The Open Respiratory Medicine Journal




ISSN: 1874-3064 ― Volume 13, 2019
LETTER

Serum CYFRA 21-1 but not Vimentin is Associated with Poor Prognosis in Advanced Lung Cancer Patients



Nobuhiro Kanaji1, *, Kyuichi Kadota2, Akira Tadokoro1, Takuya Inoue1, Naoki Watanabe1, Reiji Haba2, Norimitsu Kadowaki1, Tomoya Ishii1
1 Department of Internal Medicine, Division of Hematology, Rheumatology and Respiratory Medicine, Faculty of Medicine, Kagawa University, Kagawa, Japan
2 Department of Diagnostic Pathology, Faculty of Medicine, Kagawa University, Kagawa, Japan

Abstract

Background:

Cytokeratins and Vimentin are intermediate filament proteins. Vimentin expression in tissue samples has been reported to be associated with a poor prognosis in non-small cell lung cancer patients who underwent surgery. CYFRA 21-1 (Cytokeratin 19 Fragment) is a well known tumor marker.

Objective:

This study aimed to investigate the usefulness of serum vimentin as a tumor marker and significance of CYFRA 21-1 and vimentin expression on prognosis of advanced lung cancer patients.

Methods:

One hundred and four advanced lung cancer patients and 19 non-lung cancer patients were included. A total of 157 clinical samples obtained from 113 patients was used for immunostaining of vimentin and measurements of CYFRA 21-1 and vimentin concentrations.

Results:

Compared to low concentration, high concentration of serum CYFRA 21-1 was associated with shorter overall survival in lung cancer patients. However, there was no difference in the serum vimentin concentration between the patients with lung cancer and those with non-lung cancer. No difference in vimentin concentration was observed between the malignant and non-malignant pleural effusions. Immunostaining revealed that of the 43 tumor samples, 21 were positive and 22 were negative for vimentin. No significant difference was found in overall survival between patients with positive and negative for vimentin.

Conclusion:

An elevated serum CYFRA 21-1 concentration was associated with shorter overall survival in advanced lung cancer patients. However, serum vimentin was not as useful as a tumor marker of lung cancer. The vimentin positivity in tumor samples might not predict patients’ prognosis in patients with advanced lung cancer.

Key words: Lung cancer, Pleural effusion, Serum, Tumor marker, Vimentin, Cytokeratin, CYFRA 21-1, Prognosis.


Article Information


Identifiers and Pagination:

Year: 2019
Volume: 13
First Page: 31
Last Page: 37
Publisher Id: TORMJ-13-31
DOI: 10.2174/1874306401913010031

Article History:

Received Date: 15/03/2019
Revision Received Date: 29/05/2019
Acceptance Date: 15/06/2019
Electronic publication date: 09/07/2019
Collection year: 2019

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© 2019 Kanaji et al.

open-access license: This is an open access article distributed under the terms of the Creative Commons Attribution 4.0 International Public License (CC-BY 4.0), a copy of which is available at: https://creativecommons.org/licenses/by/4.0/legalcode. This license permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


* Address correspondence to this author at Department of Internal Medicine, Division of Hematology, Rheumatology and Respiratory Medicine, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa 761-0793, Japan., Tel: +81-87-891-2145; Fax: +81-87-891-2147.,
E-mail: kanaji@med.kagawa-u.ac.jp





