Skip to main content
Erschienen in: Journal of Neuro-Oncology 1/2017

09.01.2017 | Laboratory Investigation

Functional analysis of KIF20A, a potential immunotherapeutic target for glioma

verfasst von: Katsuya Saito, Shigeki Ohta, Yutaka Kawakami, Kazunari Yoshida, Masahiro Toda

Erschienen in: Journal of Neuro-Oncology | Ausgabe 1/2017

Einloggen, um Zugang zu erhalten

Abstract

Kinesin family member 20A (KIF20A), an ideal cancer-testis antigen, was reported to be a promising immunotherapeutic target for pancreatic cancers. Clinical trials of KIF20A peptide vaccine immunotherapy have been conducted against pancreatic cancers. To demonstrate the efficacy of KIF20A as a candidate molecular target for gliomas, we analyzed the expression and function of KIF20A in gliomas. Western blot and quantitative PCR analyses showed that KIF20A expression in glioma cell lines and glioma tissues was high compared with that found in a normal brain. KIF20A immunostaining of glioma cells and glioma tissues demonstrated that KIF20A was involved in spindle formation and cytokinesis, and that KIF20A was highly expressed, especially in glioma cells undergoing mitosis. In silico analysis of a cancer microarray database revealed that KIF20A was highly expressed in gliomas depending on the pathological grade, and glioma patients with higher expression of KIF20A showed poorer prognosis. Down-regulating KIF20A reduced cell proliferation in glioma cells due to the failure of cytokinesis and generation of binucleated cells. Additionally, KIF20A inhibition induced significant apoptosis in SF126 glioma cells. Taken together, KIF20A is a tumor-associated antigen involved in the glioma cell growth and cell survival, suggesting that KIF20A is an oncoantigen of gliomas. Thus, KIF20A is a candidate novel immunotherapeutic target for gliomas.
Anhänge
Nur mit Berechtigung zugänglich
Literatur
1.
Zurück zum Zitat Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B et al (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352:987–996CrossRefPubMed Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B et al (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352:987–996CrossRefPubMed
2.
Zurück zum Zitat Imai K, Hirata S, Irie A, Senju S, Ikuta Y et al (2011) Identification of HLA-A2-restricted CTL epitopes of a novel tumour-associated antigen, KIF20A, overexpressed in pancreatic cancer. Br J Cancer 104:300–307CrossRefPubMed Imai K, Hirata S, Irie A, Senju S, Ikuta Y et al (2011) Identification of HLA-A2-restricted CTL epitopes of a novel tumour-associated antigen, KIF20A, overexpressed in pancreatic cancer. Br J Cancer 104:300–307CrossRefPubMed
3.
Zurück zum Zitat Nakamura T, Furukawa Y, Nakagawa H, Tsunoda T, Ohigashi H et al (2004) Genome-wide cDNA microarray analysis of gene expression profiles in pancreatic cancers using populations of tumor cells and normal ductal epithelial cells selected for purity by laser microdissection. Oncogene 23:2385–2400CrossRefPubMed Nakamura T, Furukawa Y, Nakagawa H, Tsunoda T, Ohigashi H et al (2004) Genome-wide cDNA microarray analysis of gene expression profiles in pancreatic cancers using populations of tumor cells and normal ductal epithelial cells selected for purity by laser microdissection. Oncogene 23:2385–2400CrossRefPubMed
4.
Zurück zum Zitat Echard A, Jollivet F, Martinez O, Lacapere JJ, Rousselet A et al (1998) Interaction of a Golgi-associated kinesin-like protein with Rab6. Science 279:580–585CrossRefPubMed Echard A, Jollivet F, Martinez O, Lacapere JJ, Rousselet A et al (1998) Interaction of a Golgi-associated kinesin-like protein with Rab6. Science 279:580–585CrossRefPubMed
5.
Zurück zum Zitat Hirokawa N, Noda Y, Okada Y (1998) Kinesin and dynein superfamily proteins in organelle transport and cell division. Curr Opin Cell Biol 10:60–73CrossRefPubMed Hirokawa N, Noda Y, Okada Y (1998) Kinesin and dynein superfamily proteins in organelle transport and cell division. Curr Opin Cell Biol 10:60–73CrossRefPubMed
