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Development of novel lysosome-related signatures and their potential target drugs based on bulk RNA-seq and scRNA-seq for diabetic foot ulcers. 基于大样本 RNA-seq 和 scRNA-seq 开发糖尿病足溃疡溶酶体相关新特征及其潜在靶向药物。
IF 3.8 3区 医学 Q2 GENETICS & HEREDITY Pub Date : 2024-06-11 DOI: 10.1186/s40246-024-00629-1
Longhai Tan, Junjun Qu, Junxia Wang

Background: Diabetic foot ulcers (DFU) is the most serious complication of diabetes mellitus, which has become a global health problem due to its high morbidity and disability rates and the poor efficacy of conventional treatments. Thus, it is urgent to identify novel molecular targets to improve the prognosis and reduce disability rate in DFU patients.

Results: In the present study, bulk RNA-seq and scRNA-seq associated with DFU were downloaded from the GEO database. We identified 1393 DFU-related DEGs by differential analysis and WGCNA analysis together, and GO/KEGG analysis showed that these genes were associated with lysosomal and immune/inflammatory responses. Immediately thereafter, we identified CLU, RABGEF1 and ENPEP as DLGs for DFU using three machine learning algorithms (Randomforest, SVM-RFE and LASSO) and validated their diagnostic performance in a validation cohort independent of this study. Subsequently, we constructed a novel artificial neural network model for molecular diagnosis of DFU based on DLGs, and the diagnostic performance in the training and validation cohorts was sound. In single-cell sequencing, the heterogeneous expression of DLGs also provided favorable evidence for them to be potential diagnostic targets. In addition, the results of immune infiltration analysis showed that the abundance of mainstream immune cells, including B/T cells, was down-regulated in DFUs and significantly correlated with the expression of DLGs. Finally, we found latamoxef, parthenolide, meclofenoxate, and lomustine to be promising anti-DFU drugs by targeting DLGs.

Conclusions: CLU, RABGEF1 and ENPEP can be used as novel lysosomal molecular signatures of DFU, and by targeting them, latamoxef, parthenolide, meclofenoxate and lomustine were identified as promising anti-DFU drugs. The present study provides new perspectives for the diagnosis and treatment of DFU and for improving the prognosis of DFU patients.

背景:糖尿病足溃疡(DFU)是糖尿病最严重的并发症:糖尿病足溃疡(DFU)是糖尿病最严重的并发症,由于其发病率和致残率高以及传统治疗效果不佳,已成为一个全球性健康问题。因此,当务之急是确定新的分子靶点,以改善 DFU 患者的预后并降低致残率:本研究从 GEO 数据库下载了与 DFU 相关的大量 RNA-seq 和 scRNA-seq。通过差异分析和 WGCNA 分析,我们发现了 1393 个与 DFU 相关的 DEGs,GO/KEGG 分析表明这些基因与溶酶体和免疫/炎症反应相关。紧接着,我们利用三种机器学习算法(Randomforest、SVM-RFE 和 LASSO)将 CLU、RABGEF1 和 ENPEP 鉴定为 DFU 的 DLGs,并在独立于本研究的验证队列中验证了它们的诊断性能。随后,我们构建了一个基于 DLGs 的新型 DFU 分子诊断人工神经网络模型,其在训练队列和验证队列中的诊断性能良好。在单细胞测序中,DLGs的异质性表达也为其成为潜在诊断靶点提供了有利证据。此外,免疫浸润分析结果显示,DFUs 中主流免疫细胞(包括 B/T 细胞)的丰度下调,并与 DLGs 的表达显著相关。最后,我们发现拉托莫昔夫、帕芬内酯、甲氧氯芬酯和洛莫司汀是针对DLGs的抗DFU药物:结论:CLU、RABGEF1和ENPEP可作为DFU的新型溶酶体分子特征,通过靶向它们,拉托莫昔夫、帕芬内酯、甲氯芬酯和洛莫司汀被确定为有前途的抗DFU药物。本研究为DFU的诊断和治疗以及改善DFU患者的预后提供了新的视角。
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引用次数: 0
Trace amine associated receptor 1: predicted effects of single nucleotide variants on structure-function in geographically diverse populations. 痕量胺相关受体 1:单核苷酸变异对不同地域人群结构-功能的预测影响。
IF 3.8 3区 医学 Q2 GENETICS & HEREDITY Pub Date : 2024-06-11 DOI: 10.1186/s40246-024-00620-w
Britto Shajan, Shashikanth Marri, Tarun Bastiampillai, Karen J Gregory, Shane D Hellyer, Pramod C Nair