1. INTRODUCTION

Cytokeratins are type I and II intermediate filament proteins, and cytokeratin 19 fragments (CYFRA 21-1) have been used as tumor markers for Non-Small Cell Lung Cancer (NSCLC). Vimentin is the type III intermediate filament protein that is widely expressed in mesenchymal cells. Vimentin is also expressed in a variety of cancer cells such as prostate, ovarian and lung cancers, and particularly in poorly differentiated, metastatic, or invasive cancers [1Lang SH, Hyde C, Reid IN, et al. Enhanced expression of vimentin in motile prostate cell lines and in poorly differentiated and metastatic prostate carcinoma. Prostate 2002; 52(4): 253-63.[http://dx.doi.org/10.1002/pros.10088] [PMID: 12210485] -5Tadokoro A, Kanaji N, Liu D, et al. Vimentin regulates invasiveness and is a poor prognostic marker in non-small cell lung cancer. Anticancer Res 2016; 36(4): 1545-51.[PMID: 27069130] ]. In studies of lung cancer, vimentin was detected in 145 of 295 NSCLC cases (49.2%) by immunohistochemistry [6Dauphin M, Barbe C, Lemaire S, et al. Vimentin expression predicts the occurrence of metastases in non small cell lung carcinomas. Lung Cancer 2013; 81(1): 117-22.[http://dx.doi.org/10.1016/j.lungcan.2013.03.011] [PMID: 23562674] ]. Vimentin expression was associated with the histology (other types than adenocarcinoma and squamous cell carcinoma) and the poor differentiation status of NSCLCs, and with the occurrence of metastasis [6Dauphin M, Barbe C, Lemaire S, et al. Vimentin expression predicts the occurrence of metastases in non small cell lung carcinomas. Lung Cancer 2013; 81(1): 117-22.[http://dx.doi.org/10.1016/j.lungcan.2013.03.011] [PMID: 23562674] ]. Vimentin expression was also shown to be associated with a poor prognosis in NSCLC patients who underwent surgery [5Tadokoro A, Kanaji N, Liu D, et al. Vimentin regulates invasiveness and is a poor prognostic marker in non-small cell lung cancer. Anticancer Res 2016; 36(4): 1545-51.[PMID: 27069130] , 7Al-Saad S, Al-Shibli K, Donnem T, Persson M, Bremnes RM, Busund LT. The prognostic impact of NF-kappaB p105, vimentin, E-cadherin and Par6 expression in epithelial and stromal compartment in non-small-cell lung cancer. Br J Cancer 2008; 99(9): 1476-83.[http://dx.doi.org/10.1038/sj.bjc.6604713] [PMID: 18854838] ]. It is also known that vimentin is a marker of epithelial to mesenchymal transition (EMT) [8Vuoriluoto K, Haugen H, Kiviluoto S, et al. Vimentin regulates EMT induction by Slug and oncogenic H-Ras and migration by governing Axl expression in breast cancer. Oncogene 2011; 30(12): 1436-48.[http://dx.doi.org/10.1038/onc.2010.509] [PMID: 21057535] ]. Generally, cancer cells that have undergone an EMT show a high grade of malignancy and have invasive or metastatic potential [9Miyazono K. Transforming growth factor-beta signaling in epithelial-mesenchymal transition and progression of cancer. Proc Jpn Acad, Ser B, Phys Biol Sci 2009; 85(8): 314-23.[http://dx.doi.org/10.2183/pjab.85.314] [PMID: 19838011] ]. These findings suggested that the expression of vimentin in tissue samples could be positively associated with a high grade of malignancies, including lung cancer. However, the significance of vimentin expression on the prognosis of patients with advanced lung cancer has never been studied.

When tested in the serum samples of patients with hepatocellular carcinoma, the vimentin level was significantly higher in small tumors (<2 cm) than in non-neoplastic controls (p<0.01), and was found to be more useful rather than serum alpha-fetoprotein [10Sun S, Poon RT, Lee NP, et al. Proteomics of hepatocellular carcinoma: serum vimentin as a surrogate marker for small tumors (<or=2 cm). J Proteome Res 2010; 9(4): 1923-30.[http://dx.doi.org/10.1021/pr901085z] [PMID: 20121168] ]. Serum vimentin might be useful as a tumor marker in patients with lung cancer. However, the significance of the serum vimentin level in lung cancer patients has never been reported.

In the present study, we assessed the association of vimentin expression with survival in advanced lung cancer patients. In addition, we measured the vimentin concentrations in sera and pleural effusions in lung cancer patients and compared with known tumor markers such as CYFRA 21-1, to determine the significance of the serum vimentin level in lung cancer.

2. PATIENTS AND METHODS

2.1. Patients

This study was approved by the Institutional Review Board of Kagawa University (H25-053). Patients with pathologically confirmed advanced (stage III or IV) lung cancer who presented to the Department of Internal Medicine, Kagawa University Hospital between November 2013 to March 2018 and provided written informed consent were included. The lung cancers were staged according to the 7th edition of the TNM classification [11Goldstraw P, Crowley J, Chansky K, et al. The IASLC Lung Cancer Staging Project: proposals for the revision of the TNM stage groupings in the forthcoming (seventh) edition of the TNM Classification of malignant tumours. J Thorac Oncol 2007; 2(8): 706-14.[http://dx.doi.org/10.1097/JTO.0b013e31812f3c1a] [PMID: 17762 336] ]. Patients who had undergone surgical treatment for lung cancer and those who had another concomitant active malignancy were excluded. For comparison, non-lung cancer patients who provided written informed consent for their materials to be used were also included. Relevant clinical and laboratory data were collected from the patients' medical records. Patient’s daily living activities were expressed by Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) (available at https://ecog-acrin.org/resources.ecog-performance-status).

