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  • 1
    Online Resource
    Online Resource
    Defect in B Cell Production Driven By GATA2 Mutation Results in Their Absolute Reduction and Mature Phenotype in Pediatric Patients
    American Society of Hematology ; 2014
    In:  Blood Vol. 124, No. 21 ( 2014-12-06), p. 2746-2746
    Details
    In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 2746-2746
    Abstract: Introduction Germline mutations in GATA2 were recently identified as causative for several overlapping syndromes: MonoMAC (monocytopenia, mycobacterial infections), DCML (dendritic cells, monocytes, B and NK cells deficiency), Emberger syndrome (lymphedema, sensorineural deafness, multiple warts) and familiar myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML). Of note, GATA2 mutations were also found in children and young adults with “primary” MDS. Aplastic anemia (AA) constitutes an important differential diagnosis to pediatric MDS, particularly in patients with normal cytogenetics. Because of heterogeneous phenotype of GATA2 mutated patients, defining a set of typical findings would help in their earlier identification and understanding the natural course of the disease. Therefore we aimed to analyze monocytes and lymphocyte subpopulations with the emphasis on B cell lineage by flow cytometry (FC) and polymerase chain reaction (PCR) in all pediatric patients with GATA2 mutation diagnosed in the Czech Republic. Patients and methods Eleven pediatric patients were found to harbor GATA2 mutations in the Czech Republic so far. Three mutations were intronic. There was a clear male predominance (9/11). In 7 patients the disease manifested with MDS in childhood, 2 female patients were followed for immunodeficiency and developed MDS in adulthood. One another patient was diagnosed with interstitial lung disease and chronic EBV infection. His brother, carrying the same mutation, has mild neutropenia. Bone marrow (BM) and peripheral blood (PB) samples were analyzed by FC. The level of intronRSS-Kde recombination excision circles (KREC) and T-cell receptor excision circles (TREC) for assessment of proliferation history of B and T cells was examined by PCR. The control group comprised 26 GATA2 wild-type MDS (“other MDS”) patients and 36 AA patients. Results Disturbance of B cell compartment was the most frequently observed anomaly in the patients with GATA2 mutation. We observed a decrease of absolute and relative B cell numbers in PB and BM (n=9/11). In BM there was a decrease of immature CD10pos B cells (n=10) with proportional increase of plasma cells. Peripheral blood B cell immunophenotype was shifted towards memory B cells (n=5/7). Presence of normal B cell precursors CD19pos10pos34pos in BM was observed only in 1 patient in part of follow-up samples. Atypical malignant B lymphoblasts were present in another patient, whose MDS quickly progressed to AML with a clear switch to B lymphoid phenotype. Despite significantly reduced number of B cells the levels of IgG were normal in majority of patients. Only 2 patients had IgG hypogammaglobuliemia, in one patient with chronic active EBV infection IgG hypergammaglobulinemia was present. Slightly decreased IgA level was present in 6 patients. Although B cell numbers in other MDS control patients were significantly lower compared to AA, still the decrease was less prominent in comparison with GATA2. The decrease of immature and naive B cells in patients with GATA2 mutation was reflected in very low level of KREC in PB and BM. Stored newborn dry blood spots from 4 patients were evaluated for TREC and KREC numbers. Strikingly, only one patient had negative KREC levels (the youngest patient from our cohort with MDS diagnosed at age 4). The remaining 3 patients had normal TREC and KREC levels at birth. Thus, the deterioration of de novo production of B cells occurred supposedly postnatally in most patients. Low KREC levels were also present in some patients with other MDS (n=5). Relative monocytopenia was found in 2 patients, low NK cells were present in 6 patients. T cells were mostly of naive non-activated phenotype. Conclusions Changes