Details of a Researcher - Hattori, Yutaka

Papers - Hattori, Yutaka

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Immunomodulatory Effect of Proteasome Inhibitors via the Induction of Immunogenic Cell Death in Myeloma Cells.

Matsushita M, Kashiwazaki S, Kamiko S, Kobori M, Osada M, Kunieda H, Hirao M, Ichikawa D, Hattori Y

Pharmaceuticals (Basel, Switzerland) 16 ( 10 ) 2023.09

ISSN 1424-8247

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GTN057, a komaroviquinone derivative, induced myeloma cells' death in vivo and inhibited c-MET tyrosine kinase

Okayama M., Fujimori K., Sato M., Samata K., Kurita K., Sugiyama H., Suto Y., Iwasaki G., Yamada T., Kiuchi F., Ichikawa D., Matsushita M., Hirao M., Kunieda H., Yamazaki K., Hattori Y.

Cancer Medicine (Cancer Medicine) 12 ( 8 ) 9749 - 9759 2023.04

Objective: Despite the development of newly developed drugs, most multiple myeloma (MM) patients with high-risk cytogenetic abnormalities such as t(4;14) or del17p relapse at anin early stage of their clinical course. We previously reported that a natural product,komaroviquinone (KQN), isolated from the perennial semi-shrub Dracocephalum komarovi, i.e., komaroviquinone (KQN) and its derivative GTN024 induced the apoptosis of MM cells by producing reactive oxygen species (ROS), but both exhibited significant hematological toxicity. Aim of this study is to clarify anti-tumor activity, safety and pharmacokinetics of GTN057, an optimization compound of KQN in vivo. Methods: ICR/SCID xenograft model of KMS11, a t(4;14) translocation-positive MM cell line, was used for in vivo study. Mice pharmacokinetics of GTN057 and the degradation products were analyzed by LC-MS/MS. Results: Herein, our in vitro experiments revealed that GTN057 is much less toxic to normal hematopoietic cells, induced the apoptosis of both MM cell lines andpatient samples, including those with high-risk cytogenetic changes. A xenograft model of a high-risk MM cell line demonstrated that GTN057 significantly delayed the tumor growth with no apparent hematological or systemic toxicities in vivo. The pathological examination of GTN057-treated tumors in vivoshowed revealed apoptosis of MM cells and anti-angiogenesis. In addition to the production of ROS, GTN057 inhibited the downstream signaling of c-MET, a receptor tyrosine kinase a receptor forand hepatocyte growth factor (HGF) receptor. Thus, GTN057 is less toxic and is able tomay be a candidate drug for treating MM patients, via multifunctional mechanisms. We have also extensively studied the pharmacologyical analysis of GTN057. The metabolites of GTN057, (e.g.,such as GTN054), may also have anti-tumorantitumor activity. Conclusion: Natural products or and their derivatives can could be good sources of antineoplastic drugs even for high-risk cancer.

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A thermoresponsive cationic block copolymer brush-grafted silica bead interface for temperature-modulated separation of adipose-derived stem cells

Nagase K., Okada A., Matsuda J., Ichikawa D., Hattori Y., Kanazawa H.

Colloids and Surfaces B: Biointerfaces (Colloids and Surfaces B: Biointerfaces) 220 112928 2022.12

ISSN 09277765

Adipose-derived mesenchymal stem cells (ADSCs) have beneficial effects in cell transplantation therapy; these cells are collected from adipose tissue using low-invasive methods. However, to prepare ADSCs for cell therapy, a cell separation method that neither involves modification of the cell surface nor causes loss of cell activity is needed. Here, we aimed to develop ADSC separation columns using thermoresponsive cationic block copolymer brush-grafted beads as packing materials. The block copolymer brush was formed by a bottom cationic segment, poly(N,N-dimethylaminopropylacrylamide) (PDMAPAAm), and an upper thermoresponsive segment, poly(N-isopropylacrylamide) (PNIPAAm), and was grafted in two atom transfer radical polymerization reactions. The copolymer brush-grafted silica beads were packed into a column. An ADSC suspension was introduced into the columns at 37 °C and adsorbed on the copolymer brush-modified beads through electrostatic and hydrophobic interactions with the PDMAPAAm and PNIPAAm segments, respectively. The adsorbed ADSCs eluted from the column by lowering the temperature to 4 °C. In contrast, most Jurkat and vascular endothelial cells eluted at 37 °C, because of the relatively weaker electrostatic interactions with the block copolymer brush compared to ADSCs. Using the prepared column, a mixture of ADSCs and Jurkat cells was separated by changing the column temperature. The recovered ADSCs exhibited cell activity. The developed cell separation column may be useful for isolating ADSCs without cell surface modification, while maintaining cell activity.