2.2. Measurement of Serum Vimentin, CEA, and CYFRA21-1 Concentrations

The concentration of serum vimentin was measured by a human vimentin Enzyme-Linked Immunosorbent Assay (ELISA) kit (#CSB-E08982h, Cusabio Biotech, College Park, MD, USA or #MBS721933, MyBioSource, San Diego, CA) according to the manufacturer’s instructions. The serum was diluted at 1:100 (#CSB-E08982h) or not diluted (#MBS721933) for the ELISA to prepare the appropriate measurable range of vimentin concentrations. Serum carcinoembryonic antigen (CEA) was measured by a chemiluminescence immunoassay kit (Architect 47-0522/R04; Abbott Japan Co., Tokyo, Japan). Serum CYFRA21-1 was measured by an electro-chemiluminescence immunoassay kit (ECLusys reagent CYFRA; Roche Diagnostics, Ritkreuz, Switzerland).

2.3. Vimentin Immunostaining

The immunostaining and the assessment of vimentin in tissue and cell block samples were performed as described [5Tadokoro A, Kanaji N, Liu D, et al. Vimentin regulates invasiveness and is a poor prognostic marker in non-small cell lung cancer. Anticancer Res 2016; 36(4): 1545-51.[PMID: 27069130] ]. Briefly, samples were fixed with 10% phosphate-buffered formalin, and paraffin-embedded sections were immunohistochemically examined using anti-vimentin antibody (Clone V9, #M0725; Dako, Glostrup, Denmark) using a Ventana BenchMark XT autostainer (Ventana Medical Systems, Tucson, AZ). All areas of each tumor were evaluated, and the percentage of tumor cells that expressed vimentin at any intensity level was calculated. A positive case was defined as the presence of >5% of cancer cells that express vimentin.

2.4. Detection of EGFR Mutations and ALK Fusions

Epidermal Growth Factor Receptor (EGFR) mutations were examined by the Cobas EGFR Mutation Test (Roche Diagnostics). Anaplastic Lymphoma Kinase (ALK) fusions were examined by immunohistochemistry (Nichirei’s N-Histofine ALK detection kit; Nichirei Biosciences inc., Tokyo, Japan) and fluorescence in situ hybridization (Vysis LSI ALK Dual Color, Break Apart Rearrangement Probe; Abbott).

2.5. Statistical Analysis

Student’s t-test was used to compare two-group data (vimentin concentrations). The data are expressed as means ± standard error of the mean. Overall Survival (OS) was defined as the time between the date of diagnosis and the date of death from any cause. OS curves were constructed by the Kaplan-Meier method, and the differences in OS were assessed using the log-rank test. All statistical analyses were conducted using Excel 2013 and Ekuseru-Toukei 2015 software (Social Survey Research Information, Tokyo).

3. RESULTS

3.1. Patients and Clinical Samples

One hundred and four lung cancer patients and 19 non-lung cancer patients were included in this study. The characteristics of lung cancer patients are shown in Table 1. We obtained 157 clinical samples from 113 patients (94 with lung cancer and 19 with non-lung cancer) before the administration of treatment (chemotherapy and/or radiotherapy) for lung cancer. These samples include 113 peripheral blood samples and 44 pleural effusion samples. Tissue and cell block samples were prepared from liquid cell samples such as pleural effusions and the wash from a bronchoscopic examination.

Table 1
Lung cancer patients’ characteristics.


Fig. (1)
Kaplan-Meier curves of overall survival in patients with advanced lung cancer, dependent on the status of (A) ECOG performance status, (B) Presence or absence of EGFR mutations or ALK fusions, (C) Serum CYFRA21-1, and (D) Serum CEA.


