WO2021029238A1 - Agent de prévention ou de traitement des maladies induites par les cellules th17 et méthode de criblage d'agents destinés à prévenir ou à traiter des maladies induites par les cellules th17 - Google Patents

Agent de prévention ou de traitement des maladies induites par les cellules th17 et méthode de criblage d'agents destinés à prévenir ou à traiter des maladies induites par les cellules th17 Download PDF

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WO2021029238A1
WO2021029238A1 PCT/JP2020/029535 JP2020029535W WO2021029238A1 WO 2021029238 A1 WO2021029238 A1 WO 2021029238A1 JP 2020029535 W JP2020029535 W JP 2020029535W WO 2021029238 A1 WO2021029238 A1 WO 2021029238A1
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cells
disease
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洋一郎 岩倉
正承 村山
貴裕 小野
眞子 松岡
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学校法人東京理科大学
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Definitions

  • the present invention relates to a preventive or therapeutic agent for Th17 cell-induced disease and a screening method for a preventive or therapeutic agent for Th17 cell-induced disease.
  • Th17 cells are effector T cells that produce cytokines such as IL-17 and IL-22 and activate neutrophils and epithelial cells.
  • Th17 cells are autoimmune diseases such as rheumatoid arthritis, multiple sclerosis, and inflammatory bowel disease; allergic diseases such as asthma, contact hypersensitivity, and delayed hypersensitivity; psoriatic arthritis, psoriatic arthritis, tonic spondylosis; etc. It is known to play an important role in the pathogenesis of various diseases.
  • CTRP3 C1q / TNF-related protein 3
  • CTRP3 is a soluble secretory protein consisting of a short N-terminal variable region, collagen domain, and C-terminal complement C1q domain, and has a crystal structure similar to TNF and complement C1q.
  • the receptor for CTRP3 and the cells expressing the receptor have not yet been identified.
  • the C1q domain also has the secretory protein adiponectin.
  • Adiponectin is known to exert an action by binding to adiponectin receptor 1 (AdipoR1), adiponectin receptor 2 (AdipoR2), etc., and it has been reported that the C1q domain is important for the binding. ..
  • adiponectin is involved in the differentiation of naive T cells into Th17 cells.
  • adiponectin promotes differentiation into Th17 cells (see, for example, Non-Patent Documents 1 and 2)
  • it suppresses the differentiation see, for example, Non-Patent Documents 3 and 4). ..
  • the role of adiponectin in the differentiation mechanism into Th17 cells has not been clarified yet, and there is a problem that it is not easy to apply adiponectin to a preventive or therapeutic agent for Th17 cell-induced diseases.
  • the present invention has been proposed in view of the above, and is a novel prophylactic or therapeutic agent preferably used for the prevention or treatment of Th17 cell-induced diseases, and a method for screening a prophylactic or therapeutic agent for Th17 cell-induced diseases.
  • the purpose is to provide.
  • the present inventors have shown that an agonist that does not show agonist activity on adiponectin receptor 1 and that shows agonist activity on adiponectin receptor 2 suppresses the differentiation of naive T cells into Th17 cells.
  • the present invention provides the following.
  • the adiponectin receptor 1 (AdipoR1) and the adiponectin receptor 2 (AdiponR2) are receptors classified into Class I of the PAQR (progestin and AdiponQ receptors) family, and are also referred to as PAQR1 and PAQR2, respectively.
  • a prophylactic or therapeutic agent for Th17 cell-induced diseases which contains an agonist as an active ingredient, which does not exhibit agonist activity on adiponectin receptor 1 (PAQR1) and exhibits agonist activity on adiponectin receptor 2 (PAQR2).
  • ⁇ 2> The agent for preventing or treating Th17 cell-induced disease according to ⁇ 1>, wherein the agonist is any of the following (a) to (d).
  • B A protein consisting of the gC1q domain of the amino acid sequence shown in SEQ ID NO: 1.
  • C It has 80% or more sequence identity with respect to the amino acid sequence shown in SEQ ID NO: 1, does not show agonist activity on adiponectin receptor 1 (PAQR1), and is an agonist on adiponectin receptor 2 (PAQR2).
