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1.
Sci Rep ; 9(1): 1734, 2019 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-30741954

RESUMO

α-Synuclein is a protein that aggregates as amyloid fibrils in the brains of patients with Parkinson's disease and dementia with Lewy bodies. Small oligomers of α-synuclein are neurotoxic and are thought to be closely associated with disease. Whereas α-synuclein fibrillization and fibril morphologies have been studied extensively with various methods, the earliest stages of aggregation and the properties of oligomeric intermediates are less well understood because few methods are able to detect and characterize early-stage aggregates. We used fluorescence spectroscopy to investigate the early stages of aggregation by studying pairwise interactions between α-synuclein monomers, as well as between engineered tandem oligomers of various sizes (dimers, tetramers, and octamers). The hydrodynamic radii of these engineered α-synuclein species were first determined by fluorescence correlation spectroscopy and dynamic light scattering. The rate of pairwise aggregation between different species was then monitored using dual-color fluorescence cross-correlation spectroscopy, measuring the extent of association between species labelled with different dyes at various time points during the early aggregation process. The aggregation rate and extent increased with tandem oligomer size. Self-association of the tandem oligomers was found to be the preferred pathway to form larger aggregates: interactions between oligomers occurred faster and to a greater extent than interactions between oligomers and monomers, indicating that the oligomers were not as efficient in seeding further aggregation by addition of monomers. These results suggest that oligomer-oligomer interactions may play an important role in driving aggregation during its early stages.

2.
Sci Rep ; 8(1): 6755, 2018 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-29712958

RESUMO

Pre-fibrillar oligomers of α-synuclein are thought to be pathogenic molecules leading to neurotoxicity associated with Parkinson's disease and other neurodegenerative disorders. However, small oligomers are difficult to isolate for study. To gain better insight into the properties of small α-synuclein oligomers, we investigated engineered oligomers of specific size (dimers, tetramers, and octamers) linked head-to-tail in tandem, comparing the behavior of the oligomers to monomeric α-synuclein. All oligomeric constructs remained largely disordered in solution, as determined from dynamic light scattering and size-exclusion chromatography. Electron microscopy revealed that each construct could aggregate to form fibrils similar to those formed by monomeric α-synuclein. The interactions with large unilamellar vesicles (LUVs) composed of negatively-charged lipids differed depending on size, with smaller oligomers forming more extensive helical structure as determined by CD spectroscopy. Monitoring the influx of a fluorescence bleaching agent into vesicles showed that larger oligomers were somewhat more effective at degrading vesicular integrity and inducing membrane permeabilization.


Assuntos
Membrana Celular/genética , Lipídeos/química , Doença de Parkinson/genética , alfa-Sinucleína/química , Membrana Celular/química , Humanos , Lipídeos/genética , Doença de Parkinson/patologia , Polímeros , Multimerização Proteica , Estrutura Quaternária de Proteína , Lipossomas Unilamelares/química , alfa-Sinucleína/genética
3.
J Clin Oncol ; 36(19): 1963-1972, 2018 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-29746225