Trace Amine Associated Receptor 1 (TAAR1) is a novel pharmaceutical target under investigation for the treatment of several neuropsychiatric conditions. TAAR1 single nucleotide variants (SNV) have been found in patients with schizophrenia and metabolic disorders. However, the frequency of variants in geographically diverse populations and the functional effects of such variants are unknown. In this study, we aimed to characterise the distribution of TAAR1 SNVs in five different WHO regions using the Database of Genotypes and Phenotypes (dbGaP) and conducted a critical computational analysis using available TAAR1 structural data to identify SNVs affecting ligand binding and/or functional regions. Our analysis shows 19 orthosteric, 9 signalling and 16 micro-switch SNVs hypothesised to critically influence the agonist induced TAAR1 activation. These SNVs may non-proportionally influence populations from discrete regions and differentially influence the activity of TAAR1-targeting therapeutics in genetically and geographically diverse populations. Notably, our dataset presented with orthosteric SNVs D1033.32N (found only in the South-East Asian Region and Western Pacific Region) and T1945.42A (found only in South-East Asian Region), and 2 signalling SNVs (V1253.54A/T2526.36A, found in African Region and commonly, respectively), all of which have previously demonstrated to influence ligand induced functions of TAAR1. Furthermore, bioinformatics analysis using SIFT4G, MutationTaster 2, PROVEAN and MutationAssessor predicted all 16 micro-switch SNVs are damaging and may further influence the agonist activation of TAAR1, thereby possibly impacting upon clinical outcomes. Understanding the genetic basis of TAAR1 function and the impact of common mutations within clinical populations is important for the safe and effective utilisation of novel and existing pharmacotherapies.

痕量胺相关受体 1(TAAR1)是一种新型药物靶点,目前正在研究用于治疗多种神经精神疾病。在精神分裂症和代谢紊乱患者中发现了 TAAR1 单核苷酸变异(SNV)。然而,变异在不同地域人群中的频率及其功能影响尚不清楚。在这项研究中,我们旨在利用基因型和表型数据库(dbGaP)描述世界卫生组织五个不同地区 TAAR1 SNV 的分布特征,并利用现有的 TAAR1 结构数据进行关键的计算分析,以确定影响配体结合和/或功能区域的 SNV。我们的分析显示了 19 个正交、9 个信号和 16 个微开关 SNV,假设这些 SNV 对激动剂诱导的 TAAR1 激活有重要影响。这些 SNV 可能会对来自不同地区的人群产生非比例影响,并对 TAAR1 靶向疗法在不同基因和地域人群中的活性产生不同影响。值得注意的是,我们的数据集中出现了正交 SNV D1033.32N(仅在东南亚地区和西太平洋地区发现)和 T1945.42A(仅在东南亚地区发现),以及 2 个信号 SNV(V1253.54A/T2526.36A,分别在非洲地区和常见地区发现),所有这些 SNV 以前都被证明会影响 TAAR1 的配体诱导功能。此外,利用 SIFT4G、MutationTaster 2、PROVEAN 和 MutationAssessor 进行的生物信息学分析预测,所有 16 个微开关 SNV 都具有损伤性,可能会进一步影响 TAAR1 的激动剂激活,从而可能影响临床结果。了解 TAAR1 功能的遗传基础以及临床人群中常见突变的影响对于安全有效地利用新型和现有药物疗法非常重要。
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引用次数: 0
Genetic analysis of 106 sporadic cases with hearing loss in the UAE population. 对阿联酋人口中 106 例零星听力损失病例的基因分析。
IF 3.8 3区 医学 Q2 GENETICS & HEREDITY Pub Date : 2024-06-07 DOI: 10.1186/s40246-024-00630-8
Abdelaziz Tlili, Mona Mahfood, Abdullah Al Mutery, Jihen Chouchen

Background: Hereditary hearing loss is a rare hereditary condition that has a significant presence in consanguineous populations. Despite its prevalence, hearing loss is marked by substantial genetic diversity, which poses challenges for diagnosis and screening, particularly in cases with no clear family history or when the impact of the genetic variant requires functional analysis, such as in the case of missense mutations and UTR variants. The advent of next-generation sequencing (NGS) has transformed the identification of genes and variants linked to various conditions, including hearing loss. However, there remains a high proportion of undiagnosed patients, attributable to various factors, including limitations in sequencing coverage and gaps in our knowledge of the entire genome, among other factors. In this study, our objective was to comprehensively identify the spectrum of genes and variants associated with hearing loss in a cohort of 106 affected individuals from the UAE.

