Caracterización molecular y farmacogenética en una muestra de pacientes con leucemia mieloide aguda y su correlación con la estratificación del riesgo y respuesta al tratamiento. Una aproximación hacia los patrones moleculares de la leucemia mieloide aguda pediátrica en población colombiana

ilustraciones, diagramas, mapas, tablas

Autores:: Yunis Hazbun, Luz Karime

Tipo de recurso:: Doctoral thesis

Fecha de publicación:: 2024

Institución:: Universidad Nacional de Colombia

Repositorio:: Universidad Nacional de Colombia

Idioma:: spa

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network_acronym_str	UNACIONAL2
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dc.title.spa.fl_str_mv	Caracterización molecular y farmacogenética en una muestra de pacientes con leucemia mieloide aguda y su correlación con la estratificación del riesgo y respuesta al tratamiento. Una aproximación hacia los patrones moleculares de la leucemia mieloide aguda pediátrica en población colombiana
dc.title.translated.eng.fl_str_mv	Molecular and pharmacogenetic characterization in acute myeloid leukemia patients and the correlation with risk stratification and treatment response
title	Caracterización molecular y farmacogenética en una muestra de pacientes con leucemia mieloide aguda y su correlación con la estratificación del riesgo y respuesta al tratamiento. Una aproximación hacia los patrones moleculares de la leucemia mieloide aguda pediátrica en población colombiana
spellingShingle	Caracterización molecular y farmacogenética en una muestra de pacientes con leucemia mieloide aguda y su correlación con la estratificación del riesgo y respuesta al tratamiento. Una aproximación hacia los patrones moleculares de la leucemia mieloide aguda pediátrica en población colombiana 610 - Medicina y salud::615 - Farmacología y terapéutica 570 - Biología::576 - Genética y evolución 610 - Medicina y salud::616 - Enfermedades Leucemia Mielomonocítica Aguda Variantes Farmacogenómicas Resistencia a Antineoplásicos Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos Leukemia, Myelomonocytic, Acute Drug Resistance, Neoplasm Drug-Related Side Effects and Adverse Reactions Pharmacogenomic Variants Leucemia mieloide aguda Genómica Pediátrica Colombia Latinoamérica ABCB1 DCK CDA GSTT1 GSTM1 Citarabina Antraciclinas SNV Ancestría AIM-InDel Acute myeloid leukemia Genomics Pediatrics Latin America Citarabine Antracyclines Ancestry
title_short	Caracterización molecular y farmacogenética en una muestra de pacientes con leucemia mieloide aguda y su correlación con la estratificación del riesgo y respuesta al tratamiento. Una aproximación hacia los patrones moleculares de la leucemia mieloide aguda pediátrica en población colombiana
title_full	Caracterización molecular y farmacogenética en una muestra de pacientes con leucemia mieloide aguda y su correlación con la estratificación del riesgo y respuesta al tratamiento. Una aproximación hacia los patrones moleculares de la leucemia mieloide aguda pediátrica en población colombiana
title_fullStr	Caracterización molecular y farmacogenética en una muestra de pacientes con leucemia mieloide aguda y su correlación con la estratificación del riesgo y respuesta al tratamiento. Una aproximación hacia los patrones moleculares de la leucemia mieloide aguda pediátrica en población colombiana
title_full_unstemmed	Caracterización molecular y farmacogenética en una muestra de pacientes con leucemia mieloide aguda y su correlación con la estratificación del riesgo y respuesta al tratamiento. Una aproximación hacia los patrones moleculares de la leucemia mieloide aguda pediátrica en población colombiana
