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  • 1
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    Inflammation in neurodegenerative diseases – an update
    Wiley ; 2014
    In:  Immunology Vol. 142, No. 2 ( 2014-06), p. 151-166
    Details
    In: Immunology, Wiley, Vol. 142, No. 2 ( 2014-06), p. 151-166
    Abstract: Neurodegeneration, the progressive dysfunction and loss of neurons in the central nervous system ( CNS ), is the major cause of cognitive and motor dysfunction. While neuronal degeneration is well‐known in A lzheimer's and P arkinson's diseases, it is also observed in neurotrophic infections, traumatic brain and spinal cord injury, stroke, neoplastic disorders, prion diseases, multiple sclerosis and amyotrophic lateral sclerosis, as well as neuropsychiatric disorders and genetic disorders. A common link between these diseases is chronic activation of innate immune responses including those mediated by microglia, the resident CNS macrophages. Such activation can trigger neurotoxic pathways leading to progressive degeneration. Yet, microglia are also crucial for controlling inflammatory processes, and repair and regeneration. The adaptive immune response is implicated in neurodegenerative diseases contributing to tissue damage, but also plays important roles in resolving inflammation and mediating neuroprotection and repair. The growing awareness that the immune system is inextricably involved in mediating damage as well as regeneration and repair in neurodegenerative disorders, has prompted novel approaches to modulate the immune system, although it remains whether these approaches can be used in humans. Additional factors in humans include ageing and exposure to environmental factors such as systemic infections that provide additional clues that may be human specific and therefore difficult to translate from animal models. Nevertheless, a better understanding of how immune responses are involved in neuronal damage and regeneration, as reviewed here, will be essential to develop effective therapies to improve quality of life, and mitigate the personal, economic and social impact of these diseases.
    Type of Medium: Online Resource
    ISSN: 0019-2805 , 1365-2567
    URL: Issue
    URL: Article
    DOI: 10.1111/imm.2014.142.issue-2
    DOI: 10.1111/imm.12233
    RVK:
    XA 10000
    Language: English
    Publisher: Wiley
    Publication Date: 2014
    detail.hit.zdb_id: 2006481-0
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  • 2
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    Megalencephalic leukoencephalopathy with cysts: the Glialcam ‐null mouse model
    Wiley ; 2017
    In:  Annals of Clinical and Translational Neurology Vol. 4, No. 7 ( 2017-07), p. 450-465
    Details
    In: Annals of Clinical and Translational Neurology, Wiley, Vol. 4, No. 7 ( 2017-07), p. 450-465
    Abstract: Megalencephalic leukoencephalopathy with cysts ( MLC ) is a genetic infantile‐onset disease characterized by macrocephaly and white matter edema due to loss of MLC 1 function. Recessive mutations in either MLC 1 or GLIALCAM cause the disease. MLC 1 is involved in astrocytic volume regulation; Glial CAM ensures the correct membrane localization of MLC 1. Their exact role in brain ion‐water homeostasis is only partly defined. We characterized Glialcam ‐null mice for further studies. Methods We investigated the consequences of loss of Glial CAM in Glialcam ‐null mice and compared Glial CAM developmental expression in mice and men. Results Glialcam ‐null mice had early‐onset megalencephaly and increased brain water content. From 3 weeks, astrocytes were abnormal with swollen processes abutting blood vessels. Concomitantly, progressive white matter vacuolization developed due to intramyelinic edema. Glialcam ‐null astrocytes showed abolished expression of MLC 1, reduced expression of the chloride channel ClC‐2 and increased expression and redistribution of the water channel aquaporin4. Expression of other MLC 1‐interacting proteins and the volume regulated anion channel LRRC 8A was unchanged. In mice, Glial CAM expression increased until 3 weeks and then stabilized. In humans, Glial CAM expression was highest in the first 3 years to then decrease and stabilize from approximately 5 years. Interpretation Glialcam ‐null mice replicate the early stages of the human disease with early‐onset intramyelinic edema. The earliest change is astrocytic swelling, further substantiating that a defect in astrocytic volume regulation is the primary cellular defect in MLC . Glial CAM expression affects expression of MLC 1, ClC‐2 and aquaporin4, indicating that abnormal interplay between these proteins is a disease mechanism in megalencephalic leukoencephalopathy with cysts.
