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1.
Genome Res ; 2022 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-35863900

RESUMO

Genomic rearrangements are known to result in proto-oncogene deregulation in many cancers, but the link to 3D genome structure remains poorly understood. Here, we used the highly predictive heteromorphic polymer (HiP-HoP) model to predict chromatin conformations at the proto-oncogene CCND1 in healthy and malignant B cells. After confirming that the model gives good predictions of Hi-C data for the nonmalignant human B cell-derived cell line GM12878, we generated predictions for two cancer cell lines, U266 and Z-138. These possess genome rearrangements involving CCND1 and the immunoglobulin heavy locus (IGH), which we mapped using targeted genome sequencing. Our simulations showed that a rearrangement in U266 cells where a single IGH super-enhancer is inserted next to CCND1 leaves the local topologically associated domain (TAD) structure intact. We also observed extensive changes in enhancer-promoter interactions within the TAD, suggesting that it is the downstream chromatin remodeling which gives rise to the oncogene activation, rather than the presence of the inserted super-enhancer DNA sequence per se. Simulations of the IGH-CCND1 reciprocal translocation in Z-138 cells revealed that an oncogenic fusion TAD is created, encompassing CCND1 and the IGH super-enhancers. We predicted how the structure and expression of CCND1 changes in these different cell lines, validating this using qPCR and fluorescence in situ hybridization microscopy. Our work demonstrates the power of polymer simulations to predict differences in chromatin interactions and gene expression for different translocation breakpoints.

2.
Genome Res ; 32(7): 1343-1354, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-34933939

RESUMO

Chromosomal translocations are important drivers of haematological malignancies whereby proto-oncogenes are activated by juxtaposition with enhancers, often called enhancer hijacking We analyzed the epigenomic consequences of rearrangements between the super-enhancers of the immunoglobulin heavy locus (IGH) and proto-oncogene CCND1 that are common in B cell malignancies. By integrating BLUEPRINT epigenomic data with DNA breakpoint detection, we characterized the normal chromatin landscape of the human IGH locus and its dynamics after pathological genomic rearrangement. We detected an H3K4me3 broad domain (BD) within the IGH locus of healthy B cells that was absent in samples with IGH-CCND1 translocations. The appearance of H3K4me3-BD over CCND1 in the latter was associated with overexpression and extensive chromatin accessibility of its gene body. We observed similar cancer-specific H3K4me3-BDs associated with hijacking of super-enhancers of other common oncogenes in B cell (MAF, MYC, and FGFR3/NSD2) and T cell malignancies (LMO2, TLX3, and TAL1). Our analysis suggests that H3K4me3-BDs can be created by super-enhancers and supports the new concept of epigenomic translocation, in which the relocation of H3K4me3-BDs from cell identity genes to oncogenes accompanies the translocation of super-enhancers.


Assuntos
Epigenômica , Translocação Genética , Cromatina/genética , Histonas , Humanos , Oncogenes
3.
Genome Res ; 32(7): 1328-1342, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-34162697

RESUMO

Broad domains of H3K4 methylation have been associated with consistent expression of tissue-specific, cell identity, and tumor suppressor genes. Here, we identified broad domain-associated genes in healthy human thymic T cell populations and a collection of T cell acute lymphoblastic leukemia (T-ALL) primary samples and cell lines. We found that broad domains are highly dynamic throughout T cell differentiation, and their varying breadth allows the distinction between normal and neoplastic cells. Although broad domains preferentially associate with cell identity and tumor suppressor genes in normal thymocytes, they flag key oncogenes in T-ALL samples. Moreover, the expression of broad domain-associated genes, both coding and noncoding, is frequently deregulated in T-ALL. Using two distinct leukemic models, we showed that the ectopic expression of T-ALL oncogenic transcription factor preferentially impacts the expression of broad domain-associated genes in preleukemic cells. Finally, an H3K4me3 demethylase inhibitor differentially targets T-ALL cell lines depending on the extent and number of broad domains. Our results show that the regulation of broad H3K4me3 domains is associated with leukemogenesis, and suggest that the presence of these structures might be used for epigenetic prioritization of cancer-relevant genes, including long noncoding RNAs.


Assuntos
Leucemia-Linfoma Linfoblástico de Células T Precursoras , Epigênese Genética , Histonas/metabolismo , Humanos , Oncogenes , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética
4.
Bioessays ; 45(10): e2200239, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37350339

RESUMO

The human and mouse genomes are complex from a genomic standpoint. Each cell has the same genomic sequence, yet a wide array of cell types exists due to the presence of a plethora of regulatory elements in the non-coding genome. Recent advances in epigenomic profiling have uncovered non-coding gene proximal promoters and distal enhancers of transcription genome-wide. Extension of promoter-associated H3K4me3 histone mark across the gene body, known as a broad H3K4me3 domain (H3K4me3-BD), is a signature of constitutive expression of cell-type-specific regulation and of tumour suppressor genes in healthy cells. Recently, it has been discovered that the presence of H3K4me3-BDs over oncogenes is a cancer-specific feature associated with their dysregulated gene expression and tumourigenesis. Moreover, it has been shown that the hijacking of clusters of enhancers, known as super-enhancers (SE), by proto-oncogenes results in the presence of H3K4me3-BDs over the gene body. Therefore, H3K4me3-BDs and SE crosstalk in healthy and cancer cells therefore represents an important mechanism to identify future treatments for patients with SE driven cancers.