  • PAQR1 adiponectin receptor 1
  • PAQR2 adiponectin receptor 2
  • (D) It has 80% or more sequence identity with respect to the gC1q domain of the amino acid sequence shown in SEQ ID NO: 1, does not show agonist activity on adiponectin receptor 1 (PAQR1), and has adiponectin receptor 2 (PAQR2). ), A protein that exhibits agonist activity.
  • PAQR1 adiponectin receptor 1
  • PAQR2 adiponectin receptor 2
  • Th17 cell-induced disease according to ⁇ 1> or ⁇ 2>, wherein the Th17 cell-induced disease is not rheumatoid arthritis or multiple sclerosis.
  • ⁇ 4> The preventive or therapeutic agent for a Th17 cell-induced disease according to ⁇ 1> or ⁇ 2>, wherein the Th17 cell-induced disease is not an autoimmune disease.
  • Th17 cell-induced diseases are psoriasis, psoriatic arthritis, tonic spondylosis, optic neuromyelitis, Alzheimer's disease, Huntington's disease, Parkinson's disease, type 1 diabetes, type 2 diabetes, gout, leukoplakia, and melanitis. , Acute and chronic nephritis, acute and chronic pain, inflammatory bowel disease, liver fibrosis, pancreatic fibrosis, inflammatory lung disease, or allergic disease, Th17 cell-inducible according to ⁇ 1> or ⁇ 2>. Preventive or therapeutic agent for diseases.
  • ⁇ 6> Use of the above-mentioned agonist for producing a prophylactic or therapeutic agent for Th17 cell-induced disease according to any one of ⁇ 1> to ⁇ 5>.
  • a prophylactic or therapeutic agent for Th17 cell-induced diseases which comprises screening a candidate agonist that does not show agonist activity on adiponectin receptor 1 (PAQR1) and shows agonist activity on adiponectin receptor 2 (PAQR2). Screening method.
  • PAQR1 adiponectin receptor 1
  • PAQR2 adiponectin receptor 2
  • the present invention it is possible to provide a novel preventive or therapeutic agent preferably used for the prevention or treatment of Th17 cell-induced disease, and a screening method for the preventive or therapeutic agent for Th17 cell-induced disease.
  • IL-17 + T cell Th17 cell
  • .. 3 is a graph showing the ratio of IL-17 + T cells (Th17 cells) when CTRP3 was added to induce differentiation into Th17 cells with respect to naive T cells purified from C1qtnf3 ⁇ / ⁇ mice.
  • 3 is a graph showing the amount of IL-17 protein in the culture supernatant when CTRP3 is added to induce differentiation into Th17 cells from naive T cells purified from C1qtnf3 ⁇ / ⁇ mice.
  • FIG. 1 is a graph showing the population of IFN- ⁇ + T cell (Th1 cell) when the differentiation induction into Th1 cell was performed with respect to the naive T cell purified from C1qtnf3 ⁇ / ⁇ mouse.
  • 3 is a graph showing the ratio of IFN- ⁇ + T cells (Th1 cells) when differentiation induction into Th1 cells was performed on naive T cells purified from C1qtnf3 ⁇ / ⁇ mice.
  • 6 is a graph showing the amount of IFN- ⁇ protein in the culture supernatant when induction of differentiation into Th1 cells was performed on naive T cells purified from C1qtnf3 ⁇ / ⁇ mice.
  • IL-17 + T cells when CTRP3 was added to induce differentiation into Th17 cells and AdipoR1 blocker or AdipoR2 blocker was added to naive T cells purified from C1qtnf3 ⁇ / ⁇ mice. It is a figure which shows the population of Th17 cell).
  • IL-17 + T cells when CTRP3 was added to induce differentiation into Th17 cells and AdipoR1 blocker or AdipoR2 blocker was added to naive T cells purified from C1qtnf3 ⁇ / ⁇ mice. It is a graph which shows the ratio of Th17 cells).
  • C1qtnf3 ⁇ / ⁇ To naive T cells purified from mice, IL- in the culture supernatant when CTRP3 was added when inducing differentiation into Th17 cells, and AdipoR1 blocker or AdipoR2 blocker was added. 17 is a graph showing the amount of protein. 6 is a graph showing swelling (ear thickness) of the ears of mice when Bethelna cream was applied to C1qtnf3 ⁇ / ⁇ mice and WT mice.
