3 results on '"Terol Casterá, M. José"'
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2. Development of bioinformatics tools for the characterization of B cell neoplasms
- Author
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Fuentes Trillo, Azahara María, Chaves Martínez, Felipe Javier, Terol Casterá, M. José, Navarro Cubells, Blanca, García Pérez, Miguel Ángel, and Departament de Bioquímica i Biologia Molecular
- Subjects
bioinformática ,NGS ,UNESCO::CIENCIAS DE LA VIDA ,neoplasias linfoides - Abstract
El sistema inmune adaptativo está orquestado por una amplia batería de anticuerpos, secretados por linfocitos B, encargados del reconocimiento de moléculas antigénicas. Para expresar el receptor transmembrana tipo Inmunoglobulina en su superficie, las células B sufren un proceso de recombinación en las cadenas pesada y ligera del receptor. Esto ocurre durante su desarrollo, involucrando a los segmentos génicos V(D)J (uno de cada de los posibles genes V, D y J reordena, conformando el dominio variable del locus IGH). Al receptor se le confiere variabilidad adicional después de la exposición antigénica, con la introducción de mutaciones somáticas que aumentan la especificidad del reconocimiento antígeno-receptor. El grado de mutación en el locus IGH es especialmente determinante como factor pronóstico en la Leucemia Linfocítica Crónica (LLC), donde los pacientes clasificados como mutados tienden a llevar un curso de la enfermedad más indolente comparado con los pacientes con receptores de células B no mutados. El objetivo principal de esta tesis es el desarrollo de herramientas bioinformáticas para la determinación clínica del locus IGH en pacientes diagnosticados de LLC. Para ello, se empleó un método simple y de bajo coste para la preparación de las librerías de secuenciación de la región VDJ del locus IGH, y se diseñó un pipeline bioinformático específico (BMyRepCLL) basado en análisis de clonas de células B orientado a la obtención de una secuencia consenso. Un método de corte específico se implementó en este flujo de trabajo para diferenciar los reordenamientos de la fracción clonal y subclonal de cada paciente. Un segundo pipeline llamado CLL Immcantation se adaptó del “Immcantation Framework”; una suite que reúne herramientas para el análisis de datos de repertorios inmunológicos. Ambos flujos de trabajo se han usado para analizar un set de datos de 314 pacientes con LLC diagnosticados con los protocolos y criterios estándar, y comparar la determinación del estado mutacional. Además, los resultados de BMyRepCLL han sido validados exhaustivamente con respecto al gold-standard. Debido a que los dos pipelines se basan en métodos diferentes, CLL Immcantation se usó para la comparativa de la caracterización de muestras con múltiples clonas por BMyRepCLL, así 14 como también para llevar a cabo análisis posteriores específicos para datos de repertorios inmunológicos. Los resultados muestran acuerdo entre BMyRepCLL y SSeq en cuanto a la anotación de los genes IGHV e IGHJ y la extracción de las secuencias de CDR3. El estado mutacional fue caracterizado con éxito en el 99% de los reordenamientos. Las clonas fueron detectadas con una especificidad y sensibilidad del 97% y 100%, respectivamente. Con el desarrollo de estos métodos, contribuimos a la estandarización de los protocolos NGS para la determinación del locus IGH en LLC, el cuál será muy ventajoso por aumentar drásticamente el alcance de SSeq y permitir estudiar en profundidad la arquitectura clonal de la LLC. The adaptive immune system is orchestrated by a wide battery of antibodies, secreted by B lymphocytes, in charge of the recognition of antigenic molecules. In order to express the Immunoglobulin-type receptor transmembrane protein on their surface, B cells suffer recombination of the receptor Heavy and Light Chains genes. This occurs during their development and involving V(D)J gene segments (one of each of the possible V, D and J genes rearrange, conforming the IGH locus variable domain). Additional variability is conferred on the receptor after antigen exposure, when somatic mutations are introduced to augment the specificity of antigen-receptor recognition. The degree of mutation in the IGH locus is especially determinant as a prognostic factor in CLL, where patients classified as mutated tend to have more indolent disease course compared to patients with unmutated B cell receptors. The main aim of this thesis work is the development of bioinformatics tools for clinical determinations of the IGH locus in CLL patients. For that purpose, a simple and cost-effective library preparation protocol was employed to sequence the VDJ region of the IGH locus, and a specific bioinformatics pipeline for analysis of B cell clones based on the construction of a consensus sequence was designed (BMyRepCLL). A specific cut-off method was implemented within this workflow to differentiate the clonal and subclonal rearrangements fraction among patients. A second pipeline (CLL Immcantation) was adapted from the Immcantation Framework; a suite which unites tools to analyze immune repertoires data. Both workflows have been used to analyze a dataset of 314 CLL patients previously diagnosed with the standard criteria and protocols, and to compare the assessment of mutational status. Moreover, the results from BMyRepCLL have been validated exhaustively against the gold-standard. Since both pipelines are based in different methodologies, CLL Immcantation was used for benchmarking the characterization of samples with multiple clones by BMyRepCLL, as well as to perform downstream analyses specific to immune repertoire data. Results show agreement between BMyRepCLL and SSeq regarding IGHV and IGHJ genes annotation and CDR3 sequence extraction. The mutational status was characterized accordingly in 99% of the rearrangements. Clones were detected with a specificity and sensitivity of 97% and 100%, respectively. With the development of these methods we contribute to the standardization of NGS protocols for the determination of IGH locus in CLL, which will be highly advantageous for augmenting drastically the scope of SSeq and allowing to study in deep the clonal architecture in CLL.
- Published
- 2022
3. [National guidelines for the management of patients with chronic lymphocytic leukemia. Sociedad Espan˜ola de Hematologı´a y Hemoterapia and Grupo Espan˜ol de Leucemia Linfocı´tica Cro´ nica].
- Author
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García Marco JA, Giraldo Castellano P, López Jiménez J, Ríos Herranz E, Sastre Moral JL, Terol Casterá MJ, and Bosch Albareda F
- Subjects
- Blood Transfusion, Combined Modality Therapy, Comorbidity, Evidence-Based Medicine, Hematologic Diseases etiology, Hematologic Diseases therapy, Hematopoietic Stem Cell Transplantation, Humans, Immunocompromised Host, Leukemia, Lymphocytic, Chronic, B-Cell complications, Leukemia, Lymphocytic, Chronic, B-Cell diagnosis, Leukemia, Lymphocytic, Chronic, B-Cell surgery, Opportunistic Infections drug therapy, Opportunistic Infections etiology, Opportunistic Infections prevention & control, Prognosis, Recurrence, Risk Factors, Salvage Therapy, Vaccination, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Disease Management, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy
- Abstract
Chronic lymphocytic leukemia is the most common chronic lymphoproliferative disorder in Spain. The clinical management of this entity varies widely. Currently, in Spain, there are no national consensus guidelines, such as those published in other countries, to guide the diagnosis and treatment of this malignancy and the use of prognostic scores. This article reviews the current scientific literature and addresses issues on the diagnosis of chronic lymphocytic leukemia, the spread of the disease, the presence of comorbidities, the classification of prognostic scores, the common treatment regimens stratified by risk factors, and the management of complications associated with both the disease and its treatment, as well as the various controversies related to this entity. This document was drafted with the collaboration of national experts and aims to establish practical guidelines with their corresponding levels of evidence and grades of recommendation to guide the diagnosis, treatment and follow-up of patients with chronic lymphocytic leukemia., (Copyright © 2013 Elsevier España, S.L. All rights reserved.)
- Published
- 2013
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