RESUMO

Purpose Diffuse intrinsic pontine glioma (DIPG) is a brainstem malignancy with a median survival of < 1 year. The International and European Society for Pediatric Oncology DIPG Registries collaborated to compare clinical, radiologic, and histomolecular characteristics between short-term survivors (STSs) and long-term survivors (LTSs). Materials and Methods Data abstracted from registry databases included patients from North America, Australia, Germany, Austria, Switzerland, the Netherlands, Italy, France, the United Kingdom, and Croatia. Results Among 1,130 pediatric and young adults with radiographically confirmed DIPG, 122 (11%) were excluded. Of the 1,008 remaining patients, 101 (10%) were LTSs (survival ≥ 2 years). Median survival time was 11 months (interquartile range, 7.5 to 16 months), and 1-, 2-, 3-, 4-, and 5-year survival rates were 42.3% (95% CI, 38.1% to 44.1%), 9.6% (95% CI, 7.8% to 11.3%), 4.3% (95% CI, 3.2% to 5.8%), 3.2% (95% CI, 2.4% to 4.6%), and 2.2% (95% CI, 1.4% to 3.4%), respectively. LTSs, compared with STSs, more commonly presented at age < 3 or > 10 years (11% v 3% and 33% v 23%, respectively; P < .001) and with longer symptom duration ( P < .001). STSs, compared with LTSs, more commonly presented with cranial nerve palsy (83% v 73%, respectively; P = .008), ring enhancement (38% v 23%, respectively; P = .007), necrosis (42% v 26%, respectively; P = .009), and extrapontine extension (92% v 86%, respectively; P = .04). LTSs more commonly received systemic therapy at diagnosis (88% v 75% for STSs; P = .005). Biopsies and autopsies were performed in 299 patients (30%) and 77 patients (10%), respectively; 181 tumors (48%) were molecularly characterized. LTSs were more likely to harbor a HIST1H3B mutation (odds ratio, 1.28; 95% CI, 1.1 to 1.5; P = .002). Conclusion We report clinical, radiologic, and molecular factors that correlate with survival in children and young adults with DIPG, which are important for risk stratification in future clinical trials.


Assuntos
Neoplasias do Tronco Encefálico/diagnóstico , Sobreviventes de Câncer/estatística & dados numéricos , Glioma/diagnóstico , Adolescente , Adulto , Neoplasias do Tronco Encefálico/diagnóstico por imagem , Neoplasias do Tronco Encefálico/genética , Neoplasias do Tronco Encefálico/terapia , Criança , Pré-Escolar , Glioma/diagnóstico por imagem , Glioma/genética , Glioma/terapia , Humanos , Lactente , Recém-Nascido , Estimativa de Kaplan-Meier , Sistema de Registros , Adulto Jovem
4.
Neuro Oncol ; 20(1): 123-131, 2018 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-29016894

RESUMO

Background: The novel entity of "diffuse midline glioma, H3 K27M-mutant" has been defined in the 2016 revision of the World Health Organization (WHO) classification of tumors of the central nervous system (CNS). Tumors of this entity arise in CNS midline structures of predominantly pediatric patients and are associated with an overall dismal prognosis. They are defined by K27M mutations in H3F3A or HIST1H3B/C, encoding for histone 3 variants H3.3 and H3.1, respectively, which are considered hallmark events driving gliomagenesis. Methods: Here, we characterized 85 centrally reviewed diffuse gliomas on midline locations enrolled in the nationwide pediatric German HIT-HGG registry regarding tumor site, histone 3 mutational status, WHO grade, age, sex, and extent of tumor resection. Results: We found 56 H3.3 K27M-mutant tumors (66%), 6 H3.1 K27M-mutant tumors (7%), and 23 H3-wildtype tumors (27%). H3 K27M-mutant gliomas shared an aggressive clinical course independent of their anatomic location. Multivariate regression analysis confirmed the significant impact of the H3 K27M mutation as the only independent parameter predictive of overall survival (P = 0.009). In H3 K27M-mutant tumors, neither anatomic midline location nor histopathological grading nor extent of tumor resection had an influence on survival. Conclusion: These results substantiate the clinical significance of considering diffuse midline glioma, H3 K27M-mutant, as a distinct entity corresponding to WHO grade IV, carrying a universally fatal prognosis.


Assuntos
Neoplasias Encefálicas/genética , Glioma/genética , Histonas/genética , Mutação/genética , Adolescente , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/patologia , Criança , Feminino , Glioma/diagnóstico , Glioma/patologia , Humanos , Masculino , Gradação de Tumores , Prognóstico
5.
Strahlenther Onkol ; 194(3): 215-224, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29022050

