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Lineage plasticity in normal and malignant lymphocyte precursors
Rezková Řezníčková, Leona
The classical scheme of hematopoiesis presumes early separation of lymphoid and myeloid precursors. Recently, more complex models are put forward, suggesting greater flexibility of hematopoiesis with progenitors sharing lymphoid and myeloid potential. Acute hybrid leukemia is a malignancy, in which it is not possible to assess unambiguously myeloid or lymphoid lineage of origin. The behaviour of those malignancies favors new models of hematopoiesis. Our work concentrated mainly on the research of childhood leukemias with lineage switch from lymphoid to myeloid lineage during induction treatment. Our task within this extensive project was to determine lineage assignment of leukemic blasts using detection of immunoglobulin and T-cell receptor gene rearrangements. We confirmed that myeloid cells derived during the treatment in all patients descend from the original lymphoid clone. We also investigated the expression of selected genes in those cases compared to common leukemia types. Lastly, we explored prognostic impact of TCR rearrangements (and thus lymphoid lineage commitment) in T-lineage leukemia.
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Electromyographic and clinical evaluation of vincristine-induced peripheral neuropathy in pediatric patients after treatment of acute lymphoblastic leukemia and correlation with the Bruinkins-Oseretsky Test of Motor Proficiency Second edition
Bořilová, Karolína ; Jevič, Filip (advisor) ; Pánek, David (referee)
Title: Electromyographic and clinical evaluation of vincristine-induced peripheral neuropathy in pediatric patients after treatment of acute lymphoblastic leukemia and correlation with the Bruinkins-Oseretsky Test of Motor Proficiency Second Edition Objectives: The aim of this work was to characterize the neurological consequences of vincristine-induced peripheral neuropathy (VIPN) clinically and electromyographically and to evaluate motor skills of pediatric patients after the end of treatment of acute lymphoblastic leukemia. We also determined the relationship between the results of the clinical and electromyographic evaluation of VIPN and the correlation with the results of motor skills tests. Methods: The study involved 35 probands (19 girls and 16 boys) with a mean age of 10.7 years (SD ± 4.3) and a mean time since the last dose of vincristine of 2.3 years (SD ± 1.2). VIPN was assessed using a clinical pediatric-modified Total Neuropathy Score (ped-mTNS) and nerve conduction studies (NCS). Motor skills were assessed using the Bruinkins-Oseretsky Test of Motor Proficiency, Second Edition (BOT-2). Results: The clinical presence of VIPN, according to ped-mTNS, was found in 20 % of probands. Abnormalities in nerve conduction studies were reported by 60.9 % of probands. Of these, 92.9 % had motor...
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Leukaemia associated immunophenotype in childhood acute leukaemias and its development during the course of disease
Podolská, Tereza ; Fišer, Karel (advisor) ; Drbal, Karel (referee)
Acute lymphoblastic leukaemia (ALL) is the most frequent childhood malignancy. One of the recent improvements in ALL treatment was the introduction of minimal residual disease (MRD) monitoring that enables risk stratification based treatment adaptation. The same MRD monitoring helps to choose relapse treatment, to guide indication for stem cell transplantation (SCT) and allows for a more personalized management of patients undergoing SCT. One of the main routes of MRD levels detection is characterisation of leukemic blasts using flow cytometry. However, flow cytometry is limited by its mainly manual expertise-based analysis. Such analysis is subjective and clearly insufficient for current complex data. While new computational tools are available for multidimensional flow cytometry data, there is an urgent need to test and adapt them for the use in clinical environment. The goal of this thesis is to detect immunophenotypes associated with leukaemia and their development by leveraging machine-assisted analysis of a set of diagnostic files selected based on information about more than three hundred thousand of multiparameter flow cytometry datasets. Advanced bioinformatic tools will help to detect blast and healthy haematopoietic populations, to derive their immunophenotypes and to identify individual...