in B cell compartment are the most characteristic feature in patients with GATA2 mutation. Decreased number of B cells together with a shift towards mature phenotype and decreased level of KREC reflect history of substantial B cell proliferation in an environment of impaired production. This process appears to happen postnatally and resemble normal ageing process, which is accelerated due to progenitor cell impairment. Immunophenotyping is a useful tool in identifying patients for GATA2 sequencing. Supported by GAUK 802214, IGA NT/14534-3, NT/13462-4, UNCE 204012, GAČR P301/10/1877 Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V124.21.2746.2746
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2014
    detail.hit.zdb_id: 1468538-3
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  • 2
    Online Resource
    Online Resource
    Changes Identified by Flow Cytometry and WT1 Expression in Consecutive Bone Marrow Samples in Refractory Cytopenia of Childhood and Aplastic Anemia Before Start of the Therapy
    American Society of Hematology ; 2011
    In:  Blood Vol. 118, No. 21 ( 2011-11-18), p. 1342-1342
    Details
    In: Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 1342-1342
    Abstract: Abstract 1342 Introduction. Aplastic anemia (AA) and myelodysplastic syndrome (MDS) are rare diseases in childhood. The most common subtype of MDS is refractory cytopenia (RC). Both diseases typically exhibit with overlapping features and in both disorders dysregulation of immune system variably contributes to the degree of bone marrow (BM) failure. In the diagnostic algorithm plays role also analysis of consecutive BM samples by morphology. Patients and methods. Patients diagnosed between 2005 – 2011 with at least two BM samples analyzed by flow cytometry (FC) before treatment has started and with centrally evaluated BM biopsy according to EWOG MDS criteria were included into the study. We compared first and the last available sample before treatment (immunosupression or stem cell transplantation). By FC we analyzed following parameters: cell subsets (granulocytes, monocytes, lymphoid cells, erythroid precursors), BM precursors (CD34pos, CD117pos), T cells (CD3pos, CD3pos4pos, CD3pos8pos, CD3posHLA DRpos out of all cells, HLA DRpos out of CD3pos/CD3pos4pos/CD3pos8pos cells); B cells (CD19pos, CD19pos10pos, CD19pos45dim to neg, CD19pos34posout of all cells, CD10pos and CD20pos10neg out of CD19pos). In total 22 patients with AA (12 girls, 10 boys, mean age 11 years; 1.1–18 years) and 20 patients with RC (11 girls, 9 boys, mean age 11 years; 3.7–18) were included into the study. Median of time interval between both samples was 139 (1–1343) days in RC and 15 (1–56) days in AA. WT1 expression on mRNA level was analyzed in the sample before treatment with the highest number of CD34pos precursors to avoid blood contamination. All patients were screened by FISH for changes on chromosome 7 and 8. We asked following questions: Are there differences in the parameters in both bone marrow samples between SAA and RC? Is there any different pattern between d0 and before therapy sample between AA and RC? Are there any differences in WT1 expression between AA and RC group? Results. RC and AA significantly differ in both time points. AA patients have significantly decreased precursors (CD34, CD117); the difference is more pronounced at the later time point. More lymphocytes (both B and T) and less granulocytes are present at later time point in AA patients (p 〈 0.05, Mann-Whitney test). Activation of CD8 cytotoxic T cells according to HLA DR expression is more distinct in AA patients at later time point. The most significant different parameter between RC and AA is a ratio CD19/CD34 also with the significant trend between two time points (Two way ANOVA, p 〈 0.05). WT1 expression is statistically higher in RC patients; the higher expression is associated with presence of monosomy 7. Conclusion. By FC statistical differences can be identified in both samples (d0 and before treatment) between RC and AA. More pronounced differences are at later time point, which can be explained by further destruction of precursor and myeloid compartment more pronounced in AA patients compared to RC. WT1 expression is typically high in patients with RC and monosomy 7. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V118.21.1342.1342
