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EU surveys insights: analytical tools, future directions, and the essential requirement for reference materials in wastewater monitoring of SARS-CoV-2, antimicrobial resistance and beyond. 欧盟调查见解:SARS-CoV-2、抗菌药耐药性及其他废水监测中的分析工具、未来方向和对参考材料的基本要求。
IF 3.8 3区 医学 Q2 GENETICS & HEREDITY Pub Date : 2024-06-27 DOI: 10.1186/s40246-024-00641-5
Valentina Paracchini, Mauro Petrillo, Anandasagari Arcot Rajashekar, Piotr Robuch, Ursula Vincent, Philippe Corbisier, Simona Tavazzi, Barbara Raffael, Elisabetta Suffredini, Giuseppina La Rosa, Bernd Manfred Gawlik, Antonio Marchini

Background: Wastewater surveillance (WWS) acts as a vigilant sentinel system for communities, analysing sewage to protect public health by detecting outbreaks and monitoring trends in pathogens and contaminants. To achieve a thorough comprehension of present and upcoming practices and to identify challenges and opportunities for standardisation and improvement in WWS methodologies, two EU surveys were conducted targeting over 750 WWS laboratories across Europe and other regions. The first survey explored a diverse range of activities currently undertaken or planned by laboratories. The second survey specifically targeted methods and quality controls utilised for SARS-CoV-2 surveillance.

Results: The findings of the two surveys provide a comprehensive insight into the procedures and methodologies applied in WWS. In Europe, WWS primarily focuses on SARS-CoV-2 with 99% of the survey participants dedicated to this virus. However, the responses highlighted a lack of standardisation in the methodologies employed for monitoring SARS-CoV-2. The surveillance of other pathogens, including antimicrobial resistance, is currently fragmented and conducted by only a limited number of laboratories. Notably, these activities are anticipated to expand in the future. Survey replies emphasise the collective recognition of the need to enhance the accuracy of results in WWS practices, reflecting a shared commitment to advancing precision and effectiveness in WWS methodologies.

Conclusions: These surveys identified a lack of standardised common procedures in WWS practices and the need for quality standards and reference materials to enhance the accuracy and reliability of WWS methods in the future. In addition, it is important to broaden surveillance efforts beyond SARS-CoV-2 to include other emerging pathogens and antimicrobial resistance to ensure a comprehensive approach to protecting public health.

背景:污水监测(WWS)是社区的警戒哨系统,通过分析污水来检测疫情并监测病原体和污染物的趋势,从而保护公众健康。为了全面了解当前和未来的做法,并确定 WWS 方法标准化和改进所面临的挑战和机遇,欧盟针对欧洲和其他地区的 750 多个 WWS 实验室开展了两项调查。第一项调查探讨了实验室目前正在开展或计划开展的各种活动。第二项调查专门针对用于 SARS-CoV-2 监测的方法和质量控制:这两项调查的结果使人们对 WWS 所采用的程序和方法有了全面的了解。在欧洲,WWS 主要关注的是 SARS-CoV-2 病毒,99% 的调查参与者都致力于该病毒的监测。然而,调查结果显示,监测 SARS-CoV-2 所采用的方法缺乏标准化。目前,对其他病原体(包括抗菌素耐药性)的监测是分散的,只有少数实验室进行监测。值得注意的是,这些活动预计今后会扩大。调查答复强调,大家都认识到有必要提高 WWS 实践结果的准确性,这反映出大家都致力于提高 WWS 方法的准确性和有效性:这些调查发现,世界水资源统计实践中缺乏标准化的通用程序,需要质量标准和参考资料来提高世界水资源统计方法的准确性和可靠性。此外,重要的是要将监测工作从 SARS-CoV-2 扩展到其他新出现的病原体和抗菌素耐药性,以确保以全面的方法保护公众健康。
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引用次数: 0
Elucidating the role of liver enzymes as markers and regulators in ovarian cancer: a synergistic approach using Mendelian randomization, single-cell analysis, and clinical evidence. 阐明肝酶在卵巢癌中的标记和调节作用:利用孟德尔随机化、单细胞分析和临床证据的协同方法。
IF 3.8 3区 医学 Q2 GENETICS & HEREDITY Pub Date : 2024-06-24 DOI: 10.1186/s40246-024-00642-4
Yinxing Zhu, Min Jiang, Zihan Gu, Hongyu Shang, Caiyin Tang, Ting Guo

Objective: To investigate the association between liver enzymes and ovarian cancer (OC), and to validate their potential as biomarkers and their mechanisms in OC. Methods Genome-wide association studies for OC and levels of enzymes such as Alkaline phosphatase (ALP), Aspartate aminotransferase (AST), Alanine aminotransferase, and gamma-glutamyltransferase were analyzed. Univariate and multivariate Mendelian randomization (MR), complemented by the Steiger test, identified enzymes with a potential causal relationship to OC. Single-cell transcriptomics from the GSE130000 dataset pinpointed pivotal cellular clusters, enabling further examination of enzyme-encoding gene expression. Transcription factors (TFs) governing these genes were predicted to construct TF-mRNA networks. Additionally, liver enzyme levels were retrospectively analyzed in healthy individuals and OC patients, alongside the evaluation of correlations with cancer antigen 125 (CA125) and Human Epididymis Protein 4 (HE4).