3.2. Overall Survival of Lung Cancer Patients

The Kaplan-Meier survival curves illustrate that the patients with poor ECOG PS showed shorter overall survival (Fig. (1A), median 115 vs 486 days, p<0.0001). Patients with driver gene mutations, that is, EGFR mutations or ALK fusions, had longer survival (Fig. (1B), median 507 vs 317 days, p=0.0140). An elevated serum CYFRA21-1 concentration was associated with poor survival (Fig. (1C), median 258 vs 614 days, p=0.0195). Serum Carcinoembryonic Antigen (CEA) concentration were not related to survival (Fig. (1D).

3.3. Vimentin Expression in Tissue and Cell Block Samples

To confirm that some lung cancer cells express vimentin, we assessed the vimentin expression by immunostaining in 36 tissue samples and 15 cell block samples. Both tissue and cell block samples were available in 7 patients. Thus vimentin expressions in tumor samples were assessed in 43 patients. Twenty-one tumors were positive and 22 were negative for vimentin (a representative of positivity in cell block samples is shown in Figs. (2A) and (2B), demonstrating that vimentin is certainly expressed in some lung cancer cells. All 43 NSCLC patients underwent chemotherapy and/or molecular targeted therapy. No significant difference was found in the Kaplan-Meier survival curves for OS (Fig. (2C), median 507 vs. 392 days, p=0.2654) in patients with positive versus negative for vimentin. When analyzed in patients limited in stage IV, no difference in OS was still observed between vimentin positivity.


3.4. The Serum Vimentin Concentrations

When used an ELISA kit (CSB-E08982h), no significant difference was revealed in the serum vimentin concentration between the patients with lung cancer (n=69) and those with non-lung cancer (n=15, including five infectious disease and three bronchial asthma patients) (Fig. 3A) or between the patients with NSCLC (n=57) and those with small-cell lung cancer (SCLC) (n=12) (Fig. 3B), although the standard curves were drawn without any problem (data not shown). We also measured the vimentin concentration in pleural effusions (n=22). No significant difference in the concentration was observed whether cancer cells were detected (malignant pleural effusion) or not in pleural effusions (Fig. 3C). In addition, there was no significant difference in the vimentin concentration between the serum and the malignant pleural effusion in six patients for whom both samples were available (data not shown).

To determine whether the non-positivity of serum vimentin in lung cancer patients is true, we additionally measured the concentrations of vimentin using another ELISA kit (#MBS 721933). Clear standard curves were acquired with this ELISA kit (data not shown). However, there was no significant difference in the concentration of serum vimentin between the patients with lung cancer (n=25) and those with non-lung cancer (n=4, including chronic obstructive pulmonary diseases and interstitial lung diseases) (Fig. 3D), or between the patients with NSCLC (n=20) and those with SCLC (n=5) (Fig. 3E).

In addition, no significant difference in vimentin concentrations was observed in the pleural effusions between the malignant pleural effusions (n=13) and the non-malignant pleural effusions (n=9) (Fig. 3F).

Fig. (2)
(A and B) A representative of vimentin positivity in lung cancer cells. (A) Hematoxylin-eosin staining and (B) Immunostaining of vimentin in a cell block sample obtained from a patient with adenocarcinoma. (C) Kaplan-Meier curves of overall survival in patients with advanced lung cancer, dependent on the status of vimentin positivity based on immunostaining.


Fig. (3)
The vimentin concentrations in clinical samples measured by ELISA kits: (A-C) CSB-E08982h (Cusabio Biotech) and (D-F) MBS721933, (MyBioSource). (A) Serum vimentin in patients with lung cancer vs. non-lung cancer. (B) Serum vimentin in patients with NSCLC vs. SCLC. (C) Vimentin in pleural effusions in which cancer cells are present vs. absent. (D) Serum vimentin in patients with lung cancer vs. non-lung cancer. (E): Serum vimentin in patients with NSCLC vs. SCLC. (F): Vimentin in pleural effusions in which cancer cells are present vs. absent.


4. DISCUSSION

Our findings demonstrated that (1) the vimentin expression was not associated with survival in advanced lung cancer patients, (2) elevated serum CYFRA 21-1 concentration was associated with poor survival, (3) the vimentin concentration was not increased in the sera or malignant pleural effusions of patients with advanced lung cancer. The absence of a significant difference in vimentin concentrations between lung cancer and non-lung cancer was confirmed by two commercially available ELISA kits. These findings suggest that the serum vimentin concentration is not useful as a tumor marker of lung cancer.