7.
Zurück zum Zitat Gasnereau I, Boissan M, Margall-Ducos G, Couchy G, Wendum D et al (2012) KIF20A mRNA and its product MKlp2 are increased during hepatocyte proliferation and hepatocarcinogenesis. Am J Pathol 180:131–140CrossRefPubMed Gasnereau I, Boissan M, Margall-Ducos G, Couchy G, Wendum D et al (2012) KIF20A mRNA and its product MKlp2 are increased during hepatocyte proliferation and hepatocarcinogenesis. Am J Pathol 180:131–140CrossRefPubMed
8.
Zurück zum Zitat Yamashita J, Fukushima S, Jinnin M, Honda N, Makino K et al (2012) Kinesin family member 20 A is a novel melanoma-associated antigen. Acta Derm Venereol 92:593–597CrossRefPubMed Yamashita J, Fukushima S, Jinnin M, Honda N, Makino K et al (2012) Kinesin family member 20 A is a novel melanoma-associated antigen. Acta Derm Venereol 92:593–597CrossRefPubMed
9.
Zurück zum Zitat Phuphanich S, Wheeler CJ, Rudnick JD, Mazer M, Wang H et al (2012) Phase I trial of a multi-epitope-pulsed dendritic cell vaccine for patients with newly diagnosed glioblastoma. Cancer Immunol Immunother 62:125–135CrossRefPubMedPubMedCentral Phuphanich S, Wheeler CJ, Rudnick JD, Mazer M, Wang H et al (2012) Phase I trial of a multi-epitope-pulsed dendritic cell vaccine for patients with newly diagnosed glioblastoma. Cancer Immunol Immunother 62:125–135CrossRefPubMedPubMedCentral
10.
Zurück zum Zitat Yu JS, Liu G, Ying H, Yong WH, Black KL et al (2004) Vaccination with tumor lysate-pulsed dendritic cells elicits antigen-specific, cytotoxic T-cells in patients with malignant glioma. Cancer Res 64:4973–4979CrossRefPubMed Yu JS, Liu G, Ying H, Yong WH, Black KL et al (2004) Vaccination with tumor lysate-pulsed dendritic cells elicits antigen-specific, cytotoxic T-cells in patients with malignant glioma. Cancer Res 64:4973–4979CrossRefPubMed
11.
Zurück zum Zitat Asahara S, Takeda K, Yamao K, Maguchi H, Yamaue H (2013) Phase I/II clinical trial using HLA-A24-restricted peptide vaccine derived from KIF20A for patients with advanced pancreatic cancer. J Transl Med 11:291CrossRefPubMedPubMedCentral Asahara S, Takeda K, Yamao K, Maguchi H, Yamaue H (2013) Phase I/II clinical trial using HLA-A24-restricted peptide vaccine derived from KIF20A for patients with advanced pancreatic cancer. J Transl Med 11:291CrossRefPubMedPubMedCentral
12.
Zurück zum Zitat Taniuchi K, Nakagawa H, Nakamura T, Eguchi H, Ohigashi H et al (2005) Down-regulation of RAB6KIFL/KIF20A, a kinesin involved with membrane trafficking of discs large homologue 5, can attenuate growth of pancreatic cancer cell. Cancer Res 65:105–112PubMed Taniuchi K, Nakagawa H, Nakamura T, Eguchi H, Ohigashi H et al (2005) Down-regulation of RAB6KIFL/KIF20A, a kinesin involved with membrane trafficking of discs large homologue 5, can attenuate growth of pancreatic cancer cell. Cancer Res 65:105–112PubMed
14.
Zurück zum Zitat McCollum D (2004) Cytokinesis: the central spindle takes center stage. Curr Biol 14:R953–R955CrossRefPubMed McCollum D (2004) Cytokinesis: the central spindle takes center stage. Curr Biol 14:R953–R955CrossRefPubMed
15.
Zurück zum Zitat Gruneberg U, Neef R, Honda R, Nigg EA, Barr FA (2004) Relocation of Aurora B from centromeres to the central spindle at the metaphase to anaphase transition requires MKlp2. J Cell Biol 166:167–172CrossRefPubMedPubMedCentral Gruneberg U, Neef R, Honda R, Nigg EA, Barr FA (2004) Relocation of Aurora B from centromeres to the central spindle at the metaphase to anaphase transition requires MKlp2. J Cell Biol 166:167–172CrossRefPubMedPubMedCentral
16.
Zurück zum Zitat Echard A (1998) Interaction of a Golgi-Associated Kinesin-Like Protein with Rab6. Science 279:580–585CrossRefPubMed Echard A (1998) Interaction of a Golgi-Associated Kinesin-Like Protein with Rab6. Science 279:580–585CrossRefPubMed