Results: A total of 283 single nucleotide polymorphisms (SNPs) and 209 SNPs related to ALP and AST, respectively. Using the inverse-variance weighted method, univariate MR (UVMR) analysis revealed that ALP (P = 0.050, OR = 0.938) and AST (P = 0.017, OR = 0.906) were inversely associated with OC risk, suggesting their roles as protective factors. Multivariate MR (MVMR) confirmed the causal effect of ALP (P = 0.005, OR = 0.938) on OC without reverse causality. Key cellular clusters including T cells, ovarian cells, endothelial cells, macrophages, cancer-associated fibroblasts (CAFs), and epithelial cells were identified, with epithelial cells showing high expression of genes encoding AST and ALP. Notably, TFs such as TCE4 were implicated in the regulation of GOT2 and ALPL genes. OC patient samples exhibited decreased ALP levels in both blood and tumor tissues, with a negative correlation between ALP and CA125 levels observed.

Conclusion: This study has established a causal link between AST and ALP with OC, identifying them as protective factors. The increased expression of the genes encoding these enzymes in epithelial cells provides a theoretical basis for developing novel disease markers and targeted therapies for OC.

研究目的研究肝酶与卵巢癌(OC)之间的关联,并验证其作为生物标记物的潜力及其在卵巢癌中的作用机制。方法 对卵巢癌与碱性磷酸酶(ALP)、天门冬氨酸氨基转移酶(AST)、丙氨酸氨基转移酶和γ-谷氨酰转移酶等酶水平的全基因组关联研究进行分析。通过单变量和多变量孟德尔随机化(MR),并辅以Steiger检验,确定了与OC有潜在因果关系的酶。来自 GSE130000 数据集的单细胞转录组学精确定位了关键的细胞集群,从而进一步检验了酶编码基因的表达。通过预测支配这些基因的转录因子(TF),构建了TF-mRNA网络。此外,还对健康人和卵巢癌患者的肝酶水平进行了回顾性分析,并评估了与癌症抗原125(CA125)和人类附睾蛋白4(HE4)的相关性:共有 283 个单核苷酸多态性(SNPs)和 209 个 SNPs 分别与 ALP 和 AST 有关。使用逆方差加权法进行的单变量 MR(UVMR)分析表明,ALP(P = 0.050,OR = 0.938)和 AST(P = 0.017,OR = 0.906)与 OC 风险成反比,表明它们是保护因素。多变量MR(MVMR)证实了ALP(P = 0.005,OR = 0.938)对OC的因果效应,而没有反向因果关系。确定了包括 T 细胞、卵巢细胞、内皮细胞、巨噬细胞、癌相关成纤维细胞(CAFs)和上皮细胞在内的关键细胞群,其中上皮细胞显示了 AST 和 ALP 编码基因的高表达。值得注意的是,TCE4 等 TFs 与 GOT2 和 ALPL 基因的调控有关。OC患者样本的血液和肿瘤组织中ALP水平均有所下降,ALP与CA125水平呈负相关:本研究确定了 AST 和 ALP 与 OC 之间的因果关系,并将其确定为保护因素。上皮细胞中编码这些酶的基因表达增加,为开发新型疾病标记物和 OC 靶向疗法提供了理论依据。
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引用次数: 0
Polygenic subtype identified in ACCORD trial displays a favorable type 2 diabetes phenotype in the UKBiobank population. ACCORD 试验确定的多基因亚型在英国生物银行人群中显示出有利的 2 型糖尿病表型。
IF 3.8 3区 医学 Q2 GENETICS & HEREDITY Pub Date : 2024-06-22 DOI: 10.1186/s40246-024-00639-z
Courtney Hershberger, Arshiya Mariam, Kevin M Pantalone, John B Buse, Alison A Motsinger-Reif, Daniel M Rotroff

Introduction: We previously identified a genetic subtype (C4) of type 2 diabetes (T2D), benefitting from intensive glycemia treatment in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. Here, we characterized the population of patients that met the C4 criteria in the UKBiobank cohort.

Research design and methods: Using our polygenic score (PS), we identified C4 individuals in the UKBiobank and tested C4 status with risk of developing T2D, cardiovascular disease (CVD) outcomes, and differences in T2D medications.

Results: C4 individuals were less likely to develop T2D, were slightly older at T2D diagnosis, had lower HbA1c values, and were less likely to be prescribed T2D medications (P < .05). Genetic variants in MAS1 and IGF2R, major components of the C4 PS, were associated with fewer overall T2D prescriptions.

Conclusion: We have confirmed C4 individuals are a lower risk subpopulation of patients with T2D.

