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Elevated iNOS and 3′-nitrotyrosine in Kaposi's Sarcoma tumors and mouse model 卡波西肉瘤肿瘤及小鼠模型中iNOS和3′-硝基酪氨酸升高
IF 4.3 Q1 VIROLOGY Pub Date : 2023-06-01 DOI: 10.1016/j.tvr.2023.200259
Olga Vladimirova , Samantha Soldan , Chenhe Su , Andrew Kossenkov , Owen Ngalamika , For Yue Tso , John T. West , Charles Wood , Paul M. Lieberman

Kaposi's Sarcoma (KS) is a heterogenous, multifocal vascular malignancy caused by the human herpesvirus 8 (HHV8), also known as Kaposi's Sarcoma-Associated Herpesvirus (KSHV). Here, we show that KS lesions express iNOS/NOS2 broadly throughout KS lesions, with enrichment in LANA positive spindle cells. The iNOS byproduct 3-nitrotyrosine is also enriched in LANA positive tumor cells and colocalizes with a fraction of LANA-nuclear bodies. We show that iNOS is highly expressed in the L1T3/mSLK tumor model of KS. iNOS expression correlated with KSHV lytic cycle gene expression, which was elevated in late-stage tumors (>4 weeks) but to a lesser degree in early stage (1 week) xenografts. Further, we show that L1T3/mSLK tumor growth is sensitive to an inhibitor of nitric oxide, L-NMMA. L-NMMA treatment reduced KSHV gene expression and perturbed cellular gene pathways relating to oxidative phosphorylation and mitochondrial dysfunction. These finding suggest that iNOS is expressed in KSHV infected endothelial-transformed tumor cells in KS, that iNOS expression depends on tumor microenvironment stress conditions, and that iNOS enzymatic activity contributes to KS tumor growth.

卡波西肉瘤(KS)是一种由人类疱疹病毒8型(HHV8)引起的异质性多灶性血管恶性肿瘤,也称为卡波西氏肉瘤相关疱疹病毒(KSHV)。在这里,我们发现KS病变在整个KS病变中广泛表达iNOS/NOS2,在LANA阳性梭形细胞中富集。iNOS副产物3-硝基酪氨酸也在LANA阳性肿瘤细胞中富集,并与一部分LANA核体共定位。我们发现iNOS在KS的L1T3/mSLK肿瘤模型中高度表达。iNOS表达与KSHV裂解周期基因表达相关,后者在晚期肿瘤(>4周)中升高,但在早期(1周)异种移植物中升高程度较低。此外,我们发现L1T3/mSLK肿瘤生长对一氧化氮抑制剂L-NMMA敏感。L-NMMA治疗降低了KSHV基因表达,并干扰了与氧化磷酸化和线粒体功能障碍有关的细胞基因通路。这些发现表明,iNOS在KS中KSHV感染的内皮转化的肿瘤细胞中表达,iNOS的表达取决于肿瘤微环境应激条件,并且iNOS酶活性有助于KS肿瘤生长。
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引用次数: 4
Human papillomavirus genomics: Understanding carcinogenicity 人类乳头瘤病毒基因组学:了解致癌性
IF 4.3 Q1 VIROLOGY Pub Date : 2023-06-01 DOI: 10.1016/j.tvr.2023.200258
Chase W. Nelson , Lisa Mirabello

Human papillomavirus (HPV) causes virtually all cervical cancers and many cancers at other anatomical sites in both men and women. However, only 12 of 448 known HPV types are currently classified as carcinogens, and even the most carcinogenic type — HPV16 — only rarely leads to cancer. HPV is therefore necessary but insufficient for cervical cancer, with other contributing factors including host and viral genetics. Over the last decade, HPV whole genome sequencing has established that even fine-scale within-type HPV variation influences precancer/cancer risks, and that these risks vary by histology and host race/ethnicity. In this review, we place these findings in the context of the HPV life cycle and evolution at various levels of viral diversity: between-type, within-type, and within-host. We also discuss key concepts necessary for interpreting HPV genomic data, including features of the viral genome; events leading to carcinogenesis; the role of APOBEC3 in HPV infection and evolution; and methodologies that use deep (high-coverage) sequencing to characterize within-host variation, as opposed to relying on a single representative (consensus) sequence. Given the continued high burden of HPV-associated cancers, understanding HPV carcinogenicity remains important for better understanding, preventing, and treating cancers attributable to infection.