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PAX5-positive plasma cell leukemia presenting as lymphocytosis.

Tateno S, Hirao M, Kikuchi T, Tsukada Y, Kunieda H, Osada M, Yamazaki K, Denda R, Hirose S, Matsushita M, Ichikawa D, Hattori Y

[Rinsho ketsueki] The Japanese journal of clinical hematology (Japanese Society of Hematology) 63 ( 10 ) 1415 - 1420 2022.10

Research paper (scientific journal), Joint Work, Last author, Corresponding author, Accepted, ISSN 0485-1439

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Negative E-cadherin expression on bone marrow myeloma cell membranes is associated with extramedullary disease.

Hirao M, Yamazaki K, Watanabe K, Mukai K, Hirose S, Osada M, Tsukada Y, Kunieda H, Denda R, Kikuchi T, Sugimori H, Okamoto S, Hattori Y.

F1000 Research (Taylor & Francis) 11 245 - 245 2022.02

Research paper (scientific journal), Joint Work, Last author, Corresponding author, Accepted, ISSN 20461402

Background: The loss of E-cadherin expression and the induction of N-cadherin are known as hallmarks of the epithelial-to-mesenchymal transition, an essential initial step in the process of metastasis in solid tumors. Although several studies have reported expressions of these cadherins in patients with multiple myeloma (MM), their clinical significance is unknown as MM cells are non-epithelial. Methods: In this study, we examined the expression of E- and N-cadherins by immunohistochemistry using bone marrow (BM) biopsy specimens from 31 newly diagnosed MM patients and in subsequent biopsy specimens from six of these. Results: Negative E-cadherin expression on BM myeloma cell membranes was significantly associated with the presence of soft-tissue masses arising from bone lesions and breaking through the cortical bone, referred to as extramedullary disease (EMD). Conclusions: Given the aggressive nature of EMD, our study suggests that screening for E-cadherin using BM immunohistochemistry is one measure that could predict the development of EMD in patients with MM.

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Integrin β5 and β7 expression in lenalidomide-resistant multiple myeloma cells

Yutaka Hattori · Takumi Futo · Ryo Uozaki · Daiju Ichikawa · Takashi Yamaguchi · Tomofumi Yamamoto · Maiko Matsushita · Maki Hirao

International Journal of Hematology (Springer Nature) 2022.02

Research paper (scientific journal), Joint Work, Accepted

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SORT1/LAMP2-mediated Extracellular Vesicle Secretion and Cell Adhesion Are Linked to Lenalidomide Resistance in Multiple Myeloma

Tomofumi Yamamoto, Jun Nakayama, Yusuke Yamamoto, Masahiko Kuroda, Yutaka Hattori, Takahiro Ochiya

Blood Advance (American Society of Hematology) 2022.01

Research paper (scientific journal), Accepted

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Thermally-modulated cell separation columns using a thermoresponsive block copolymer brush as a packing material for the purification of mesenchymal stem cells

Nagase K., Edatsune G., Nagata Y., Matsuda J., Ichikawa D., Yamada S., Hattori Y., Kanazawa H.