    Type of Medium: Online Resource
    ISSN: 2328-9503 , 2328-9503
    URL: Issue
    URL: Article
    DOI: 10.1002/acn3.2017.4.issue-7
    DOI: 10.1002/acn3.405
    Language: English
    Publisher: Wiley
    Publication Date: 2017
    detail.hit.zdb_id: 2740696-9
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  • 3
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    Metachromatic leukodystrophy and transplantation: remyelination, no cross‐correction
    Wiley ; 2020
    In:  Annals of Clinical and Translational Neurology Vol. 7, No. 2 ( 2020-02), p. 169-180
    Details
    In: Annals of Clinical and Translational Neurology, Wiley, Vol. 7, No. 2 ( 2020-02), p. 169-180
    Abstract: In metachromatic leukodystrophy, a lysosomal storage disorder due to decreased arylsulfatase A activity, hematopoietic stem cell transplantation may stop brain demyelination and allow remyelination, thereby halting white matter degeneration. This is the first study to define the effects and therapeutic mechanisms of hematopoietic stem cell transplantation on brain tissue of transplanted metachromatic leukodystrophy patients. Methods Autopsy brain tissue was obtained from eight (two transplanted and six nontransplanted) metachromatic leukodystrophy patients, and two age‐matched controls. We examined the presence of donor cells by immunohistochemistry and microscopy. In addition, we assessed myelin content, oligodendrocyte numbers, and macrophage phenotypes. An unpaired t ‐test, linear regression or the nonparametric Mann–Whitney U ‐test was performed to evaluate differences between the transplanted, nontransplanted, and control group. Results In brain tissue of transplanted patients, we found metabolically competent donor macrophages expressing arylsulfatase A distributed throughout the entire white matter. Compared to nontransplanted patients, these macrophages preferentially expressed markers of alternatively activated, anti‐inflammatory cells that may support oligodendrocyte survival and differentiation. Additionally, transplanted patients showed higher numbers of oligodendrocytes and evidence for remyelination. Contrary to the current hypothesis on therapeutic mechanism of hematopoietic cell transplantation in metachromatic leukodystrophy, we detected no enzymatic cross‐correction to resident astrocytes and oligodendrocytes. Interpretation In conclusion, donor macrophages are able to digest accumulated sulfatides and may play a neuroprotective role for resident oligodendrocytes, thereby enabling remyelination, albeit without evidence of cross‐correction of oligo‐ and astroglia. These results emphasize the importance of immunomodulation in addition to the metabolic correction, which might be exploited for improved outcomes.
    Type of Medium: Online Resource
    ISSN: 2328-9503 , 2328-9503
    URL: Issue
    URL: Article
    DOI: 10.1002/acn3.v7.2
    DOI: 10.1002/acn3.50975
    Language: English
    Publisher: Wiley
    Publication Date: 2020
    detail.hit.zdb_id: 2740696-9
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  • 4
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    ATRT-18. SHH-SUBTYPE ATYPICAL TERATOID/RHABDOID TUMORS ARE SELECTIVELY SENSITIVE TO GEMCITABINE TREATMENT
    Oxford University Press (OUP) ; 2020
    In:  Neuro-Oncology Vol. 22, No. Supplement_3 ( 2020-12-04), p. iii279-iii279
    Details
    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 22, No. Supplement_3 ( 2020-12-04), p. iii279-iii279
    Abstract: Atypical Teratoid Rhabdoid Tumors (ATRT) are highly malignant embryonal tumors of the central nervous system with a dismal prognosis. ATRT can be divided into three molecular subgroups of which the Sonic Hedgehog (SHH) subgroup is most prevalent. In this study, we developed and validated a novel patient-derived ATRT model, which we used along a panel of other primary ATRT models for large scale drug discovery assays. We found that ATRTs are selectively sensitive to the nucleoside analogue gemcitabine, with SHH-subtype ATRTs being the most sensitive subgroup. Gene expression profiles and protein analysis indicated that gemcitabine treatment causes degradation of Sirtuin 1 (SIRT1), which causes ATRT specific cell-death through NF-kB and p53 activation. Furthermore, we found that this gemcitabine induced loss of SIRT1 results in a nucleus-to-cytoplasm shift of the SHH signaling activator Gli, explaining the additional gemcitabine sensitivity in SHH-subtype ATRT. Treatment of SHH-subgroup ATRT xenograft-bearing mice resulted in a & gt;40% increase in median survival (p & lt;0.01, log-rank test) and long-term survivors in two independent models. To prepare translation of our findings to the clinic, we investigated potential gemcitabine induced resistance mechanisms by conducting kinome-wide CRISPR/Cas9 knockout screens in primary ATRT cells. Through these experiments we found that low-dose gemcitabine treatment combined with inhibition of protein kinase C zeta (PKCζ) prevents regrowth of resistant ATRT subclones. Together, these findings show that ATRT are highly sensitive to gemcitabine treatment; and as such we suggest that gemcitabine may be rapidly incorporated into future treatment regimens for SHH-ATRT.