Results: In this study, we investigated 106 sporadic cases of hearing impairment and performed genetic analyses to identify causative mutations. Screening of the GJB2 gene in these cases revealed its involvement in 24 affected individuals, with specific mutations identified. For individuals without GJB2 mutations, whole exome sequencing (WES) was conducted. WES revealed 33 genetic variants, including 6 homozygous and 27 heterozygous DNA changes, two of which were previously implicated in hearing loss, while 25 variants were novel. We also observed multiple potential pathogenic heterozygous variants across different genes in some cases. Notably, a significant proportion of cases remained without potential pathogenic variants.

Conclusions: Our findings confirm the complex genetic landscape of hearing loss and the limitations of WES in achieving a 100% diagnostic rate, especially in conditions characterized by genetic heterogeneity. These results contribute to our understanding of the genetic basis of hearing loss and emphasize the need for further research and comprehensive genetic analyses to elucidate the underlying causes of this condition.

背景:遗传性听力损失是一种罕见的遗传性疾病,在近亲结婚人群中发病率很高。尽管听力损失很普遍,但其遗传多样性却很明显,这给诊断和筛查带来了挑战,尤其是在没有明确家族史的病例中,或者当遗传变异的影响需要功能分析时,如错义突变和 UTR 变异。下一代测序技术(NGS)的出现改变了与包括听力损失在内的各种疾病相关的基因和变异的鉴定。然而,由于各种因素,包括测序覆盖面的局限性和我们对整个基因组知识的空白等,仍有很高比例的患者未被确诊。在这项研究中,我们的目标是在阿联酋的 106 名受影响者中全面鉴定与听力损失相关的基因和变异:在这项研究中,我们调查了 106 例散发性听力损伤病例,并进行了基因分析以确定致病突变。对这些病例中的 GJB2 基因进行筛查后发现,有 24 例患者的 GJB2 基因受累,并发现了特定的突变。对于没有 GJB2 基因突变的患者,则进行了全外显子组测序(WES)。WES 发现了 33 个基因变异,包括 6 个同源 DNA 变异和 27 个异源 DNA 变异,其中两个变异以前曾与听力损失有关,而 25 个变异则是新出现的。在一些病例中,我们还观察到不同基因间存在多个潜在的致病杂合变异。值得注意的是,相当一部分病例仍然没有潜在的致病变异:我们的研究结果证实了听力损失复杂的遗传结构,以及 WES 在实现 100% 诊断率方面的局限性,尤其是在以遗传异质性为特征的情况下。这些结果有助于我们了解听力损失的遗传基础,并强调了进一步研究和全面遗传分析的必要性,以阐明听力损失的根本原因。
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引用次数: 0
Deep learning-based pathway-centric approach to characterize recurrent hepatocellular carcinoma after liver transplantation 以深度学习为基础、以通路为中心的肝移植后复发性肝细胞癌特征描述方法
IF 4.5 3区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-06-05 DOI: 10.1186/s40246-024-00624-6
Jeffrey To, Soumita Ghosh, Xun Zhao, Elisa Pasini, Sandra Fischer, Gonzalo Sapisochin, Anand Ghanekar, Elmar Jaeckel, Mamatha Bhat
Liver transplantation (LT) is offered as a cure for Hepatocellular carcinoma (HCC), however 15–20% develop recurrence post-transplant which tends to be aggressive. In this study, we examined the transcriptome profiles of patients with recurrent HCC to identify differentially expressed genes (DEGs), the involved pathways, biological functions, and potential gene signatures of recurrent HCC post-transplant using deep machine learning (ML) methodology. We analyzed the transcriptomic profiles of primary and recurrent tumor samples from 7 pairs of patients who underwent LT. Following differential gene expression analysis, we performed pathway enrichment, gene ontology (GO) analyses and protein-protein interactions (PPIs) with top 10 hub gene networks. We also predicted the landscape of infiltrating immune cells using Cibersortx. We next develop pathway and GO term-based deep learning models leveraging primary tissue gene expression data from The Cancer Genome Atlas (TCGA) to identify gene signatures in recurrent HCC. The PI3K/Akt signaling pathway and cytokine-mediated signaling pathway were particularly activated in HCC recurrence. The recurrent tumors exhibited upregulation of an immune-escape related gene, CD274, in the top 10 hub gene analysis. Significantly higher infiltration of monocytes and lower M1 macrophages were found in recurrent HCC tumors. Our deep learning approach identified a 20-gene signature in recurrent HCC. Amongst the 20 genes, through multiple analysis, IL6 was found to be significantly associated with HCC recurrence. Our deep learning approach identified PI3K/Akt signaling as potentially regulating cytokine-mediated functions and the expression of immune escape genes, leading to alterations in the pattern of immune cell infiltration. In conclusion, IL6 was identified to play an important role in HCC recurrence.
肝移植(LT)是治疗肝细胞癌(HCC)的一种方法,但15-20%的患者在移植后会复发,而且复发的肝细胞癌往往具有侵袭性。在这项研究中,我们研究了复发 HCC 患者的转录组图谱,利用深度机器学习(ML)方法识别差异表达基因(DEGs)、相关通路、生物学功能以及移植后复发 HCC 的潜在基因特征。我们分析了7对接受LT治疗的患者的原发性和复发性肿瘤样本的转录组图谱。在差异基因表达分析之后,我们进行了通路富集、基因本体(GO)分析以及前 10 个枢纽基因网络的蛋白质-蛋白质相互作用(PPI)分析。我们还利用 Cibersortx 预测了浸润免疫细胞的分布情况。接下来,我们利用癌症基因组图谱(TCGA)的原始组织基因表达数据,开发了基于通路和GO术语的深度学习模型,以确定复发性HCC的基因特征。PI3K/Akt信号通路和细胞因子介导的信号通路在HCC复发中尤其活跃。在前10个中心基因分析中,复发肿瘤表现出免疫相关基因CD274的上调。在复发的HCC肿瘤中,单核细胞的浸润显著增加,M1巨噬细胞的浸润降低。我们的深度学习方法确定了复发性 HCC 中的 20 个基因特征。通过多重分析发现,在这20个基因中,IL6与HCC复发有显著相关性。我们的深度学习方法发现,PI3K/Akt 信号可能调节细胞因子介导的功能和免疫逃逸基因的表达,从而导致免疫细胞浸润模式的改变。总之,IL6在HCC复发中发挥着重要作用。
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引用次数: 0
Sperm epigenetics and male infertility: unraveling the molecular puzzle. 精子表观遗传学与男性不育:揭开分子之谜。
IF 3.8 3区 医学 Q2 GENETICS & HEREDITY Pub Date : 2024-06-04 DOI: 10.1186/s40246-024-00626-4
Maryam Hosseini, Anis Khalafiyan, Mohammadreza Zare, Haniye Karimzadeh, Basireh Bahrami, Behnaz Hammami, Mohammad Kazemi

