Classic articles in Apoptotic Research: A Bibliometric Analysis

Background Classic articles are defined as research papers with a total citation of one thousand or more. The present study is to identify and analyse the characteristics of the classic articles in apoptosis research. Method Classic articles with total of 1,000 or more citations from Web of Science Core Collection since year of publication to the end of 2017 were basically assessed regarding their document types, languages, journals, and Web of Science categories within 1900 to 2017. Result The study showed 418 classic documents in apoptotic research including 260 articles published between 1972 and 2012. The most productive Web of Science category was multidisciplinary sciences. Nature published most of these classic articles followed by Cell, and Science. The most productive country and institution were United States and Harvard University respectively. The author S.J. Korsmeyer from Harvard University was the most productive in apoptosis field and published 13 classic apoptosis articles while the author J.C Reed had more potential to publish classic apoptosis articles in future. The author J.C. Reed and V.A. Fadok had equal potential to publish the same number of classic articles as first- and corresponding-author. Article of Kerr et al. in 1972 was the most popular and cited apoptosis article. The most impact article in 2017 was article entitled “Tumor-associated B7-H1 promotes T-cell apoptosis: A potential mechanism of immune evasion” by Dong et al. in 2002. Conclusion This study seems to identify the most industrious authors, institutions, and countries in the field of apoptosis research. It also tends to reveal the historical and discoveries related to the pathophysiology of apoptosis as well as the most impact publications on apoptosis studies.


INTRODUCTION
Decades, after the discovery of the term apoptosis by Kerr, Wyllie, and Currie in 1972 (1) and the involvement of program cell death in the pathogenesis of various diseases and abnormalities in human, gave an extensive interest in the research of apoptosis. John Foxton Ross Kerr was the first to describe the phenomenon of apoptosis and placing the roles of cell death in normal adult mammals and diseases into scientific focus (2). Million cells die in our body every second committing suicide by the mechanism of apoptosis. Apoptosis is also significant for the survival of the body and play vital roles in various developmental process and the immune system (3). Conditions such as cancers, Autoimmune diseases, inflammatory diseases and viral infection can be as a result of apoptosis hindrances and also been known that accumulation of cells is due to decrease cell death (4). Kerr and his group studied the process of cell death in different conditions such as in neoplasms, liver and adrenal injury, and ontogenesis. They found out that the morphological and ultra-structural features displayed by the phenomenon of cell death in each case were similar (5). The occurrence of cell death is interesting where it is being controlled in an event such as embryonic development, metamorphosis and hormone-dependent atrophy but where it is as a result of toxin agents, will undergo different morphology and necrosis will be observed (6). Death of several type of normal and neoplastic lymphoid cell is caused by physiological concentration and glucocorticoid hormones but the mechanisms are unknown (7). A classic article with at least 1,000 citations (8) by Evan in 1992 entitled "Induction of apoptosis in fibroblasts by c-myc protein" was referred as 'hot paper' in Scientist (9) because it partly explained the phenomenon of cancer as well as the growth and suicidal pathway of cells. In another classic article, reported that engaging CD3/T-cell receptor complex with anti-CD3 antibodies can induced apoptosis by DNA degradation (10). For many years, neither apoptosis nor programmed cell death was a highly cited term. But after the discovery of the components of cell death, mechanisms and involvement of abnormal cell death in diseases, increased apoptosis researches substantially in the early 1990s (3). Apoptosis may play role in cell turnover in many healthy adult tissues and is accountable for expelling of cells during normal embryonic development (1). In dying epidermal cells, the morphological changes that occur are similar with those in programmed cell death then has essential role in the development of vertebrate embryos and can also contribute in controlling the size of tissues in adult under both normal and pathological state (11). In addition, Kerr and Searle (1973) also presented deletion of cells by apoptosis during castration-induced involution of rat prostate.
Bibliometric method can be applied to determine the impact of publications and research groups in their research field (12). It is also an ideal way to quantify the quality of published work for organizations, authors, and countries (13). High quality paper with exemplary for other researchers is considered classic (14). Today, it is essential to determine the countries and institutions research performances using Science Citation Index Expanded or Social Science Citation Index to evaluate their research performances in various aspects (15,16). In recent years, analysis of classic articles with 1,000 total citations or more in Web of Science categories of surgery (8), psychology (16), neurosciences (17), and orthopedics (18) have been conducted to assess the research performances and productivity among countries and institutions. Publication indicators such as number of total, independent, collaborative, firstauthor, corresponding-author, and single author classic articles as well as citation indicators including total citations from publication to the end of the most recent year and citations the most recent year only were applied to evaluate publication performances of countries and institutions.
This current study will show the results of classic articles in apoptosis extracted from SCI-EXPANDED. Description and analysis of classic articles in terms of document types, publication language, publication outputs, citation impact and comparison of performances among countries, institutions, and author applying the six publication indicators. We also applied the Y-index parameter introduced by Ho (13,19) to distinguish researchers' characteristics and who had higher potential in publishing classic articles. Data were clearly drafted and represented in tables and figures for clear evidence and explanation.
Total citations from Web of Science Core Collection since date of publication to the end of 2017 with the notation TC 2017 (22,23). Classic articles were defined as TC 2017  1,000 (8).
Similarly, C 2017 was defined as the total citations within 2017 (13) and was used to characterize the classic articles (8). All the records and citations for each paper was recorded yearly then downloaded and confirmed in spreadsheet software. It was pointed that it is necessary to have a data treatment when using the Web of Science database for bibliometric studies (24).
Thus we manipulated using Microsoft Excel 2016 (25,26). Publication performance of countries and institutions were analysed by using the six Ho's publication indicators such as total number of publications (TP), independent publications (IP), collaborative publications (CP), first-author publications (FP), corresponding-author publications (RP), and singleauthor publications (SP) (12,27,28). Affiliations such as England, Scotland, Northern Ireland, and Wales were reclassified to be part of United Kingdom (UK) (27). Affiliations in Fed Rep Ger (Federal Republic of Germany) reclassified to be part Germany (13). The corresponding-author is designated as the "reprint author" in the SCI-EXPANDED database.
Therefore, we will hereby be using the term "corresponding-author" in this study (29). In a situation where authorship is unspecified in a single author paper, the author is both the firstand corresponding-author (13). Similarly, as in a single institutional paper, the institution is classified as the first-and corresponding-author institution.
We also applied the Y-index indicator proposed by Ho to assess and compare publication potentials of different authors and their contribution characteristic in single index within the same research field. The Y-index is related to the number of first-author publications (FP) and corresponding-author publications (RP). The Y-index combines the two parameters j and h, denoted as (j, h) (13,19). This indicator was also being applied to compare authors' publication performances in classic articles published by American scientists (30).
The Y-index (j, h) is defined as: where FP is the number of first-author articles; RP as number of corresponding-author articles; j is the publication potential which is a constant related to publication quantity, and h   Table 1). Document of articles was further studied. All the classic apoptotic articles in SCI-EXPANDED were published in English.   Table 2 showed that 65% of 260 articles were published in the top four productive journals with IF 2017 higher than 30 (IF 2017 > 30). As listed in the Table 2 In total, 220 articles (85% of 260 articles) were published in the top three categories such as multidisciplinary sciences (44% of 260 articles), cell biology (95 articles; 37%), and biochemistry and molecular biology (93; 36%). Other categories with less articles include, 20 articles in research and experimental medicine and 13 articles in oncology and immunology were found respectively. It has been noticed that journals could be classified in two or more categories in Web of Science, for example Nature Medicine was classified in the categories of biochemistry and molecular biology, cell biology, and research and experimental medicine thus the sum of percentages was higher than 100% (19).