Assuntos
Elementos Facilitadores Genéticos , Neoplasias , Humanos , Animais , Camundongos , Elementos Facilitadores Genéticos/genética , Histonas/genética , Histonas/metabolismo , Regiões Promotoras Genéticas/genética , Código das Histonas/genética , Neoplasias/genética
5.
Blood ; 140(17): 1875-1890, 2022 10 27.
Artigo em Inglês | MEDLINE | ID: mdl-35839448

RESUMO

The fusion gene MLL/AF4 defines a high-risk subtype of pro-B acute lymphoblastic leukemia. Relapse can be associated with a lineage switch from acute lymphoblastic to acute myeloid leukemia, resulting in poor clinical outcomes caused by resistance to chemotherapies and immunotherapies. In this study, the myeloid relapses shared oncogene fusion breakpoints with their matched lymphoid presentations and originated from various differentiation stages from immature progenitors through to committed B-cell precursors. Lineage switching is linked to substantial changes in chromatin accessibility and rewiring of transcriptional programs, including alternative splicing. These findings indicate that the execution and maintenance of lymphoid lineage differentiation is impaired. The relapsed myeloid phenotype is recurrently associated with the altered expression, splicing, or mutation of chromatin modifiers, including CHD4 coding for the ATPase/helicase of the nucleosome remodelling and deacetylation complex. Perturbation of CHD4 alone or in combination with other mutated epigenetic modifiers induces myeloid gene expression in MLL/AF4+ cell models, indicating that lineage switching in MLL/AF4 leukemia is driven and maintained by disrupted epigenetic regulation.


Assuntos
Proteína de Leucina Linfoide-Mieloide , Leucemia-Linfoma Linfoblástico de Células Precursoras , Humanos , Proteína de Leucina Linfoide-Mieloide/genética , Proteína de Leucina Linfoide-Mieloide/metabolismo , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo , Epigênese Genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Genes Reguladores , Cromatina
6.
J Clin Nurs ; 33(7): 2476-2495, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38284462

RESUMO

AIM: To address: What are the experiences of 2SLGBTQQIA+ parents using parenting supports and services to meet their children's early childhood development needs (<5 years of age)? DESIGN: Whittemore and Knafl's (2005) integrative review methodology. METHODS: Electronic databases were searched from 2000 to October 14, 2022 for empirical studies or reviews addressing the research question. The title and abstract of 12,158 articles were screened for inclusion in the review by two independent researchers; 175 of these articles underwent full-text review. Studies selected were critically appraised using a Joanna Briggs Institute Critical Appraisal tool. Relevant key findings were extracted from each study and entered into N-VIVO-12. Thematic content analysis was employed and PRISMA guidelines were adhered to. RESULTS: A total of 18 articles (15 qualitative and three multi-method studies) met the inclusion criteria and were selected for the review. Seven themes were revealed from analysis of the studies: (1) 2SLGBTQQIA+ Status kept a secret; (2) Forced to come out; (3) Heteronormative messaging; (4) Feeling excluded; (5) Stigmatised; (6) Parents act as educators; and (7) Positive experiences. CONCLUSION: This integrative review provides nurses with insight into the experiences of 2SLGBTQQIA+ parents using health care services for their young child. IMPLICATIONS FOR THE PROFESSION: This article highlights what changes nurses need to make to their practice to ensure appropriate, inclusive care for clients of diverse sexual and gender identities and their families. IMPACT: Health care providers, especially nurses, have an opportunity to improve the experiences of these families and positively impact their health and well-being. Additionally, there is a need for research with the 2SLGBTQQIA+ parent community and the use of rigorous methodological techniques, including clearly linking participants' gender and sexual identities with study findings, to improve our understanding of 2SLGBTQQIA+ parent experiences. PATIENT OR PUBLIC CONTRIBUTION: Although there was no direct patient contribution to the work since it was an integrative review of the literature, indirectly patient contributions are incorporated from the original research results of studies incorporated into this review.