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2011
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  • 3
    Online Resource
    Online Resource
    Acute Bilineal Leukemia Is a Very Rare Entity in Childhood
    American Society of Hematology ; 2011
    In:  Blood Vol. 118, No. 21 ( 2011-11-18), p. 4871-4871
    Details
    In: Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 4871-4871
    Abstract: Abstract 4871 Recent WHO 2008 classification introduced a new category named Mixed Phenotype Acute Leukemia (MPAL) for leukemias in which primary lineage cannot be determined by morphology, cytochemistry and/or flow cytometry (FC). Acute bilineal leukemia (ABL) is a subtype of MPAL and is defined by presence of distinct myeloid and lymphoid clonal populations simultaneously at diagnosis. No epidemiological data on ABL have been published so far and there are also few data on the origin of distinct leukemic clones. We examined the incidence and biology of ABL cases among children with primary acute leukemia in the period between 1996 and 2011 in the Czech Republic. Morphology and FC were centrally evaluated in all patients. In total 1065 patients were diagnosed (919 ALL, 146 AML); out of them 3 patients were classified as ABL. Two cases had simultaneous presence of distinct B-cell precursor (BCP) and myeloid clones (BCP-My) at diagnosis, one patient had discrete T ALL and myeloid population (T-My). All ABL patients were screened for immunoglobulin (Ig) and T-cell receptor (TCR) clonality, BCR-ABL, MLL gene rearrangements and FLT3-ITD. All three patients had detectable clonality in lymphoid-specific Ig/TCR rearrangements. In pt1 (BCP-My), FLT3-ITD abnormality and in pt3 (BCP-My), BCR-ABL fusion gene were found. Both patients with BCP-My ABL had Ikaros (IKZF1) gene deletion. In pt2 complex karyotype with MLL gene translocation was identified. Using high speed cell sorting we evaluated the presence or absence of previously mentioned changes in separated subpopulations. In patients with BCP-My ABL, identical clonal Ig rearrangements were found in both lymphoid and myeloid clones. Also FLT3-ITD and BCR-ABL aberrations were present in both clones of respective patients. In pt2 (T-My) TCR gene rearrangement was absent in myeloid population. All three patients achieved complete remission (CR) by lymphoid-directed induction treatment followed by switch to myeloid-oriented blocks according Interfant 99, resp. 2006 protocol in pt 1 and 2 and ALL treatment combined with tyrosine kinase inhibitor (TKI) in pt3. Finally all patients underwent allogeneic hematopoietic stem cell transplantation (SCT) in first CR. Pt1 relapsed after SCT as “typical” cALL. However, the plasticity was maintained and the myeloid clone reappeared at day 28 of relapse therapy. Pt2 relapsed as AML with undetectable TCR gene rearrangements. Pt3 is in complete remission 23 months after SCT with detectable low-level MRD and mixed chimerism with repeated lowering MRD after re-administered TKI dasatinib. Conclusions: ABL is an extremely rare entity in childhood accounting for less than 0.3 % of all acute leukemia cases. Surprisingly, the same genetic changes can be identified in both clonal populations making the “true” ABL even rarer. FC in combination with morphology is the basic method for identifying ABL and should be followed by detailed genetic analysis. The prognosis of ABL patients in our cohort was poor, despite SCT preceded by the application of treatment modalities targeting both lymphoid and myeloid clones. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V118.21.4871.4871
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2011
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 4
    Online Resource
    Online Resource
    Composition of Cellular Subsets by Flow Cytometry Identifies Differences Between MDS Subtypes and Aplastic Anemia but No Differences Are Identified Between Cases with and without Monosomy 7.