17.
Zurück zum Zitat Hirokawa N, Noda Y, Tanaka Y, Niwa S (2009) Kinesin superfamily motor proteins and intracellular transport. Nat Rev Mol Cell Biol 10:682–696CrossRefPubMed Hirokawa N, Noda Y, Tanaka Y, Niwa S (2009) Kinesin superfamily motor proteins and intracellular transport. Nat Rev Mol Cell Biol 10:682–696CrossRefPubMed
18.
Zurück zum Zitat Jordens I, Marsman M, Kuijl C, Neefjes J (2005) Rab proteins, connecting transport and vesicle fusion. Traffic 6:1070–1077CrossRefPubMed Jordens I, Marsman M, Kuijl C, Neefjes J (2005) Rab proteins, connecting transport and vesicle fusion. Traffic 6:1070–1077CrossRefPubMed
19.
Zurück zum Zitat Okuyama R, Aruga A, Hatori T, Takeda K, Yamamoto M (2013) Immunological responses to a multi-peptide vaccine targeting cancer-testis antigens and VEGFRs in advanced pancreatic cancer patients. Oncoimmunology 2:e27010CrossRefPubMedPubMedCentral Okuyama R, Aruga A, Hatori T, Takeda K, Yamamoto M (2013) Immunological responses to a multi-peptide vaccine targeting cancer-testis antigens and VEGFRs in advanced pancreatic cancer patients. Oncoimmunology 2:e27010CrossRefPubMedPubMedCentral
20.
Zurück zum Zitat Tomita Y, Yuno A, Tsukamoto H, Senju S, Kuroda Y et al (2013) Identification of promiscuous KIF20A long peptides bearing both CD4+ and CD8+ T-cell epitopes: KIF20A-specific CD4+ T-cell immunity in patients with malignant tumor. Clin Cancer Res 19:4508–4520CrossRefPubMed Tomita Y, Yuno A, Tsukamoto H, Senju S, Kuroda Y et al (2013) Identification of promiscuous KIF20A long peptides bearing both CD4+ and CD8+ T-cell epitopes: KIF20A-specific CD4+ T-cell immunity in patients with malignant tumor. Clin Cancer Res 19:4508–4520CrossRefPubMed
21.
Zurück zum Zitat Eggert US, Mitchison TJ, Field CM (2006) Animal cytokinesis: from parts list to mechanisms. Annu Rev Biochem 75:543–566CrossRefPubMed Eggert US, Mitchison TJ, Field CM (2006) Animal cytokinesis: from parts list to mechanisms. Annu Rev Biochem 75:543–566CrossRefPubMed
22.
23.
Zurück zum Zitat Miki H, Setou M, Kaneshiro K, Hirokawa N (2001) All kinesin superfamily protein, KIF genes in mouse and human. Proc Natl Acad Sci USA 98:7004–7011CrossRefPubMedPubMedCentral Miki H, Setou M, Kaneshiro K, Hirokawa N (2001) All kinesin superfamily protein, KIF genes in mouse and human. Proc Natl Acad Sci USA 98:7004–7011CrossRefPubMedPubMedCentral
24.
Zurück zum Zitat Straight AF, Field CM (2000) Microtubules, membranes and cytokinesis. Curr Biol 10:R760–R770CrossRefPubMed Straight AF, Field CM (2000) Microtubules, membranes and cytokinesis. Curr Biol 10:R760–R770CrossRefPubMed
25.
Zurück zum Zitat Wheatley SP, Wang Y (1996) Midzone microtubule bundles are continuously required for cytokinesis in cultured epithelial cells. J Cell Biol 135:981–989CrossRefPubMed Wheatley SP, Wang Y (1996) Midzone microtubule bundles are continuously required for cytokinesis in cultured epithelial cells. J Cell Biol 135:981–989CrossRefPubMed
26.
Zurück zum Zitat Yan GR, Zou FY, Dang BL, Zhang Y, Yu G et al (2012) Genistein-induced mitotic arrest of gastric cancer cells by downregulating KIF20A, a proteomics study. Proteomics 12:2391–2399CrossRefPubMed Yan GR, Zou FY, Dang BL, Zhang Y, Yu G et al (2012) Genistein-induced mitotic arrest of gastric cancer cells by downregulating KIF20A, a proteomics study. Proteomics 12:2391–2399CrossRefPubMed
27.
Zurück zum Zitat Yu Y, Feng YM (2010) The role of kinesin family proteins in tumorigenesis and progression: potential biomarkers and molecular targets for cancer therapy. Cancer 116:5150–5160CrossRefPubMed Yu Y, Feng YM (2010) The role of kinesin family proteins in tumorigenesis and progression: potential biomarkers and molecular targets for cancer therapy. Cancer 116:5150–5160CrossRefPubMed
28.
