Mapping the history and current situation of research on John Cunningham virus – a bibliometric analysis

John Cunningham virus (JCV) constitutes a family of polyoma viruses, which contain small, circular and double-stranded DNA genomes. The early region is alternatively spliced to produce large T antigen and small t antigen [1]. T antigen, a large nuclear phosphoprotein for viral DNA replication, binds to viral replication region to promote the unwinding of double helix and recruitment of cell proteins that are required for DNA synthesis. The late region encodes the capsid structural protein VP1, VP2 and VP3 due to alternative splicing and the small regulatory protein known as agnoprotein [1, 2]. VP proteins are essential to assemble with viral DNA to form virons. Serological studies have indicated an asymptomatic JCV infection in about 90% of the adult population, but it may be activated under immunosuppressive conditions, leading to the lethal demyelinating disease, progressive multifocal leukoencephalopathy (PML) [1‐5]. Evidences from transgenic and infectious animal models indicated that JCV could transform cells and cause various malignancies [6‐9]. In recent years, links have been suggested between JCV and various types of human cancers, including colorectal, prostate and esophageal cancers, brain tumors, bronchopulmonary carcinoma and B cell lymphoma [1‐9], pointing out its roles as oncovirus. However, no bibliometric investigation has been reported to guide the researchers and potential readers.

Investigators in some fields commonly predict that decision making for the following experiments, clinical practice and paper's submission should be based on the findings of scientific studies published in journals. Although scientific papers have provided useful and helpful information to the readers, it is a little difficult to learn about the history, status and future trend of some study field. The bibliometric method employs empiric data and quantitative analysis to trace the core production or citation, the content or quality of publications, and motivations of the researchers in the form of published literature so that it proves to be a valid and reliable way to map external and internal features of a scientific field [10]. A key assumption underpinning this method to catch insight into the flow of knowledge is that investigation papers represent knowledge produced by scientific research. Generally, academic productivity of individuals or groups is measured by counting the number of publications. The number of times that one work is cited is viewed as a measure of research impact. That is, the more frequently a paper is cited, the higher its impact or quality [10, 11]. Examination of bibliometric information shows the communication patterns of the investigation within the field and the patterns of influence among different work. Authors who publish earlier and experience frequent citations tend to accrue the number of citations over time as Matthew effect describes. For example, co-citation analysis (in which two papers are cited together in a paper) can indicate a strong conceptual relationship between the studies. On the other hand, PubMed indexes journal articles using MeSH terms, which constitute a thesaurus that embodies all the concepts appearing in the medical literature and are arranged in a hierarchical, tree-like structure by subject categories. Associated with MeSH is a list of corresponding subheadings to enhance the focus of MeSH searches. The combination of MeSH terms and subheadings can not only facilitate the sensitivity and specificity of search, but also indicate the research contents and the relationship between papers [12‐14]. If the further co-occurrence cluster analysis of MeSH is applied in some field, the close link between subtrees of the field will be well established.

In the present study, production and citation of JCV research have been analyzed using such bibliometric methods as chronological, co-citation and co-occurrence analysis to explore the whole history, current status and frontier about JCV study.

A systematic view of JCV papers to discern the distinct set of core researchers, institutional affiliations and corresponding countries helps us to gain a deeper understanding of approaches to JCV. As shown in our bibliometric analysis, the document type of JCV was original articles (1307/1785) and many data (209/1785) had been communicated in meeting activities. The review part occupies 6.9% (123/1785). The results indicated that JCV research was very active and interesting many investigators, and some scientists had begun to summary the achievement of JCV. Among 33 core authors, 19 persons come from Temple University, University of Tokyo, and National Institute of Neurological Disorder and Stroke, which ranked the top in the highly-produced institutes. Additionally, 14 (66.7%) core institutes of USA also focused on the investigation of JCV and USA was the first top producer of JCV papers until now. JVC was discovered in 1971 by American Padgett and named after the two initials of a patient with progressive multifocal leukoencephalopathy (PML). It was suggested that the JCV investigation originated from USA, which consequently became the top source information for JCV. It is rational and helpful for the scientists to tack the core authors and institutes to grasp the frontier of this field, open new projects and submit their distinguished work.

The list of top-cited articles about JCV identified the authors, articles and topics that reflected history and development of this specialty. Among highly-cited authors, Padgett is the discoverer for JCV in PML and published the first article in Lancet. The paper has been cited for 366 times and ranks the top in the highly-cited ones. His outstanding was also due to another article in Journal of Infectious disease, which described the detection of the antibody against JCV in PML. Therefore, it is explanatory for Padgett BL to be the most highly cited. These top-cited articles produced valuable information for readers, but also tell us some historical achievement in some field. According to these highly-cited papers, the research about JCV was chronologically separated into beginning and developing stages including discovery and isolation of JCV in PML disease, and clarification of JCV genomic DNA sequence and its relationship with diseases by polymerase chain reaction (PCR) respectively.