  • the prophylactic or therapeutic agent for Th17 cell-induced disease does not show an agonist activity against adiponectin receptor 1 (AdipoR1) and shows an agonist activity against adiponectin receptor 2 (AdipoR2) (hereinafter, "" Also referred to as "specific agonist”) as an active ingredient.
  • AdipoR1 adiponectin receptor 1
  • AdipoR2 adiponectin receptor 2
  • AdipoRon which is an agonist of the above-mentioned adiponectin and adiponectin receptor, is known to exhibit agonist activity against both AdipoR1 and AdipoR2. As shown in Examples described later, AdipoRon suppressed the differentiation into both Th17 cells and Th1 cells, whereas the specific agonist suppressed only the differentiation into Th17 cells and affected the differentiation into Th1 cells. There wasn't. From these facts, it was clarified that the activation of AdiponR1 suppresses the differentiation into Th1 cells.
  • the active ingredient contained in the preventive or therapeutic agent for Th17 cell-induced diseases is a selective agonist that does not suppress the differentiation into Th1 cells but only suppresses the differentiation into Th17 cells. Since the specific agonist does not show an agonist activity against AdiponR1 but shows an agonist activity only against AdiponR2 (in other words, it suppresses only the differentiation into Th17 cells and not the differentiation into Th1 cells), the above-mentioned selective agonist It is useful as.
  • Th17 cell-induced disease refers to a disease induced by Th17 cells.
  • the Th17 cell-induced disease according to the present embodiment is not particularly limited, but in one embodiment, it is a disease that is not rheumatoid arthritis and multiple sclerosis, and in another embodiment, it is a disease that is not an autoimmune disease.
  • Specific examples of such Th17 cell-induced diseases include psoriasis, psoriatic arthritis, tonic spondylosis, optic neuromyelitis, Alzheimer's disease, Huntington's disease, Parkinson's disease, type 1 diabetes, type 2 diabetes, gout, and white spots.
  • Inflammatory bowel diseases such as vasculitis, acute and chronic nephritis, acute and chronic pain, ulcerative colitis; liver fibrosis, pancreatic fibrosis, inflammatory lung disease, or asthma and contact dermatitis, delayed hypersensitivity Allergic diseases such as illness; etc.
  • the specific agonist is not particularly limited as long as it does not show an agonist activity against AdiponR1 and shows an agonist activity against AdiponR2.
  • CTRP3 which is one of the proteins belonging to the CTRP (C1q / TNF-related protein) family, does not show an agonist activity against AdipoR1 and shows an agonist activity against AdiponR2. was confirmed. Therefore, CTRP3 is mentioned as an example of the specific agonist in this embodiment.
  • the origin of CTRP3 is not particularly limited and may be derived from humans or other animals such as mice, but it is preferably derived from humans.
  • the amino acid sequence of CTRP3 the information registered in the GenBank database of the National Center for Biotechnology Information (NCBI) can be referred to.
  • accession numbers AAI12926 and the like are registered as amino acid sequences of human CTRP3
  • accession numbers AAY21928 and the like are registered as amino acid sequences of mouse CTRP3 in the GenBank database.
  • a typical amino acid sequence is as follows. The underlined portion of the amino acid sequence indicates a spherical domain (gC1q domain).
  • the overall homology in the amino acid sequences of human CTRP3 and mouse CTRP3 is as high as 96%, and the spherical domain (gC1q domain) portion has even higher homology as 99%.
  • CTRP3 may be a commercially available product, or may be produced by a gene recombination method or a chemical synthesis method.
  • CTRP3 is produced by the gene recombination method, for example, if a gene encoding CTRP3 is introduced into microorganisms such as Escherichia coli and yeast, plant cells, insect cells, or animal cells using an expression vector to express the protein. Good.
  • human CTRP3 or mouse CTRP3 mammalian cells are preferably used from the viewpoint of maintaining the three-dimensional structure and post-translational modification.