Biomaterials Science (Biomaterials Science) 9 ( 21 ) 7054 - 7064 2021.11

Research paper (scientific journal), Joint Work, Accepted, ISSN 20474830

Cell therapy using mesenchymal stem cells (MSCs) is used as effective regenerative treatment. Cell therapy requires effective cell separation without cell modification and cellular activity reduction. In this study, we developed a temperature-modulated mesenchymal stem cell separation column. A temperature-responsive cationic block copolymer, poly(N,N-dimethylaminopropylacrylamide)-b-poly(N-isopropylacrylamide)(PDMAPAAm-b-PNIPAAm) brush with various cationic copolymer compositions, was grafted onto silica beads via two-step atom transfer radical polymerization. Using the packed beads, the elution behavior of the MSCs was observed. At 37 °C, the MSCs were adsorbed onto the column via both hydrophobic and electrostatic interactions with the PNIPAAm and PDMAPAAm segments of the copolymer brush, respectively. By reducing the temperature to 4 °C, the adsorbed MSCs were eluted from the column by reducing the hydrophobic and electrostatic interactions attributed to the hydration and extension of the PNIPAAm segment of the block copolymer brush. From the temperature-modulated adsorption and elution behavior of MSCs, a suitable DMAPAAm composition of the block copolymer brush was determined. Using the column, a mixture of MSC and BM-CD34+ cells was separated by simply changing the column temperature. The column was used to purify the MSCs, with purities of 78.2%, via a temperature change from 37 °C to 4 °C. Additionally, the cellular activity of the MSCs was retained throughout the column separation step. Overall, the obtained results show that the developed column is useful for MSC separation without cell modification and cellular activity reduction. This journal is

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Antibody drug separation using thermoresponsive anionic polymer brush modified beads with optimised electrostatic and hydrophobic interactions

Nagase K., Ishii S., Ikeda K., Yamada S., Ichikawa D., Akimoto A.M., Hattori Y., Kanazawa H.

Scientific Reports (Nature Research) 10 ( 1 ) 2020.12

Research paper (scientific journal), Joint Work, Accepted

© 2020, The Author(s). Antibody drugs play an important role in biopharmaceuticals, because of the specificity for target biomolecules and reduction of side effects. Thus, separation and analysis techniques for these antibody drugs have increased in importance. In the present study, we develop functional chromatography matrices for antibody drug separation and analysis. Three types of polymers, poly(N-isopropylacrylamide (NIPAAm)-co-2-acrylamido-2-methylpropanesulfonic acid (AMPS)-co-N-phenyl acrylamide (PhAAm)), P(NIPAAm-co-AMPS-co-n-butyl methacrylate (BMA)), and P(NIPAAm-co-AMPS-co-tert-butylacrylamide (tBAAm)), were modified on silica beads through atom transfer radical polymerisation. Rituximab elution profiles were observed using the prepared beads-packed column. Rituximab adsorption at high temperature and elution at low temperature from the column were observed, as a result of the temperature-modulated electrostatic and hydrophobic interactions. Using the column, rituximab purification from contaminants was performed simply by changing the temperature. Additionally, three types of antibody drugs were separated using the column through temperature-modulated hydrophobic and electrostatic interactions. These results demonstrate that the temperature-responsive column can be applied for the separation and analysis of biopharmaceuticals through a simple control of the column temperature.

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Characteristics of a novel target antigen against myeloma cells for immunotherapy

Matsushita M., Saito S., Yokoe S., Ichikawa D., Hattori Y.

Vaccines (MDPI) 8 ( 4 ) 1 - 13 2020.12

Research paper (scientific journal), Joint Work, Accepted

© 2020 by the authors. Licensee MDPI, Basel, Switzerland. Despite the availability of therapeutic treatments, multiple myeloma is an incurable haematological disorder. In this study, we aimed to clarify the role of CXorf48 as a therapeutic target in multiple myeloma. Based on a previously identified HLA-A*24:02-restiricted epitope from this novel cancer/testis antigen, we characterized the activities of cytotoxic T lymphocytes (CTLs) specific to this antigen against myeloma cells and evaluated the effects of demethylating agents in increasing antigen expression and enhancing the cytotoxic activity of CTLs. CXorf48 expression was examined by reverse transcription polymerase chain reaction (RT-PCR) using nine myeloma cell lines. Cell lines with low CXorf48 expression were treated by demethylating agents (DMAs), 5-azacytidine (5-aza), and 5-aza-2'-deoxycytidine (DAC) to evaluate gene expression using quantitative RT-PCR. Furthermore, CXorf48-specific CTLs were induced from peripheral blood mononuclear cells of HLA-A*24:02-positive healthy donors to evaluate antigen recognition using ELISpot and51 Cr cytotoxicity assays. CXorf48 was widely expressed in myeloma cells, and gene expression was significantly increased by DMAs. Furthermore, CXorf48-specific CTLs recognized DMA-treated myeloma cells. These findings suggest that CXorf48 is a useful target for immunotherapy, such as vaccination, in combination with demethylating agents for the treatment of patients with myeloma.