简介:我们曾在控制糖尿病心血管风险行动(ACCORD)试验中发现了一种2型糖尿病(T2D)遗传亚型(C4),该亚型可从强化血糖治疗中获益。在此,我们对英国生物库队列中符合 C4 标准的患者群体进行了特征描述:利用多基因评分(PS),我们确定了英国生物库中的 C4 患者,并测试了 C4 状态与 T2D 发病风险、心血管疾病(CVD)结局以及 T2D 药物治疗差异的关系:结果:C4人群罹患T2D的几率较低、确诊T2D时年龄稍大、HbA1c值较低,且较少被处方T2D药物(P我们已经证实,C4人群是T2D患者中风险较低的亚人群。
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引用次数: 0
Bayesian-frequentist hybrid inference framework for single cell RNA-seq analyses. 用于单细胞 RNA-seq 分析的贝叶斯-频数混合推断框架。
IF 3.8 3区 医学 Q2 GENETICS & HEREDITY Pub Date : 2024-06-20 DOI: 10.1186/s40246-024-00638-0
Gang Han, Dongyan Yan, Zhe Sun, Jiyuan Fang, Xinyue Chang, Lucas Wilson, Yushi Liu

Background: Single cell RNA sequencing technology (scRNA-seq) has been proven useful in understanding cell-specific disease mechanisms. However, identifying genes of interest remains a key challenge. Pseudo-bulk methods that pool scRNA-seq counts in the same biological replicates have been commonly used to identify differentially expressed genes. However, such methods may lack power due to the limited sample size of scRNA-seq datasets, which can be prohibitively expensive.

Results: Motivated by this, we proposed to use the Bayesian-frequentist hybrid (BFH) framework to increase the power and we showed in simulated scenario, the proposed BFH would be an optimal method when compared with other popular single cell differential expression methods if both FDR and power were considered. As an example, the method was applied to an idiopathic pulmonary fibrosis (IPF) case study.

Conclusion: In our IPF example, we demonstrated that with a proper informative prior, the BFH approach identified more genes of interest. Furthermore, these genes were reasonable based on the current knowledge of IPF. Thus, the BFH offers a unique and flexible framework for future scRNA-seq analyses.

背景:单细胞 RNA 测序技术(scRNA-seq)已被证明有助于了解细胞特异性疾病机制。然而,识别感兴趣的基因仍是一项关键挑战。在相同生物重复序列中汇集 scRNA-seq 计数的伪大量方法常用于识别差异表达基因。然而,由于 scRNA-seq 数据集的样本量有限,这种方法可能缺乏威力,而且成本过高:受此启发,我们提出了使用贝叶斯-频率主义混合(BFH)框架来提高功率,并在模拟场景中表明,如果同时考虑FDR和功率,与其他流行的单细胞差异表达方法相比,所提出的BFH将是一种最佳方法。以特发性肺纤维化(IPF)病例研究为例,我们应用了该方法:在我们的 IPF 案例中,我们证明了在适当的信息先验条件下,BFH 方法能识别出更多的相关基因。此外,根据目前对 IPF 的了解,这些基因也是合理的。因此,BFH 为未来的 scRNA-seq 分析提供了一个独特而灵活的框架。
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引用次数: 0
Germline mutations of breast cancer susceptibility genes through expanded genetic analysis in unselected Colombian patients. 通过对未入选的哥伦比亚患者进行扩展基因分析,发现乳腺癌易感基因的种系突变。
IF 3.8 3区 医学 Q2 GENETICS & HEREDITY Pub Date : 2024-06-18 DOI: 10.1186/s40246-024-00623-7
Diana Carolina Sierra-Díaz, Adrien Morel, Dora Janeth Fonseca-Mendoza, Nora Contreras Bravo, Nicolas Molano-Gonzalez, Mariana Borras, Isabel Munevar, Mauricio Lema, Henry Idrobo, Daniela Trujillo, Norma Serrano, Ana Isabel Orduz, Diego Lopera, Jaime González, Gustavo Rojas, Paula Londono-De Los Ríos, Ray Manneh, Rodrigo Cabrera, Wilson Rubiano, Jairo de la Peña, María Catalina Quintero, William Mantilla, Carlos M Restrepo

Background: In Colombia and worldwide, breast cancer (BC) is the most frequently diagnosed neoplasia and the leading cause of death from cancer among women. Studies predominantly involve hereditary and familial cases, demonstrating a gap in the literature regarding the identification of germline mutations in unselected patients from Latin-America. Identification of pathogenic/likely pathogenic (P/LP) variants is important for shaping national genetic analysis policies, genetic counseling, and early detection strategies. The present study included 400 women with unselected breast cancer (BC), in whom we analyzed ten genes, using Whole Exome Sequencing (WES), know to confer risk for BC, with the aim of determining the genomic profile of previously unreported P/LP variants in the affected population. Additionally, Multiplex Ligation-dependent Probe Amplification (MLPA) was performed to identify Large Genomic Rearrangements (LGRs) in the BRCA1/2 genes. To ascertain the functional impact of a recurrent intronic variant (ATM c.5496 + 2_5496 + 5delTAAG), a minigene assay was conducted.

Results: We ascertained the frequency of P/LP germline variants in BRCA2 (2.5%), ATM (1.25%), BRCA1 (0.75%), PALB2 (0.50%), CHEK2 (0.50%), BARD1 (0.25%), and RAD51D (0.25%) genes in the population of study. P/LP variants account for 6% of the total population analyzed. No LGRs were detected in our study. We identified 1.75% of recurrent variants in BRCA2 and ATM genes. One of them corresponds to the ATM c.5496 + 2_5496 + 5delTAAG. Functional validation of this variant demonstrated a splicing alteration probably modifying the Pincer domain and subsequent protein structure.