Background: The prevalence of infertility among couples is estimated to range from 8 to 12%. A paradigm shift has occurred in understanding of infertility, challenging the notion that it predominantly affects women. It is now acknowledged that a significant proportion, if not the majority, of infertility cases can be attributed to male-related factors. Various elements contribute to male reproductive impairments, including aberrant sperm production caused by pituitary malfunction, testicular malignancies, aplastic germ cells, varicocele, and environmental factors.

Main body: The epigenetic profile of mammalian sperm is distinctive and specialized. Various epigenetic factors regulate genes across different levels in sperm, thereby affecting its function. Changes in sperm epigenetics, potentially influenced by factors such as environmental exposures, could contribute to the development of male infertility.

Conclusion: In conclusion, this review investigates the latest studies pertaining to the mechanisms of epigenetic changes that occur in sperm cells and their association with male reproductive issues.

背景:据估计,不孕症在夫妇中的发病率为 8%至 12%。人们对不孕症的认识发生了范式转变,对不孕症主要影响女性的观念提出了挑战。现在人们认识到,即使不是大多数,也有相当一部分不孕症可归因于与男性有关的因素。导致男性生殖障碍的因素有很多,包括垂体功能失调导致的精子生成异常、睾丸恶性肿瘤、再生障碍性生殖细胞、精索静脉曲张以及环境因素:哺乳动物精子的表观遗传特征是独特而专业的。各种表观遗传因子对精子中不同水平的基因进行调控,从而影响精子的功能。精子表观遗传学的变化可能受到环境暴露等因素的影响,从而导致男性不育症的发生:总之,本综述调查了有关精子细胞表观遗传学变化机制及其与男性生殖问题相关性的最新研究。
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引用次数: 0
Mendelian randomization evidence based on European ancestry for the causal effects of leukocyte telomere length on prostate cancer. 基于欧洲血统的孟德尔随机证据,证明白细胞端粒长度对前列腺癌的因果效应。
IF 3.8 3区 医学 Q2 GENETICS & HEREDITY Pub Date : 2024-06-03 DOI: 10.1186/s40246-024-00622-8
Xinrui Wu, Cong Hu, Tianyang Wu, Xinxing Du, Zehong Peng, Wei Xue, Yonghui Chen, Liang Dong