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A phenylphthalimide derivative, TC11, induces apoptosis by degrading MCL1 in multiple myeloma cells

Ichikawa D., Nakamura M., Murota W., Osawa S., Matsushita M., Yanagawa H., Hattori Y.

Biochemical and Biophysical Research Communications (Elsevier) 521 ( 1 ) 252 - 258 2020.01

Research paper (scientific journal), Joint Work, Accepted, ISSN 0006291X

© 2019 To date, the prognosis of multiple myeloma (MM) in patients harboring cytogenetic abnormalities (CA) involving t (4; 14) and deletion of chromosome 17 remains poor despite recent advances in drug development that include the use of immunomodulatory drugs (IMiDs) such as lenalidomide for MM. To address this issue, we have developed a novel phenylphthalimide derivative, TC11, that is structurally related to IMiDs. It remains unclear how TC11 induces apoptosis of MM cells with high-risk CA. Here, we show that TC11 does not induce degradation of CRBN's substrates, IKZF1/3 and CK1α, and induces apoptosis of CRBN-silenced MM; this effect was independent of the cereblon (CRBN) pathway, which is involved in the mechanism of action of IMiDs used for the treatment of MM. We also revealed that TC11, in contrast to existing IMiDs, induced degradation of MCL1 and activation of caspase-9. Furthermore, inhibition of CDK1 by CGP74514A prevented TC11-induced MCL1 degradation, caspase-9 activation, and the subsequent apoptotic cell death. We showed that ectopic MCL1 expression rescued apoptosis of MM. These observations suggest that TC11 induces apoptotic death caused by degradation of MCL1 during prolonged mitotic arrest. Therefore, our findings suggest that TC11 is a potential drug candidate for high-risk MM.

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Significance of peripheral mononuclear cells producing interferon-γ in response to insulin B:9–23-related peptides in subtypes of type 1 diabetes

Oikawa Y., Sakamoto K., Satomura A., Haisa A., Katsuki T., Hattori Y., Inoue I., Noda M., Shimada A.

Clinical Immunology (Elsevier) 208 ( Nov ) 108260 - 108260 2019.11

Research paper (scientific journal), Joint Work, Accepted, ISSN 15216616

© 2019 Elsevier Inc. Type 1 diabetes is largely caused by β-cell destruction through anti-islet autoimmunity. Reportedly, interferon (IFN)-γ-secreting peripheral blood mononuclear cells (PBMCs) specific to four insulin B-chain amino acid 9–23-related peptides (B:9–23rPep) were increased in type 1 diabetes participants. This study aimed to investigate the PBMC frequencies in subtypes of type 1 diabetes using enzyme-linked immunospot assay. In this cross-sectional study, peripheral blood samples were obtained from 148 participants including 72 with acute-onset type 1 diabetes (AT1D), 51 with slowly progressive insulin-dependent diabetes mellitus (SPIDDM), and 25 with type 2 diabetes. The frequency of B:9–23rPep-specific IFN-γ-producing PBMCs was significantly higher in AT1D participants than in SPIDDM and type 2 diabetes participants. Meanwhile, a significant inverse correlation was observed between the PMBC frequencies and insulin secretion capacity in SPIDDM participants. These findings suggest that the increased peripheral B:9–23rPep-specific IFN-γ immunoreactivity reflects decreased functional β-cell mass and greater disease activity of type 1 diabetes.

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Temperature-modulated cell-separation column using temperature-responsive cationic copolymer hydrogel-modified silica beads

Nagase K., Inanaga D., Ichikawa D., Mizutani Akimoto A., Hattori Y., Kanazawa H.