Conclusion: This study described for the first time the genomic profile of ten risk genes in Colombian women with unselected BC. Our findings underscore the significance of population-based research, advocating the consideration of molecular testing in all women with cancer.

背景:在哥伦比亚和全世界,乳腺癌(BC)是最常见的肿瘤,也是女性死于癌症的主要原因。研究主要涉及遗传性和家族性病例,这表明在拉丁美洲未经选择的患者的种系突变鉴定方面存在文献空白。致病/可能致病(P/LP)变异的鉴定对于制定国家遗传分析政策、遗传咨询和早期检测策略非常重要。本研究纳入了 400 名未经筛选的乳腺癌(BC)女性患者,我们利用全外显子组测序(WES)技术分析了其中 10 个已知具有 BC 风险的基因,目的是确定受影响人群中以前未报告的 P/LP 变异基因组概况。此外,还进行了多重连接依赖性探针扩增(MLPA),以确定 BRCA1/2 基因中的大基因组重排(LGR)。为了确定复发性内含子变异(ATM c.5496 + 2_5496 + 5delTAAG)的功能影响,进行了一项微型基因检测:我们确定了研究人群中 BRCA2(2.5%)、ATM(1.25%)、BRCA1(0.75%)、PALB2(0.50%)、CHEK2(0.50%)、BARD1(0.25%)和 RAD51D(0.25%)基因的 P/LP 种系变异频率。P/LP变异占分析人群总数的6%。在我们的研究中没有发现 LGR。我们在 BRCA2 和 ATM 基因中发现了 1.75% 的复发性变异。其中一个对应于 ATM c.5496 + 2_5496 + 5delTAAG。该变异的功能验证表明,剪接改变可能会改变 Pincer 结构域和随后的蛋白质结构:本研究首次描述了哥伦比亚女性非选择性 BC 患者中 10 个风险基因的基因组概况。我们的研究结果强调了基于人群的研究的重要性,提倡考虑对所有癌症妇女进行分子检测。
{"title":"Germline mutations of breast cancer susceptibility genes through expanded genetic analysis in unselected Colombian patients.","authors":"Diana Carolina Sierra-Díaz, Adrien Morel, Dora Janeth Fonseca-Mendoza, Nora Contreras Bravo, Nicolas Molano-Gonzalez, Mariana Borras, Isabel Munevar, Mauricio Lema, Henry Idrobo, Daniela Trujillo, Norma Serrano, Ana Isabel Orduz, Diego Lopera, Jaime González, Gustavo Rojas, Paula Londono-De Los Ríos, Ray Manneh, Rodrigo Cabrera, Wilson Rubiano, Jairo de la Peña, María Catalina Quintero, William Mantilla, Carlos M Restrepo","doi":"10.1186/s40246-024-00623-7","DOIUrl":"10.1186/s40246-024-00623-7","url":null,"abstract":"<p><strong>Background: </strong>In Colombia and worldwide, breast cancer (BC) is the most frequently diagnosed neoplasia and the leading cause of death from cancer among women. Studies predominantly involve hereditary and familial cases, demonstrating a gap in the literature regarding the identification of germline mutations in unselected patients from Latin-America. Identification of pathogenic/likely pathogenic (P/LP) variants is important for shaping national genetic analysis policies, genetic counseling, and early detection strategies. The present study included 400 women with unselected breast cancer (BC), in whom we analyzed ten genes, using Whole Exome Sequencing (WES), know to confer risk for BC, with the aim of determining the genomic profile of previously unreported P/LP variants in the affected population. Additionally, Multiplex Ligation-dependent Probe Amplification (MLPA) was performed to identify Large Genomic Rearrangements (LGRs) in the BRCA1/2 genes. To ascertain the functional impact of a recurrent intronic variant (ATM c.5496 + 2_5496 + 5delTAAG), a minigene assay was conducted.</p><p><strong>Results: </strong>We ascertained the frequency of P/LP germline variants in BRCA2 (2.5%), ATM (1.25%), BRCA1 (0.75%), PALB2 (0.50%), CHEK2 (0.50%), BARD1 (0.25%), and RAD51D (0.25%) genes in the population of study. P/LP variants account for 6% of the total population analyzed. No LGRs were detected in our study. We identified 1.75% of recurrent variants in BRCA2 and ATM genes. One of them corresponds to the ATM c.5496 + 2_5496 + 5delTAAG. Functional validation of this variant demonstrated a splicing alteration probably modifying the Pincer domain and subsequent protein structure.</p><p><strong>Conclusion: </strong>This study described for the first time the genomic profile of ten risk genes in Colombian women with unselected BC. Our findings underscore the significance of population-based research, advocating the consideration of molecular testing in all women with cancer.</p>","PeriodicalId":13183,"journal":{"name":"Human Genomics","volume":"18 1","pages":"68"},"PeriodicalIF":3.8,"publicationDate":"2024-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11184794/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141418727","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Application of mendelian randomization in ocular diseases: a review. 泯灭随机法在眼科疾病中的应用:综述。
IF 3.8 3区 医学 Q2 GENETICS & HEREDITY Pub Date : 2024-06-17 DOI: 10.1186/s40246-024-00637-1
Xiran Zhang, Weichen Yuan, Jun Xu, Fangkun Zhao

Ocular disorders can significantly lower patients' quality of life and impose an economic burden on families and society. However, for the majority of these diseases, their prevalence and mechanisms are yet unknown, making prevention, management, and therapy challenging. Although connections between exposure factors and diseases can be drawn through observational research, it is challenging to rule out the interference of confounding variables and reverse causation. Mendelian Randomization (MR), a method of research that combines genetics and epidemiology, has its advantage to solve this problem and thus has been extensively utilized in the etiological study of ophthalmic diseases. This paper reviews the implementation of MR in the research of ocular diseases and provides approaches for the investigation of related mechanisms as well as the intervention strategies.