    American Society of Hematology ; 2009
    In:  Blood Vol. 114, No. 22 ( 2009-11-20), p. 3802-3802
    Details
    In: Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 3802-3802
    Abstract: Abstract 3802 Poster Board III-738 Introduction Monosomy 7 or del(7q) are frequent cytogenetic abnormalities in children with myelodysplastic syndrome (MDS) and associates with poor prognosis. MDS globally affects all cellular subsets in bone marrow and in peripheral blood. We asked whether flow cytometry (FC) can separate individual subtypes of MDS from each other and from aplastic anemia (SAA) and whether in individual subtypes of childhood MDS can separate patients with and without monosomy 7. Patients/analyzed parameters In total we analyzed 94 children with centrally analyzed immunophenotype in the reference lab who were diagnosed and treated for MDS or SAA between 1998 and 2009. In total we analyzed 14 patients with refractory cytopenia, 37 patients with advanced forms of MDS (JMML 10, RAEB 25, CMML 2) and 43 patients with SAA. Monosomy 7/del(7q) was present in 17 patients (RC 6, JMML 3, RAEB 8). Analyzed parameters were as follows: B cells, CD10+CD19+, CD19+45dim/neg, CD19+34+, CD19/CD34 ratio, CD34+, CD117 cells, CD34+38dim/neg, CD3+, CD3+4+, CD3+8+, CD3+HLADR+. Statistics We analyzed all parameters using non parametric tests (Mann-Whitney, Kruskal Wallis) and principal component analysis (PCA). Results Principal component analysis of all analyzed patients together clearly separates advanced forms of MDS from RC and SAA, the most contributing factor being the number of CD34 and CD117+ cells. In non parametric statistics following factors significantly differ among MDS subtypes and SAA (Kruskal-Wallis): CD19, CD117, CD34, CD3, CD3+4+, CD8+ and CD3+HLADR+. RC and SAA patients are separated mainly by the number of B cells and the CD34:CD19 ratio. In addition, the following parameters differ between RC and SAA (Mann-Whitney): CD34, CD117 and CD3+HLADR+. Unlike the CD34:CD19 ratio, the number of CD19+34+ precursors does not differ between RC and SAA patients. Patients with monosomy 7 do not differ from the remaining patients when all MDS patients are analyzed together or separately in the respective subgroups (RC, non RC, JMML) by PCA or by non parametric statistics. Conclusion PCA separates advanced MDS forms from RC and SAA. Advanced forms of MDS are characterized by increased percentage of CD34+ and CD117+ cells compared to RC and SAA patients. The global reduction of B cell progenitor compartment is pronounced especially in non-JMML cases of MDS, whereas SAA patients typically present with isolated reduction of cells at early stages (CD19+34+) of B cell development. Patients with monosomy 7 cluster within the respective disease category, they do not form own cluster in PCA. Supported by MSMT VZ MSM0021620813, MZO 00064203 VZ FNM, MZO VFN2005, IGA NR/9531-3, NPV 2B06064. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V114.22.3802.3802
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2009
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 5
    Online Resource
    Online Resource
    Inherited coagulation disorders
    Galen, spol. s r.o. ; 2022
    In:  Česko-slovenská pediatrie Vol. 77, No. 5 ( 2022-9-23), p. 310-313
    Details
    In: Česko-slovenská pediatrie, Galen, spol. s r.o., Vol. 77, No. 5 ( 2022-9-23), p. 310-313
    Type of Medium: Online Resource
    ISSN: 0069-2328 , 1805-4501
    Uniform Title: Vrozené poruchy krevního srážení
    URL: Article
    DOI: 10.55095/CSPediatrie2022/051
    Language: cs
    Publisher: Galen, spol. s r.o.