人乳头瘤病毒(HPV)几乎会导致男性和女性的所有宫颈癌和许多其他解剖部位的癌症。然而,在448种已知的HPV类型中,目前只有12种被归类为致癌物,即使是最致癌的类型——HPV16——也很少导致癌症。因此,HPV对于宫颈癌症是必要的,但不充分,其他因素包括宿主和病毒遗传。在过去的十年中,HPV全基因组测序已经证实,即使是n型HPV变异中的细微规模也会影响癌前/癌症风险,并且这些风险因组织学和宿主种族/民族而异。在这篇综述中,我们将这些发现放在HPV生命周期和不同病毒多样性水平的进化背景下:类型之间、类型内和宿主内。我们还讨论了解释HPV基因组数据所必需的关键概念,包括病毒基因组的特征;导致致癌的事件;APOBEC3在HPV感染和进化中的作用;以及使用深度(高覆盖率)测序来表征宿主内变异的方法,而不是依赖于单一的代表性(一致性)序列。鉴于HPV相关癌症的持续高负担,了解HPV的致癌性对于更好地理解、预防和治疗可归因于感染的癌症仍然很重要。
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引用次数: 4
Tegument proteins of Epstein-Barr virus: Diverse functions, complex networks, and oncogenesis eb病毒被膜蛋白:多种功能、复杂网络与肿瘤发生
IF 4.3 Q1 VIROLOGY Pub Date : 2023-06-01 DOI: 10.1016/j.tvr.2023.200260
Takayuki Murata

The tegument is the structure between the envelope and nucleocapsid of herpesvirus particles. Viral (and cellular) proteins accumulate to create the layers of the tegument. Some Epstein-Barr virus (EBV) tegument proteins are conserved widely in Herpesviridae, but others are shared only by members of the gamma-herpesvirus subfamily. As the interface to envelope and nucleocapsid, the tegument functions in virion morphogenesis and budding of the nucleocapsid during progeny production. When a virus particle enters a cell, enzymes such as kinase and deubiquitinase, and transcriptional activators are released from the virion to promote virus infection. Moreover, some EBV tegument proteins are involved in oncogenesis. Here, we summarize the roles of EBV tegument proteins, in comparison to those of other herpesviruses.

外壳是疱疹病毒颗粒的外壳和核衣壳之间的结构。病毒(和细胞)蛋白质积累形成被盖层。一些EB病毒(Epstein-Barr virus,EBV)盖蛋白在疱疹病毒科中广泛保守,但另一些仅由γ疱疹病毒亚家族成员共享。作为包膜和核衣壳的界面,盖层在子代生产过程中起到病毒粒子形态发生和核衣衣壳出芽的作用。当病毒颗粒进入细胞时,激酶和去泛素酶等酶以及转录激活剂会从病毒颗粒中释放出来,以促进病毒感染。此外,一些EB病毒外壳蛋白参与了肿瘤的发生。在这里,我们总结了EBV盖蛋白与其他疱疹病毒的作用。
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引用次数: 0
Unresolved issues in the management of human papillomavirus-associated mucosal high-grade pre-cancers 人乳头瘤病毒相关的粘膜高级别癌前病变治疗中尚未解决的问题
IF 4.3 Q1 VIROLOGY Pub Date : 2023-06-01 DOI: 10.1016/j.tvr.2022.200250
Charles JN. Lacey

This article reviews human papillomavirus-associated mucosal high-grade pre-cancers and their management. It examines pre-cancer classification systems, the natural history of HPV-associated pre-cancers, the various types of management and treatment for HPV pre-cancers, the various mucosal site-specific considerations, and then some of the unresolved issues. Different conclusions are reached for each of the relevant mucosal sites, which are cervix, vagina, vulva, anus, penis and oro-pharynx, and indeed there are differing volumes of evidence relating to each of these sites, and thus differing degrees of certainty/uncertainty in the recommendations.

本文综述了人乳头瘤病毒相关的粘膜高级癌前病变及其治疗。它检查了癌前分类系统、与HPV相关的癌前自然史、HPV癌前的各种管理和治疗类型、各种粘膜特定部位的考虑因素,以及一些尚未解决的问题。对于每个相关的粘膜部位,即宫颈、阴道、外阴、肛门、阴茎和口咽,都得出了不同的结论,事实上,这些部位的证据量不同,因此建议的确定性/不确定性程度也不同。
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引用次数: 0
Association of PNPLA3 (rs738409) & TM6SF2 (rs58542926) and ATG16L1 (rs2241880) genetic variants with susceptibility to hepatocellular carcinoma in a group of Egyptian patients with HCV-induced liver cirrhosis PNPLA3 (rs738409)、TM6SF2 (rss58542926)和ATG16L1 (rs2241880)基因变异与埃及hcv诱导的肝硬化患者肝细胞癌易感性的关联
IF 4.3 Q1 VIROLOGY Pub Date : 2023-06-01 DOI: 10.1016/j.tvr.2023.200256
Asmaa Mohamed Fteah , Ali Abdel Rahim , Afaf Ahmed AbdelHady , Hanan Shawky , Mohamed A Elrefaiy , Doaa Mamdouh Aly
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引用次数: 0
The adenoviral E4orf3/4 is a regulatory polypeptide with cell transforming properties in vitro 腺病毒E4orf3/4是一种在体外具有细胞转化特性的调节多肽
IF 4.3 Q1 VIROLOGY Pub Date : 2023-06-01 DOI: 10.1016/j.tvr.2023.200254
Wing-Hang Ip, Luca D. Bertzbach, Thomas Speiseder, Thomas Dobner