Background: Several lines of evidence suggest that leukocyte telomere length (LTL) can affect the development of prostate cancer (PC).

Methods: Here, we employed single nucleoside polymorphisms (SNPs) as instrumental variables (IVs) for LTL (n = 472,174) and conducted Mendelian randomization analysis to estimate their causal impact on PCs (79,148 patients/61,106 controls and 6311 patients/88,902 controls).

Results: Every 1-s.d extension of LTL increased the risk of PCs by 34%. Additionally, the analysis of candidate mediators between LTL and PCs via two-step Mendelian randomization revealed that among the 23 candidates, Alzheimer's disease, liver iron content, sex hormone binding global levels, naive CD4-CD8-T cell% T cell, and circulating leptin levels played substantial mediating roles. There is no robust evidence to support the reverse causal relationship between LTL and the selected mediators of PCs. Adjusting for the former four mediators, rather than adjusting for circulating leptin levels, decreased the impact of LTL on PCs.

Conclusion: This study provides potential intervention measures for preventing LTL-induced PCs.

背景:多项证据表明,白细胞端粒长度(LTL)会影响前列腺癌(PC)的发病:方法:在此,我们采用单核苷多态性(SNPs)作为LTL(n = 472 174)的工具变量(IVs),并进行孟德尔随机分析,以估计它们对PC(79 148例患者/61 106例对照和6311例患者/88 902例对照)的因果影响:结果:LTL每延长1个s.d,PCs的风险就会增加34%。此外,通过两步孟德尔随机法分析LTL与多发性硬化症之间的候选介导因素发现,在23个候选介导因素中,阿尔茨海默病、肝脏铁含量、性激素结合全局水平、幼稚CD4-CD8-T细胞% T细胞和循环瘦素水平发挥了重要的介导作用。没有强有力的证据支持LTL与所选的PCs介导因子之间存在反向因果关系。对前四种介导因素进行调整,而不是对循环瘦素水平进行调整,会降低LTL对PCs的影响:本研究为预防LTL诱发的多发性硬化症提供了潜在的干预措施。
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引用次数: 0
Pan-cancer analysis of CDKN2A alterations identifies a subset of gastric cancer with a cold tumor immune microenvironment. 对 CDKN2A 改变的泛癌分析发现了一个具有冷肿瘤免疫微环境的胃癌亚群。
IF 3.8 3区 医学 Q2 GENETICS & HEREDITY Pub Date : 2024-05-31 DOI: 10.1186/s40246-024-00615-7
Chao Deng, Zi-Xi Li, Chen-Jun Xie, Qing-Lin Zhang, Ben-Shun Hu, Mei-Dan Wang, Jie Mei, Chen Yang, Zhangfeng Zhong, Ke-Wei Wang

Background: Although CDKN2A alteration has been explored as a favorable factor for tumorigenesis in pan-cancers, the association between CDKN2A point mutation (MUT) and intragenic deletion (DEL) and response to immune checkpoint inhibitors (ICIs) is still disputed. This study aims to determine the associations of CDKN2A MUT and DEL with overall survival (OS) and response to immune checkpoint inhibitors treatment (ICIs) among pan-cancers and the clinical features of CDKN2A-altered gastric cancer.

Methods: This study included 45,000 tumor patients that underwent tumor sequencing across 33 cancer types from four cohorts, the MSK-MetTropism, MSK-IMPACT, OrigiMed2020 and TCGA cohorts. Clinical outcomes and genomic factors associated with response to ICIs, including tumor mutational burden, copy number alteration, neoantigen load, microsatellite instability, tumor immune microenvironment and immune-related gene signatures, were collected in pan-cancer. Clinicopathologic features and outcomes were assessed in gastric cancer. Patients were grouped based on the presence of CDKN2A wild type (WT), CDKN2A MUT, CDKN2A DEL and CDKN2A other alteration (ALT).

