预后的生物标志物。方法:在本研究中，我们分析了TCGA-UCEC队列中544例EC患者的大量rna测序数据和430例EC患者的DNA甲基化数据。我们应用加权相关网络分析选择了一个与泛光症相关的关键基因集。我们将所选关键基因的转录组学数据与DNA甲基化数据进行相关性分析，以确定有价值的DNA甲基化位点。通过Cox回归、最小绝对收缩和选择算子分析进一步筛选这些位点。使用单样本基因集富集分析、xCell和MCPcounter算法评估高危组和低危组之间的免疫微环境差异。结果:我们的研究结果鉴定出5个DNA甲基化位点(cg03906681、cg04549977、cg06029846、cg10043253和cg15658376)在EC中具有显著的预后价值。我们利用这些位点构建了一个预测模型，显示出令人满意的预测性能。低危组免疫细胞浸润较高。值得注意的是，位点cg03906681的甲基化与CD8 T细胞浸润呈负相关，而位点cg04549977与免疫浸润呈正相关，特别是在巨噬细胞、活化的B细胞、树突状细胞和髓源性抑制细胞中。PD0325901_1060与风险评分密切相关，表明其对高危EC患者有潜在的治疗效果。结论:我们已经建立了一个强大的基于DNA甲基化的EC预后模型，有望改善预后预测和个性化治疗方法。这些发现可能有助于更好地管理EC患者，特别是在识别那些可能从量身定制的干预措施中受益的高风险患者方面。

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引用次数: 0

Long non-coding RNA linc00659 promotes tumour progression by regulating FZD6/Wnt/β-catenin signalling pathway in colorectal cancer via m6A reader IGF2BP1 长链非编码RNA linc00659通过m6A读取器IGF2BP1调控结直肠癌FZD6/Wnt/β-catenin信号通路，促进肿瘤进展。

IF 3.5 4区医学 Q2 Biochemistry, Genetics and Molecular Biology

Journal of Gene Medicine

Pub Date : 2023-11-27 DOI: 10.1002/jgm.3636

Shufen Xu, Zichun Liu, Qian Luo, Lisha Chang, Jie Ding, Yanan Xiao, Yangyang Zhang, Guoren Zhou, Keming Wang

Background

Abnormal N6-methyladenosine (m6A) modification has become a driving factor in tumour development and progression. The linc00659 is abnormally highly expressed in digestive tract tumours and promotes cancer progression, but there is little research on the mechanism of linc00659 and m6A.

Methods

The expression of linc00659 in colorectal cancer (CRC) tissues and cells was assessed by a quantitative real-time PCR. The proliferative capacity of CRC cells was determined by colony formation, Cell Counting Kit-8 and 5-ethynyl-2 deoxyuridine assays, and the migratory capacity of CRC was determined by wound healing and transwell assays and tube formation. In vivo, a xenograft tumour model was used to detect the effect of linc00659 on tumour growth. The Wnt/β-catenin signalling pathway and related protein expression levels were measured by western blotting. The binding of linc00659 to insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) was assessed by RNA pull-down and an immunoprecipitation assay. The effect of IGF2BP1 on FZD6 was detected by an RNA stability assay.

Results

The expression of linc00659 was abnormally elevated in CRC tissues and cells compared to normal colonic tissues and cells. We confirm that linc00659 promotes the growth of CRC cells both in vivo and in vitro. Mechanistically, linc00659 binds to IGF2BP1 and specifically enhances its activity to stabilize the target gene FZD6. Therefore, linc00659 and IGF2BP1 activate the Wnt/β-catenin signalling pathway, promoting cell proliferation in CRC.

Conclusions

Our results show that linc00659 and IGF2BP1 cooperate to promote the stability of the target FZD6 mRNA, thereby facilitating CRC progression, which may represent a potential diagnostic, prognostic and therapeutic target for CRC.