title_sort	Caracterización molecular y farmacogenética en una muestra de pacientes con leucemia mieloide aguda y su correlación con la estratificación del riesgo y respuesta al tratamiento. Una aproximación hacia los patrones moleculares de la leucemia mieloide aguda pediátrica en población colombiana
dc.creator.fl_str_mv	Yunis Hazbun, Luz Karime
dc.contributor.advisor.spa.fl_str_mv	Yunis Londoño, Juan José Linares Ballesteros, Teresa Adriana Elvira
dc.contributor.author.spa.fl_str_mv	Yunis Hazbun, Luz Karime
dc.contributor.researchgroup.spa.fl_str_mv	Patología Molecular Oncohematologia Pediatrica
dc.contributor.orcid.spa.fl_str_mv	Yunis Hazbun, Luz Karime [0000000333655196]
dc.subject.ddc.spa.fl_str_mv	610 - Medicina y salud::615 - Farmacología y terapéutica 570 - Biología::576 - Genética y evolución 610 - Medicina y salud::616 - Enfermedades
topic	610 - Medicina y salud::615 - Farmacología y terapéutica 570 - Biología::576 - Genética y evolución 610 - Medicina y salud::616 - Enfermedades Leucemia Mielomonocítica Aguda Variantes Farmacogenómicas Resistencia a Antineoplásicos Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos Leukemia, Myelomonocytic, Acute Drug Resistance, Neoplasm Drug-Related Side Effects and Adverse Reactions Pharmacogenomic Variants Leucemia mieloide aguda Genómica Pediátrica Colombia Latinoamérica ABCB1 DCK CDA GSTT1 GSTM1 Citarabina Antraciclinas SNV Ancestría AIM-InDel Acute myeloid leukemia Genomics Pediatrics Latin America Citarabine Antracyclines Ancestry
dc.subject.decs.spa.fl_str_mv	Leucemia Mielomonocítica Aguda Variantes Farmacogenómicas Resistencia a Antineoplásicos Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos
dc.subject.decs.eng.fl_str_mv	Leukemia, Myelomonocytic, Acute Drug Resistance, Neoplasm Drug-Related Side Effects and Adverse Reactions
dc.subject.lemb.eng.fl_str_mv	Pharmacogenomic Variants
dc.subject.proposal.spa.fl_str_mv	Leucemia mieloide aguda Genómica Pediátrica Colombia Latinoamérica ABCB1 DCK CDA GSTT1 GSTM1 Citarabina Antraciclinas SNV Ancestría AIM-InDel
dc.subject.proposal.eng.fl_str_mv	Acute myeloid leukemia Genomics Pediatrics Latin America Citarabine Antracyclines Ancestry
description	ilustraciones, diagramas, mapas, tablas
publishDate	2024
dc.date.accessioned.none.fl_str_mv	2024-09-03T16:27:48Z
dc.date.available.none.fl_str_mv	2024-09-03T16:27:48Z
dc.date.issued.none.fl_str_mv	2024
dc.type.spa.fl_str_mv	Trabajo de grado - Doctorado
dc.type.driver.spa.fl_str_mv	info:eu-repo/semantics/doctoralThesis
dc.type.version.spa.fl_str_mv	info:eu-repo/semantics/acceptedVersion
dc.type.coar.spa.fl_str_mv	http://purl.org/coar/resource_type/c_db06
dc.type.content.spa.fl_str_mv	Text
dc.type.redcol.spa.fl_str_mv	http://purl.org/redcol/resource_type/TD
format	http://purl.org/coar/resource_type/c_db06
status_str	acceptedVersion
dc.identifier.uri.none.fl_str_mv	https://repositorio.unal.edu.co/handle/unal/86783
dc.identifier.instname.spa.fl_str_mv	Universidad Nacional de Colombia
dc.identifier.reponame.spa.fl_str_mv	Repositorio Institucional Universidad Nacional de Colombia
dc.identifier.repourl.spa.fl_str_mv	https://repositorio.unal.edu.co/
url	https://repositorio.unal.edu.co/handle/unal/86783 https://repositorio.unal.edu.co/
identifier_str_mv	Universidad Nacional de Colombia Repositorio Institucional Universidad Nacional de Colombia
dc.language.iso.spa.fl_str_mv	spa
language	spa