Assuntos
Pais , Minorias Sexuais e de Gênero , Humanos , Feminino , Masculino , Pais/psicologia , Pré-Escolar , Minorias Sexuais e de Gênero/psicologia , Adulto , Lactente , Poder Familiar/psicologia
7.
Haematologica ; 108(3): 717-731, 2023 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-35484682

RESUMO

Rarely, immunophenotypically immature B-cell precursor acute lymphoblastic leukemia (BCP-ALL) carries an immunoglobulin- MYC rearrangement (IG-MYC-r). This can result in diagnostic confusion with Burkitt lymphoma/leukemia and use of individualized treatment schedules of unproven efficacy. Here we compare the molecular characteristics of these conditions and investigate historic clinical outcome data. We identified 90 cases registered in a national BCP-ALL clinical trial/registry. When present, diagnostic material underwent cytogenetic, exome, methylome and transcriptome analyses. The outcomes analyzed were 3-year event-free survival and overall survival. IG-MYC-r was identified in diverse cytogenetic backgrounds, co-existing with either established BCP-ALL-specific abnormalities (high hyperdiploidy, n=3; KMT2A-rearrangement, n=6; iAMP21, n=1; BCR-ABL1, n=1); BCL2/BCL6-rearrangements (n=15); or, most commonly, as the only defining feature (n=64). Within this final group, precursor-like V(D)J breakpoints predominated (8/9) and KRAS mutations were common (5/11). DNA methylation identified a cluster of V(D)J-rearranged cases, clearly distinct from Burkitt leukemia/lymphoma. Children with IG-MYC-r within that subgroup had a 3-year event-free survival of 47% and overall survival of 60%, representing a high-risk BCP-ALL. To develop effective management strategies this group of patients must be allowed access to contemporary, minimal residual disease-adapted, prospective clinical trial protocols.


Assuntos
Linfoma de Burkitt , Leucemia-Linfoma Linfoblástico de Células Precursoras B , Criança , Humanos , Linfoma de Burkitt/diagnóstico , Linfoma de Burkitt/genética , Linfoma de Burkitt/terapia , Estudos Prospectivos , Imunoglobulinas/genética , Rearranjo Gênico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia
8.
Public Health Nutr ; 24(11): 3488-3497, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33138886

RESUMO

OBJECTIVE: While organisational change in substance use disorder (SUD) treatment has been extensively studied, there is no research describing facility-wide changes related to nutrition interventions. This study evaluates staff-perceived barriers to change before and after a wellness initiative. DESIGN: A pre-intervention questionnaire was administered to participating staff prior to facility-wide changes (n 40). The questions were designed to assess barriers across five domains: (1) provision of nutrition-related treatment; (2) implementation of nutrition education; (3) screening, detecting and monitoring (nutrition behaviours); (4) facility-wide collaboration and (5) menu changes and client satisfaction. A five-point Likert scale was used to indicate the extent to which staff anticipate difficulty or ease in implementing facility-wide nutrition changes, perceived as organisational barriers. Follow-up questionnaires were identical to the pre-test except that it examined barriers experienced, rather than anticipated (n 50). SETTING: A multisite SUD treatment centre in Northern California which began implementing nutrition programming changes in order to improve care. PARTICIPANTS: Staff members who consented to participate. RESULTS: From pre to post, we observed significant decreases in perceived barriers related to the provision of nutrition-related treatment (P = 0·019), facility-wide collaboration (P = 0·036), menu changes and client satisfaction (P = 0·024). Implementation of nutrition education and the domain of screening, detecting and monitoring did not reach statistical significance. CONCLUSIONS: Our results show that staff training, food service changes, the use of targeted curriculum for nutrition groups and the encouragement of discussing self-care in individual counselling sessions can lead to positive shifts about nutrition-related organisational change among staff.


Assuntos
Educação em Saúde , Transtornos Relacionados ao Uso de Substâncias , Humanos , Inovação Organizacional , Satisfação do Paciente , Transtornos Relacionados ao Uso de Substâncias/terapia
9.
Blood ; 127(16): 1998-2006, 2016 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-26869395

RESUMO

Prevention of central nervous system (CNS) relapse is critical for cure of childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Despite this, mechanisms of CNS infiltration are poorly understood, and the timing, frequency, and properties of BCP-ALL blasts entering the CNS compartment are unknown. We investigated the CNS-engrafting potential of BCP-ALL cells xenotransplanted into immunodeficient NOD.Cg- ITALIC! Prkdc (ITALIC! scid) ITALIC! Il2rg (ITALIC! tm1Wjl)/SzJ mice. CNS engraftment was seen in 23 of 29 diagnostic samples (79%): 2 of 2 from patients with overt CNS disease and 21 of 27 from patients thought to be CNS negative by diagnostic lumbar puncture. Histologic findings mimic human pathology and demonstrate that leukemic cells transit the blood-cerebrospinal fluid barrier situated close to the dural sinuses, the site of recently discovered CNS lymphatics. Retrieval of blasts from the CNS showed no evidence for chemokine receptor-mediated selective trafficking. The high frequency of infiltration and lack of selective trafficking led us to postulate that CNS tropism is a generic property of leukemic cells. To test this, we performed serial dilution experiments which showed CNS engraftment in 5 of 6 mice after transplant of as few as 10 leukemic cells. Clonal tracking techniques confirmed the polyclonal nature of CNS-infiltrating cells, with multiple clones engrafting in both the CNS and periphery. Overall, these findings suggest that subclinical seeding of the CNS is likely to be present in most BCP-ALL patients at original diagnosis, and efforts to prevent CNS relapse should concentrate on effective eradication of disease from this site rather than targeting entry mechanisms.