Colloids and Surfaces B: Biointerfaces (Elsevier) 178 253 - 262 2019.06

Research paper (scientific journal), Joint Work, Accepted, ISSN 09277765

© 2019 Elsevier B.V. There is strong demand for cell separation methods that do not decrease cell activity or modify cell surfaces. Here, new temperature-modulated cell-separation columns not requiring cell-surface premodification are described. The columns were packed with temperature-responsive cationic polymer hydrogel-modified silica beads. Poly(N-isopropylacrylamide-co-n-butyl methacrylate-co-N,N-dimethylaminopropyl acrylamide) hydrogels with various cationic moieties were attached to silica-bead surfaces by radical polymerization using N,Nʹ-methylenebisacrylamide as a crosslinking agent. The beads were packed into solid-phase extraction columns, and temperature-dependent cell elution from the columns was found using HL-60 and Jurkat cells. The retention HL-60 and Jurkat cells in columns containing cationic beads at 37 °C was 95.3% to 99.6% and 95.0% to 98.8%, respectively. By contrast, beads without cationic properties exhibited low cell retention (20.6% for HL-60 and 32.5% for Jurkat cells). The cells were mainly retained through both electrostatic and hydrophobic interactions. The retained HL-60 (4.9%) and Jurkat cells (40%) were eluted at 4 °C from the column with a low composition of cationic monomer (DMAPAAm, 1 mol% in copolymer), because the temperature-responsive hydrogels on the beads became hydrophilic, decreasing the hydrophobic interactions between the cells and the beads. A higher number of Jurkat cells than HL-60 cells were eluted because of differences in their electrostatic properties (Jurkat cells: −2.53 mV; HL-60 cells: −20.7 mV). The results indicated that cell retention by the hydrogel-coated beads packed in a solid phase extraction column could be modulated simply by changing the temperature.

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A novel derivative (GTN024) from a natural product, komaroviquinone, induced the apoptosis of high-risk myeloma cells via reactive oxygen production and ER stress.

Okayama M, Kitabatake S, Sato M, Fujimori K, Ichikawa D, Matsushita M, Suto Y, Iwasaki G, Yamada T, Kiuchi F, Hirao M, Kunieda H, Osada M, Okamoto S, Hattori Y

Biochem Biophys Res Commun. (Elsevier) 505 ( 3 ) 787 - 793 2018.10

Research paper (scientific journal), Joint Work, Accepted, ISSN 0006291X

© 2018 Elsevier Inc. New drugs have significantly improved the survival of patients with multiple myeloma (MM), but the prognosis of MM patients with high-risk cytogenetic changes such as t(4; 14), t(14; 16) or del17p remains very poor. A natural product, komaroviquinone (KQN), was originally isolated from the perennial semi-shrub Dracocephalum komarovi and has anti-protozoal activity against Trypanosoma cruzi, the organism causing Chagas’ disease. Here we demonstrate that a novel KQN-derivative, GTN024, has an anti-MM effect both in vitro and in vivo. GTN024 induced the apoptosis of MM cell lines including those with high-risk cytogenetic changes. GTN024 produced reactive oxygen species (ROS) and increased phosphorylated eIF2α. The ROS production and subsequent endoplasmic reticulum (ER) stress are thought to play a key role in GTN024-induced apoptosis, as the apoptosis was completely abrogated by anti-oxidant treatment. In a mouse xenograft model, an intraperitoneal injection of 20 mg/kg of GTN024 significantly delayed tumor growth. Hematological toxicity and systemic toxicity as indicated by weight loss were not observed. These results suggest that the novel KQN-derivative GTN024 could become a candidate drug for treating high-risk MM.

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A challenge to aging society by microRNA in extracellular vesicles: MicroRNA in extracellular vesicles as promising biomarkers and novel therapeutic targets in multiple myeloma

Yamamoto T., Kosaka N., Hattori Y., Ochiya T.

Journal of Clinical Medicine (MDPI) 7 ( 3 ) 2018.03

Research paper (scientific journal), Joint Work

Multiple myeloma (MM) is a malignancy of terminally differentiated plasma cells and is the second most common hematological cancer. MM frequently occurs in the elderly population with the median age as the middle sixties. Over the last 10 years, the prognosis of MM has been dramatically improved by new therapeutic drugs; however, MM is still incurable. The pathogenesis of MM is still unclear, thus greater understanding of the molecular mechanisms of MM malignancy is desirable. Recently, microRNAs (miRNAs) were shown to modulate the expression of genes critical for MM pathogenesis. In addition, miRNAs are secreted via extracellular vesicles (EVs), which are released from various cell types including MM cells, and these miRNAs are involved in multiple types of cell-cell interactions, which lead to the malignancy of MM. In this review, we summarize the current knowledge regarding the role of miRNA secretion via EVs and of EVs themselves in MM development. We also discuss the potential clinical applications of EVs as promising biomarkers and new therapeutic targets for improving the outcome of MM, resulting in a brighter future for aging societies.

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A novel phenylphthalimide derivative, pegylated TC11, improves pharmacokinetic properties and induces apoptosis of high-risk myeloma cells via G2/M cell-cycle arrest.