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Searching for and Evaluating the Severity of Endothelial Dysfunction in Children with Chronic Autoimmune Disease
Sýkorová, Aneta ; Jehlička, Petr (advisor) ; Urbanová, Zuzana (referee) ; Klásková, Eva (referee)
We aimed to evaluate the endothelial function by combining RHI measurements and specific biochemical markers in the children with possible risk of premature manifestation of atherosclerosis and in the control group of healthy children. In all, 124 children (of which 106 patients divided into five groups according to diagnosis - type 1 diabetes mellitus, Crohn's disease, cystic fibrosis, familial hypercholesterolemia and acute lymphoblastic leukemia and 18 healthy controls) were enrolled in the study. During the study, we measured RHI using a new plethysmographic method and further evaluated biochemical markers of endothelial dysfunction (ADMA, E-selectin, hsCRP and VCAM) and lipidogram in individual groups of children. The primary objective of our study was the determination of RHI and biochemical parameters in healthy subjects and in selected risk groups of children (type 1 diabetes mellitus, Crohn's disease, cystic fibrosis, familial hypercholesterolemia and children after successful treatment of acute lymphoblastic leukemia). At the same time, we compared patients from individual groups with the control group. We found significantly elevated RHI values in groups of children with type 1 diabetes, Crohn's disease, cystic fibrosis, and children after successful treatment of acute lymphoblastic leukemia....
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Impact of glucocorticoid treatment on musculosceletal system of pediatric patients with acute lymphoblastic leukemia.
Petráčková, Karolína ; Jevič, Filip (advisor) ; Šrámková, Lucie (referee)
This bachelor thesis aims to provide a general overview of complications of musculoskeletal system in pediatric patients diagnosed with acute lymphoblastic leukemia (ALL) undergoing chemotherapy treatment involving high cumulative doses of glucocorticoids. Musculoskeletal complications include steroid myopathy, osteonecrosis and reduced bone mineral density. The first part describes their basic pathophysiological mechanisms and the risk factors of their origin. The second part presents the current possibilities of muscle strength assessment and available exercise programs. Furthermore, diagnosis of osteonecrosis and bone mineral density are presented together with current possibilities of therapeutic intervention. The thesis also covers characteristics of muscle strength measuring methods and exercise programs along with presentation of the results of individual studies. In the discussion part, there are broken down the limits, advantages and disadvantages of using the muscle strength measuring methods and exercise programs in clinical practice.
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The Influence of Motivational Elements in Paediatric Physiotherapy Focused on the Patients with Acute Lymphoblastic Leukemia - Pilot Study
Chytrá, Markéta ; Jevič, Filip (advisor) ; Králová, Aneta (referee)
THE INFLUENCE OF MOTIVATIONAL ELEMENTS IN PAEDIATRIC PHYSIOTHERAPY FOCUSED ON THE PATIENTS WITH ACUTE LYMPHOBLASTIC LEUKEMIA - PILOT STUDY Abstract The efficacy of acute lymphoblastic leukemia (ALL) treatment in childhood is still increasing and the quality of life of these children is starting to be the focus of interest. The physiotherapy affects in preventive and reactive way the late effects of treatment which may reduce the quality of life. An insufficient motivation of children can be a reason of a reduced adherence to a physiotherapeutic intervention. The goal of this study was to ascertain the influence of the motivational elements in the paediatric physiotherapy in the improvement of motor functions, the quality of life, the motivation to the exercise and the frequency of exercise. There were 9 patients diagnosed with ALL in the maintenance phase of treatment (average age 7,3 years, age range 5,2 - 10,1, 5 girls and 4 boys). All probands underwent a 6- weeks-excercise programme that contains the exercise from the DNS method, yoga for children and stretching. The assessment was performed by Bruninks-Oseretsky Test (BOT2), 6 minute walking test (6MWT), goniometric measurement of ankle joint dorsiflexion, Pediatric Quality of Life Inventory (PedsQL), Intrinsic Motivation Inventory (IMI) and the...
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Lineage plasticity in normal and malignant lymphocyte precursors
Rezková Řezníčková, Leona
The classical scheme of hematopoiesis presumes early separation of lymphoid and myeloid precursors. Recently, more complex models are put forward, suggesting greater flexibility of hematopoiesis with progenitors sharing lymphoid and myeloid potential. Acute hybrid leukemia is a malignancy, in which it is not possible to assess unambiguously myeloid or lymphoid lineage of origin. The behaviour of those malignancies favors new models of hematopoiesis. Our work concentrated mainly on the research of childhood leukemias with lineage switch from lymphoid to myeloid lineage during induction treatment. Our task within this extensive project was to determine lineage assignment of leukemic blasts using detection of immunoglobulin and T-cell receptor gene rearrangements. We confirmed that myeloid cells derived during the treatment in all patients descend from the original lymphoid clone. We also investigated the expression of selected genes in those cases compared to common leukemia types. Lastly, we explored prognostic impact of TCR rearrangements (and thus lymphoid lineage commitment) in T-lineage leukemia.