Results: Our research showed that CDKN2A-MUT patients had shorter survival times than CDKN2A-WT patients in the MSK MetTropism and TCGA cohorts, but longer OS in the MSK-IMPACT cohort with ICIs treatment, particularly in patients having metastatic disease. Similar results were observed among pan-cancer patients with CDKN2A DEL and other ALT. Notably, CDKN2A ALT frequency was positively related to tumor-specific objective response rates to ICIs in MSK MetTropism and OrigiMed 2020. Additionally, individuals with esophageal carcinoma or stomach adenocarcinoma who had CDKN2A MUT had poorer OS than patients from the MSK-IMPACT group, but not those with adenocarcinoma. We also found reduced levels of activated NK cells, T cells CD8 and M2 macrophages in tumor tissue from CDKN2A-MUT or DEL pan-cancer patients compared to CDKN2A-WT patients in TCGA cohort. Gastric cancer scRNA-seq data also showed that CDKN2A-ALT cancer contained less CD8 T cells but more exhausted T cells than CDKN2A-WT cancer. A crucial finding of the pathway analysis was the inhibition of three immune-related pathways in the CDKN2A ALT gastric cancer patients, including the interferon alpha response, inflammatory response, and interferon gamma response.

Conclusions: This study illustrates the CDKN2A MUT and DEL were associated with a poor outcome across cancers. CDKN2A ALT, on the other hand, have the potential to be used as a biomarker for choosing patients for ICI treatment, notably in esophageal carcinoma and stomach adenocarcinoma.

背景:尽管CDKN2A改变已被视为泛癌中肿瘤发生的有利因素,但CDKN2A点突变(MUT)和基因内缺失(DEL)与免疫检查点抑制剂(ICIs)反应之间的关系仍存在争议。本研究旨在确定CDKN2A点突变(MUT)和基因内缺失(DEL)与泛癌患者总生存期(OS)和对免疫检查点抑制剂治疗(ICIs)反应的关系,以及CDKN2A变异胃癌的临床特征:这项研究纳入了4个队列(MSK-MetTropism、MSK-IMPACT、OrigiMed2020和TCGA队列)中的4.5万名肿瘤患者,这些患者接受了33种癌症类型的肿瘤测序。在泛癌症中收集了与对 ICIs 反应相关的临床结果和基因组因素,包括肿瘤突变负荷、拷贝数改变、新抗原负荷、微卫星不稳定性、肿瘤免疫微环境和免疫相关基因特征。对胃癌的临床病理特征和预后进行了评估。根据CDKN2A野生型(WT)、CDKN2A MUT、CDKN2A DEL和CDKN2A其他改变(ALT)对患者进行分组:我们的研究表明,在MSK MetTropism和TCGA队列中,CDKN2A-MUT患者的生存时间比CDKN2A-WT患者短,但在接受ICIs治疗的MSK-IMPACT队列中,尤其是转移性疾病患者的OS更长。在患有CDKN2A DEL和其他ALT的泛癌症患者中也观察到了类似的结果。值得注意的是,在 MSK MetTropism 和 OrigiMed 2020 中,CDKN2A ALT 频率与肿瘤特异性对 ICIs 的客观反应率呈正相关。此外,与MSK-IMPACT组患者相比,CDKN2A MUT的食管癌或胃腺癌患者的OS较差,但腺癌患者的OS则不尽相同。我们还发现,与TCGA队列中的CDKN2A-WT患者相比,CDKN2A-MUT或DEL泛癌患者肿瘤组织中的活化NK细胞、T细胞CD8和M2巨噬细胞水平降低。胃癌 scRNA-seq 数据还显示,与 CDKN2A-WT 癌症相比,CDKN2A-ALT 癌症含有较少的 CD8 T 细胞,但含有较多的衰竭 T 细胞。通路分析的一个重要发现是,CDKN2A ALT 胃癌患者的三个免疫相关通路受到抑制,包括干扰素α反应、炎症反应和干扰素γ反应:本研究表明,CDKN2A MUT 和 DEL 与各种癌症的不良预后有关。另一方面,CDKN2A ALT有可能被用作选择患者接受ICI治疗的生物标志物,尤其是在食管癌和胃腺癌中。
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引用次数: 0
Assessment of nucleic acid extraction protocols for antibiotic resistance genes (ARGs) quantification in aircraft wastewater. 评估用于飞机废水中抗生素耐药基因 (ARG) 定量的核酸提取方案。
IF 3.8 3区 医学 Q2 GENETICS & HEREDITY Pub Date : 2024-05-30 DOI: 10.1186/s40246-024-00617-5
Wendy J M Smith, Yawen Liu, Stuart L Simpson, Aaron Bivins, Warish Ahmed