Publication Performances: Countries, Institutions, and Authors
The 259 articles with author affiliations from 26 countries, 189 (73% of 259 articles) were single country articles from 13 countries and 70 (27%) were internationally collaborative articles from 25 countries. The top 10 productive countries published seven articles or more with 97% of 259 classic articles as listed in Table 3. The seven major industrialized countries (G7) including the USA, the UK, Japan, Canada, Germany, France, and Italy published majority of the apoptosis papers, contributing 93% of the 259 classic articles, especially the USA with 201 articles (78% of 259 articles). In total, 83 (32% of 259 articles) were single institution articles and 176 (68%) were inter-institutionally collaborative articles including 106 (60% of 176 articles) nationally collaborative articles and 70 (40%) internationally collaborative articles. Table 4 shows the 13 most productive institutions whose authors  In Fig. 5, the author C. Reed and V.A. Fadok have more potential to publish classic apoptosis article in the future. Takahashi had a low publication characteristic (h) and with more firstauthor articles than corresponding-author articles, indicating that the top productive authors contributing to apoptosis research field were more likely to be designated as the corresponding-authors. The same result was also reported in the classic articles published by American scientists (30) and the highly cited articles in health care sciences and services field (32)

Highly cited articles and high impact articles in the most recent year
The top 10 classic articles with TC 2017 of 4,112 or more were listed in Table 5 history, but much less impact in 2017 (Fig. 3). Sharply increasing trends of citations after publication year and then reached a citation peak could be found most in the top 10 articles but Kerr et al. (1972) and  had low citations after publication for more than a decade (Fig. 3). One of the top 10 most impact articles in 2017, was published in the 1970s and the 2010s respectively and others were published in the 2000s (Fig. 4). Articles entitled "Tumor-associated B7-H1 promotes T-cell apoptosis: A potential mechanism of immune evasion" by 13 authors from Mayo Clinic in USA was the most impact article in 2017 with C 2017 of 363. We expect this to receive more citation in the future (Fig. 4).