Zurück zum Zitat Adams RR, Carmena M, Earnshaw WC (2001) Chromosomal passengers and the (aurora) ABCs of mitosis. Trends Cell Biol 11:49–54CrossRefPubMed Adams RR, Carmena M, Earnshaw WC (2001) Chromosomal passengers and the (aurora) ABCs of mitosis. Trends Cell Biol 11:49–54CrossRefPubMed
29.
Zurück zum Zitat D’Avino PP, Savoian MS, Glover DM (2005) Cleavage furrow formation and ingression during animal cytokinesis: a microtubule legacy. J Cell Sci 118:1549–1558CrossRefPubMed D’Avino PP, Savoian MS, Glover DM (2005) Cleavage furrow formation and ingression during animal cytokinesis: a microtubule legacy. J Cell Sci 118:1549–1558CrossRefPubMed
30.
Zurück zum Zitat Ainsztein AM, Kandels-Lewis SE, Mackay AM, Earnshaw WC (1998) INCENP centromere and spindle targeting: identification of essential conserved motifs and involvement of heterochromatin protein HP1. J Cell Biol 143:1763–1774CrossRefPubMedPubMedCentral Ainsztein AM, Kandels-Lewis SE, Mackay AM, Earnshaw WC (1998) INCENP centromere and spindle targeting: identification of essential conserved motifs and involvement of heterochromatin protein HP1. J Cell Biol 143:1763–1774CrossRefPubMedPubMedCentral
31.
Zurück zum Zitat Ruchaud S, Carmena M, Earnshaw WC (2007) Chromosomal passengers: conducting cell division. Nat Rev Mol Cell Biol 8:798–812CrossRefPubMed Ruchaud S, Carmena M, Earnshaw WC (2007) Chromosomal passengers: conducting cell division. Nat Rev Mol Cell Biol 8:798–812CrossRefPubMed
32.
Zurück zum Zitat Buczkowicz P, Zarghooni M, Bartels U, Morrison A, Misuraca KL et al (2013) Aurora kinase B is a potential therapeutic target in pediatric diffuse intrinsic pontine glioma. Brain Pathol 23:244–253CrossRefPubMed Buczkowicz P, Zarghooni M, Bartels U, Morrison A, Misuraca KL et al (2013) Aurora kinase B is a potential therapeutic target in pediatric diffuse intrinsic pontine glioma. Brain Pathol 23:244–253CrossRefPubMed
33.
Zurück zum Zitat Carvajal RD, Tse A, Schwartz GK (2006) Aurora kinases: new targets for cancer therapy. Clin Cancer Res 12:6869–6875CrossRefPubMed Carvajal RD, Tse A, Schwartz GK (2006) Aurora kinases: new targets for cancer therapy. Clin Cancer Res 12:6869–6875CrossRefPubMed
34.
Zurück zum Zitat Portella G, Passaro C, Chieffi P (2011) Aurora B: a new prognostic marker and therapeutic target in cancer. Curr Med Chem 18:482–496CrossRefPubMed Portella G, Passaro C, Chieffi P (2011) Aurora B: a new prognostic marker and therapeutic target in cancer. Curr Med Chem 18:482–496CrossRefPubMed
35.
Zurück zum Zitat Yeung SC, Gully C, Lee MH (2008) Aurora-B kinase inhibitors for cancer chemotherapy. Mini Rev Med Chem 8:1514–1525CrossRefPubMed Yeung SC, Gully C, Lee MH (2008) Aurora-B kinase inhibitors for cancer chemotherapy. Mini Rev Med Chem 8:1514–1525CrossRefPubMed
36.
Zurück zum Zitat Zeng WF, Navaratne K, Prayson RA, Weil RJ (2007) Aurora B expression correlates with aggressive behaviour in glioblastoma multiforme. J Clin Pathol 60:218–221CrossRefPubMedPubMedCentral Zeng WF, Navaratne K, Prayson RA, Weil RJ (2007) Aurora B expression correlates with aggressive behaviour in glioblastoma multiforme. J Clin Pathol 60:218–221CrossRefPubMedPubMedCentral
37.
Zurück zum Zitat Jung Y, Joo KM, Seong DH, Choi YL, Kong DS et al (2012) Identification of prognostic biomarkers for glioblastomas using protein expression profiling. Int J Oncol 40:1122–1132PubMed Jung Y, Joo KM, Seong DH, Choi YL, Kong DS et al (2012) Identification of prognostic biomarkers for glioblastomas using protein expression profiling. Int J Oncol 40:1122–1132PubMed
38.
Zurück zum Zitat Kajiwara Y, Yamasaki F, Hama S, Yahara K, Yoshioka H et al (2003) Expression of survivin in astrocytic tumors: correlation with malignant grade and prognosis. Cancer 97:1077–1083CrossRefPubMed Kajiwara Y, Yamasaki F, Hama S, Yahara K, Yoshioka H et al (2003) Expression of survivin in astrocytic tumors: correlation with malignant grade and prognosis. Cancer 97:1077–1083CrossRefPubMed