RESUMO

PURPOSE: As the efficacy of all pediatric high-grade glioma (HGG) treatments is similar and still disappointing, it is essential to also investigate the toxicity of available treatments. METHODS: Prospectively recorded hematologic and nonhematologic toxicities of children treated with radiochemotherapy in the HIT GBM-C/D and HIT-HGG-2007 trials were compared. Children aged 3-18 years with histologically proven HGG (WHO grade III and IV tumors) or unequivocal radiologic diagnosis of diffuse intrinsic pontine glioma (DIPG) were included in these trials. The HIT-HGG-2007 protocol comprised concomitant radiochemotherapy with temozolomide, while cisplatinum/etoposide (PE) and PE plus ifosfamide (PEI) in combination with weekly vincristine injections were applied during radiochemotherapy in the HIT GBM-C/D protocol. RESULTS: Regular blood counts and information about cellular nadirs were available from 304 patients (leukocytes) and 306 patients (thrombocytes), respectively. Grade 3-4 leukopenia was much more frequent in the HIT GBM-C/D cohort (n = 88, 52%) vs. HIT-HGG-2007 (n = 13, 10%; P <0.001). Grade 3-4 thrombopenia was also more likely in the HIT GBM-C/D cohort (n = 21, 12% vs. n = 3,2%; P <0.001). Grade 3-4 leukopenia appeared more often in children aged 3-7 years (n = 38/85, 45%) than in children aged 8-12 years (n = 39/120, 33%) and 13-18 years (24/100, 24%; P =0.034). In addition, sickness was more frequent in the HIT GBM-C/D cohort (grade 1-2: 44%, grade 3-4: 6% vs. grade 1-2: 28%, grade 3-4: 1%; P <0.001). CONCLUSION: Radiochemotherapy involving cisplatinum-based polychemotherapy is more toxic than radiotherapy in combination with temozolomide. Without evidence of differences in therapeutic efficacy, the treatment with lower toxicity, i. e., radiotherapy with temozolomide should be used.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias Encefálicas/terapia , Quimiorradioterapia/efeitos adversos , Cisplatino/efeitos adversos , Dacarbazina/análogos & derivados , Glioma/terapia , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Encefálicas/patologia , Quimiorradioterapia/métodos , Criança , Pré-Escolar , Cisplatino/administração & dosagem , Estudos de Coortes , Dacarbazina/administração & dosagem , Dacarbazina/efeitos adversos , Etoposídeo/administração & dosagem , Etoposídeo/efeitos adversos , Feminino , Glioma/patologia , Humanos , Ifosfamida/administração & dosagem , Ifosfamida/efeitos adversos , Leucopenia/induzido quimicamente , Masculino , Gradação de Tumores , Estudos Prospectivos , Temozolomida , Resultado do Tratamento , Vincristina/administração & dosagem , Vincristina/efeitos adversos
6.
Eur J Cancer ; 81: 1-8, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28586748

RESUMO

BACKGROUND: Temozolomide (TMZ) is widely used in high-grade glioma (HGG). There is a major concern of treatment-induced secondary haematological malignancies (SHMs). Due to the poor overall survival of HGG patients, the true incidence is yet elusive. Thus, the aim of this study was to determine the risk of SHMs following TMZ in paediatric HGG. METHODS: We analysed 487 patients from the HIT-HGG database of the German-speaking Society of Pediatric Oncology and Hematology with follow up beyond 1 year. RESULTS: The incidence of SHM was 7.7 ± 3.2% at 10 years. No SHM occurred in 194 patients after first-line TMZ therapy, but four out of 131 patients treated with TMZ for relapse following first-line multiagent chemotherapy experienced SHM (20% at 10 years; p = 0.041). SHMs occurred in two out of 162 patients who underwent multiagent chemotherapy without TMZ (4.1% at 10 years). Gender, patient age and acute haematological toxicity during treatment did not affect the incidence of SHMs. CONCLUSION: Data of our cohort do not indicate an increased risk of SHM following TMZ treatment when compared to previous chemotherapy regimen. However, if TMZ is administered as a second-line treatment following conventional chemotherapy regimen, the risk might be disproportionately increasing.