Major findings
There were 418 classic apoptosis publications in SCI-EXPANDED within seven document types. Articles were found slightly higher in citations per publication than that of reviews. All  The most frequently cited articles are usually published in journals with high impact factor (IF) (37). Nature, Cell, Science and Nature Medicine were the most productive journals.
Theses journals received more classic articles with high IF 2017. Majority of the articles were published in the top three subject categories including multidisciplinary sciences, cell biology, and biochemistry and molecular biology.
In recent year, Ho's group introduced a relationship between number of classic articles in a year (TP) and their citations per publication (CPP year = TC year / TP) by decade as a figure in medical related fields, for example surgery (8), psychology (16), and neurosciences (17). Table 3 In terms of country publication performances with the indicators TP, TPR, IPR, FPR, and RPR introduced by Ho and his group. We found USA as the most industrious followed by UK and then Japan.

Table 4
Harvard University was considered the most productive and then follow by Washington University with far distance. Children's Hospital and Massachusetts Institute of Technology (MIT) both ranked equal in terms of total publication (TP). Harvard University has the authors name S.J Korsmeyer who published the most 13 classic apoptosis articles with two corresponding-authors. Therefore, we may conclude by recommending Harvard University as the best institution for apoptosis studies worldwide.

Table 5
The articles in table 5 were the most highly cited with TC 2017 > 4,000. This study has shown that these articles were highly cited to foster more understanding on the pathophysiology of apoptosis. The most highly cited articles will be explained as follows:

1) Apoptosis: Basic biological phenomenon with wide-ranging implications in tissue
kinetics Kerr et al. (1972) (1): This was the first classic article on apoptosis. The researchers described the nature of apoptosis and its involvement in certain disease conditions. The term apoptosis became popular after this article was published then follow by the discoveries of latest technologies to detect apoptosis in the 1990s.

2) Identification of programmed cell-death Insitu via specific labeling of nuclear-DNA
fragmentation   (38): This article was the fastest growing in citations and reached high plateau within a decade. In this article, the researchers developed an observation technique to identify apoptosis (cell death) through staining a fragmented DNA. It was concluded that DNA fragmentation is associated with programmed cell death and therefore contributing to the gate way for more apoptosis studies. This explains why it was rapidly cited.
3) Significance analysis of microarrays applied to the ionizing radiation response ) (34): The Significance analysis of microarrays has paved way for researchers to further investigate genes and their functions. This article introduced a method called Significance Analysis of Microarrays (SAM) to determine genes expression at different biological states. Cells were exposed in ironizing radiation to examine their respond by measuring with microarray. Genes that involves in regulating cell cycle and apoptosis (cell death) were identified. Interestingly, genes that repair DNA damages were also found. This article contributed greatly for apoptosis studies and was swiftly cited to reach a high peak. Cytochrome c is released from the mitochondria to bind with procaspase 9 and Apaf-1 for caspase 9 activation. Activated caspase 9 will trigger caspase 3 to execute apoptosis (cell death). This article was highly cited for describing the mitochondria apoptotic pathway.

5) Bcl-2 heterodimerizes in vivo with a conserved homolog, bax, that accelerates
programmed cell death (Oltvai et al., 1993) (40): The role of Bcl-2 protein in initiating apoptosis was also investigated in the article. The Bcl-2 interacts with other components for example Bax to progress apoptosis. This article was also highly cited. 6) Opposing effects of erk and JNK-p38 map kinases on apoptosis      (42): The purpose of this study on the role of akt in apoptosis was also similar to that of article by Datta et al. (1997).
Surprisingly, this article took shorter period to accumulate more than one hundred citations compared to other articles. It could be due to its extensive study on the transcription factor (FKHRL1) related to apoptosis. Suppression of apoptosis transcription factors by Akt will promote cell survival. 9) Glucocorticoid-induced thymocyte apoptosis is associated with endogenous endonuclease activation   (6): This was the second oldest apoptosis article after the first article of Kerr et al. (1972). The author was also part of the group in the first article. This study investigated endogenous endonuclease in apoptosis. Activation of the endonuclease was found to induced chromatin cleavage for DNA degradation (apoptosis). Therefore, inhibiting endogenous endonuclease could be a strategy to prevent apoptosis. This article was highly cited in the 1990s.

Figure 5. Y-index
In this study, applying the Y-index method was able to help in identifying the most industrious and well-known authors in the research of apoptosis. The memos of few greatest authors who contributed immensely in the field of apoptosis will be discuss as follows.
Stanley J. Korsmeyer (1950 gene to treat cancer. Scott was recognised for his tremendous effort on cancer and apoptosis (46). In this study, he published the most three first-author articles with K. Kuida.

Julian Downward (1960, age 59 years):
He is also another top researcher with scientific visionary in the area of cancer. Julian is from Francis Crick Institute and Senior Group Leader at the Institute of Cancer Research. He was known for his contribution for enlighten cellular signal transduction pathways on oncogenes (47). John potentials was recognised when this study reported him to be among the four authors to publish a single author article.          Article list is shown in Table 5.