The human adenovirus species C type 5 (HAdV-C5) early region 4 (E4) encodes several distinct polypeptides, defined as E4orf1 to E4orf6/7 according to the order and arrangement of the corresponding open reading frames (ORFs). All E4 gene products operate through a complex network of interactions with key viral and cellular regulatory proteins involved in transcription, apoptosis, cell cycle control, and DNA repair. Here, we generated a set of virus mutants carrying point mutations in the individual E4 genes. The phenotypic characterizations of these mutants revealed that mutations of these ORFs had no or only moderate effects on virus replication. Even a triple mutant that fails to produce E4orf3, E4orf4, and the yet uncharacterized alternatively spliced E4orf3/4 fusion protein, was replicating to wild type levels. The E4orf3/4 protein consists of the N-terminal 33 amino acid residues from E4orf3 and the C-terminal 28 amino acid residues from E4orf4. Intriguingly, we found that, similar to E4orf3, E4orf3/4 possesses properties that support the E1A/E1B-induced transformation of primary rodent cells. These results identify and functionally characterize E4orf3/4 and conclude that E4orf3/4 is another E4 region protein that is dispensable for virus replication but promotes the E1A/E1B-induced transformation of primary rodent cells.

人类腺病毒C型5(HAdV-C5)早期区4(E4)编码几种不同的多肽,根据相应开放阅读框(ORF)的顺序和排列,定义为E4orf1至E4orf6/7。所有E4基因产物都通过与关键病毒和细胞调节蛋白的复杂相互作用网络运作,这些蛋白涉及转录、细胞凋亡、细胞周期控制和DNA修复。在这里,我们产生了一组在单个E4基因中携带点突变的病毒突变体。这些突变体的表型特征表明,这些ORF的突变对病毒复制没有或只有中等影响。即使是一个不能产生E4orf3、E4orf4和尚未表征的选择性剪接E4orf3/4融合蛋白的三重突变体,也在复制到野生型水平。E4orf3/4蛋白由E4orf3的N端33个氨基酸残基和E4orf4的C端28个氨基酸残基组成。有趣的是,我们发现,与E4orf3类似,E4orf3/4具有支持E1A/E1B诱导的原代啮齿动物细胞转化的特性。这些结果鉴定了E4orf3/4并对其进行了功能表征,并得出结论,E4orf3%4是另一种对病毒复制可有可无的E4区蛋白,但促进了E1A/E1B诱导的原代啮齿动物细胞的转化。
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引用次数: 0
Editorial board member 编委会成员
IF 4.3 Q1 VIROLOGY Pub Date : 2023-06-01 DOI: 10.1016/S2666-6790(23)00012-5
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引用次数: 0
Detection of high-risk HPV in FFPE specimens of various tumours using the BD Onclarity™ HPV Assay 使用BD Onclarity™HPV Assay检测各种肿瘤FFPE标本中的高危HPV
IF 4.3 Q1 VIROLOGY Pub Date : 2022-12-01 DOI: 10.1016/j.tvr.2022.200243
Robert van der Geize , Natalie Methorst , Maarten Niemantsverdriet

Analysis of high-risk HPV status on formalin-fixed paraffin-embedded (FFPE) tissue material is valuable for cervical-, head and neck-, anogenital- and other types of cancer, but commercial HPV assays have been developed specifically for cervix swab cells. We evaluated the BD Onclarity™ HPV Assay for the detection of high-risk HPV on an assortment of relevant FFPE tissues with known HPV status. Detection of high-risk HPV types using the BD Onclarity™ HPV Assay in FFPE specimens was easy and accurate.