  • CTRP3 is produced by a chemical synthesis method, it may be produced by the liquid phase method, the solid phase method, the Boc method, the Fmoc method or the like alone or in combination.
  • CTRP3 does not show agonistic activity against AdiponR1 and shows agonistic activity against AdiponR2, from the amino acid sequence in which one or several amino acid residues are substituted, deleted, or added in the amino acid sequence of wild-type CTRP3. It may be a mutant CTRP3.
  • sequence identity between each mutant amino acid sequence and each wild-type amino acid sequence may be, for example, 80% or more, 85% or more, 90% or more, 93. It may be% or more, and may be 95% or more.
  • sequence identity of the spherical domain portion described later is preferably 80% or more, more preferably 90% or more, further preferably 93% or more, and particularly preferably 95% or more. It is preferably 100%, which is extremely preferable.
  • sequence identity means the matching between sequences when two amino acid sequences are aligned, and for example, a BLAST program (https://www.ncbi.nlm.nih.gov/Blast/). It can be calculated using cgi).
  • the protein belonging to the CTRP family exists in the living body only in the spherical domain (gC1q domain), and the spherical domain is considered to be a functional site (Trends. Immunol., 25 (10): 551-61). (2004)). Therefore, the specific agonist may be a peptide constituting the spherical domain of CTRP3.
  • each mutant amino acid sequence and each wild-type amino acid sequence may be, for example, 80% or more, 85% or more, or 90% or more. It may be 93% or more, or 95% or more.
  • Suitable examples of the specific agonist include those selected from the following (a) to (d).
  • A A protein consisting of the amino acid sequence shown in SEQ ID NO: 1.
  • B A protein consisting of the gC1q domain of the amino acid sequence shown in SEQ ID NO: 1.
  • C It has 80% or more sequence identity with respect to the amino acid sequence shown in SEQ ID NO: 1, does not show agonist activity against adiponectin receptor 1 (AdipoR1), and is an agonist against adiponectin receptor 2 (AdipoR2). A protein that exhibits activity.
  • (D) It has 80% or more sequence identity with respect to the gC1q domain of the amino acid sequence shown in SEQ ID NO: 1, does not show agonist activity on adiponectin receptor 1 (AdipoR1), and has adiponectin receptor 2 (AdipoR2). ), A protein that exhibits agonist activity.
  • the specific agonist may be in a form other than a protein or peptide (for example, a low molecular weight compound) as long as it does not show an agonist activity against AdipoR1 and shows an agonist activity against AdipoR2.
  • the preventive or therapeutic agent for Th17 cell-induced disease may contain a component other than the specific agonist, if necessary.
  • Ingredients other than specific agonists include excipients, disintegrants, binders, lubricants, surfactants, buffers, solubilizers, stabilizers, tonicity agents, suspending agents, emulsifiers, buffers. Agents, solvents; etc.
  • the dosage form of the preventive or therapeutic agent for Th17 cell-induced disease according to the present embodiment is not particularly limited and can be selected according to the intended use.
  • the dosage form of the Th17 cell-induced disease preventive or therapeutic agent according to the present embodiment includes parenteral preparations such as injection liquid preparations and lyophilized powder preparations for injection; tablets, granules, capsules, liquid preparations and the like. Oral preparations; etc.
  • the preventive or therapeutic agent for Th17 cell-induced disease according to the present embodiment can be produced by any method adopted in the field of pharmaceuticals or a method with appropriate improvements.
  • the dose of the preventive or therapeutic agent for Th17 cell-induced disease according to the present embodiment is appropriately determined according to the administration target, administration route, target disease, symptom and the like. Further, the number of administrations, the administration interval, and the like are not particularly limited, and the administration may be a single administration or a plurality of administrations.
  • the animal species to which the Th17 cell-induced disease prophylaxis or therapeutic agent according to the present embodiment is administered is not particularly limited, and humans may be administered, and monkeys, pigs, cows, dogs, cats, mice and the like may be administered. Non-human animals may be the subject of administration.
  • prevention includes not only preventing the onset but also delaying the onset time.
  • treatment also includes suppressing the degree of progression of symptoms.
  • the use of a specific agonist for producing a prophylactic or therapeutic agent for Th17 cell-induced disease is also provided.