39.
Zurück zum Zitat Uematsu M, Ohsawa I, Aokage T, Nishimaki K, Matsumoto K et al (2005) Prognostic significance of the immunohistochemical index of survivin in glioma: a comparative study with the MIB-1 index. J Neurooncol 72:231–238CrossRefPubMed Uematsu M, Ohsawa I, Aokage T, Nishimaki K, Matsumoto K et al (2005) Prognostic significance of the immunohistochemical index of survivin in glioma: a comparative study with the MIB-1 index. J Neurooncol 72:231–238CrossRefPubMed
40.
Zurück zum Zitat Zhen HN, Zhang X, Hu PZ, Yang TT, Fei Z et al (2005) Survivin expression and its relation with proliferation, apoptosis, and angiogenesis in brain gliomas. Cancer 104:2775–2783CrossRefPubMed Zhen HN, Zhang X, Hu PZ, Yang TT, Fei Z et al (2005) Survivin expression and its relation with proliferation, apoptosis, and angiogenesis in brain gliomas. Cancer 104:2775–2783CrossRefPubMed
41.
Zurück zum Zitat Ngan CY, Yamamoto H, Takagi A, Fujie Y, Takemasa I et al (2008) Oxaliplatin induces mitotic catastrophe and apoptosis in esophageal cancer cells. Cancer Sci 99:129–139PubMed Ngan CY, Yamamoto H, Takagi A, Fujie Y, Takemasa I et al (2008) Oxaliplatin induces mitotic catastrophe and apoptosis in esophageal cancer cells. Cancer Sci 99:129–139PubMed
42.
Zurück zum Zitat Vitale I, Galluzzi L, Castedo M, Kroemer G (2011) Mitotic catastrophe: a mechanism for avoiding genomic instability. Nat Rev Mol Cell Biol 12:385–392CrossRefPubMed Vitale I, Galluzzi L, Castedo M, Kroemer G (2011) Mitotic catastrophe: a mechanism for avoiding genomic instability. Nat Rev Mol Cell Biol 12:385–392CrossRefPubMed
43.
Zurück zum Zitat Wonsey DR, Follettie MT (2005) Loss of the forkhead transcription factor FoxM1 causes centrosome amplification and mitotic catastrophe. Cancer Res 65:5181–5189CrossRefPubMed Wonsey DR, Follettie MT (2005) Loss of the forkhead transcription factor FoxM1 causes centrosome amplification and mitotic catastrophe. Cancer Res 65:5181–5189CrossRefPubMed
44.
Zurück zum Zitat Kenney-Herbert EM, Ball SL, Al-Mayhani TM, Watts C (2011) Glioblastoma cell lines derived under serum-free conditions can be used as an in vitro model system to evaluate therapeutic response. Cancer Lett 305:50–57CrossRefPubMed Kenney-Herbert EM, Ball SL, Al-Mayhani TM, Watts C (2011) Glioblastoma cell lines derived under serum-free conditions can be used as an in vitro model system to evaluate therapeutic response. Cancer Lett 305:50–57CrossRefPubMed
45.
Zurück zum Zitat Lee J, Kotliarova S, Kotliarov Y, Li A, Su Q et al (2006) Tumor stem cells derived from glioblastomas cultured in bFGF and EGF more closely mirror the phenotype and genotype of primary tumors than do serum-cultured cell lines. Cancer Cell 9:391–403CrossRefPubMed Lee J, Kotliarova S, Kotliarov Y, Li A, Su Q et al (2006) Tumor stem cells derived from glioblastomas cultured in bFGF and EGF more closely mirror the phenotype and genotype of primary tumors than do serum-cultured cell lines. Cancer Cell 9:391–403CrossRefPubMed
46.
Zurück zum Zitat Vik-Mo EO, Sandberg C, Olstorn H, Varghese M, Brandal P et al (2010) Brain tumor stemcells maintain overall phenotype and tumorigenicity after in vitro culturing in serum-free conditions. Neuro Oncol 12:1220–1230PubMedPubMedCentral Vik-Mo EO, Sandberg C, Olstorn H, Varghese M, Brandal P et al (2010) Brain tumor stemcells maintain overall phenotype and tumorigenicity after in vitro culturing in serum-free conditions. Neuro Oncol 12:1220–1230PubMedPubMedCentral
Metadaten
Titel
Functional analysis of KIF20A, a potential immunotherapeutic target for glioma
verfasst von
Katsuya Saito
Shigeki Ohta
Yutaka Kawakami
Kazunari Yoshida
Masahiro Toda
Publikationsdatum
09.01.2017
Verlag
Springer US
Erschienen in
Journal of Neuro-Oncology / Ausgabe 1/2017
Print ISSN: 0167-594X
Elektronische ISSN: 1573-7373
DOI
https://doi.org/10.1007/s11060-016-2360-1