This study evaluated ten nucleic acid extraction protocols (EP1 to EP10) for measuring five endogenous antibiotic resistance genes (ARGs) in four aircraft wastewater samples (AWW1 to AWW4). The targeted ARGs, including blaCTX-M, blaNDM-1, ermB, qnrS, and tetA, encompassed highly and minimally abundant ARGs. TetA and ermB were consistently detected across four aircraft wastewater samples using the DNeasy Blood and Tissue Kit and the AllPrep PowerViral DNA/RNA kit. QnrS displayed high detection rates with specific extraction protocols and aliquot volumes. Concentrations of ARGs varied across aircraft wastewater samples, with differing extraction protocols influencing quantitative results. The concentrations of tetA, ermB, and qnrS in AWW1 were distinct, while AWW2 to AWW4 exhibited a broader range for tetA, ermB, qnrS, blaCTX-M, and blaNDM-1. EP1 consistently produced the highest concentrations for several ARGs. Collective data analysis revealed varying ARG concentrations across the ten extraction protocols, suggesting the importance of careful extraction protocol selection in ARG monitoring in aircraft wastewater samples. Based on the results, we suggest that a small sample volume (as low as 0.2 mL) may be sufficient for ARG characterization in aircraft wastewater samples. The findings also emphasize the need for considering toilet paper removal without compromising nucleic acid extraction efficiency. The study highlights promising prospects for aircraft wastewater monitoring of ARGs, calling for further investigation into the import and spread of unique ARGs through transport hubs.

本研究评估了十种核酸提取方案(EP1 至 EP10),以测定四种飞机废水样本(AWW1 至 AWW4)中的五种内源性抗生素耐药基因 (ARGs)。目标 ARG 包括 blaCTX-M、blaNDM-1、ermB、qnrS 和 tetA,涵盖了高含量和低含量 ARG。使用 DNeasy 血液和组织试剂盒以及 AllPrep PowerViral DNA/RNA 试剂盒,在四份飞机废水样本中都能持续检测到 TetA 和 ermB。使用特定的提取方案和等分体积,QnrS 的检出率很高。飞机废水样本中 ARGs 的浓度各不相同,不同的提取方案会影响定量结果。AWW1 中 tetA、ermB 和 qnrS 的浓度各不相同,而 AWW2 至 AWW4 中 tetA、ermB、qnrS、blaCTX-M 和 blaNDM-1 的浓度范围更广。EP1 始终是几种 ARGs 浓度最高的地方。综合数据分析显示,十种提取方案的 ARG 浓度各不相同,这表明在飞机废水样本中进行 ARG 监测时,谨慎选择提取方案非常重要。根据研究结果,我们认为小样本量(低至 0.2 mL)就足以表征飞机废水样本中的 ARG。研究结果还强调了在不影响核酸提取效率的前提下考虑去除卫生纸的必要性。这项研究强调了飞机废水中 ARG 监测的广阔前景,并呼吁进一步调查独特 ARG 通过运输枢纽的进口和传播情况。
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引用次数: 0
Evolutionary and functional analyses of LRP5 in archaic and extant modern humans. 古人类和现代人中 LRP5 的进化和功能分析。
IF 3.8 3区 医学 Q2 GENETICS & HEREDITY Pub Date : 2024-05-27 DOI: 10.1186/s40246-024-00616-6
Neus Roca-Ayats, Iago Maceda, Carlos David Bruque, Núria Martínez-Gil, Natàlia Garcia-Giralt, Mónica Cozar, Leonardo Mellibovsky, Wim Van Hul, Oscar Lao, Daniel Grinberg, Susanna Balcells

Background: The human lineage has undergone a postcranial skeleton gracilization (i.e. lower bone mass and strength relative to body size) compared to other primates and archaic populations such as the Neanderthals. This gracilization has been traditionally explained by differences in the mechanical load that our ancestors exercised. However, there is growing evidence that gracilization could also be genetically influenced.