  • a method for preventing or treating Th17 cell-induced disease which comprises administering a drug containing a specific agonist to a subject in need of prevention or treatment of Th17 cell-induced disease. Will be done.
  • the administration target and the number of administrations in the method the above-mentioned administration target and the number of administrations for the preventive or therapeutic agent for Th17 cell-induced disease can be adopted.
  • the preventive or therapeutic agent for Th17 cell-induced disease according to the present embodiment may be administered in combination with a drug or the like containing another active ingredient.
  • the method for screening a prophylactic or therapeutic agent for a Th17 cell-induced disease is a candidate agonist that does not show an agonist activity against adiponectin receptor 1 (AdipoR1) and shows an agonist activity against adiponectin receptor 2 (AdipoR2).
  • AdipoR1 adiponectin receptor 1
  • AdiponR2 adiponectin receptor 2
  • a prophylactic or therapeutic agent for Th17 cell-induced disease can be screened by using the presence or absence of activation that does not show agonist activity against AdiponR1 and shows agonist activity against AdiponR2 as an index.
  • the method for evaluating the activation of AdipoR1 and AdipoR2 is not particularly limited, and any method can be adopted.
  • mice were bred under SPF conditions in a clean room with a lighting cycle from 8:00 to 20:00. Mice were fed a normal ⁇ -ray sterilized F1 diet (Funabashi Farm) and acidified tap water (adjusted to pH 2.5 with 0.002N HCl). The following tests used mice of the same age (8-12 weeks) and gender.
  • Naive T cells were purified from the spleens of C1qtnf3 ⁇ / ⁇ mice and WT mice using Naive CD 4+ T cell Isolation Kit (Miltenyi Biotec).
  • Naive T cells were plate-coated with 4 ⁇ g / mL anti-CD3 (Clone 145-2C11, BioLegend) and soluble 1 ⁇ g / mL anti-CD28 (Clone 37.51, BioLegend), 10 ⁇ g / mL anti-CD4 (Clone 11B11). , BioLegend), and X-VIVO 20 medium (Lonza) containing 5 ng / mL recombinant murine IL-12 (PeproTech) and containing 10% FBS for 3 days stimulation. Cultures were performed in recombinant human CTRP3 (Aviscera Bioscience), AdipoRon (Cayman Chemical), AdipoR1 blocker (Alpha Diagnostic), and in the presence of AdipoR2 blocker (Alpha).
  • Naive T cells were plate coated with 4 ⁇ g / mL anti-CD3 (clone 145-2C11, BioLegend) and soluble 1 ⁇ g / mL anti-CD28 (clone 37.51, BioLegend), 10 ⁇ g / mL anti-IFN ⁇ (clone R4).
  • ELISA ELISA
  • IL-17 ELISA MAX standard R & D Systems
  • mouse IFN- ⁇ ELISA MAX standard R & D Systems
  • the differentiation of naive T cells of C1qtnf3 ⁇ / ⁇ mice and WT mice into Th17 cells was induced by the method described above, and the population of IL-17 + T cells (Th17 cells) was analyzed by flow cytometry.
  • the amount of IL-17 protein in the culture supernatant was analyzed by ELISA.
  • the population of IL-17 + T cells was significantly increased in C1qtnf3 ⁇ / ⁇ mice as compared with WT mice.
  • the amount of IL-17 protein in the culture supernatant was significantly increased in C1qtnf3 ⁇ / ⁇ mice as compared with WT mice. From these results, it was found that CTRP3 deficiency promotes the differentiation of naive T cells into Th17 cells.
  • the population of IL-17 + T cells was significantly reduced in a concentration-dependent manner of CTRP3.
  • the amount of IL-17 protein in the culture supernatant was significantly decreased depending on the concentration of CTRP3. From these results, it was found that CTRP3 suppresses the differentiation of naive T cells into Th17 cells.
  • CTRP3 does not affect the differentiation of naive T cells into Th1 cells.
  • Test Example 4 In Test Example 4, the effect on the differentiation into Th17 cells and Th1 cells when AdipoRon, which is an agonist of the adiponectin receptor, was confirmed.