    Publication Date: 2022
    detail.hit.zdb_id: 2641017-5
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  • 6
    Online Resource
    Online Resource
    Data_Sheet_1.pdf
    Frontiers Media SA ; 2019
    In:  Frontiers in Immunology Vol. 10 ( 2019-9-18)
    Details
    In: Frontiers in Immunology, Frontiers Media SA, Vol. 10 ( 2019-9-18)
    Type of Medium: Online Resource
    ISSN: 1664-3224
    URL: Article
    URL: Article
    DOI: 10.3389/fimmu.2019.02194
    DOI: 10.3389/fimmu.2019.02194.s001
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2019
    detail.hit.zdb_id: 2606827-8
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  • 7
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    Online Resource
    Analysis of von Willebrand Disease in the “Heart of Europe”
    Georg Thieme Verlag KG ; 2022
    In:  TH Open Vol. 06, No. 04 ( 2022-10), p. e335-e346
    Details
    In: TH Open, Georg Thieme Verlag KG, Vol. 06, No. 04 ( 2022-10), p. e335-e346
    Abstract: Background von Willebrand disease (VWD) is a genetic bleeding disorder caused by defects of von Willebrand factor (VWF), quantitative (type 1 and 3) or qualitative (type 2). The laboratory phenotyping is heterogenic making diagnosis difficult. Objectives Complete laboratory analysis of VWD as an expansion of the previously reported cross-sectional family-based VWD study in the Czech Republic (BRNO-VWD) and Slovakia (BRA-VWD) under the name “Heart of Europe,” in order to improve the understanding of laboratory phenotype/genotype correlation. Patients and Methods In total, 227 suspected VWD patients were identified from historical records. Complete laboratory analysis was established using all available assays, including VWF multimers and genetic analysis. Results A total of 191 patients (from 119 families) were confirmed as having VWD. The majority was characterized as a type 1 VWD, followed by type 2. Multimeric patterns concordant with laboratory phenotypes were found in approximately 83% of all cases. A phenotype/genotype correlation was present in 84% (77% type 1, 99% type 2, and 61% type 3) of all patients. Another 45 candidate mutations (23 novel variations), not found in the initial study, could be identified (missense 75% and truncating 24%). An exon 1–3 gene deletion was identified in 14 patients where no mutation was found by direct DNA sequencing, increasing the linkage up to 92%, overall. Conclusion This study provides a cross-sectional overview of the VWD population in a part of Central Europe. It is an addition to the previously published BRNO-VWD study, and provides important data to the International Society of Thrombosis and Haemostasis/European Association for Haemophilia and Allied Disorders VWD mutation database with identification of novel causal mutations.
    Type of Medium: Online Resource
    ISSN: 2512-9465
    URL: Article
    DOI: 10.1055/s-0042-1757635
    Language: English
    Publisher: Georg Thieme Verlag KG
    Publication Date: 2022
    detail.hit.zdb_id: 2893939-6
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  • 8
    Online Resource
    Online Resource
    Inhibition of β-catenin signalling promotes DNA damage elicited by benzo[a]pyrene in a model of human colon cancer cells via CYP1 deregulation
    Oxford University Press (OUP) ; 2015
    In:  Mutagenesis Vol. 30, No. 4 ( 2015-7), p. 565-576
    Details
    In: Mutagenesis, Oxford University Press (OUP), Vol. 30, No. 4 ( 2015-7), p. 565-576
    Type of Medium: Online Resource
    ISSN: 1464-3804 , 0267-8357
    URL: Article
    DOI: 10.1093/mutage/gev019
    RVK:
    WA 15000
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2015
    detail.hit.zdb_id: 1497468-X
    SSG: 12
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  • 9
    Online Resource
    Online Resource
    Butyrate as a modulator of xenobiotic-metabolizing enzymes in colon epithelial cells
    Elsevier BV ; 2017
    In:  Toxicology Letters Vol. 280 ( 2017-10), p. S170-
    Details
    In: Toxicology Letters, Elsevier BV, Vol. 280 ( 2017-10), p. S170-
    Type of Medium: Online Resource
    ISSN: 0378-4274
    URL: Article
    DOI: 10.1016/j.toxlet.2017.07.476
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2017
    detail.hit.zdb_id: 1500784-4
    SSG: 12
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  • 10
    Online Resource
    Online Resource
    Novel homozygous fibrinogen Aα chain truncation causes severe afibrinogenemia with life threatening complications in a two-year-old boy
    Elsevier BV ; 2013
    In:  Thrombosis Research Vol. 132, No. 4 ( 2013-10), p. 490-492
    Details
    In: Thrombosis Research, Elsevier BV, Vol. 132, No. 4 ( 2013-10), p. 490-492
    Type of Medium: Online Resource
    ISSN: 0049-3848
    URL: Article
    DOI: 10.1016/j.thromres.2013.08.022
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2013
    detail.hit.zdb_id: 1500780-7
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