背景:n6 -甲基腺苷(m6A)异常修饰已成为肿瘤发生发展的驱动因素。linc00659在消化道肿瘤中异常高表达，促进肿瘤进展，但对linc00659与m6A的作用机制研究甚少。方法:采用实时荧光定量PCR法检测结直肠癌组织和细胞中linc00659的表达。通过集落形成、细胞计数试剂盒-8和5-乙基-2脱氧尿苷测定结直肠癌细胞的增殖能力，通过伤口愈合、通孔试验和小管形成测定结直肠癌细胞的迁移能力。在体内，采用异种移植肿瘤模型检测linc00659对肿瘤生长的影响。western blotting检测Wnt/β-catenin信号通路及相关蛋白表达水平。通过RNA拉下和免疫沉淀法评估linc00659与胰岛素样生长因子2 mrna结合蛋白1 (IGF2BP1)的结合。通过RNA稳定性实验检测IGF2BP1对FZD6的影响。结果:与正常结肠组织细胞相比，结直肠癌组织细胞中linc00659的表达异常升高。我们证实linc00659在体内和体外都能促进CRC细胞的生长。从机制上讲，linc00659与IGF2BP1结合并特异性增强其活性以稳定靶基因FZD6。因此，linc00659和IGF2BP1激活Wnt/β-catenin信号通路，促进结直肠癌细胞增殖。结论:我们的研究结果表明，linc00659和IGF2BP1共同促进了靶基因FZD6 mRNA的稳定性，从而促进了CRC的进展，这可能是CRC潜在的诊断、预后和治疗靶点。

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引用次数: 0

Homologous recombination deficiency reflects the heterogeneity and monitoring treatment response for patients with breast cancer 同源重组缺乏反映了乳腺癌患者的异质性和监测治疗反应。

IF 3.5 4区医学 Q2 Biochemistry, Genetics and Molecular Biology

Journal of Gene Medicine

Pub Date : 2023-11-23 DOI: 10.1002/jgm.3637

Quanyi Long, Yunfei Wang, Hongjiang Li

Background

In breast cancer (BC), homologous recombination defect (HRD) is a common carcinogenic mechanism. It is meaningful to classify BC according to HRD biomarkers and to develop a platform for identifying BC molecular features, pathological features and therapeutic responses.

Methods

In total, 109 HRD genes were collected and screened by univariate Cox regression analysis to determine the prognostic genes, which were used to construct a consensus matrix to identify BC subtype. Differentially expressed genes (DEGs) were filtered by the Limma package and screened by random forest analysis to build a model to analyze the immunotherapy response and sensitivity and prognosis of patients suffering from BC to different drugs.

Results

Thirteen out of 109 HRD genes were prognostic genes of BC, and BC was classified into two subgroups based on their expression. Cluster 1 had a significantly backward survival outcome and a significantly higher adaptive immunity score relative to cluster 2. Six genes were identified by random forest analysis as factors for developing the model. The model provided a prediction called risk score, which showed a significant stratification effect on BC prognosis, immunotherapy response and IC₅₀ values of 62 drugs.

Conclusions

In the present study, two HRD subtypes of BC were successfully identified, for which mutation and immunological features were determined. A model based on differential genes of HRD subtypes was established, which was a potential predictor of prognosis, immunotherapy response and drug sensitivity of BC.

背景:在乳腺癌中，同源重组缺陷(HRD)是一种常见的致癌机制。根据HRD生物标志物对BC进行分类，为BC分子特征、病理特征和治疗反应的鉴别建立平台具有重要意义。方法:共收集109个HRD基因，采用单因素Cox回归分析筛选预后基因，构建共识矩阵确定BC亚型。采用Limma包筛选差异表达基因(differential expressed genes, DEGs)，采用随机森林分析法筛选，建立模型分析BC患者对不同药物的免疫治疗反应、敏感性及预后。结果:109个HRD基因中有13个是BC的预后基因，根据表达情况将BC分为两个亚组。第1类患者的生存结果明显落后，适应性免疫评分明显高于第2类患者。通过随机森林分析确定了6个基因作为建立模型的因子。该模型提供了一个称为风险评分的预测，该预测对62种药物的BC预后、免疫治疗反应和IC50值有显著的分层效应。结论:在本研究中，成功鉴定了两种HRD亚型BC，并确定了其突变和免疫学特征。建立了基于HRD亚型差异基因的模型，该模型可作为预测BC预后、免疫治疗反应和药物敏感性的潜在指标。