眼部疾病会大大降低患者的生活质量,并给家庭和社会带来经济负担。然而,大多数此类疾病的发病率和发病机制尚不清楚,因此,预防、管理和治疗都具有挑战性。虽然可以通过观察性研究得出暴露因素与疾病之间的联系,但要排除混杂变量和反向因果关系的干扰却很有难度。孟德尔随机法(Mendelian Randomization,MR)是一种将遗传学和流行病学相结合的研究方法,其优势在于可以解决这一问题,因此被广泛应用于眼科疾病的病因学研究中。本文回顾了 MR 在眼科疾病研究中的应用,并提供了相关机制的研究方法和干预策略。
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引用次数: 0
Comprehensive bioinformatics analysis of human cytomegalovirus pathway genes in pan-cancer. 泛癌症中人类巨细胞病毒通路基因的综合生物信息学分析。
IF 3.8 3区 医学 Q2 GENETICS & HEREDITY Pub Date : 2024-06-17 DOI: 10.1186/s40246-024-00633-5
Tengyue Yan, Xianwu Pang, Boying Liang, Qiuxia Meng, Huilin Wei, Wen Li, Dahai Liu, Yanling Hu

Background: Human cytomegalovirus (HCMV) is a herpesvirus that can infect various cell types and modulate host gene expression and immune response. It has been associated with the pathogenesis of various cancers, but its molecular mechanisms remain elusive.

Methods: We comprehensively analyzed the expression of HCMV pathway genes across 26 cancer types using the Cancer Genome Atlas (TCGA) and The Genotype-Tissue Expression (GTEx) databases. We also used bioinformatics tools to study immune invasion and tumor microenvironment in pan-cancer. Cox regression and machine learning were used to analyze prognostic genes and their relationship with drug sensitivity.

Results: We found that HCMV pathway genes are widely expressed in various cancers. Immune infiltration and the tumor microenvironment revealed that HCMV is involved in complex immune processes. We obtained prognostic genes for 25 cancers and significantly found 23 key genes in the HCMV pathway, which are significantly enriched in cellular chemotaxis and synaptic function and may be involved in disease progression. Notably, CaM family genes were up-regulated and AC family genes were down-regulated in most tumors. These hub genes correlate with sensitivity or resistance to various drugs, suggesting their potential as therapeutic targets.

Conclusions: Our study has revealed the role of the HCMV pathway in various cancers and provided insights into its molecular mechanism and therapeutic significance. It is worth noting that the key genes of the HCMV pathway may open up new doors for cancer prevention and treatment.

背景:人类巨细胞病毒(HCMV)是一种疱疹病毒,可感染多种类型的细胞,并可调节宿主的基因表达和免疫反应。它与多种癌症的发病机制有关,但其分子机制仍难以捉摸:我们利用癌症基因组图谱(TCGA)和基因型-组织表达(GTEx)数据库全面分析了 26 种癌症类型中 HCMV 通路基因的表达。我们还利用生物信息学工具研究了泛癌症中的免疫侵袭和肿瘤微环境。我们使用 Cox 回归和机器学习分析预后基因及其与药物敏感性的关系:结果:我们发现 HCMV 通路基因在各种癌症中广泛表达。免疫浸润和肿瘤微环境显示,HCMV 参与了复杂的免疫过程。我们获得了 25 种癌症的预后基因,并在 HCMV 通路中发现了 23 个关键基因,这些基因在细胞趋化和突触功能中明显富集,可能参与了疾病的进展。值得注意的是,在大多数肿瘤中,CaM 家族基因上调,AC 家族基因下调。这些中枢基因与对各种药物的敏感性或耐药性相关,表明它们有可能成为治疗靶点:我们的研究揭示了 HCMV 通路在各种癌症中的作用,并深入探讨了其分子机制和治疗意义。值得注意的是,HCMV 通路的关键基因可能为癌症预防和治疗打开新的大门。
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引用次数: 0
Growth characteristics of HCT116 xenografts lacking asparagine synthetase vary according to sex. 缺乏天冬酰胺合成酶的 HCT116 异种移植物的生长特征因性别而异。
IF 3.8 3区 医学 Q2 GENETICS & HEREDITY Pub Date : 2024-06-17 DOI: 10.1186/s40246-024-00635-3
Oladimeji Aladelokun, Lingeng Lu, Jie Zheng, Hong Yan, Abhishek Jain, Joanna Gibson, Sajid A Khan, Caroline H Johnson

Background: Sex-related differences in colorectal (CRC) incidence and mortality are well-documented. However, the impact of sex on metabolic pathways that drive cancer growth is not well understood. High expression of asparagine synthetase (ASNS) is associated with inferior survival for female CRC patients only. Here, we used a CRISPR/Cas9 technology to generate HCT116 ASNS-/- and HCT 116 ASNS+/+ cancer cell lines. We examine the effects of ASNS deletion on tumor growth and the subsequent rewiring of metabolic pathways in male and female Rag2/IL2RG mice.