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    URL: Article
    DOI: 10.1093/neuonc/noaa222.017
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2020
    detail.hit.zdb_id: 2094060-9
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  • 5
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    MEK/MELK inhibition and blood–brain barrier deficiencies in atypical teratoid/rhabdoid tumors
    Oxford University Press (OUP) ; 2020
    In:  Neuro-Oncology Vol. 22, No. 1 ( 2020-01-11), p. 58-69
    Details
    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 22, No. 1 ( 2020-01-11), p. 58-69
    Abstract: Atypical teratoid/rhabdoid tumors (AT/RT) are rare, but highly aggressive. These entities are of embryonal origin occurring in the central nervous system (CNS) of young children. Molecularly these tumors are driven by a single hallmark mutation, resulting in inactivation of SMARCB1 or SMARCA4. Additionally, activation of the MAPK signaling axis and preclinical antitumor efficacy of its inhibition have been described in AT/RT. Methods We established and validated a patient-derived neurosphere culture and xenograft model of sonic hedgehog (SHH) subtype AT/RT, at diagnosis and relapse from the same patient. We set out to study the vascular phenotype of these tumors to evaluate the integrity of the blood–brain barrier (BBB) in AT/RT. We also used the model to study combined mitogen-activated protein kinase kinase (MEK) and maternal embryonic leucine zipper kinase (MELK) inhibition as a therapeutic strategy for AT/RT. Results We found MELK to be highly overexpressed in both patient samples of AT/RT and our primary cultures and xenografts. We identified a potent antitumor efficacy of the MELK inhibitor OTSSP167, as well as strong synergy with the MEK inhibitor trametinib, against primary AT/RT neurospheres. Additionally, vascular phenotyping of AT/RT patient material and xenografts revealed significant BBB aberrancies in these tumors. Finally, we show in vivo efficacy of the non-BBB penetrable drugs OTSSP167 and trametinib in AT/RT xenografts, demonstrating the therapeutic implications of the observed BBB deficiencies and validating MEK/MELK inhibition as a potential treatment. Conclusion Altogether, we developed a combination treatment strategy for AT/RT based on MEK/MELK inhibition and identify therapeutically exploitable BBB deficiencies in these tumors.
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    URL: Article
    DOI: 10.1093/neuonc/noz151
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2020
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  • 6
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    DIPG-33. CHARACTERIZING THE NEURO-VASCULAR UNIT IN DIFFUSE INTRINSIC PONTINE GLIOMA
    Oxford University Press (OUP) ; 2020
    In:  Neuro-Oncology Vol. 22, No. Supplement_3 ( 2020-12-04), p. iii293-iii293
    Details
    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 22, No. Supplement_3 ( 2020-12-04), p. iii293-iii293
    Abstract: Diffuse intrinsic pontine glioma (DIPG) is a childhood brainstem tumor with a median overall survival of eleven months. Lack of chemotherapy efficacy may be related to an intact blood-brain-barrier (BBB). In this study we aim to compare the neuro-vascular unit (NVU) of DIPG to healthy pons tissue. End-stage DIPG autopsy samples (n=5) and age-matched healthy pons samples (n=22), obtained from the NIH NeuroBioBank, were immunohistochemically stained for tight-junction proteins claudin-5 and zonula occludens-1 (ZO-1), basement membrane component laminin, and pericyte marker PDGFRβ. Claudin-5 stains were also used to determine vascular density and diameters. In DIPG, expression of claudin-5 and ZO-1 was reduced, and claudin-5 was dislocated to the abluminal side of endothelial cells. Laminin expression at the glia limitans was reduced in both pre-existent vessels and neovascular proliferation. In contrast to healthy pons, no PDGFRβ expression was detected. The number of blood vessels in DIPG was significantly reduced compared to healthy pons, 13.9±11.8/mm2 versus 26.3±14.2/mm2, respectively (P & lt;0.01). Especially the number of smaller blood vessels ( & lt;10µm) was significantly lower (P & lt;0.01). Distribution of larger blood vessels (≥10µm) did not differ between groups (P=0.223). Mean vascular diameter was 9.3±9.9µm for DIPG versus 7.7±9.0µm in healthy pons (P=0.016). Our study demonstrates evidence of structural changes in the NVU in end-stage DIPG. Chemotherapeutic inefficacy could be the result of reduced vascular density. However, further research is needed to determine meaning and extent of these changes and to determine whether these observations are caused by the tumor or the result of treatment.