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引用次数: 0

Multiomics blueprint of PANoptosis in deciphering immune characteristics and prognosis stratification of glioma patients PANoptosis的多组学蓝图在胶质瘤患者免疫特征和预后分层中的解读。

IF 3.5 4区医学 Q2 Biochemistry, Genetics and Molecular Biology

Journal of Gene Medicine

Pub Date : 2023-11-23 DOI: 10.1002/jgm.3621

Maohua Chen, Min Huang, Xiaoxiang Chen, Xiaoyu Lin, Xianglin Chen

Background

As the most prevalent primary brain tumor in adults, glioma accounts for the majority of all central nervous system malignant tumors. The concept of PANoptosis is a relatively new, underlining the interconnection and synergy among three distinct pathways: pyroptosis, apoptosis and necroptosis.

Methods

We performed single-cell annotations of glioma cells and determined crucial signaling pathways through cell chat analysis. Using least absolute shrinkage and selection operator (LASSO) and Cox analyses, we identified a gene set with prognostic values. Our model was validated using independent external cohort. In addition, we employed single-sample gene set enrichment analysis and xCell analyses to describe the detailed profile of infiltrated immune cells and depicted the gene mutation landscape in the two groups.

Results

We identified seven distinct cell clusters in glioma samples, including oligodendrocyte precursor cells (OPCs), myeloid cells, tumor cells, oligodendrocytes, astrocytes, vascular cells and neuronal cells. We found that myeloid cells showed the highest PANoptosis activity. An intense mutual cell communication pattern between the tumor cells and OPCs and oligodendrocytes was observed. Differentially expressed genes between the high-PANoptosis and low-PANoptosis cell groups were obtained, which were enriched to actin cytoskeleton, cell adhesion molecules and gamma R-mediated phagocytosis pathways. We determined a set of five genes of prognostic significance: SAA1, SLPI, DCX, S100A8 and TNR. The prognostic differences between the two groups in the internal and external sets were found to be statistically significant. We found a marked correlation between S100A8 and activated dendritic cell, macrophage, mast cell, myeloid derived suppressor cell and Treg infiltration. Moreover, we have observed a significant increase of PTEN mutation in the high risk (HR) group of glioma patients.

Conclusions

In the present study, we have constructed a prognostic model that is based on the PANoptosis, and we have demonstrated its significant efficacy in stratifying patients with glioma. This innovative prognostic model offers novel insights into precision immune treatments that could be used to combat this disease and improve patient outcomes, thereby providing a new avenue for personalized treatment options.