Assuntos
Antineoplásicos Alquilantes/efeitos adversos , Dacarbazina/análogos & derivados , Glioma/tratamento farmacológico , Neoplasias Hematológicas/induzido quimicamente , Adolescente , Áustria/epidemiologia , Criança , Pré-Escolar , Dacarbazina/efeitos adversos , Feminino , Seguimentos , Alemanha/epidemiologia , Neoplasias Hematológicas/epidemiologia , Humanos , Incidência , Lactente , Estimativa de Kaplan-Meier , Masculino , Suíça/epidemiologia , Temozolomida
7.
Comput Methods Biomech Biomed Engin ; 20(11): 1175-1181, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28628751

RESUMO

Accurate muscle geometry (muscle length and moment arm) is required to estimate muscle function when using musculoskeletal modelling. In shoulder, muscles are often modelled as a collection of independent line segments, leading to non-physiological muscles trajectory, especially for the rotator cuff muscles. To prevent this, a surface mesh model was developed and validated against 7 MRI positions in one participant. Mean moment arm errors was 11.4% for the line vs. 8.8% for the mesh model. While the model with independent lines led to some non-physiological trajectories, the mesh model gave lower misestimations of muscle lengths and moment arms.


Assuntos
Modelos Biológicos , Músculo Esquelético/anatomia & histologia , Manguito Rotador/anatomia & histologia , Adulto , Fenômenos Biomecânicos , Humanos , Imagem por Ressonância Magnética , Músculo Esquelético/fisiologia , Postura , Manguito Rotador/diagnóstico por imagem , Manguito Rotador/fisiologia , Tomografia Computadorizada por Raios X
8.
J Neurooncol ; 132(2): 255-266, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28110411

RESUMO

Diffuse intrinsic pontine glioma (DIPG) is a rare and deadly childhood malignancy. After 40 years of mostly single-center, often non-randomized trials with variable patient inclusions, there has been no improvement in survival. It is therefore time for international collaboration in DIPG research, to provide new hope for children, parents and medical professionals fighting DIPG. In a first step towards collaboration, in 2011, a network of biologists and clinicians working in the field of DIPG was established within the European Society for Paediatric Oncology (SIOPE) Brain Tumour Group: the SIOPE DIPG Network. By bringing together biomedical professionals and parents as patient representatives, several collaborative DIPG-related projects have been realized. With help from experts in the fields of information technology, and legal advisors, an international, web-based comprehensive database was developed, The SIOPE DIPG Registry and Imaging Repository, to centrally collect data of DIPG patients. As for April 2016, clinical data as well as MR-scans of 694 patients have been entered into the SIOPE DIPG Registry/Imaging Repository. The median progression free survival is 6.0 months (95% Confidence Interval (CI) 5.6-6.4 months) and the median overall survival is 11.0 months (95% CI 10.5-11.5 months). At two and five years post-diagnosis, 10 and 2% of patients are alive, respectively. The establishment of the SIOPE DIPG Network and SIOPE DIPG Registry means a paradigm shift towards collaborative research into DIPG. This is seen as an essential first step towards understanding the disease, improving care and (ultimately) cure for children with DIPG.


Assuntos
Neoplasias do Tronco Encefálico/diagnóstico por imagem , Glioma/diagnóstico por imagem , Serviços de Informação , Cooperação Internacional , Imagem por Ressonância Magnética , Sistema de Registros , Criança , Pré-Escolar , Europa (Continente) , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Masculino , Ponte/diagnóstico por imagem , Adulto Jovem
9.
Pediatr Hematol Oncol ; 32(7): 467-73, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26237586

RESUMO

Due to the poor survival in high-grade glioma (HGG), secondary solid malignancies (SSM) following pediatric HGG are scarce. The authors present the experience from the HIT-HGG database in Germany, Austria, and Switzerland. Five out of 1228 pediatric HGG patients developed a SSM following a latency of 29-122 months from primary HGG diagnosis. In 4 patients, the SSM may be attributed to previous radiotherapy or a tumor predisposition syndrome, reflected by a markedly increased cumulative incidence rate of SSM in patients with tumor predisposition. Survival was devastating, since none of the patients survived beyond 18 months from SSM diagnosis.