Previous studies using mesenchymal cells cultured in vitro have indicated that vimentin is largely insoluble [12Blikstad I, Lazarides E. Vimentin filaments are assembled from a soluble precursor in avian erythroid cells. J Cell Biol 1983; 96(6): 1803-8.[http://dx.doi.org/10.1083/jcb.96.6.1803] [PMID: 6682861] , 13Murray ME, Mendez MG, Janmey PA. Substrate stiffness regulates solubility of cellular vimentin. Mol Biol Cell 2014; 25(1): 87-94.[http://dx.doi.org/10.1091/mbc.e13-06-0326] [PMID: 24173714] ]. Vimentin solubility was reported to be associated with substrate stiffness as well as aspects of the cellular environment such as serum starvation, cell-cell contacts, and other cytoskeletal assemblies including myosin and actin [13Murray ME, Mendez MG, Janmey PA. Substrate stiffness regulates solubility of cellular vimentin. Mol Biol Cell 2014; 25(1): 87-94.[http://dx.doi.org/10.1091/mbc.e13-06-0326] [PMID: 24173714] ]. Although the expression of vimentin as well as, those of cytokeratin and actin would be dynamically dependent on the in vivo cellular environment, the vimentin release into sera seems to be too faint for use as a tumor marker of lung cancer.

In NSCLC patients who underwent surgery, the vimentin expression assessed by immunostaining was associated with a poor prognosis [5Tadokoro A, Kanaji N, Liu D, et al. Vimentin regulates invasiveness and is a poor prognostic marker in non-small cell lung cancer. Anticancer Res 2016; 36(4): 1545-51.[PMID: 27069130] , 7Al-Saad S, Al-Shibli K, Donnem T, Persson M, Bremnes RM, Busund LT. The prognostic impact of NF-kappaB p105, vimentin, E-cadherin and Par6 expression in epithelial and stromal compartment in non-small-cell lung cancer. Br J Cancer 2008; 99(9): 1476-83.[http://dx.doi.org/10.1038/sj.bjc.6604713] [PMID: 18854838] ]. In the present study, however, there was no significant difference in OS between the vimentin-positive and negative patients. Judged from small sample size (n=43), vimentin expression might not predict the prognosis of patients with advanced lung cancer.