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dc.rights.license.spa.fl_str_mv	Atribución-NoComercial 4.0 Internacional
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dc.format.extent.spa.fl_str_mv	94 páginas
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dc.coverage.country.spa.fl_str_mv	Colombia
dc.publisher.spa.fl_str_mv	Universidad Nacional de Colombia
dc.publisher.program.spa.fl_str_mv	Bogotá - Medicina - Doctorado en Oncología
dc.publisher.faculty.spa.fl_str_mv	Facultad de Medicina
dc.publisher.place.spa.fl_str_mv	Bogotá, Colombia
dc.publisher.branch.spa.fl_str_mv	Universidad Nacional de Colombia - Sede Bogotá
institution	Universidad Nacional de Colombia
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spelling	Atribución-NoComercial 4.0 Internacionalhttp://creativecommons.org/licenses/by-nc/4.0/info:eu-repo/semantics/openAccesshttp://purl.org/coar/access_right/c_abf2Yunis Londoño, Juan José900883724ed1be45c24ef9e18a9f99dbLinares Ballesteros, Teresa Adriana Elvira56a47e0a2ca74099013ea390ce0bc1a2Yunis Hazbun, Luz Karime9dfd91dfc5a9bb08437e414e3255bbb6Patología MolecularOncohematologia PediatricaYunis Hazbun, Luz Karime [0000000333655196]2024-09-03T16:27:48Z2024-09-03T16:27:48Z2024https://repositorio.unal.edu.co/handle/unal/86783Universidad Nacional de ColombiaRepositorio Institucional Universidad Nacional de Colombiahttps://repositorio.unal.edu.co/ilustraciones, diagramas, mapas, tablasIntroducción y objetivo: Existen pocos estudios describiendo las alteraciones genómicas en pacientes pediátricos con leucemia mieloide aguda (LMA) en países latinoamericanos. El objetivo fue identificar alteraciones genómicas, características clínicas y desenlaces en una cohorte de pacientes pediátricos con LMA no promielocítica de Bogotá D.C. Diferentes estudios han demostrado variantes farmacogenéticas relacionadas con la toxicidad de fármacos en pacientes con leucemia mieloide aguda. El desarrollo de resistencia a la quimioterapia es un factor relevante en el tratamiento de la LMA y es responsable en parte de las recaídas y el aumento de la toxicidad en las terapias de segunda línea. Por otro lado, siendo Colombia un país multiétnico y pluricultural, compuesto por tres grupos étnicos principales: población mixta derivada de Europa (Adm-Col), afrodescendientes (Afr-Col) y población amerindia (Amer), es importante determinar los componentes de ancestría en los pacientes pediátricos con LMA, así como en una muestra representativa de los tres grupos étnicos principales del país para conocer si la ancestría podría estar asociada a desenlaces en la muestra analizada. El objetivo fue identificar la frecuencia de alteraciones genómicas (cromosómicas, y genéticas) mediante estudios de citogenómica, pruebas rápidas por PCR-electroforesis capilar y análisis mediante secuencia de próxima generación con un panel de 30 genes recurrentemente alterados en LMA, así como la frecuencia alélica y genotípica de las variantes de algunos genes asociados a respuesta terapéutica o toxicidad como ABCB1, CDA, DCK, GSTT1 y GSTM1 en pacientes pediátricos con LMA y en una muestra representativa de la población colombiana y el análisis de ancestría mediante 46 marcadores informativos de ancestría tipo Indel (AIM-Indel) y evaluar la asociación de estas variantes genéticas con los resultados clínicos y la toxicidad en pacientes pediátricos con leucemia mieloide aguda. Materiales y métodos: Estudio observacional descriptivo de cohorte, se incluyeron 51 pacientes con LMA de novo (no promielocítica) hasta los 18 años de edad. Se realizó análisis de citogenética