Results: ASNS loss reduces cancer burden in male and female tumor-bearing mice (40% reduction, q < 0.05), triggers metabolic reprogramming including gluconeogenesis, but confers a survival improvement (30 days median survival, q < 0.05) in female tumor-bearing mice alone. Transcriptomic analyses revealed upregulation of G-protein coupled estrogen receptor (GPER1) in tumors from male and female mice with HCT116 ASNS-/- xenograft. Estradiol activates GPER1 in vitro in the presence of ASNS and suppresses tumor growth.

Conclusions: Our study indicates that inferior survival for female CRC patients with high ASNS may be due to metabolic reprogramming that sustains tumor growth. These findings have translational relevance as ASNS/GPER1 signaling could be a future therapeutic target to improve the survival of female CRC patients.

背景:结直肠癌(CRC)发病率和死亡率的性别差异已得到充分证实。然而,人们对性别对驱动癌症生长的代谢途径的影响还不甚了解。天冬酰胺合成酶(ASNS)的高表达仅与女性 CRC 患者的低生存率有关。在这里,我们使用 CRISPR/Cas9 技术生成了 HCT116 ASNS-/- 和 HCT 116 ASNS+/+ 癌细胞系。我们研究了 ASNS 缺失对肿瘤生长的影响,以及随后在雄性和雌性 Rag2/IL2RG 小鼠体内对代谢途径的重新布线:结果:ASNS缺失降低了雄性和雌性肿瘤小鼠的癌症负担(减少40%,q < 0.05),引发了包括葡萄糖生成在内的代谢重编程,但仅改善了雌性肿瘤小鼠的存活率(30天的中位存活率,q < 0.05)。转录组分析表明,在HCT116 ASNS-/-异种移植的雄性和雌性小鼠肿瘤中,G蛋白偶联雌激素受体(GPER1)上调。雌二醇在体外激活ASNS存在下的GPER1,并抑制肿瘤生长:我们的研究表明,高 ASNS 女性 CRC 患者的生存率较低可能是由于新陈代谢重编程导致了肿瘤的持续生长。这些发现具有转化意义,因为 ASNS/GPER1 信号转导可能是未来改善女性 CRC 患者生存率的治疗靶点。
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引用次数: 0
Next-generation sequencing profiling of miRNAs in individuals with 22q11.2 deletion syndrome revealed altered expression of miR-185-5p. 22q11.2缺失综合征患者的 miRNAs 下一代测序分析表明,miR-185-5p 的表达发生了改变。
IF 3.8 3区 医学 Q2 GENETICS & HEREDITY Pub Date : 2024-06-13 DOI: 10.1186/s40246-024-00625-5
Anelisa Gollo Dantas, Beatriz Carvalho Nunes, Natália Nunes, Pedro Galante, Paula Fontes Asprino, Vanessa Kiyomi Ota, Maria Isabel Melaragno

Background: The 22q11.2 deletion syndrome (22q11.2DS) is a microdeletion syndrome with highly variable phenotypic manifestations, even though most patients present the typical 3 Mb microdeletion, usually affecting the same ~ 106 genes. One of the genes affected by this deletion is DGCR8, which plays a crucial role in miRNA biogenesis. Therefore, the haploinsufficiency of DGCR8 due to this microdeletion can alter the modulation of the expression of several miRNAs involved in a range of biological processes.

Results: In this study, we used next-generation sequencing to evaluate the miRNAs profiles in the peripheral blood of 12 individuals with typical 22q11DS compared to 12 healthy matched controls. We used the DESeq2 package for differential gene expression analysis and the DIANA-miTED dataset to verify the expression of differentially expressed miRNAs in other tissues. We used miRWalk to predict the target genes of differentially expressed miRNAs. Here, we described two differentially expressed miRNAs in patients compared to controls: hsa-miR-1304-3p, located outside the 22q11.2 region, upregulated in patients, and hsa-miR-185-5p, located in the 22q11.2 region, which showed downregulation. Expression of miR-185-5p is observed in tissues frequently affected in patients with 22q11DS, and previous studies have reported its downregulation in individuals with 22q11DS. hsa-miR-1304-3p has low expression in blood and, thus, needs more validation, though using a sensitive technology allowed us to identify differences in expression between patients and controls.

Conclusions: Thus, lower expression of miR-185-5p can be related to the 22q11.2 deletion and DGCR8 haploinsufficiency, leading to phenotypic consequences in 22q11.2DS patients, while higher expression of hsa-miR-1304-3p might be related to individual genomic variances due to the heterogeneous background of the Brazilian population.