The current study demonstrated that elevated serum CYFRA 21-1 concentration was associated with poor survival. Several studies have reported an association of CYFRA 21-1 with prognosis in NSCLC patients [14Xu Y, Xu L, Qiu M, et al. Prognostic value of serum cytokeratin 19 fragments (Cyfra 21-1) in patients with non-small cell lung cancer. Sci Rep 2015; 5: 9444.[http://dx.doi.org/10.1038/srep09444] [PMID: 25901419] -21Shirasu H, Ono A, Omae K, et al. CYFRA 21-1 predicts the efficacy of nivolumab in patients with advanced lung adenocarcinoma. Tumour Biol 2018; 40(2)1010428318760420[http://dx.doi.org/10.1177/1010428318760420] [PMID: 29463190] ]. An elevated serum CYFRA 21-1 concentration showed shorter survival in patients treated with pemetrexed-based chemotherapy or EG FR-TKIs [15Sone K, Oguri T, Nakao M, et al. CYFRA 21-1 as a predictive marker for non-small cell lung cancer treated with pemetrexed-based chemotherapy. Anticancer Res 2017; 37(2): 935-9.[http://dx.doi.org/10.21873/anticanres.11402] [PMID: 28179355] -18Takeuchi A, Oguri T, Sone K, et al. Predictive and prognostic value of CYFRA 21-1 for advanced Non-small cell lung cancer treated with EGFR-TKIs. Anticancer Res 2017; 37(10): 5771-6.[PMID: 28982900] ]. Another study reported that NSCLC patients with high serum CEA and normal serum CYFRA 21-1 concentrations had a longer survival [19Baek AR, Seo HJ, Lee JH, et al. Prognostic value of baseline carcinoembryonic antigen and cytokeratin 19 fragment levels in advanced non-small cell lung cancer. Cancer Biomark 2018; 22(1): 55-62.[http://dx.doi.org/10.3233/CBM-170885] [PMID: 29630519] ]. Basically, cytokeratins negatively regulate the invasive potentials of several kinds of cancer cells including lung cancer [22Crowe DL, Milo GE, Shuler CF. Keratin 19 downregulation by oral squamous cell carcinoma lines increases invasive potential. J Dent Res 1999; 78(6): 1256-63.[http://dx.doi.org/10.1177/00220345990780061001] [PMID: 10371 250] -24Kanaji N, Bandoh S, Ishii T, et al. Cytokeratins negatively regulate the invasive potential of lung cancer cell lines. Oncol Rep 2011; 26(4): 763-8.[http://dx.doi.org/10.3892/or.2011.1357] [PMID: 21701782] ]. Nevertheless, an elevated CYFRA 21-1 is commonly associated with poor prognosis. Such a negative correlation of CYFRA 21-1 and prognosis could reflect tumor burden [24Kanaji N, Bandoh S, Ishii T, et al. Cytokeratins negatively regulate the invasive potential of lung cancer cell lines. Oncol Rep 2011; 26(4): 763-8.[http://dx.doi.org/10.3892/or.2011.1357] [PMID: 21701782] ]. In fact, a high CYFRA 21-1 concentration was correlated with the advanced stage as well as shorter OS [20Yu Z, Zhang G, Yang M, et al. Systematic review of CYFRA 21-1 as a prognostic indicator and its predictive correlation with clinicopathological features in Non-small Cell Lung Cancer: A meta-analysis. Oncotarget 2017; 8(3): 4043-50.[http://dx.doi.org/10.18632/oncotarget.14022] [PMID: 28008142] ]. Interestingly, it was recently reported that a higher serum CYFRA 21-1 concentration (more than 2.2 ng/mL) is a predictor of a favorable outcome in patients treated with nivolumab [21Shirasu H, Ono A, Omae K, et al. CYFRA 21-1 predicts the efficacy of nivolumab in patients with advanced lung adenocarcinoma. Tumour Biol 2018; 40(2)1010428318760420[http://dx.doi.org/10.1177/1010428318760420] [PMID: 29463190] ]. In the era of combination of chemotherapy and immune checkpoint inhibitors, the significance of serum CYFRA 21-1 as a predictor of prognosis would change.

CONCLUSION

The serum vimentin concentration is not as useful as a tumor marker of lung cancer. Vimentin expression in tumor samples might not predict patients’ prognosis in patients with advanced lung cancer. An elevated serum CYFRA 21-1 concentration is associated with poor overall survival in advanced lung cancer patients.

LIST OF ABBREVIATIONS

NSCLC = Non-Small Cell Lung Cancer
EMT = Epithelial to Mesenchymal Transition
OS = Overall Survival
ECOG = Eastern Cooperative Oncology Group
PS = Performance Status
CEA = Carcinoembryonic Antigen
EGFR = Epidermal Growth Factor Receptor
ALK = Anaplastic Lymphoma Kinase

ETHICS APPROVAL AND CONSENT TO PARTICIPATE

This study was approved by the Institutional Review Board of Kagawa University (H25-053).

HUMAN AND ANIMAL RIGHTS

All procedures performed in the study involving human participants were in accordance with the ethical standards of the institutional research committee and with the 2013 Helsinki Declaration and its later amendments or comparable ethical standards.

CONSENT FOR PUBLICATION

Written informed consent was obtained from all individual participants.

AVAILABILITY OF DATA AND MATERIALS

Not applicable.

FUNDING

None.

CONFLICT OF INTEREST

The author declares no conflict of interest, financial or otherwise.

ACKNOWLEDGEMENTS

Nobuhiro Kanaji designed the study, collected clinical data, and wrote paper. Kyuichi Kadota collected and analyzed pathological data. Akira Tadokoro, Takuya Inoue, Naoki Watanabe, Reiji Haba, Norimitsu Kadowaki, and Tomoya Ishii revised paper.

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Endorsements



"Open access will revolutionize 21st century knowledge work and accelerate the diffusion of ideas and evidence that support just in time learning and the evolution of thinking in a number of disciplines."


Daniel Pesut
(Indiana University School of Nursing, USA)

"It is important that students and researchers from all over the world can have easy access to relevant, high-standard and timely scientific information. This is exactly what Open Access Journals provide and this is the reason why I support this endeavor."