convencional y FISH, secuencia de nueva generación (ABL1, ASXL1, BRAF, CALR, CBL, CEBPA, CSF3R, DNMT3A, ETV6, EZH2, FLT3, HRAS, IDH1, IDH2, JAK2, KIT, KRAS, MPL, NPM1, NRAS, PTPN11, RUNX1, SETBP1, SF3B1, SRSF2, TET2, TP53, U2AF1, WT1, ZRSR2) utilizando el panel Myeloid Plus kit de SOPHIA Genetics (Sophia Genetics SA, Saint Sulpice, Suiza) y pruebas rápidas de PCR-EC para FLT3, NPM1 y CEBPA. Se evaluó la correlación entre los datos genómicos, la respuesta al tratamiento y los desenlaces. Adicionalmente, se incluyeron 457 muestras de los tres grupos étnicos principales de Colombia (Adm-Col, Afr-Col y Amer). Se utilizó una prueba de SNaPshot™ y una PCR convencional para evaluar las variantes ABCB1 rs1045642 (3435G>A), rs1128503 (1236G>A), rs2032582 (2677C>A/T); CDA rs2072671 (79A>C), rs532545 (-451C>T); DCK rs2306744 (-201C>T), rs3771182313 (72C>T) como control, y genotipo nulo en GSTT1 y GSTM1. El análisis de ancestría se realizó mediante la amplificación de 46 AIM-Indel mediante PCR múltiplex, seguido de electroforesis capilar y comparación con poblaciones de referencia. Los resultados clínicos y las asociaciones de toxicidad se evaluaron utilizando odds ratio y análisis de chi-cuadrado, adicionalmente se evaluó la supervivencia libre de evento. El componente de ancestría se evaluó mediante el programa STRUCTURE. Resultados: El 67,4% de la cohorte presentó una alteración citogenética y el 74,5% variantes genéticas. Se identificaron variantes en FLT3 en el 27,4 %, seguidas de NRAS (21,6 %), KRAS (13,7 %), WT1 y KIT (11,8 %). El 66% de los pacientes fueron estratificados como alto riesgo al final de la inducción. FLT3-ITD presentó una probabilidad mayor a recaída 11,25 OR (IC 95 % 1,89-66,72, p 0,006) y NRAS con muerte durante la inducción 16,71 OR (IC 95 % 1,51-184,59, p 0,022). Los pacientes portadores del genotipo GG en ABCB1 (1236G>A, rs1128503) tuvieron un mayor probabilidad a presentar cardiotoxicidad OR de 6,8 (IC 95 % 1,08-42,73, p 0,044) en comparación con los pacientes portadores de los genotipos AA o GA 0,14 OR (IC 95 % 0,023- 0,92, p 0,044). Para ABCB1 (1236G>A rs1128503/ 2677C>A/T rs2032582/ 3435G>A rs1045642) los genotipos combinados AA/AA/AA tuvieron con una mayor probabilidad a presentar muerte después del trasplante de precursores hematopoyéticos OR 13,73 (IC 95% 1,94-97,17, p 0,009). Los genotipos combinados GG/CC/GG con genotipo CA de CDA (79A>C, rs2072671) o el genotipo CT en CDA (-451C>T rs532545), tuvieron un OR de 4,11 (IC 95% 2,32-725, p 0,007) y OR de 3,8 (IC 95% 2,23-6,47, p 0,027) con enfermedad residual medible >0,1% después del primer ciclo de quimioterapia, respectivamente. Se encontraron frecuencias alélicas y genotípicas diferentes para las variantes genéticas analizadas en los tres principales grupos étnicos de Colombia. En general, se encontraron frecuencias más altas de genotipos asociados con riesgo de toxicidad en Afr-Col en comparación con Adm-Col y población Amer. Por otro lado, el análisis de ancestría en las muestras de pacientes pediátricos con LMA mostró una distribución similar de mezcla étnica a la encontrada en la población Adm-Col. Este resultado por el momento descarta que el componente de ancestría en la muestra de pacientes pediátricos con LMA en esta cohorte esté asociado a un mayor riesgo de eventos adversos y toxicidad en la muestra analizada. Conclusiones: Nuestro estudio destaca la importancia de una rápida incorporación de las pruebas genéticas en el diagnóstico y tratamiento de la LMA pediátrica en Colombia, ya que incide directamente