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    URL: Article
    DOI: 10.1093/neuonc/noaa222.081
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2020
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  • 7
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    MELK Inhibition in Diffuse Intrinsic Pontine Glioma
    American Association for Cancer Research (AACR) ; 2018
    In:  Clinical Cancer Research Vol. 24, No. 22 ( 2018-11-15), p. 5645-5657
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 24, No. 22 ( 2018-11-15), p. 5645-5657
    Abstract: Purpose: Diffuse intrinsic pontine glioma (DIPG) is a highly aggressive pediatric brain tumor, for which no effective therapeutic options currently exist. We here determined the potential of inhibition of the maternal embryonic leucine zipper kinase (MELK) for the treatment of DIPG. Experimental Design: We evaluated the antitumor efficacy of the small-molecule MELK inhibitor OTSSP167 in vitro in patient-derived DIPG cultures, and identified the mechanism of action of MELK inhibition in DIPG by RNA sequencing of treated cells. In addition, we determined the blood–brain barrier (BBB) penetration of OTSSP167 and evaluated its translational potential by treating mice bearing patient-derived DIPG xenografts. Results: This study shows that MELK is highly expressed in DIPG cells, both in patient samples and in relevant in vitro and in vivo models, and that treatment with OTSSP167 strongly decreases proliferation of patient-derived DIPG cultures. Inhibition of MELK in DIPG cells functions through reducing inhibitory phosphorylation of PPARγ, resulting in an increase in nuclear translocation and consequent transcriptional activity. Brain pharmacokinetic analyses show that OTSSP167 is a strong substrate for both MDR1 and BCRP, limiting its BBB penetration. Nonetheless, treatment of Mdr1a/b;Bcrp1 knockout mice carrying patient-derived DIPG xenografts with OTSSP167 decreased tumor growth, induced remissions, and resulted in improved survival. Conclusions: We show a strong preclinical effect of the kinase inhibitor OTSSP167 in the treatment of DIPG and identify the MELK–PPARγ signaling axis as a putative therapeutic target in this disease. Clin Cancer Res; 24(22); 5645–57. ©2018 AACR.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-18-0924
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
    detail.hit.zdb_id: 1225457-5
    detail.hit.zdb_id: 2036787-9
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  • 8
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    Biallelic variants in LARS2 and KARS cause deafness and (ovario)leukodystrophy
    Ovid Technologies (Wolters Kluwer Health) ; 2019
    In:  Neurology Vol. 92, No. 11 ( 2019-03-12), p. e1225-e1237
    Details
    In: Neurology, Ovid Technologies (Wolters Kluwer Health), Vol. 92, No. 11 ( 2019-03-12), p. e1225-e1237
    Abstract: To describe the leukodystrophy caused by pathogenic variants in LARS2 and KARS , encoding mitochondrial leucyl transfer RNA (tRNA) synthase and mitochondrial and cytoplasmic lysyl tRNA synthase, respectively. Methods We composed a group of 5 patients with leukodystrophy, in whom whole-genome or whole-exome sequencing revealed pathogenic variants in LARS2 or KARS . Clinical information, brain MRIs, and postmortem brain autopsy data were collected. We assessed aminoacylation activities of purified mutant recombinant mitochondrial leucyl tRNA synthase and performed aminoacylation assays on patients' lymphoblasts and fibroblasts. Results Patients had a combination of early-onset deafness and later-onset neurologic deterioration caused by progressive brain white matter abnormalities on MRI. Female patients with LARS2 pathogenic variants had premature ovarian failure. In 2 patients, MRI showed additional signs of early-onset vascular abnormalities. In 2 other patients with LARS2 and KARS pathogenic variants, magnetic resonance spectroscopy revealed elevated white matter lactate, suggesting mitochondrial disease. Pathology in one patient with LARS2 pathogenic variants displayed evidence of primary disease of oligodendrocytes and astrocytes with lack of myelin and deficient astrogliosis. Aminoacylation activities of purified recombinant mutant leucyl tRNA synthase showed a 3-fold loss of catalytic efficiency. Aminoacylation assays on patients' lymphoblasts and fibroblasts showed about 50% reduction of enzyme activity. Conclusion This study adds LARS2 and KARS pathogenic variants as gene defects that may underlie deafness, ovarian failure, and leukodystrophy with mitochondrial signature. We discuss the specific MRI characteristics shared by leukodystrophies caused by mitochondrial tRNA synthase defects. We propose to add aminoacylation assays as biochemical diagnostic tools for leukodystrophies.