在福尔马林固定石蜡包埋(FFPE)组织材料上分析高危HPV状态对于宫颈癌、头颈癌、肛门生殖器癌和其他类型的癌症是有价值的,但是商业化的HPV检测已经开发出来,专门用于宫颈拭子细胞。我们评估了BD Onclarity™HPV检测在已知HPV状态的相关FFPE组织中检测高危HPV的效果。在FFPE标本中使用BD Onclarity™HPV Assay检测高危HPV类型是简单和准确的。
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引用次数: 0
HPV and head and neck cancers: Towards early diagnosis and prevention HPV和头颈癌:早期诊断和预防
IF 4.3 Q1 VIROLOGY Pub Date : 2022-12-01 DOI: 10.1016/j.tvr.2022.200245
Luisa Galati , Susanna Chiocca , Daria Duca , Marta Tagliabue , Cindy Simoens , Tarik Gheit , Marc Arbyn , Massimo Tommasino

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide with an increasing trend of its incidence. Alcohol consumption, smoking, and viral infections, such as the mucosal high-risk (HR) human papillomaviruses (HPVs) are major risk factors for HNSCC development. In particular, HR HPVs are mainly associated with a subset of oropharyngeal squamous cell carcinoma (OPSCC), while other head and neck sites are marginally affected by HPV infection. HPV16 is the most frequently HR HPV type associated with HNSCC. In contrast to the cervix, no screening programs or identifiable pre-malignant lesions have been characterized for HPV-related HNSCC. Therefore, identification of general diagnostic algorithms and HPV biomarkers that could facilitate the early diagnosis, disease evolution and recurrence for HPV-driven HNSCCs are urgently needed. We herein review the role of HPV in HNSCC with a focus on epidemiology, biology, applied diagnostic algorithms and available biomarkers in body fluids as early diagnostic tools in HPV-driven HNSCCs.

头颈部鳞状细胞癌(HNSCC)是全球第六大常见癌症,其发病率呈上升趋势。饮酒、吸烟和病毒感染,如粘膜高危(HR)人乳头瘤病毒(hpv)是HNSCC发展的主要危险因素。特别是,HR HPV主要与口咽鳞状细胞癌(OPSCC)的一个亚群相关,而其他头颈部部位受HPV感染的影响很小。HPV16是与HNSCC相关的最常见的HR型HPV。与子宫颈相反,hpv相关的HNSCC没有筛查程序或可识别的恶性前病变。因此,迫切需要确定通用的诊断算法和HPV生物标志物,以促进HPV驱动的HNSCCs的早期诊断、疾病发展和复发。我们在此回顾HPV在HNSCC中的作用,重点关注流行病学,生物学,应用诊断算法和体液中可用的生物标志物作为HPV驱动的HNSCC的早期诊断工具。
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引用次数: 8
Synergistic targeting of the PI3K/mTOR and MAPK/ERK pathways in Merkel cell carcinoma 默克尔细胞癌中PI3K/mTOR和MAPK/ERK通路的协同靶向
IF 4.3 Q1 VIROLOGY Pub Date : 2022-12-01 DOI: 10.1016/j.tvr.2022.200244
Arturo Temblador , Dimitrios Topalis , Graciela Andrei , Robert Snoeck

Merkel cell carcinoma (MCC) is an aggressive type of skin cancer, which is caused either by integration of the oncogenic Merkel cell polyomavirus (MCPyV) or by accumulation of UV-light induced mutations. Since the response to immune-checkpoint inhibitors is limited, new therapeutic agents need to be explored. Previous studies have shown that MCC cell lines and xenografts are sensitive to MLN0128, a dual mTOR1/2 inhibitor. Prompted by these results and considering that the PI3K/mTOR and MAPK/ERK pathways are the most commonly deregulated pathways in cancer, the combination of MLN0128 with the MEK1/2 inhibitor trametinib was investigated. Importantly, the combined targeting showed to be synergistic in MCC cell lines and induced alterations in the protein levels of downstream elements of the targeted pathways. This synergistic activity implies a reduction in the dose of each inhibitor necessary to reach the same effect that when used as single agents. Therefore, this is a promising approach to improve the clinical management of MCC and to overcome the limited efficacy of single drug regimens owed to the appearance of toxicity or drug resistance.

默克尔细胞癌(MCC)是一种侵袭性皮肤癌,由致癌性默克尔细胞多瘤病毒(MCPyV)的整合或紫外线诱导突变的积累引起。由于对免疫检查点抑制剂的反应是有限的,因此需要探索新的治疗药物。先前的研究表明,MCC细胞系和异种移植物对mTOR1/2双抑制剂MLN0128敏感。鉴于这些结果,并考虑到PI3K/mTOR和MAPK/ERK通路是癌症中最常见的失调通路,我们研究了MLN0128与MEK1/2抑制剂曲美替尼的联合应用。重要的是,联合靶向在MCC细胞系中显示出协同作用,并诱导靶向途径下游元件蛋白水平的改变。这种协同作用意味着减少每一种抑制剂的剂量,以达到与单独使用时相同的效果。因此,这是改善MCC临床管理和克服单一药物方案因出现毒性或耐药而导致疗效有限的一个有希望的途径。
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引用次数: 1
期刊
Tumour Virus Research
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