en la estratificación del riesgo y el tratamiento. Por otro lado, estos resultados resaltan la importancia del análisis farmacogenético en la LMA pediátrica, particularmente en poblaciones con un alto grado de mezcla, los cuales podrían ser útiles como una herramienta futura en la estratificación de pacientes para el tratamiento. Por último, los resultados de ancestría obtenidos en la muestra de pacientes pediátricos analizados son similares a los obtenidos para la muestra de población colombiana mezclada derivada de europeos (Adm-Col) de la región andina colombiana, y descartarían la contribución de un componente de ancestría específico (Adm-Col) asociado a eventos adversos o toxicidad (Texto tomado de la fuente).Introduction and objective: There are few studies that describe genomic alterations in pediatric patients with acute myeloid leukemia (AML) in Latin American countries. The objective was to identify genomic alterations, clinical characteristics and outcomes in a cohort of pediatric patients with non-promyelocytic AML from Bogotá D.C. On the other hand, different studies have demonstrated pharmacogenetic variants related to drug toxicity in patients with acute myeloid leukemia. Resistance development to chemotherapy is a relevant factor in the treatment of AML and is partly responsible for relapses and increased toxicity in second-line therapies. On the other hand, Colombia is a multiethnic and pluricultural country, composed of three main ethnic groups: mixed population derived from Europe (Adm-Col), Afro-descendants (Afr-Col) and Amerindian population (Amer); therefore, it was important to determine the ancestry components in pediatric patients with AML, as well as in a representative sample of the three main ethnic groups of the country to know if ancestry could be associated with outcomes in the analyzed sample. The aim was to identify the frequency of genomic alterations (chromosomal and genetic) through cytogenomics studies, rapid PCR-capillary electrophoresis tests, next-generation sequencing analysis with a panel of 30 genes recurrently altered in AML, the allelic frequency and genotypic analysis of the ABCB1, CDA, DCK, GSTT1 and GSTM1 gene variants in pediatric patients with AML and in a representative sample of the Colombian population, ancestry analysis using 46 Indel-type ancestry informative markers (AIM-Indel) and to evaluate the association of these genetic variants with clinical outcomes and toxicity in pediatric patients with acute myeloid leukemia. Materials and methods: Descriptive observational cohort study, 51 patients with de novo AML (non-promyelocytic) up to 18 years of age were included. Conventional cytogenetics and FISH analysis, next generation sequence (ABL1, ASXL1, BRAF, CALR, CBL, CEBPA, CSF3R, DNMT3A, ETV6, EZH2, FLT3, HRAS, IDH1, IDH2, JAK2, KIT, KRAS, MPL, NPM1, NRAS, PTPN11, RUNX1, SETBP1, SF3B1, SRSF2, TET2, TP53, U2AF1, WT1, ZRSR2) using the Myeloid Plus panel kit from SOPHIA Genetics (Sophia Genetics SA, Saint Sulpice, Switzerland) and rapid EC-PCR tests for FLT3, NPM1 and CEBPA was carried out in each sample. The correlation between genomic data, treatment response and outcomes were evaluated. Additionally, 457 samples from the three main ethnic groups of Colombia (Adm-Col, Afr-Col and Amer) were included. A SNaPshot™ test and conventional PCR were used to evaluate the ABCB1 variants rs1045642 (3435G>A), rs1128503 (1236G>A), rs2032582 (2677C>A/T); CDA rs2072671 (79A>C), rs532545 (-451C>T); DCK rs2306744 (-201C>T), rs3771182313 (72C>T) as