背景:22q11.2 缺失综合征(22q11.2DS)是一种微缺失综合征,尽管大多数患者表现为典型的 3 Mb 微缺失,通常影响相同的约 106 个基因,但其表型表现却千差万别。受这种缺失影响的基因之一是 DGCR8,它在 miRNA 生物发生过程中起着至关重要的作用。因此,由于这种微缺失导致的 DGCR8 的单倍性不足会改变参与一系列生物过程的多个 miRNA 的表达调控:在这项研究中,我们使用新一代测序技术评估了12名典型22q11DS患者外周血中的miRNAs谱,并与12名健康的匹配对照进行了比较。我们使用 DESeq2 软件包进行差异基因表达分析,并使用 DIANA-miTED 数据集验证差异表达的 miRNA 在其他组织中的表达情况。我们利用 miRWalk 预测了差异表达 miRNA 的靶基因。在这里,我们描述了与对照组相比,患者体内两种不同表达的 miRNA:位于 22q11.2 区域外的 hsa-miR-1304-3p 在患者体内上调,而位于 22q11.2 区域内的 hsa-miR-185-5p 则出现下调。hsa-miR-1304-3p在血液中的表达量较低,因此还需要更多的验证,尽管使用敏感的技术使我们能够确定患者与对照组之间的表达差异:因此,miR-185-5p的低表达可能与22q11.2缺失和DGCR8单倍体缺陷有关,导致22q11.2DS患者的表型后果,而hsa-miR-1304-3p的高表达可能与巴西人口的异质性背景导致的个体基因组差异有关。
{"title":"Next-generation sequencing profiling of miRNAs in individuals with 22q11.2 deletion syndrome revealed altered expression of miR-185-5p.","authors":"Anelisa Gollo Dantas, Beatriz Carvalho Nunes, Natália Nunes, Pedro Galante, Paula Fontes Asprino, Vanessa Kiyomi Ota, Maria Isabel Melaragno","doi":"10.1186/s40246-024-00625-5","DOIUrl":"10.1186/s40246-024-00625-5","url":null,"abstract":"<p><strong>Background: </strong>The 22q11.2 deletion syndrome (22q11.2DS) is a microdeletion syndrome with highly variable phenotypic manifestations, even though most patients present the typical 3 Mb microdeletion, usually affecting the same ~ 106 genes. One of the genes affected by this deletion is DGCR8, which plays a crucial role in miRNA biogenesis. Therefore, the haploinsufficiency of DGCR8 due to this microdeletion can alter the modulation of the expression of several miRNAs involved in a range of biological processes.</p><p><strong>Results: </strong>In this study, we used next-generation sequencing to evaluate the miRNAs profiles in the peripheral blood of 12 individuals with typical 22q11DS compared to 12 healthy matched controls. We used the DESeq2 package for differential gene expression analysis and the DIANA-miTED dataset to verify the expression of differentially expressed miRNAs in other tissues. We used miRWalk to predict the target genes of differentially expressed miRNAs. Here, we described two differentially expressed miRNAs in patients compared to controls: hsa-miR-1304-3p, located outside the 22q11.2 region, upregulated in patients, and hsa-miR-185-5p, located in the 22q11.2 region, which showed downregulation. Expression of miR-185-5p is observed in tissues frequently affected in patients with 22q11DS, and previous studies have reported its downregulation in individuals with 22q11DS. hsa-miR-1304-3p has low expression in blood and, thus, needs more validation, though using a sensitive technology allowed us to identify differences in expression between patients and controls.</p><p><strong>Conclusions: </strong>Thus, lower expression of miR-185-5p can be related to the 22q11.2 deletion and DGCR8 haploinsufficiency, leading to phenotypic consequences in 22q11.2DS patients, while higher expression of hsa-miR-1304-3p might be related to individual genomic variances due to the heterogeneous background of the Brazilian population.</p>","PeriodicalId":13183,"journal":{"name":"Human Genomics","volume":"18 1","pages":"64"},"PeriodicalIF":3.8,"publicationDate":"2024-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11170780/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141317016","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Systematic analysis of IGF2BP family members in non-small-cell lung cancer. 系统分析非小细胞肺癌中的 IGF2BP 家族成员。
IF 3.8 3区 医学 Q2 GENETICS & HEREDITY Pub Date : 2024-06-12 DOI: 10.1186/s40246-024-00632-6
Liping Gong, Qin Liu, Ming Jia, Xifeng Sun

Background: The insulin-like growth factor-2 mRNA-binding proteins 1, 2, and 3 (IGF2BP1, IGF2BP2, and IGF2BP3) are known to be involved in tumorigenesis, metastasis, prognosis, and cancer immunity in various human cancers, including non-small cell lung cancer (NSCLC). However, the literature on NSCLC largely omits the specific context of lung squamous cell carcinoma (LUSC), an oversight we aim to address.

Methods: Our study evaluated the differential expression of IGF2BP family members in tumors and normal tissues. Meta-analyses were conducted to assess the prognostic value of IGF2BPs in lung adenocarcinoma (LUAD) and LUSC. Additionally, correlations between IGF2BPs and tumor immune cell infiltration, mutation characteristics, chemotherapy sensitivity, and tumor mutation burden (TMB) were investigated. GSEA was utilized to delineate biological processes and pathways associated with IGF2BPs.