Assuntos
Bases de Dados Factuais , Glioma , Adolescente , Criança , Pré-Escolar , Intervalo Livre de Doença , Feminino , Glioma/mortalidade , Glioma/terapia , Humanos , Incidência , Lactente , Recém-Nascido , Masculino , Segunda Neoplasia Primária/mortalidade , Segunda Neoplasia Primária/terapia , Taxa de Sobrevida
10.
Radiat Oncol ; 9: 177, 2014 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-25112658

RESUMO

BACKGROUND AND PURPOSE: The aim of the present analysis was to assess the feasibility, toxicity, and the tumor control of reirradiation as a salvage treatment for progressive pediatric non-pontine high-grade gliomas (HGG). PATIENTS AND METHODS: The database of the Reference Center for Radiation Oncology of the German HIT (HIT = German acronym for brain tumor) treatment network for childhood brain tumors was screened for children who were reirradiated for progressive non-pontine HGG. RESULTS: We identified eight patients (WHO grade III: n = 5; WHO grade IV: n = 3) who underwent reirradiation between April 2006 and July 2012. Median age was 13.5 years at primary diagnosis and 14.8 years at first progression. All patients initially underwent surgery (incomplete resection, n = 7; biopsy, n = 1) followed by radiochemotherapy. Relapses occurred inside (n = 2), at the margin (n = 4), and outside of the preirradiated area (n = 2). In all patients, reirradiation was tolerated well without significant acute toxicity. Temporary clinical improvement and tumor regression on magnetic resonance imaging (MRI) following reirradiation was reported (n = 3). However, all patients finally died by disease progression. Median survival time was 26.2 months from initial diagnosis and 11.4 months after first progression. Median time interval between initial radiotherapy and first reirradiation was 9.0 months. In six patients, all macroscopic tumor deposits were reirradiated. In these patients, median progression-free (overall) survival from the start of reirradiation was 2.4 (4.6) months. CONCLUSION: Our analysis, although based on a limited patient number, suggests that reirradiation of progressive non-pontine HGG is feasible in children. Benefit in terms of quality of life and/or survival needs to be assessed in a prospective and ideally in a randomized manner.


Assuntos
Neoplasias Encefálicas/radioterapia , Glioma/radioterapia , Recidiva Local de Neoplasia/radioterapia , Radioterapia/métodos , Terapia de Salvação/métodos , Adolescente , Neoplasias Encefálicas/mortalidade , Criança , Terapia Combinada , Progressão da Doença , Intervalo Livre de Doença , Feminino , Glioma/mortalidade , Humanos , Estimativa de Kaplan-Meier , Masculino , Gradação de Tumores , Estudos Retrospectivos
11.
Cancer Res ; 70(6): 2328-38, 2010 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-20215507

RESUMO

NAD(P)H oxidase is a major endogenous source of reactive oxygen species (ROS). ROS may not only be involved in carcinogenesis but also in efficacy of chemotherapeutic agents like doxorubicin. By a comprehensive genotyping approach covering 48 genetic polymorphisms (single-nucleotide polymorphisms) in five subunits of phagocytic NAD(P)H oxidase, we asked whether they affect gene expression, enzymatic activity, and outcome of CHO(E)P chemotherapy. A highly consistent effect was observed for the CYBA 640A>G variant. In peripheral blood granulocytes of 125 healthy volunteers, the G allele of 640A>G was associated with lower NAD(P)H oxidase activity (P = 0.006). Moreover, the G allele was associated with lower mRNA and protein expression (both P = 0.02). Of clinical importance, the outcome of patients suffering from non-Hodgkin lymphoma and treated with CHO(E)P regimen was dependent on the CYBA 640A>G polymorphism. In an exploratory study (n = 401), carriers of 640GG had an event-free survival (EFS) risk ratio of 1.95 [95% confidence interval (95% CI), 1.31-2.90; P = 0.001] compared with 640AA. In a confirmatory set (n = 477), the risk ratios were 1.53 (1.04-2.25, P = 0.03). The complete set of 878 patients showed a relative risk of 1.72 (1.30-2.26) and 1.59 (1.14-2.21) for EFS and overall survival, respectively. Further molecular-biological experiments showed lower expression and reduced stability of transcripts with the G allele in lymphoblastoid cell lines. Transfection of allele-specific plasmids into HEK293 cells elicited lower activity for the G allele in a luciferase reporter gene construct. Thus, CYBA 640A>G was shown to be a functional polymorphism with possible consequences for patients receiving CHO(E)P chemotherapy and might have further implications for other ROS-mediated modalities.