Results: We have analyzed the LRP5 gene, which is known to be associated with high bone mineral density conditions, from an evolutionary and functional point of view. Taking advantage of the published genomes of archaic Homo populations, our results suggest that this gene has a complex evolutionary history both between archaic and living humans and within living human populations. In particular, we identified the presence of different selective pressures in archaics and extant modern humans, as well as evidence of positive selection in the African and South East Asian populations from the 1000 Genomes Project. Furthermore, we observed a very limited evidence of archaic introgression in this gene (only at three haplotypes of East Asian ancestry out of the 1000 Genomes), compatible with a general erasing of the fingerprint of archaic introgression due to functional differences in archaics compared to extant modern humans. In agreement with this hypothesis, we observed private mutations in the archaic genomes that we experimentally validated as putatively increasing bone mineral density. In particular, four of five archaic missense mutations affecting the first β-propeller of LRP5 displayed enhanced Wnt pathway activation, of which two also displayed reduced negative regulation.

Conclusions: In summary, these data suggest a genetic component contributing to the understanding of skeletal differences between extant modern humans and archaic Homo populations.

背景:与其他灵长类动物和尼安德特人等古人类相比,人类的颅后骨骼出现了 gracilization(即骨量和强度相对于体型较低)。传统的解释是,我们的祖先所承受的机械负荷不同。然而,越来越多的证据表明,匍匐也可能受到基因的影响:结果:我们从进化和功能的角度分析了已知与高骨矿物质密度相关的 LRP5 基因。利用已公布的古人类种群基因组,我们的研究结果表明,该基因在古人类和活人之间以及活人种群内部都有着复杂的进化历史。特别是,我们在古人类和现存现代人中发现了不同的选择性压力,并在 "千人基因组计划 "的非洲和东南亚人群中发现了正选择的证据。此外,我们在该基因中观察到了非常有限的古人类引入的证据(在 1000 个基因组中只有三个东亚祖先的单倍型),这与古人类与现存现代人在功能上的差异导致古人类引入的指纹被普遍消除是一致的。与这一假设一致的是,我们在古人类基因组中观察到了经实验验证可增加骨矿物质密度的私人突变。特别是,影响 LRP5 第一个 β-推进器的五个古基因错义突变中有四个显示出 Wnt 通路激活增强,其中两个还显示出负性调节减少:总之,这些数据表明,遗传因素有助于理解现存现代人与古智人之间的骨骼差异。
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引用次数: 0
Critical insights on "Association of the C allele of rs479200 in the EGLN1 gene with COVID‑19 severity in Indian population: a novel finding". 关于 "印度人群中 EGLN1 基因中 rs479200 的 C 等位基因与 COVID-19 严重程度的关联:一项新发现 "的重要见解。
IF 3.8 3区 医学 Q2 GENETICS & HEREDITY Pub Date : 2024-05-24 DOI: 10.1186/s40246-024-00618-4
Nimita Deora, Priya Agrohi, Prashant K Mallick, Abhinav Sinha

The recent article by Harit et al. in Human Genomics reported a novel association of the C allele of rs479200 in the human EGLN1 gene with severe COVID-19 in Indian patients. The gene in context is an oxygen-sensor gene whose T allele has been reported to contribute to the inability to cope with hypoxia due to increased expression of the EGLN1 gene and therefore persons with TT genotype of EGLN1 rs479200 are more susceptible to severe manifestations of hypoxia. In contrast to this dogma, Harit et al. showed that the C allele is associated with the worsening of COVID-19 hypoxia without suggesting or even discussing the scientific plausibility of the association. The article also suffers from certain epidemiological, statistical, and mathematical issues that need to be critically elaborated and discussed. In this context, the findings of Harit et al. may be re-evaluated.

最近,Harit 等人在《人类基因组学》(Human Genomics)杂志上发表的文章报道了人类 EGLN1 基因中的 C 等位基因 rs479200 与印度患者重度 COVID-19 的新关联。该基因是一个氧传感器基因,据报道,其 T 等位基因会因 EGLN1 基因表达的增加而导致无法应对缺氧,因此 EGLN1 rs479200 基因 TT 型的人更容易出现严重的缺氧表现。与这一教条相反,Harit 等人的研究表明,C 等位基因与 COVID-19 缺氧的恶化有关,但却没有提出甚至讨论这种关联的科学合理性。这篇文章还存在某些流行病学、统计学和数学问题,需要进行批判性的阐述和讨论。在这种情况下,可以重新评估 Harit 等人的研究结果。
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引用次数: 0
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Human Genomics
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