Assuntos
Barreira Hematoencefálica/patologia , Movimento Celular/fisiologia , Sistema Nervoso Central/patologia , Infiltração Leucêmica/patologia , Leucócitos/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Animais , Células Cultivadas , Neoplasias do Sistema Nervoso Central/líquido cefalorraquidiano , Neoplasias do Sistema Nervoso Central/secundário , Humanos , Camundongos , Camundongos Endogâmicos NOD , Camundongos Transgênicos , Transplante de Neoplasias , Recidiva , Transplante Heterólogo
10.
Haematologica ; 103(4): 634-644, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29449437

RESUMO

Intrachromosomal amplification of chromosome 21 is a heterogeneous chromosomal rearrangement occurring in 2% of cases of childhood precursor B-cell acute lymphoblastic leukemia. These abnormalities are too complex to engineer faithfully in animal models and are unrepresented in leukemia cell lines. As a resource for future functional and preclinical studies, we have created xenografts from the leukemic blasts of patients with intrachromosomal amplification of chromosome 21 and characterized them by in-vivo and ex-vivo luminescent imaging, flow immunophenotyping, and histological and ultrastructural analyses of bone marrow and the central nervous system. Investigation of up to three generations of xenografts revealed phenotypic evolution, branching genomic architecture and, compared with other B-cell acute lymphoblastic leukemia genetic subtypes, greater clonal diversity of leukemia-initiating cells. In support of intrachromosomal amplification of chromosome 21 as a primary genetic abnormality, it was always retained through generations of xenografts, although we also observed the first example of structural evolution of this rearrangement. Clonal segregation in xenografts revealed convergent evolution of different secondary genomic abnormalities implicating several known tumor suppressor genes and a region, containing the B-cell adaptor, PIK3AP1, and nuclear receptor co-repressor, LCOR, in the progression of B-cell acute lymphoblastic leukemia. Tracking of mutations in patients and derived xenografts provided evidence for co-operation between abnormalities activating the RAS pathway in B-cell acute lymphoblastic leukemia and for their aggressive clonal expansion in the xeno-environment. Bi-allelic loss of the CDKN2A/B locus was recurrently maintained or emergent in xenografts and also strongly selected as RNA sequencing demonstrated a complete absence of reads for genes associated with the deletions.


Assuntos
Aberrações Cromossômicas , Cromossomos Humanos Par 21 , Células Clonais/patologia , Xenoenxertos/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Animais , Criança , Evolução Clonal , Progressão da Doença , Evolução Molecular , Humanos , Camundongos , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia
11.
Intern Med J ; 48(3): 269-275, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29083111

RESUMO

BACKGROUND: The prevalence of hypertensive disorders of pregnancy (HDP) in Australia's urban indigenous women is unknown. AIM: To explore the risk factors associated with HDP for a cohort of urban indigenous women in South-Western Sydney, Australia. METHODS: This study was conducted in partnership with the Tharawal Aboriginal Medical Service. Women (18-45 years) were recruited at the clinic and community events. The quantitative questionnaire included obstetric history, personal and family history of hypertension. Anthropometric measurements and blood pressure were conducted. Rates were compared with Australian Bureau of Statistics (ABS) national rates. RESULTS: Eighty-three participants completed the questionnaire. The rate of ever having HDP in a pregnancy was 36.1%. The overall ABS rate was 9.8% and for indigenous women, 14%. The mean maternal age at first pregnancy was 20.8 years (SD 3.7 years). The mean body mass index (BMI) of the sample population (n = 81) was 32.2 kg/m2 (SD 9.5 kg/m2 ) and BMI was not related to HDP (P = 0.197). Of those questioned, 25.3% had an individual history and 63.9% had a family history of hypertension. The effect of family history of hypertension (P = 0.020) (odds ratio (OR) 4.29; 95% confidence interval (CI); 1.42-12.93) and individual history of hypertension (P < 0.001) (OR 15.69; 95% CI; 4.50-54.76) were associated with HDP. CONCLUSION: There was a higher rate of HDP in urban indigenous women compared to the national indigenous prevalence. The family history, or individual history of hypertension was the most significant risk factors and BMI was not identified as a risk factor for HDP in this population.