背景:神经胶质瘤是成人最常见的原发性脑肿瘤，在所有中枢神经系统恶性肿瘤中占绝大多数。PANoptosis是一个相对较新的概念，强调了焦亡、凋亡和坏死三种不同途径之间的相互联系和协同作用。方法:我们对胶质瘤细胞进行了单细胞注释，并通过细胞聊天分析确定了关键的信号通路。使用最小绝对收缩和选择算子(LASSO)和Cox分析，我们确定了一组具有预后价值的基因。我们的模型通过独立的外部队列验证。此外，我们采用单样本基因集富集分析和xCell分析来描述浸润免疫细胞的详细情况，并描绘了两组的基因突变景观。结果:我们在胶质瘤样本中鉴定出七种不同的细胞簇，包括少突胶质细胞前体细胞(OPCs)、髓细胞、肿瘤细胞、少突胶质细胞、星形胶质细胞、血管细胞和神经元细胞。我们发现骨髓细胞表现出最高的PANoptosis活性。观察到肿瘤细胞与OPCs和少突胶质细胞之间存在强烈的相互细胞通讯模式。在高panoptosis细胞组和低panoptosis细胞组之间获得了差异表达基因，这些基因富集于肌动蛋白细胞骨架、细胞粘附分子和γ r介导的吞噬途径。我们确定了一组具有预后意义的五个基因:SAA1, SLPI, DCX, S100A8和TNR。两组内、外组预后差异有统计学意义。我们发现S100A8与活化的树突状细胞、巨噬细胞、肥大细胞、髓源性抑制细胞和Treg浸润有显著的相关性。此外，我们观察到PTEN突变在胶质瘤患者的高风险(HR)组中显著增加。结论:在本研究中，我们构建了一个基于PANoptosis的预后模型，并证明了其对胶质瘤患者分层的显著疗效。这种创新的预后模型为精确免疫治疗提供了新的见解，可用于对抗这种疾病并改善患者的预后，从而为个性化治疗选择提供了新的途径。

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引用次数: 0

Reducing the transcriptional read-through rate of a lentiviral vector for β-thalassemia gene therapy 降低慢病毒载体用于β-地中海贫血基因治疗的转录通读率。

IF 3.5 4区医学 Q2 Biochemistry, Genetics and Molecular Biology

Journal of Gene Medicine

Pub Date : 2023-11-21 DOI: 10.1002/jgm.3640

Jiahui Wu, Yuan Chen, Wenchen Shen, Jingzhi Zhang, Fanyi Zeng

Background

LentiGlobin BB305 is a self-inactivating lentiviral vector carrying a human β-globin expressing cassette for treating β-thalassemia. Initially, a 2 × 250 bp chicken Locus Control Region fragment of cHS4, functioning as an insulator, was placed at its ΔU3, which was removed after the first clinical trial led by a French team to avoid abnormal splicing, etc. This action could potentially lead to an increasing risk of the transcriptional read-through rate driven by the β-globin promoter to a significant level, posing a biosafety risk in clinical trials.

Methods

In the present study, a read-through reducing agent (C-U+ or WPRE) was designed to be placed at the 3′ UTR of the β-globin gene. The Enhancer Activities and/or Transcriptional Read-Through (EATRT) rate at the mRNA level and the protein expression level regarding lentiviral preparation titer were examined.

Results

We found that the insertion of the element (C-U+ or WPRE) reduced the EATRT effectively by 53% or 41%, respectively. C-U+ has less impact on virus package efficiency. Furthermore, there was no significant difference in the protein expression level after the C-U+ or WPRE insertion.

Conclusions

The results of the present study show that inserting C-U+ or WPRE before the polyA sequence of the BB305 would reduce the EATRT rate at no cost of its expressing efficacy and viral preparation titers. Thus, we present an alternative improvement for a safer lentiviral vector for β-thalassemia clinical trials.

背景:LentiGlobin BB305是一种自身失活的慢病毒载体，携带人β-珠蛋白表达盒，用于治疗β-地中海贫血。首先，将鸡cHS4基因座控制区(Locus Control Region)的2 × 250 bp片段作为绝缘体放置在其ΔU3位置，在法国团队领导的第一次临床试验后将其移除，以避免剪接异常等。这一行为可能导致β-珠蛋白启动子驱动的转录通读率风险显著增加，在临床试验中构成生物安全风险。方法:在本研究中，设计了一种读透还原剂(C-U+或WPRE)，放置在β-珠蛋白基因的3' UTR上。在mRNA水平和慢病毒制备滴度的蛋白表达水平上检测增强子活性和/或转录读透率(EATRT)。结果:我们发现元素(C-U+或WPRE)的插入分别有效降低了53%和41%的EATRT。C-U+对病毒包效率的影响较小。此外，插入C-U+或WPRE后，蛋白表达水平无显著差异。结论:本研究结果表明，在BB305的polyA序列前插入C-U+或WPRE可以在不影响其表达效果和病毒制备滴度的情况下降低EATRT率。因此，我们提出了一个替代改进的更安全的慢病毒载体β-地中海贫血临床试验。