Results: IGF2BP2 and IGF2BP3 expression were found to be upregulated in LUSC patients. IGF2BP2 mRNA levels were correlated with cancer immunity in both LUSC and LUAD patients. A higher frequency of gene mutations was observed in different IGF2BP1/2/3 expression groups in LUAD compared to LUSC. Meta-analyses revealed a significant negative correlation between overall survival (OS) and IGF2BP2/3 expression in LUAD patients but not in LUSC patients. GSEA indicated a positive association between VEGF and IGF2BP family genes in LUAD, while matrix metallopeptidase activity was inversely correlated with IGF2BP family genes in LUSC. Several chemotherapy drugs showed significantly lower IC50 values in high IGF2BP expression groups in both LUAD and LUSC.

Conclusion: Our findings indicated that IGF2BPs play different roles in LUAD and LUSC. This divergence highlights the need for tailored therapeutic strategies and prognostic tools, cognizant of the unique molecular profiles of LUAD and LUSC.

背景:已知胰岛素样生长因子-2 mRNA结合蛋白1、2和3(IGF2BP1、IGF2BP2和IGF2BP3)参与了包括非小细胞肺癌(NSCLC)在内的多种人类癌症的肿瘤发生、转移、预后和癌症免疫。然而,有关非小细胞肺癌的文献大多忽略了肺鳞癌(LUSC)的具体情况,我们旨在解决这一疏忽:我们的研究评估了肿瘤和正常组织中 IGF2BP 家族成员的不同表达。我们进行了元分析,以评估 IGF2BPs 在肺腺癌(LUAD)和 LUSC 中的预后价值。此外,还研究了IGF2BPs与肿瘤免疫细胞浸润、突变特征、化疗敏感性和肿瘤突变负荷(TMB)之间的相关性。利用GSEA划分了与IGF2BPs相关的生物学过程和通路:结果:发现IGF2BP2和IGF2BP3在LUSC患者中表达上调。IGF2BP2 mRNA水平与LUSC和LUAD患者的癌症免疫相关。与LUSC相比,在LUAD的不同IGF2BP1/2/3表达组中观察到更高的基因突变频率。元分析显示,在LUAD患者中,总生存期(OS)与IGF2BP2/3表达呈显著负相关,而在LUSC患者中则不然。GSEA显示,在LUAD患者中,血管内皮生长因子与IGF2BP家族基因呈正相关,而在LUSC患者中,基质金属肽酶活性与IGF2BP家族基因呈反相关。在LUAD和LUSC中,一些化疗药物在IGF2BP高表达组中的IC50值明显较低:我们的研究结果表明,IGF2BPs 在 LUAD 和 LUSC 中发挥着不同的作用。结论:我们的研究结果表明,IGF2BPs 在 LUAD 和 LUSC 中发挥着不同的作用。这种差异突出表明,需要针对 LUAD 和 LUSC 独特的分子特征,制定量身定制的治疗策略和预后工具。
{"title":"Systematic analysis of IGF2BP family members in non-small-cell lung cancer.","authors":"Liping Gong, Qin Liu, Ming Jia, Xifeng Sun","doi":"10.1186/s40246-024-00632-6","DOIUrl":"10.1186/s40246-024-00632-6","url":null,"abstract":"<p><strong>Background: </strong>The insulin-like growth factor-2 mRNA-binding proteins 1, 2, and 3 (IGF2BP1, IGF2BP2, and IGF2BP3) are known to be involved in tumorigenesis, metastasis, prognosis, and cancer immunity in various human cancers, including non-small cell lung cancer (NSCLC). However, the literature on NSCLC largely omits the specific context of lung squamous cell carcinoma (LUSC), an oversight we aim to address.</p><p><strong>Methods: </strong>Our study evaluated the differential expression of IGF2BP family members in tumors and normal tissues. Meta-analyses were conducted to assess the prognostic value of IGF2BPs in lung adenocarcinoma (LUAD) and LUSC. Additionally, correlations between IGF2BPs and tumor immune cell infiltration, mutation characteristics, chemotherapy sensitivity, and tumor mutation burden (TMB) were investigated. GSEA was utilized to delineate biological processes and pathways associated with IGF2BPs.</p><p><strong>Results: </strong>IGF2BP2 and IGF2BP3 expression were found to be upregulated in LUSC patients. IGF2BP2 mRNA levels were correlated with cancer immunity in both LUSC and LUAD patients. A higher frequency of gene mutations was observed in different IGF2BP1/2/3 expression groups in LUAD compared to LUSC. Meta-analyses revealed a significant negative correlation between overall survival (OS) and IGF2BP2/3 expression in LUAD patients but not in LUSC patients. GSEA indicated a positive association between VEGF and IGF2BP family genes in LUAD, while matrix metallopeptidase activity was inversely correlated with IGF2BP family genes in LUSC. Several chemotherapy drugs showed significantly lower IC50 values in high IGF2BP expression groups in both LUAD and LUSC.</p><p><strong>Conclusion: </strong>Our findings indicated that IGF2BPs play different roles in LUAD and LUSC. This divergence highlights the need for tailored therapeutic strategies and prognostic tools, cognizant of the unique molecular profiles of LUAD and LUSC.</p>","PeriodicalId":13183,"journal":{"name":"Human Genomics","volume":"18 1","pages":"63"},"PeriodicalIF":3.8,"publicationDate":"2024-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11167947/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141310611","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
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Human Genomics
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