Assuntos
Índice de Massa Corporal , Hipertensão Induzida pela Gravidez/diagnóstico , Hipertensão Induzida pela Gravidez/etnologia , Havaiano Nativo ou Outro Ilhéu do Pacífico/etnologia , Fumar/etnologia , População Urbana , Adolescente , Adulto , Feminino , Humanos , Hipertensão/diagnóstico , Hipertensão/etnologia , Pessoa de Meia-Idade , New South Wales/etnologia , Gravidez , Fatores de Risco , Fumar/efeitos adversos , Inquéritos e Questionários , População Urbana/tendências , Adulto Jovem
12.
Genes Chromosomes Cancer ; 56(5): 363-372, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28033648

RESUMO

Deregulated expression of the type I cytokine receptor, CRLF2, is observed in 5-15% of precursor B-cell acute lymphoblastic leukaemia (B-ALL). We aimed to determine the clinical and genetic landscape of those with IGH-CRLF2 or P2RY8-CRLF2 (CRLF2-r) using multiple genomic approaches. Clinical and demographic features of CRLF2-r patients were characteristic of B-ALL. Patients with IGH-CRLF2 were older (14 y vs. 4 y, P < .001), while the incidence of CRLF2-r among Down syndrome patients was high (50/161, 31%). CRLF2-r co-occurred with primary chromosomal rearrangements but the majority (111/161, 69%) had B-other ALL. Copy number alteration (CNA) profiles were similar to B-other ALL, although CRLF2-r patients harbored higher frequencies of IKZF1 (60/138, 43% vs. 77/1351, 24%) and BTG1 deletions (20/138, 15% vs. 3/1351, 1%). There were significant differences in CNA profiles between IGH-CRLF2 and P2RY8-CRLF2 patients: IKZF1 (25/35, 71% vs. 36/108, 33%, P < .001), BTG1 (11/35, 31% vs. 10/108, 9%, P =.004), and ADD3 deletions (9/19, 47% vs. 5/38, 13%, P =.008). A novel gene fusion, USP9X-DDX3X, was discovered in 10/54 (19%) of patients. Pathway analysis of the mutational profile revealed novel involvement for focal adhesion. Although the functional relevance of many of these abnormalities are unknown, they likely activate additional pathways, which may represent novel therapeutic targets.


Assuntos
Biomarcadores Tumorais/genética , Rearranjo Gênico , Genoma Humano , Mutação/genética , Proteínas de Fusão Oncogênica/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Receptores de Citocinas/genética , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Seguimentos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Hibridização in Situ Fluorescente , Lactente , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Prognóstico , Adulto Jovem
13.
J Immunol ; 195(8): 3574-83, 2015 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-26355157

RESUMO

The differentiation and survival of autoreactive B cells is normally limited by a variety of self-tolerance mechanisms, including clonal deletion, anergy, and clonal ignorance. The transcription factor c-ets-1 (encoded by the Ets1 gene) has B cell-intrinsic roles in regulating formation of Ab-secreting cells by controlling the activity of Blimp1 and Pax5 and may be required for B cell tolerance to self-antigen. To test this, we crossed Ets1(-/-) mice to two different transgenic models of B cell self-reactivity, the anti-hen egg lysozyme BCR transgenic strain and the AM14 rheumatoid factor transgenic strain. BCR transgenic Ets1(-/-) mice were subsequently crossed to mice either carrying or lacking relevant autoantigens. We found that B cells lacking c-ets-1 are generally hyperresponsive in terms of Ab secretion and form large numbers of Ab-secreting cells even in the absence of cognate Ags. When in the presence of cognate Ag, different responses were noted depending on the physical characteristics of the Ag. We found that clonal deletion of highly autoreactive B cells in the bone marrow was intact in the absence of c-ets-1. However, peripheral B cells lacking c-ets-1 failed to become tolerant in response to stimuli that normally induce B cell anergy or B cell clonal ignorance. Interestingly, high-affinity soluble self-antigen did cause B cells to adopt many of the classical features of anergic B cells, although such cells still secreted Ab. Therefore, maintenance of appropriate c-ets-1 levels is essential to prevent loss of self-tolerance in the B cell compartment.


Assuntos
Autoantígenos/imunologia , Linfócitos B/imunologia , Anergia Clonal , Deleção Clonal , Proteína Proto-Oncogênica c-ets-1/imunologia , Receptores de Antígenos de Linfócitos B/imunologia , Animais , Autoantígenos/genética , Camundongos , Camundongos Knockout , Proteína Proto-Oncogênica c-ets-1/genética , Receptores de Antígenos de Linfócitos B/genética
14.
J Immunol ; 195(5): 1955-63, 2015 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-26209625