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引用次数: 0

Metabolic and immune-related gene signatures: Predictive stratification and prognostic implications in gastric cancer 代谢和免疫相关基因特征:胃癌的预测分层和预后意义。

IF 3.5 4区医学 Q2 Biochemistry, Genetics and Molecular Biology

Journal of Gene Medicine

Pub Date : 2023-11-20 DOI: 10.1002/jgm.3635

Jian Shao, Wenjia Zhang, Yiguang Li, Yi Tang, Lihong Fan

Background

Gastric cancer, marked by its heterogeneous nature, showcases various molecular subtypes and clinical trajectories. This research delves into the significance of metabolic and immune-driven pathways in gastric cancer, constructing a prognostic signature derived from differentially expressed metabolic and immune-correlated genes (DE-MIGs).

Methods

Metabolic and immune-associated gene were sourced from the GeneCards database. Differential expression analysis on the TCGA-STAD dataset was executed using the limma package, unveiling 51 DE-MIGs that underwent functional enrichment scrutiny. The LASSO Cox regression methodology guided the creation of the prognostic signature, and individual patient risk scores were determined. Assessment tools like CIBERSORT, ESTIMATE and ssGSEA were deployed to study the immune microenvironment, while mutation profiles, genomic stability, resistance to chemotherapy and immunotherapy responsiveness were scrutinized across distinct signature categorizations.

Results

Among the identified DE-MIGs, 26 were significantly tied to the overall survival of gastric cancer patients. The developed prognostic signature proficiently differentiated patients into high-risk and low-risk cohorts, with the latter showing markedly better outcomes. The study underscored the centrality of the immune microenvironment in influencing gastric cancer outcomes. Key pathways such as TGF-Beta, TP53 and NRF2 dominated the high-risk group, whereas the LRTK−RAS and WNT pathways characterized the low-risk group. Interestingly, the low-risk segment also manifested a heightened tumor mutation burden and enhanced susceptibility to immunotherapy.

Conclusions

Our findings introduce a pivotal prognostic signature, rooted in DE-MIGs, that effectively segregates gastric cancer patients into distinct risk-based segments. Insights into the influential role of the immune microenvironment in gastric cancer progression pave the way for more refined therapeutic interventions.

背景:胃癌以其异质性为特征，表现出不同的分子亚型和临床轨迹。本研究探讨了代谢和免疫驱动通路在胃癌中的意义，构建了基于差异表达的代谢和免疫相关基因(DE-MIGs)的预后特征。方法:代谢和免疫相关基因来源于GeneCards数据库。使用limma软件包对TCGA-STAD数据集进行差异表达分析，揭示了51个进行功能富集审查的de - migg。LASSO Cox回归方法指导预后特征的创建，并确定个体患者风险评分。使用CIBERSORT、ESTIMATE和ssGSEA等评估工具来研究免疫微环境，同时在不同的特征分类中仔细检查突变谱、基因组稳定性、化疗耐药性和免疫治疗反应性。结果:在鉴定的DE-MIGs中，26个与胃癌患者的总生存期显著相关。发达的预后特征熟练地将患者分为高风险和低风险队列，后者表现出明显更好的结果。该研究强调了免疫微环境在影响胃癌预后中的中心地位。高危组以tgf - β、TP53和NRF2等关键通路为主，低危组以LRTK-RAS和WNT通路为主。有趣的是，低风险部分也表现出更高的肿瘤突变负担和对免疫治疗的易感性。结论:我们的研究结果引入了一个关键的预后特征，植根于DE-MIGs，有效地将胃癌患者划分为不同的基于风险的部分。了解免疫微环境在胃癌进展中的影响作用为更精细的治疗干预铺平了道路。

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