control, and null genotype in GSTT1 and GSTM1. Ancestry analysis was performed by amplification of 46 AIM-Indels by multiplex PCR, followed by capillary electrophoresis and comparison with reference populations. Clinical outcomes and toxicity associations were evaluated using odds ratios and chi-square analyses. Also, we evaluated event-free survival. The ancestry component was evaluated using the STRUCTURE program. Results: 67.4% of the cohort presented a cytogenetic alteration and 74.5% had genetic variants. Variants in FLT3 were identified in 27.4%, followed by NRAS (21.6%), KRAS (13.7%), WT1, and KIT (11.8%). 66% of patients were stratified as high risk at the end of induction. FLT3-ITD was associated with relapse 11.25 OR (CI 1.89-66.72, p 0.006) and NRAS with death during induction 16.71 OR (CI 1.51-184.59, p 0.022). Patients carrying the GG genotype in ABCB1 (1236G>A, rs1128503) had an OR of 6.8 (95% CI 1.08-42.73, p 0.044) for cardiotoxicity compared to patients carrying the AA or GA 0.14 OR (95% CI 0.023- 0.92, p 0.044). For ABCB1 (1236G>A rs1128503/ 2677C>A/T rs2032582/ 3435G>A rs1045642) the combined AA/AA/AA genotypes were associated with death after transplantation of hematopoietic precursors OR 13.73 (95% CI 1.94- 97.17, p 0.009). The combined GG/CC/GG genotypes with CA genotype of CDA (79A>C, rs2072671) or the CT genotype in CDA (-451C>T rs532545), had an OR of 4.11 (95% CI 2.32-725, p 0.007) and OR of 3.8 (95% CI 2.23-6.47, p 0.027) with measurable residual disease >0.1% after the first cycle of chemotherapy, respectively. Different allelic and genotypic frequencies were found for the genetic variants analyzed in the three main ethnic groups of Colombia. Overall, higher frequencies of genotypes associated with toxicity risk were found in Afr-Col compared to Adm-Col and Amer populations. On the other hand, the ancestry analysis in the samples of pediatric patients with AML showed a similar distribution of ethnic mixture to that found in the Adm-col population. This result, for the moment, rules out that the ancestry component in the sample of pediatric patients with AML in this cohort is associated with a higher risk of adverse events and toxicity in the sample analyzed. Conclusions: Our study highlights the importance of rapid incorporation of genetic testing in the diagnosis and treatment of pediatric AML in Colombia, since it directly affects risk stratification and treatment. On the other hand, these results highlight the importance of pharmacogenetic analysis in pediatric AML, particularly in populations with a high degree of admixture, which could be useful as a future tool in the stratification of patients for treatment. Finally, the ancestry results obtained in the sample of pediatric patients are similar to those obtained for the mixed Colombian population sample derived from Europeans (Adm-Col) from the Colombian Andean region, and would rule out the contribution of a specific ancestry component (Adm-Col) associated with adverse events or toxicity.DoctoradoDoctora en OncologíaAlteraciones moleculares en leucemias y linfomasCáncer Infantil94 páginasapplication/pdfspaUniversidad Nacional de ColombiaBogotá - Medicina - Doctorado en OncologíaFacultad de MedicinaBogotá, ColombiaUniversidad Nacional de Colombia - Sede Bogotá610 - Medicina y salud::615 - Farmacología y terapéutica570 - Biología::576 - Genética y evolución610 - Medicina y salud::616 - EnfermedadesLeucemia Mielomonocítica AgudaVariantes FarmacogenómicasResistencia a AntineoplásicosEfectos Colaterales