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Heteroploidy in bone marrow cells of children with acute lymphoblastic leukemia (ALL)
Matějčková, Nicole ; Zemanová, Zuzana (advisor) ; Krylov, Vladimír (referee)
Acute lymphoblastic leukemia is the most common type of cancer in children. It is a very heterogenous disease in which many recurrent chromosomal abnormalities have been described. The most important chromosomal abnormalities associated with a good prognosis are t(12;21)(p13;q22) which result in ETV6/RUNX1 fusion and hyperdiploidy. On the contrary findings suggesting a poor prognosis are t(9;22)(q34;q11) leading to fusion gene BCR/ABL1, MLL rearrangements or hypodiploidy. Heteroploidy is one of the most frequent findings in childhood ALL. It is characterised by nonrandom gain or loss of chromosomes from diploid cells. One of the most important findings in childhood ALL is hyperdiploidy where a non-random gain of chromosomes is present. Hyperdiploidy has a favorable prognosis and the impact of additional structural aberations requires further research. Another prognostically important group of heteroploidy is hypodiploidy. It is a quite rare finding and has a very poor outcome. There are non-random acquired chromosome losses observed in hypodiploid cells. Hypodiploid cell line may be masked with a doubled hyperdiploid clone which makes it difficult to identify. Proper and early cytogenetical analysis of heteroploid cells is very important as it contributes assigning correct diagnosis and risk stratification,...
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Leukaemias with BCR/ABL fusion gene.
Hovorková, Lenka ; Zuna, Jan (advisor) ; Zemanová, Karla (referee)
Philadelphia (Ph) chromosome, as a result of reciprocal translocation, is in majority of cases connected to two types of leukaemia - chronic myelogenous (CML) and acute lymphoblastic (ALL). The translocation occurs within large intronic sequences of BCR and ABL genes. The breakpoints are specific for individual patient and may be used as a target for monitoring of leukemic burden (MRD, minimal residual disease) during the treatment. In general, MRD is an important prognostic factor, which influences the treatment intensity. Two standardized methods are currently used for its monitoring. The first one is based on the detection of clonal specific Immunoglobulin and/or T-cell receptor genes rearrangements (and thus cannot be used for CML cases) at the DNA level, the second one utilizes detection of the BCR/ABL fusion gene at the mRNA level. Our aim was to optimize and standardize the process to find individual patient breakpoints on Ph chromosome and to use it for MRD quantification. We found the breakpoint in 80 % cases. The MRD data from 15 patients obtained by our method were compared to the levels obtained by standard methods (Ig/TCR and BCR/ABL transcript quantification). In all but 1 patient we found significant discrepancies, raising the questions about leukemic origin and the most accurate method for...
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Elucidating the interactions of interleukin-1alpha with components of the eukaryotic transcription machinery
Zámostná, Blanka ; Pospíšek, Martin (advisor) ; Černý, Jan (referee) ; Mělková, Zora (referee)
4 ABSTRACT Interleukin-1α (IL-1α) is a pleiotropic cytokine and a key mediator of host immune response. It is synthesised as a 31-kDa precursor, that is cleaved by the cysteine protease calpain into the 17-kDa mature IL-1α and the 16-kDa N- terminal peptide of IL-1α (IL-1αNTP). Although IL-1α can be secreted, act on target cells through the surface receptor IL-1RI and trigger the signal transduction pathway, increasing evidence points toward the involvement of IL-1α in certain nuclear processes. IL-1αNTP is highly conserved among higher eukaryotes and contains a nuclear localisation sequence; indeed, both the precursor and IL-1αNTP are found in the cell nucleus. Previously, a genetic interaction of IL-1α with nuclear histone acetyltransferase (HAT) complexes has been reported from mammalian cells and, interestingly, also from the heterologous yeast model. This thesis extends the research of the nuclear function of IL-1α and demonstrates that IL-1α physically associates with the HAT/Core module of yeast SAGA and ADA HAT complexes. Results of the HAT subunit gene knock-out experiments followed by a set of co-immunoprecipitations also suggest a novel model of the yeast SAGA complex assembly, in which ADA appears to represent only a partly functional HAT complex. In its natural milieu of mammalian cells, IL-1α...
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