Jacques Descotes
(Centre Antipoison-Centre de Pharmacovigilance, France)

"Publishing research articles is the key for future scientific progress. Open Access publishing is therefore of utmost importance for wider dissemination of information, and will help serving the best interest of the scientific community."


Patrice Talaga
(UCB S.A., Belgium)

"Open access journals are a novel concept in the medical literature. They offer accessible information to a wide variety of individuals, including physicians, medical students, clinical investigators, and the general public. They are an outstanding source of medical and scientific information."


Jeffrey M. Weinberg
(St. Luke's-Roosevelt Hospital Center, USA)

"Open access journals are extremely useful for graduate students, investigators and all other interested persons to read important scientific articles and subscribe scientific journals. Indeed, the research articles span a wide range of area and of high quality. This is specially a must for researchers belonging to institutions with limited library facility and funding to subscribe scientific journals."


Debomoy K. Lahiri
(Indiana University School of Medicine, USA)

"Open access journals represent a major break-through in publishing. They provide easy access to the latest research on a wide variety of issues. Relevant and timely articles are made available in a fraction of the time taken by more conventional publishers. Articles are of uniformly high quality and written by the world's leading authorities."


Robert Looney
(Naval Postgraduate School, USA)

"Open access journals have transformed the way scientific data is published and disseminated: particularly, whilst ensuring a high quality standard and transparency in the editorial process, they have increased the access to the scientific literature by those researchers that have limited library support or that are working on small budgets."


Richard Reithinger
(Westat, USA)

"Not only do open access journals greatly improve the access to high quality information for scientists in the developing world, it also provides extra exposure for our papers."


J. Ferwerda
(University of Oxford, UK)

"Open Access 'Chemistry' Journals allow the dissemination of knowledge at your finger tips without paying for the scientific content."


Sean L. Kitson
(Almac Sciences, Northern Ireland)

"In principle, all scientific journals should have open access, as should be science itself. Open access journals are very helpful for students, researchers and the general public including people from institutions which do not have library or cannot afford to subscribe scientific journals. The articles are high standard and cover a wide area."


Hubert Wolterbeek
(Delft University of Technology, The Netherlands)

"The widest possible diffusion of information is critical for the advancement of science. In this perspective, open access journals are instrumental in fostering researches and achievements."


Alessandro Laviano
(Sapienza - University of Rome, Italy)

"Open access journals are very useful for all scientists as they can have quick information in the different fields of science."


Philippe Hernigou
(Paris University, France)

"There are many scientists who can not afford the rather expensive subscriptions to scientific journals. Open access journals offer a good alternative for free access to good quality scientific information."


Fidel Toldrá
(Instituto de Agroquimica y Tecnologia de Alimentos, Spain)

"Open access journals have become a fundamental tool for students, researchers, patients and the general public. Many people from institutions which do not have library or cannot afford to subscribe scientific journals benefit of them on a daily basis. The articles are among the best and cover most scientific areas."


M. Bendandi
(University Clinic of Navarre, Spain)

"These journals provide researchers with a platform for rapid, open access scientific communication. The articles are of high quality and broad scope."


Peter Chiba
(University of Vienna, Austria)

"Open access journals are probably one of the most important contributions to promote and diffuse science worldwide."


Jaime Sampaio
(University of Trás-os-Montes e Alto Douro, Portugal)

"Open access journals make up a new and rather revolutionary way to scientific publication. This option opens several quite interesting possibilities to disseminate openly and freely new knowledge and even to facilitate interpersonal communication among scientists."


Eduardo A. Castro
(INIFTA, Argentina)

"Open access journals are freely available online throughout the world, for you to read, download, copy, distribute, and use. The articles published in the open access journals are high quality and cover a wide range of fields."


Kenji Hashimoto
(Chiba University, Japan)

"Open Access journals offer an innovative and efficient way of publication for academics and professionals in a wide range of disciplines. The papers published are of high quality after rigorous peer review and they are Indexed in: major international databases. I read Open Access journals to keep abreast of the recent development in my field of study."


Daniel Shek
(Chinese University of Hong Kong, Hong Kong)

"It is a modern trend for publishers to establish open access journals. Researchers, faculty members, and students will be greatly benefited by the new journals of Bentham Science Publishers Ltd. in this category."


Jih Ru Hwu
(National Central University, Taiwan)


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