y Reacciones Adversas Relacionados con MedicamentosLeukemia, Myelomonocytic, AcuteDrug Resistance, NeoplasmDrug-Related Side Effects and Adverse ReactionsPharmacogenomic VariantsLeucemia mieloide agudaGenómicaPediátricaColombiaLatinoaméricaABCB1DCKCDAGSTT1GSTM1CitarabinaAntraciclinasSNVAncestríaAIM-InDelAcute myeloid leukemiaGenomicsPediatricsLatin AmericaCitarabineAntracyclinesAncestryCaracterización molecular y farmacogenética en una muestra de pacientes con leucemia mieloide aguda y su correlación con la estratificación del riesgo y respuesta al tratamiento. 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WwgdHJhdGFtaWVudG8gZGUgZGF0b3MgcGVyc29uYWxlcywgZGUgYWN1ZXJkbyBjb24gbGEgbGV5IDE1ODEgZGUgMjAxMiBlbnRlbmRpZW5kbyBxdWUgc2UgZW5jdWVudHJhbiBiYWpvIG1lZGlkYXMgcXVlIGdhcmFudGl6YW4gbGEgc2VndXJpZGFkLCBjb25maWRlbmNpYWxpZGFkIGUgaW50ZWdyaWRhZCwgeSBzdSB0cmF0YW1pZW50byB0aWVuZSB1bmEgZmluYWxpZGFkIGhpc3TDs3JpY2EsIGVzdGFkw61zdGljYSBvIGNpZW50w61maWNhIHNlZ8O6biBsbyBkaXNwdWVzdG8gZW4gbGEgUG9sw610aWNhIGRlIFRyYXRhbWllbnRvIGRlIERhdG9zIFBlcnNvbmFsZXMuCgoKClBBUlRFIDIuIEFVVE9SSVpBQ0nDk04gUEFSQSBQVUJMSUNBUiBZIFBFUk1JVElSIExBIENPTlNVTFRBIFkgVVNPIERFIE9CUkFTIEVOIEVMIFJFUE9TSVRPUklPIElOU1RJVFVDSU9OQUwgVU5BTC4KClNlIGF1dG9yaXphIGxhIHB1YmxpY2FjacOzbiBlbGVjdHLDs25pY2EsIGNvbnN1bHRhIHkgdXNvIGRlIGxhIG9icmEgcG9yIHBhcnRlIGRlIGxhIFVuaXZlcnNpZGFkIE5hY2lvbmFsIGRlIENvbG9tYmlhIHkgZGUgc3VzIHVzdWFyaW9zIGRlIGxhIHNpZ3VpZW50ZSBtYW5lcmE6CgphLglDb25jZWRvIGxpY2VuY2lhIGVuIGxvcyB0w6lybWlub3Mgc2XDsWFsYWRvcyBlbiBsYSBwYXJ0ZSAxIGRlbCBwcmVzZW50ZSBkb2N1bWVudG8sIGNvbiBlbCBvYmpldGl2byBkZSBxdWUgbGEgb2JyYSBlbnRyZWdhZGEgc2VhIHB1YmxpY2FkYSBlbiBlbCBSZXBvc2l0b3JpbyBJbnN0aXR1Y2lvbmFsIGRlIGxhIFVuaXZlcnNpZGFkIE5hY2lvbmFsIGRlIENvbG9tYmlhIHkgcHVlc3RhIGEgZGlzcG9zaWNpw7NuIGVuIGFjY2VzbyBhYmllcnRvIHBhcmEgc3UgY29uc3VsdGEgcG9yIGxvcyB1c3VhcmlvcyBkZSBsYSBVbml2ZXJzaWRhZCBOYWNpb25hbCBkZSBDb2xvbWJpYSAgYSB0cmF2w6lzIGRlIGludGVybmV0LgoKCgpQQVJURSAzIEFVVE9SSVpBQ0nDk04gREUgVFJBVEFNSUVOVE8gREUgREFUT1MgUEVSU09OQUxFUy4KCkxhIFVuaXZlcnNpZGFkIE5hY2lvbmFsIGRlIENvbG9tYmlhLCBjb21vIHJlc3BvbnNhYmxlIGRlbCBUcmF0YW1pZW50byBkZSBEYXRvcyBQZXJzb25hbGVzLCBpbmZvcm1hIHF1ZSBsb3MgZGF0b3MgZGUgY2Fyw6FjdGVyIHBlcnNvbmFsIHJlY29sZWN0YWRvcyBtZWRpYW50ZSBlc3RlIGZvcm11bGFyaW8sIHNlIGVuY3VlbnRyYW4gYmFqbyBtZWRpZGFzIHF1ZSBnYXJhbnRpemFuIGxhIHNlZ3VyaWRhZCwgY29uZmlkZW5jaWFsaWRhZCBlIGludGVncmlkYWQgeSBzdSB0cmF0YW1pZW50byBzZSByZWFsaXphIGRlIGFjdWVyZG8gYWwgY3VtcGxpbWllbnRvIG5vcm1hdGl2byBkZSBsYSBMZXkgMTU4MSBkZSAyMDEyIHkgZGUgbGEgUG9sw610aWNhIGRlIFRyYXRhbWllbnRvIGRlIERhdG9zIFBlcnNvbmFsZXMgZGUgbGEgVW5pdmVyc2lkYWQgTmFjaW9uYWwgZGUgQ29sb21iaWEuIFB1ZWRlIGVqZXJjZXIgc3VzIGRlcmVjaG9zIGNvbW8gdGl0dWxhciBhIGNvbm9jZXIsIGFjdHVhbGl6YXIsIHJlY3RpZmljYXIgeSByZXZvY2FyIGxhcyBhdXRvcml6YWNpb25lcyBkYWRhcyBhIGxhcyBmaW5hbGlkYWRlcyBhcGxpY2FibGVzIGEgdHJhdsOpcyBkZSBsb3MgY2FuYWxlcyBkaXNwdWVzdG9zIHkgZGlzcG9uaWJsZXMgZW4gd3d3LnVuYWwuZWR1LmNvIG8gZS1tYWlsOiBwcm90ZWNkYXRvc19uYUB1bmFsLmVkdS5jbyIKClRlbmllbmRvIGVuIGN1ZW50YSBsbyBhbnRlcmlvciwgYXV0b3Jpem8gZGUgbWFuZXJhIHZvbHVudGFyaWEsIHByZXZpYSwgZXhwbMOtY2l0YSwgaW5mb3JtYWRhIGUgaW5lcXXDrXZvY2EgYSBsYSBVbml2ZXJzaWRhZCBOYWNpb25hbCBkZSBDb2xvbWJpYSBhIHRyYXRhciBsb3MgZGF0b3MgcGVyc29uYWxlcyBkZSBhY3VlcmRvIGNvbiBsYXMgZmluYWxpZGFkZXMgZXNwZWPDrWZpY2FzIHBhcmEgZWwgZGVzYXJyb2xsbyB5IGVqZXJjaWNpbyBkZSBsYXMgZnVuY2lvbmVzIG1pc2lvbmFsZXMgZGUgZG9jZW5jaWEsIGludmVzdGlnYWNpw7NuIHkgZXh0ZW5zacOzbiwgYXPDrSBjb21vIGxhcyByZWxhY2lvbmVzIGFjYWTDqW1pY2FzLCBsYWJvcmFsZXMsIGNvbnRyYWN0dWFsZXMgeSB0b2RhcyBsYXMgZGVtw6FzIHJlbGFjaW9uYWRhcyBjb24gZWwgb2JqZXRvIHNvY2lhbCBkZSBsYSBVbml2ZXJzaWRhZC4gCgo=

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