  • AdipoRon was added to the medium to a concentration of 1, 2, 3 ⁇ g / mL and cultured, and IL-17 + T cells were cultured.
  • Populations of (Th17 cells) and IFN- ⁇ + T cells (Th1 cells) were analyzed by flow cytometry.
  • the amount of IL-17 protein and the amount of IFN- ⁇ protein in the culture supernatant were analyzed by ELISA.
  • the same experiment was performed 4 times, and the average value and standard deviation were calculated.
  • the results of flow cytometry for Th17 cells are shown in FIGS. 4A and 4B, and the results of ELISA are shown in FIG. 4C.
  • the results of flow cytometry for Th1 cells are shown in FIGS. 4D and 4E, and the results of ELISA are shown in FIG. 4F.
  • the population of IL-17 + T cells was significantly reduced in a concentration-dependent manner of AdipoRon.
  • the amount of IL-17 protein in the culture supernatant was significantly decreased depending on the concentration of AdipoRon.
  • the population of IFN- ⁇ + T cells was significantly reduced in a concentration-dependent manner of AdipoRon.
  • the amount of IFN- ⁇ protein in the culture supernatant was significantly decreased depending on the concentration of AdipoRon. From these results, it was found that AdipoRon suppresses the differentiation into both Th17 cells and Th1 cells.

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Abstract

L'invention concerne : un agent qui permet de prévenir ou de traiter des maladies induites par les cellules Th17, l'agent contenant en tant que principe actif un agoniste qui présente une activité agoniste envers les récepteurs de l'adiponectine de type 2 (PAQR2) sans présenter d'activité agoniste envers les récepteurs de l'adiponectine de type 1 (PAQR1) ; une méthode de criblage d'agents capable de prévenir ou de traiter des maladies induites par les cellules Th17, la méthode comprenant le criblage d'agonistes candidats qui présentent une activité agoniste envers les récepteurs de l'adiponectine de type 2 (PAQR2) sans présenter d'activité agoniste envers les récepteurs de l'adiponectine de type 1 (PAQR1).
PCT/JP2020/029535 2019-08-09 2020-07-31 Agent de prévention ou de traitement des maladies induites par les cellules th17 et méthode de criblage d'agents destinés à prévenir ou à traiter des maladies induites par les cellules th17 WO2021029238A1 (fr)

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20160175396A1 (en) * 2013-03-15 2016-06-23 The Johns Hopkins University Methods for treating or preventing fatty liver disease using ctrp3

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20160175396A1 (en) * 2013-03-15 2016-06-23 The Johns Hopkins University Methods for treating or preventing fatty liver disease using ctrp3

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
C HENG, C. T. ET AL.: "CTRP3 attenuates hepatic stellate cell activation through transforming growth factor-beta/smad pathway", BIOMED PHARMACOTHE R, vol. 89, 2017, pages 1387 - 1391, XP029987207, DOI: 10.1016/j.biopha.2017.03.021 *
ELSAID, H. H. ET AL.: "Complement clq tumor necrosis factor-related protein 3 a novel adipokine, protect against diabetes mellitus in young adult egyptian s", DIABETES METAB SYND R, vol. 13, no. 1, 12 October 2018 (2018-10-12), pages 434 - 438, XP085577627 *
MOHAMADINARAB, M. ET AL.: "Serum levels of Clq/TNF- related protein-3 in inflammatory bowel disease patients and its inverse association with inflammatory cytokines and insulin resistance", IUBMB LIFE, vol. 72, no. 8, 20 April 2020 (2020-04-20), pages 1698 - 1704, XP055793194 *
XUE, K. ET AL.: "No. 309 A novel adipokine Clq/TNF-related proteins-3 decreases in psoriasis patients and ameliorates imiquimod-induced psoriasis-like skin lesions by inhibiting the proliferation and inflammatory cytokines expression of keratinocytes", J INVEST DERMATOL, vol. 137, no. 10, 2017, pages S245, XP055793323 *
YAMAUCHI TOSHIMASA ET AL: "Adiponectin receptors agonists", JOURNAL OF CLINICAL AND EXPERIMENTAL MEDICINE, vol. 252, no. 5, 2015, pages 633 - 637 *

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