RESUMO

Tight control of B cell differentiation into plasma cells (PCs) is critical for proper immune responses and the prevention of autoimmunity. The Ets1 transcription factor acts in B cells to prevent PC differentiation. Ets1(-/-) mice accumulate PCs and produce autoantibodies. Ets1 expression is downregulated upon B cell activation through the BCR and TLRs and is maintained by the inhibitory signaling pathway mediated by Lyn, CD22 and SiglecG, and SHP-1. In the absence of these inhibitory components, Ets1 levels are reduced in B cells in a Btk-dependent manner. This leads to increased PCs, autoantibodies, and an autoimmune phenotype similar to that of Ets1(-/-) mice. Defects in inhibitory signaling molecules, including Lyn and Ets1, are associated with human lupus, although the effects are more subtle than the complete deficiency that occurs in knockout mice. In this study, we explore the effect of partial disruption of the Lyn/Ets1 pathway on B cell tolerance and find that Lyn(+/-)Ets1(+/-) mice demonstrate greater and earlier production of IgM, but not IgG, autoantibodies compared with Lyn(+/-) or Ets1(+/-) mice. We also show that Btk-dependent downregulation of Ets1 is important for normal PC homeostasis when inhibitory signaling is intact. Ets1 deficiency restores the decrease in steady state PCs and Ab levels observed in Btk(-/-) mice. Thus, depending on the balance of activating and inhibitory signals to Ets1, there is a continuum of effects on autoantibody production and PC maintenance. This ranges from full-blown autoimmunity with complete loss of Ets1-maintaining signals to reduced PC and Ab levels with impaired Ets1 downregulation.


Assuntos
Anticorpos/imunologia , Proteínas Tirosina Quinases/imunologia , Proteína Proto-Oncogênica c-ets-1/imunologia , Quinases da Família src/imunologia , Tirosina Quinase da Agamaglobulinemia , Animais , Anticorpos/metabolismo , Autoanticorpos/sangue , Autoanticorpos/imunologia , Linfócitos B/imunologia , Linfócitos B/metabolismo , Western Blotting , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Ensaio de Imunoadsorção Enzimática , Epistasia Genética , Citometria de Fluxo , Expressão Gênica/imunologia , Imunoglobulina M/sangue , Imunoglobulina M/imunologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Plasmócitos/imunologia , Plasmócitos/metabolismo , Proteínas Tirosina Quinases/genética , Proteínas Tirosina Quinases/metabolismo , Proteína Proto-Oncogênica c-ets-1/genética , Proteína Proto-Oncogênica c-ets-1/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Baço/imunologia , Baço/metabolismo , Esplenomegalia/genética , Esplenomegalia/imunologia , Esplenomegalia/metabolismo , Quinases da Família src/genética , Quinases da Família src/metabolismo
15.
J Immunol ; 194(10): 4717-28, 2015 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-25833397

RESUMO

In health, long-lived plasma cells (LLPC) are essential for durable protective humoral immunity, and, conversely, in disease are a major source of pathogenic Abs in autoimmunity, graft rejection, and allergy. However, the molecular basis for their longevity is largely unknown. We have recently found that CD28 signaling in plasma cells (PC) is essential for sustaining Ab titers, by supporting the survival of LLPC, but not short-lived PC (SLPC). We now find that, unlike SLPC, CD28 activation in LLPC induces prosurvival downstream Vav signaling. Knockin mice with CD28 cytoplasmic tail mutations that abrogate Vav signaling (CD28-AYAA) had significantly fewer LLPC but unaffected SLPC numbers, whereas mice with mutations that abrogate PI3K signaling (CD28-Y170F) were indistinguishable from wild-type controls. This was consistent with the loss of CD28's prosurvival effect in LLPC from CD28-AYAA, but not CD28-Y170F, mice. Furthermore, the CD28 Vav motif in the B lineage was essential for the long-term maintenance of Ag-specific LLPC populations and Ab titers in vivo. Signaling downstream of the CD28 Vav motif induced previously undescribed transcriptional regulation of B lymphocyte-induced maturation protein-1, a key mediator of PC differentiation and maintenance. These findings suggest CD28 signaling in LLPC modulates the central B lymphocyte-induced maturation protein-1 transcriptional nexus involved in long-term survival and function.


Assuntos
Antígenos CD28/metabolismo , Plasmócitos/citologia , Plasmócitos/imunologia , Transdução de Sinais/imunologia , Fatores de Transcrição/biossíntese , Motivos de Aminoácidos , Animais , Formação de Anticorpos/imunologia , Western Blotting , Antígenos CD28/imunologia , Diferenciação Celular/imunologia , Sobrevivência Celular/imunologia , Ensaio de Imunoadsorção Enzimática , Feminino , Citometria de Fluxo , Imunoprecipitação , Subpopulações de Linfócitos/citologia , Subpopulações de Linfócitos/imunologia , Subpopulações de Linfócitos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Plasmócitos/metabolismo , Fator 1 de Ligação ao Domínio I Regulador Positivo , Prolina , Reação em Cadeia da Polimerase em Tempo Real , Fatores de Transcrição/imunologia , Regulação para Cima
16.
J Calif Dent Assoc ; 45(4): 185-7, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-29068620

RESUMO

Dental X-ray machine inspections are conducted by the California Department of Public Health's Radiologic Health Branch (RHB). RHB's mission is to protect public health and safety throughout California by ensuring the safe use of radiologic equipment and materials within industry, medicine and research, preventing radiologic health hazards and educating and enforcing applicable state and federal radiation laws and regulations.