Assuntos
Linfoma não Hodgkin/enzimologia , NADPH Oxidases/genética , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ciclofosfamida/administração & dosagem , Doxorrubicina/administração & dosagem , Etoposídeo/administração & dosagem , Feminino , Expressão Gênica , Humanos , Linfoma não Hodgkin/tratamento farmacológico , Linfoma não Hodgkin/genética , Masculino , Pessoa de Meia-Idade , NADPH Oxidases/biossíntese , NADPH Oxidases/metabolismo , Polimorfismo de Nucleotídeo Único , Prednisolona/administração & dosagem , Subunidades Proteicas , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Resultado do Tratamento , Vincristina/administração & dosagem , Adulto Jovem
12.
Pharmacogenet Genomics ; 19(4): 249-59, 2009 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19214138

RESUMO

OBJECTIVES: The transforming growth factor-beta (TGFB) pathway has substantial impact on cellular functions, cell proliferation, and apoptosis. We used bioinformatics, gene expression, and cell biological assays to evaluate the functionality of frequent inherited germline polymorphisms in the TGFB receptor 1 (TGFBR1). METHODS: In an exploratory (n=55) and confirmatory (n=106) study, we analyzed the TGFB1 pathway after incubation with TGFbeta1 ligand and after exposure to X-rays in peripheral blood human mononuclear cells. Expression of TGFB pathway genes was assessed by real-time PCR, and cellular viability was analyzed by flow cytometry. A total of six polymorphisms including the deletion variant (*6A) were identified to tag currently known common genetic variations in TGFBR1 and were analyzed in relation to the phenotypes. RESULTS: In accordance with a negative feedback mechanism, incubations with the ligand TGFbeta1 was followed by up-regulation of the intracellular SMAD7 and down-regulation of the SMAD3 mRNA molecules. The TGFBR1*6A deletion variant attenuated the suppression of SMAD3 in response to TGFbeta1 (P=0.02, in both studies). Moreover, cells harboring *6A were more sensitive toward cytotoxic effects of irradiation (P=0.001 after adjustment for age and sex). Cells were particularly prone toward radiation toxicity when carrying, in addition to *6A, the variant allele of rs11568785, which exhibits a strong genetic selection signature. CONCLUSION: The *6A deletion and the linked rs11568785 polymorphisms seem to attenuate TGFB signaling. This should be considered not only for clinical-epidemiological studies on cancer susceptibility but may also be relevant for side effects from drugs or radiotherapy.


Assuntos
Biologia Computacional/métodos , Polimorfismo Genético , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Receptores de Fatores de Crescimento Transformadores beta/genética , Receptores de Fatores de Crescimento Transformadores beta/metabolismo , Transdução de Sinais , Adulto , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Células Cultivadas , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos da radiação , Variação Genética , Haplótipos , Humanos , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/efeitos da radiação , Pessoa de Meia-Idade , Proteínas Serina-Treonina Quinases/farmacologia , RNA Mensageiro/metabolismo , Receptor do Fator de Crescimento Transformador beta Tipo I , Proteínas Recombinantes/metabolismo , Transdução de Sinais/genética , Raios X , Adulto Jovem
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