    Type of Medium: Online Resource
    ISSN: 0028-3878 , 1526-632X
    URL: Article
    DOI: 10.1212/WNL.0000000000007098
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2019
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  • 9
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    Combined Therapy of AXL and HDAC Inhibition Reverses Mesenchymal Transition in Diffuse Intrinsic Pontine Glioma
    American Association for Cancer Research (AACR) ; 2020
    In:  Clinical Cancer Research Vol. 26, No. 13 ( 2020-07-01), p. 3319-3332
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 26, No. 13 ( 2020-07-01), p. 3319-3332
    Abstract: Diffuse intrinsic pontine glioma (DIPG) is an incurable type of pediatric brain cancer, which in the majority of cases is driven by mutations in genes encoding histone 3 (H3K27M). We here determined the preclinical therapeutic potential of combined AXL and HDAC inhibition in these tumors to reverse their mesenchymal, therapy-resistant, phenotype. Experimental Design: We used public databases and patient-derived DIPG cells to identify putative drivers of the mesenchymal transition in these tumors. Patient-derived neurospheres, xenografts, and allografts were used to determine the therapeutic potential of combined AXL/HDAC inhibition for the treatment of DIPG. Results: We identified AXL as a therapeutic target and regulator of the mesenchymal transition in DIPG. Combined AXL and HDAC inhibition had a synergistic and selective antitumor effect on H3K27M DIPG cells. Treatment of DIPG cells with the AXL inhibitor BGB324 and the HDAC inhibitor panobinostat resulted in a decreased expression of mesenchymal and stem cell genes. Moreover, this combination treatment decreased expression of DNA damage repair genes in DIPG cells, strongly sensitizing them to radiation. Pharmacokinetic studies showed that BGB324, like panobinostat, crosses the blood–brain barrier. Consequently, treatment of patient-derived DIPG xenograft and murine DIPG allograft-bearing mice with BGB324 and panobinostat resulted in a synergistic antitumor effect and prolonged survival. Conclusions: Combined inhibition of AXL and HDACs in DIPG cells results in a synergistic antitumor effect by reversing their mesenchymal, stem cell-like, therapy-resistant phenotype. As such, this treatment combination may serve as part of a future multimodal therapeutic strategy for DIPG.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-19-3538
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
    detail.hit.zdb_id: 1225457-5
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  • 10
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    GM‐CSF promotes migration of human monocytes across the blood brain barrier
    Wiley ; 2015
    In:  European Journal of Immunology Vol. 45, No. 6 ( 2015-06), p. 1808-1819
    Details
    In: European Journal of Immunology, Wiley, Vol. 45, No. 6 ( 2015-06), p. 1808-1819
    Abstract: Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS). Infiltration of monocytes into the CNS is crucial for disease onset and progression. Animal studies indicate that granulocyte‐macrophages colony‐stimulating factor (GM‐CSF) may play an essential role in this process, possibly by acting on the migratory capacities of myeloid cells across the blood–brain barrier. This study describes the effect of GM‐CSF on human monocytes, macrophages, and microglia. Furthermore, the expression of GM‐CSF and its receptor was investigated in the CNS under healthy and pathological conditions. We show that GM‐CSF enhances monocyte migration across human blood–brain barrier endothelial cells in vitro. Next, immunohistochemical analysis on human brain tissues revealed that GM‐CSF is highly expressed by microglia and macrophages in MS lesions. The GM‐CSF receptor is expressed by neurons in the rim of combined gray/white matter lesions and astrocytes. Finally, the effect of GM‐CSF on human macrophages was determined, revealing an intermediate activation status, with a phenotype similar to that observed in active MS lesions. Together our data indicate that GM‐CSF is a powerful stimulator of monocyte migration, and is abundantly present in the inflamed CNS where it may act as an activator of macrophages and microglia.
    Type of Medium: Online Resource
    ISSN: 0014-2980 , 1521-4141
    URL: Issue
    URL: Article
    DOI: 10.1002/eji.v45.6
    DOI: 10.1002/eji.201444960
    RVK:
    XA 10000
    Language: English
    Publisher: Wiley
    Publication Date: 2015
    detail.hit.zdb_id: 1491907-2
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