Assuntos
Proteção Radiológica/normas , Radiografia Dentária/instrumentação , Radiografia Dentária/normas , California , Fidelidade a Diretrizes , Humanos
17.
J Immunol ; 193(2): 909-920, 2014 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-24929000

RESUMO

Signaling through the BCR can drive B cell activation and contribute to B cell differentiation into Ab-secreting plasma cells. The positive BCR signal is counterbalanced by a number of membrane-localized inhibitory receptors that limit B cell activation and plasma cell differentiation. Deficiencies in these negative signaling pathways may cause autoantibody generation and autoimmune disease in both animal models and human patients. We have previously shown that the transcription factor Ets1 can restrain B cell differentiation into plasma cells. In this study, we tested the roles of the BCR and inhibitory receptors in controlling the expression of Ets1 in mouse B cells. We found that Ets1 is downregulated in B cells by BCR or TLR signaling through a pathway dependent on PI3K, Btk, IKK2, and JNK. Deficiencies in inhibitory pathways, such as a loss of the tyrosine kinase Lyn, the phosphatase Src homology region 2 domain-containing phosphatase 1 (SHP1) or membrane receptors CD22 and/or Siglec-G, result in enhanced BCR signaling and decreased Ets1 expression. Restoring Ets1 expression in Lyn- or SHP1-deficient B cells inhibits their enhanced plasma cell differentiation. Our findings indicate that downregulation of Ets1 occurs in response to B cell activation via either BCR or TLR signaling, thereby allowing B cell differentiation and that the maintenance of Ets1 expression is an important function of the inhibitory Lyn → CD22/SiglecG → SHP1 pathway in B cells.


Assuntos
Diferenciação Celular/imunologia , Plasmócitos/imunologia , Proteína Proto-Oncogênica c-ets-1/imunologia , Receptores de Antígenos de Linfócitos B/imunologia , Transdução de Sinais/imunologia , Tirosina Quinase da Agamaglobulinemia , Animais , Linfócitos B/imunologia , Linfócitos B/metabolismo , Western Blotting , Diferenciação Celular/genética , Linhagem Celular Tumoral , Expressão Gênica/imunologia , Lectinas/deficiência , Lectinas/genética , Lectinas/imunologia , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Fosfatidilinositol 3-Quinases/imunologia , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação/imunologia , Plasmócitos/metabolismo , Proteína Tirosina Fosfatase não Receptora Tipo 6/imunologia , Proteína Tirosina Fosfatase não Receptora Tipo 6/metabolismo , Proteínas Tirosina Quinases/imunologia , Proteínas Tirosina Quinases/metabolismo , Proteína Proto-Oncogênica c-ets-1/deficiência , Proteína Proto-Oncogênica c-ets-1/genética , Receptores de Antígenos de Linfócitos B/deficiência , Receptores de Antígenos de Linfócitos B/genética , Receptores de Antígenos de Linfócitos B/metabolismo , Receptores de Superfície Celular/imunologia , Receptores de Superfície Celular/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Lectina 2 Semelhante a Ig de Ligação ao Ácido Siálico/deficiência , Lectina 2 Semelhante a Ig de Ligação ao Ácido Siálico/genética , Lectina 2 Semelhante a Ig de Ligação ao Ácido Siálico/imunologia , Lectinas Semelhantes a Imunoglobulina de Ligação ao Ácido Siálico , Transdução de Sinais/genética , Quinases da Família src/deficiência , Quinases da Família src/genética , Quinases da Família src/imunologia
18.
Blood ; 122(15): 2622-9, 2013 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-23974192

RESUMO

Most relapses in childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL) are not predicted using current prognostic features. Here, we determined the co-occurrence and independent prognostic relevance of 3 recently identified prognostic features: BCR-ABL1-like gene signature, deletions in IKZF1, and high CRLF2 messenger RNA expression (CRLF2-high). These features were determined in 4 trials representing 1128 children with ALL: DCOG ALL-8, ALL9, ALL10, and Cooperative ALL (COALL)-97/03. BCR-ABL1-like, IKZF1-deleted, and CRLF2-high cases constitute 33.7% of BCR-ABL1-negative, MLL wild-type BCP-ALL cases, of which BCR-ABL1-like and IKZF1 deletion (co)occurred most frequently. Higher cumulative incidence of relapse was found for BCR-ABL1-like and IKZF1-deleted, but not CRLF2-high, cases relative to remaining BCP-ALL cases, reflecting the observations in each of the cohorts analyzed separately. No relapses occurred among cases with CRLF2-high as single feature, whereas 62.9% of all relapses in BCR-ABL1-negative, MLL wild-type BCP-ALL occurred in cases with BCR-ABL1-like signature and/or IKZF1 deletion. Both the BCR-ABL1-like signature and IKZF1 deletions were prognostic features independent of conventional prognostic markers in a multivariate model, and both remained prognostic among cases with intermediate minimal residual disease. The BCR-ABL1-like signature and an IKZF1 deletion, but not CRLF2-high, are prognostic factors and are clinically of importance to identify high-risk patients who require more intensive and/or alternative therapies.