Most of highly-cited journals almost come from Virology, Neurology, and comprehensive journals, indicating JCV paper mainly absorbs frontier knowledge from these fields. Oncogene, Journal of Biological Chemistry, and International Journal of Cancer also become the highly-cited journal (data not shown), indicating the attempts of JCV study to combine with Molecular Biology and Oncology. This data also demonstrate the close link of JCV with these specialties. In the overall references of JCV papers, most highly-cited articles were published in Proceeding of National Academy and Science, USA and New England Journal of Medicine, indicating that these famous-brand journals highlight the investigation of JCV and emphasized the scientific achievement of JCV. Therefore, investigators of JCV not only read the journals of Virology, but also emphasized the novel findings of JCV published in other journals with high impact factor.

Methodologically, the cluster techniques include text segmentation, summary extraction, feature selection, term association, cluster generation, topic identification, and information mapping [19]. Clustering algorithms prominently used in co-citation analysis has proved very useful in revealing research streams in some discipline [20‐23]. Here, we carried out empirical co-citation analysis to map the network of highly-cited papers about JCV. Our data indicated that these top highly-cited articles were grouped into such 4 aspects as the correlation between JC virus and tumors, causal correlation of JCV with PML, polyoma virus infection and its related diseases in renal-allograft recipients, detection of JCV antibody, oncogene and its encoding protein, and genetics and molecular biology of JCV. These findings might not only enrich the knowledge of students and specialists about the development's history of JCV research, but also open new bursts of scientific investigation.

Co-occurrence has been considered as carriers of meaning across different domains in studies of science. Based on this principle, we performed co-occurrence cluster analysis using Pubmed MeSH/subheading words to construct a new tie between two words depending on the co-existing frequencies [24]. Consequently, most of the top highly-frequent MeSH/subheading words are mainly classified into C02 subcategory of MeSH (Viral Disease) and B04 subcategory (Viruses). The analytic data showed that the contents of published papers about JCV included JCV isolation and detection, as well as JCV and virus infectious diseases like PML or tumors. It was suggested that JCV investigation centered on its isolation, its pathogenicity of PML and its genetics at early time. Recently, the causal relationship between JCV and tumors has been emphasized by the scientists. It was demonstrated that JCV investigation like isolation and detection mainly aimed to clarify the molecular mechanism of its relevant diseases including PML and tumors.

As well known, JCV infection experiences two outcomes as other viruses. In un-permissive condition, JCV infection initiates binding to the JCV-sensitive cell surface and JCV capsids undergo endocytosis and are transported to the nucleus where the viral DNA is uncoated and the early and late region begins to be transcripted. Subsequently, JCV genomic DNA is assembled with caspid protein to undergo the lytic viral release, finally to cause demyelinating disease, PML. Under permissive infection, viral DNA can replicate, resulting in lytic infection with viral amplification and non-permissive cells don't allow the viral replication, leading to an abortive infection or cell transformation [6‐9]. The evidence provided enough reasons for the following data: (1) The core and highly-cited journals mainly contained the field of virology, neurology and oncology; (2) The highly-cited articles and highly-frequent MeSH/subheading also mentioned the research contents of JCV, PML and tumors.

Recently, the further clarification of JCV genetics promoted the scientists to detect its genomic existence in tumors or make the transgenic mice to study the oncogenic role of JCV. Our group had examined the JCV targeting T antigen using nested-PCR, real-time PCR, in situ PCR, in situ hybridization, and immunohistochemistry [6‐9]. It was found that positive rate and copies of JCV were higher in gastric, lung and tongue carcinomas than corresponding normal tissues, indicating its oncogenic role in epithelial carcinogenesis. Furthermore, JCV T antigen can serve as helicase, and polymerase, orchestrate the assembly and function of cellular proteins, disrupt the signal pathways of p53, Rb and Wnt signaling pathway, and should be considered as a viral oncogene [2‐4]. Therefore, we are establishing a transgenic model of gastric neoplasia induced by JCV T antigen, which will help to verify the oncogenic role of JCV in gastric carcinoma and provide a novel tool to investigate gastric carcinomas. It was hypothesized that application of JCV T antigen in tumor transgenic animal model would be a novel and hot project in the future.

In this study, we successfully performed the scientometric analysis of JCV literature. Our data indicated that JCV mainly centered on PML and tumors. The bibliometric study assists researchers to know the history and frontier of JCV investigation, guide them to open new projects and submit the distinguished work. These cluster methods employed in this investigation can clarify the history, status and development in the field of JCV.