Weitere Artikel der Ausgabe 1/2017

Journal of Neuro-Oncology 1/2017 Zur Ausgabe

Leitlinien kompakt für die Neurologie

Mit medbee Pocketcards sicher entscheiden.

Seit 2022 gehört die medbee GmbH zum Springer Medizin Verlag

Stuhltransfusion könnte Fortschreiten von Parkinson-Symptomen bremsen

03.05.2024 Parkinson-Krankheit Nachrichten

Kann eine frühzeitige Stuhltransplantation das Fortschreiten von Parkinson-Symptomen verlangsamen? Die Ergebnisse einer randomisierten Phase-2-Studie scheinen dafür zu sprechen.

Frühe Tranexamsäure-Therapie nützt wenig bei Hirnblutungen

02.05.2024 Hirnblutung Nachrichten

Erhalten Personen mit einer spontanen Hirnblutung innerhalb von zwei Stunden nach Symptombeginn eine Tranexamsäure-Therapie, kann dies weder die Hämatomexpansion eindämmen noch die Mortalität senken.

Sind Frauen die fähigeren Ärzte?

30.04.2024 Gendermedizin Nachrichten

Patienten, die von Ärztinnen behandelt werden, dürfen offenbar auf bessere Therapieergebnisse hoffen als Patienten von Ärzten. Besonders scheint das auf weibliche Kranke zuzutreffen, wie eine Studie zeigt.

Akuter Schwindel: Wann lohnt sich eine MRT?

28.04.2024 Schwindel Nachrichten

Akuter Schwindel stellt oft eine diagnostische Herausforderung dar. Wie nützlich dabei eine MRT ist, hat eine Studie aus Finnland untersucht. Immerhin einer von sechs Patienten wurde mit akutem ischämischem Schlaganfall diagnostiziert.

Update Neurologie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.