Aida S, Hozumi M, Ichikawa D, Iida K, Yonemura Y, Tabata N, Yamada T, Matsushita M, Sugai T, Yanagawa H, Hattori Y

Biochem. Biophysic. Res. Commun. (Elsevier) 493 ( 1 ) 514 - 520 2017.09

Research paper (scientific journal), Joint Work, Accepted, ISSN 0006-291X

Despite the development of new drugs for multiple myeloma (MM), the prognosis of MM patients with high-risk cytogenetic abnormalities such as t (4; 14) and del17p remains poor. We reported that a novel phenylphthalimide derivative, TC11, induced apoptosis of MM cells in vitro and in vivo, and TC11 directly bound to a-tubulin and nucleophosmin-1 (NPM1). However, TC11 showed low water solubility and poor pharmacokinetic properties. Here we synthesized a water-soluble TC11-derivative, PEG(E)-TC11, in which HOEtO-TC11 is pegylated with PEG through an ester bond, and we examined its anti-myeloma activity. We observed that PEG(E)-TC11 and its hydrolyzed product, HOEtO-TC11, induced G2/M arrest and the apoptosis of MM cells. Intraperitoneal administration of PEG(E)-TC11 to xenografted mice revealed improved pharmacokinetic properties and significantly delayed tumor growth. TC11 and its derivatives did not bind to cereblon (CRBN), which is a responsible molecule for thalidomide-induced teratogenicity. These results suggest that PEG(E)-TC11 is a good candidate drug for treating high-risk MM.

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Synthesis and biological evaluation of the natural product komaroviquinone and related compounds aiming at a potential therapeutic lead compound for high-risk multiple myeloma.

Suto Y, Sato M, Fujimori K, Kitabatake S, Okayama M, Ichikawa D, Matsushita M, Yamagiwa N, Iwasaki G, Kiuchi F, Hattori Y.

Bioorganic & Medicinal Chemistry Letters (Elsevier) 27 ( 19 ) 4558 - 4563 2017

Research paper (scientific journal), Joint Work, Accepted, ISSN 0960-894X

Alternatives of treatments for multiple myeloma (MM) have become increasingly available with the advent of new drugs such as proteasome inhibitors, thalidomide derivatives, histone deacetylase inhibitors, and antibody drugs. However, high-risk MM cases that are refractory to novel drugs remain, and further optimization of chemotherapeutics is urgently needed.
We had achieved asymmetric total synthesis of komaroviquinone, which is a natural product from the plant Dracocephalum komarovi. Similar to several leading antitumor agents that have been developed from natural compounds, we describe the antitumor activity and cytotoxicity of komaroviquinone and related compounds in bone marrow cells. Our data suggested that komaroviquinone-related agents have potential as starting compounds for anticancer drug development. (C) 2017 Elsevier Ltd. All rights reserved.

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CXorf48 is a potential therapeutic target for achieving treatment-free remission in CML patients

Matsushita M, Ozawa K, Suzuki T, Nakamura M, Nakano N, Kanchi S, Ichikawa D, Matsuki E, Sakurai M, Karigane D, Kasahara H, Tsukamoto N, Shimizu T, Mori T, Nakajima H, Okamoto S, Kawakami Y, Hattori Y

Blood Cancer J (Springer Nature) 7 e701 2017

Research paper (scientific journal), Joint Work, Accepted

Identification of novel HLA-A*24:02-restricted epitope derived from a homeobox protein expressed in hematological malignancies.

Matsushita　M, Otsuka Y, Tsutsumida N, Tanaka C, Uchiumi A, Ozawa K, Suzuki T, Ichikawa D, Aburatani H, Okamoto S, Kawakami Y and Hattori Y

PLoS One 11 ( 1 ) e0146371 2016.01

Research paper (scientific journal), Joint Work, Accepted

A novel phthalimide derivative, TC11, has preclinical effects on high-risk myeloma cells and osteoclasts.

1. Matsushita　M, Yoshie Ozaki Y, Hasegawa Y, Terada F, Tabata N, Shiheido H, Yanagawa H, Oikawa T, Matsuo K, Du W, Yamada T, Hozumi M, Ichikawa D, and Hattori Y.

PLoS One 10 ( 1 ) e0116135 2015.01

Research paper (scientific journal), Joint Work, Accepted

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