Assuntos
Proteínas de Fusão bcr-abl/genética , Fator de Transcrição Ikaros/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/epidemiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Receptores de Citocinas/genética , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Incidência , Lactente , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras B/epidemiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Valor Preditivo dos Testes , Prognóstico , Recidiva , Fatores de Risco
19.
Cleft Palate Craniofac J ; 52(5): 605-13, 2015 09.
Artigo em Inglês | MEDLINE | ID: mdl-25642966

RESUMO

OBJECTIVE: To determine the relationship between infant cleft size and dental arch relationship in the mixed dentition in patients with complete unilateral cleft lip and palate. DESIGN: Retrospective analysis of mixed longitudinal records. PATIENTS: A total of 29 consecutively enrolled patients with unilateral cleft lip and palate participated in a longitudinal study that included dental casts prior to lip surgery (T1: age 1 month), prior to palate surgery (T2: age 10 months), and in mixed dentition (T3: age 9 years). INTERVENTIONS: All infants were managed with lip repair (2.5 months), hard palate repair (12 months), and soft palate repair (16 months) but without any presurgical orthopedic treatment and no orthodontic intervention prior to mixed dentition records. MAIN OUTCOME MEASURES: The outcome measures included determination of an infant cleft severity ratio, defined as the ratio of palatal cleft area to palatal surface area, at both T1 and T2, and the 9-year-old (T3) dental arch relationship as determined using the GOSLON Yardstick. The correlation between the infant cleft severity ratio at T1 and T2 and the later GOSLON Yardstick score at T3 was determined using Pearson r. The intrarater reliability of the infant cleft severity ratio was assessed with Pearson r and the interrater reliability of the GOSLON Yardstick ratings, by weighted kappa. RESULTS: Reliability for the infant cleft severity ratio method was r = .92 to .95, and for GOSLON ratings κ = .81 to .91. There was no significant correlation between 1-month infant cleft severity ratio and GOSLON (r = .3) and 10-month infant cleft severity ratio and GOSLON (r = .1). CONCLUSIONS: Cleft size versus the amount of palatal tissue available for repair and concern over more scarring with a greater infant cleft severity ratio were not factors in affecting the eventual dental arch relationship.


Assuntos
Fenda Labial/patologia , Fissura Palatina/patologia , Arco Dental/anormalidades , Dentição Mista , Criança , Fenda Labial/cirurgia , Fissura Palatina/cirurgia , Feminino , Humanos , Lactente , Estudos Longitudinais , Masculino , Estudos Retrospectivos
20.
Blood ; 120(26): 5134-42, 2012 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-23091296

RESUMO

The P2RY8-CRLF2 fusion defines a particular relapse-prone subset of childhood acute lymphoblastic leukemia (ALL) in Italian Association of Pediatric Hematology and Oncology Berlin-Frankfurt-Münster (AIEOP-BFM) 2000 protocols. To investigate whether and to what extent different clone sizes influence disease and relapse development, we quantified the genomic P2RY8-CRLF2 fusion product and correlated it with the corresponding CRLF2 expression levels in patients enrolled in the BFM-ALL 2000 protocol in Austria. Of 268 cases without recurrent chromosomal translocations and high hyperdiploidy, representing approximately 50% of all cases, 67 (25%) were P2RY8-CRLF2 positive. The respective clone sizes were ≥ 20% in 27% and < 20% in 73% of them. The cumulative incidence of relapse of the entire fusion-positive group was clone size independent and significantly higher than that of the fusion-negative group (35% ± 8% vs 13% ± 3%, P = .008) and primarily confined to the non-high-risk group. Of 22 P2RY8-CRLF2-positive diagnosis/relapse pairs, only 4/8 had the fusion-positive dominant clone conserved at relapse, whereas none of the original 14 fusion-positive small clones reappeared as the dominant relapse clone. We conclude that the majority of P2RY8-CRLF2-positive clones are small at diagnosis and virtually never generate a dominant relapse clone. Our findings therefore suggest that P2RY8-CRLF2-positive clones do not have the necessary proliferative or selective advantage to evolve into a disease-relevant relapse clone.


Assuntos
Evolução Clonal/fisiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Receptores de Citocinas/fisiologia , Receptores Purinérgicos P2Y/fisiologia , Adolescente , Tamanho Celular , Criança , Pré-Escolar , Evolução Clonal/genética , Células Clonais/patologia , Estudos de Coortes , Progressão da Doença , Feminino , Regulação Leucêmica da Expressão Gênica/fisiologia , Humanos , Lactente , Masculino , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo , Proteínas de Fusão Oncogênica/fisiologia , Receptores de Citocinas/genética , Receptores de Citocinas/metabolismo , Receptores Purinérgicos P2Y/genética , Receptores Purinérgicos P2Y/metabolismo , Recidiva , Fatores de Tempo
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