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1.
Proc Natl Acad Sci U S A ; 118(13)2021 03 30.
Artigo em Inglês | MEDLINE | ID: mdl-33753490

RESUMO

A long-standing discrepancy exists between general circulation models (GCMs) and satellite observations: The multimodel mean temperature of the midtroposphere (TMT) in the tropics warms at approximately twice the rate of observations. Using a large ensemble of simulations from a single climate model, we find that tropical TMT trends (1979-2018) vary widely and that a subset of realizations are within the range of satellite observations. Realizations with relatively small tropical TMT trends are accompanied by subdued sea-surface warming in the tropical central and eastern Pacific. Observed changes in sea-surface temperature have a similar pattern, implying that the observed tropical TMT trend has been reduced by multidecadal variability. We also assess the latest generation of GCMs from the Coupled Model Intercomparison Project Phase 6 (CMIP6). CMIP6 simulations with muted warming over the central and eastern Pacific also show reduced tropical tropospheric warming. We find that 13% of the model realizations have tropical TMT trends within the observed trend range. These simulations are from models with both small and large climate sensitivity values, illustrating that the magnitude of tropical tropospheric warming is not solely a function of climate sensitivity. For global averages, one-quarter of model simulations exhibit TMT trends in accord with observations. Our results indicate that even on 40-y timescales, natural climate variability is important to consider when comparing observed and simulated tropospheric warming and is sufficiently large to explain TMT trend differences between models and satellite data.

2.
Proc Natl Acad Sci U S A ; 116(40): 19821-19827, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31527233

RESUMO

Large initial condition ensembles of a climate model simulation provide many different realizations of internal variability noise superimposed on an externally forced signal. They have been used to estimate signal emergence time at individual grid points, but are rarely employed to identify global fingerprints of human influence. Here we analyze 50- and 40-member ensembles performed with 2 climate models; each was run with combined human and natural forcings. We apply a pattern-based method to determine signal detection time [Formula: see text] in individual ensemble members. Distributions of [Formula: see text] are characterized by the median [Formula: see text] and range [Formula: see text], computed for tropospheric and stratospheric temperatures over 1979 to 2018. Lower stratospheric cooling-primarily caused by ozone depletion-yields [Formula: see text] values between 1994 and 1996, depending on model ensemble, domain (global or hemispheric), and type of noise data. For greenhouse-gas-driven tropospheric warming, larger noise and slower recovery from the 1991 Pinatubo eruption lead to later signal detection (between 1997 and 2003). The stochastic uncertainty [Formula: see text] is greater for tropospheric warming (8 to 15 y) than for stratospheric cooling (1 to 3 y). In the ensemble generated by a high climate sensitivity model with low anthropogenic aerosol forcing, simulated tropospheric warming is larger than observed; detection times for tropospheric warming signals in satellite data are within [Formula: see text] ranges in 60% of all cases. The corresponding number is 88% for the second ensemble, which was produced by a model with even higher climate sensitivity but with large aerosol-induced cooling. Whether the latter result is physically plausible will require concerted efforts to reduce significant uncertainties in aerosol forcing.


Assuntos
Aerossóis , Mudança Climática , Clima , Efeito Estufa , Atmosfera , Conservação dos Recursos Naturais , Geografia , Humanos , Análise dos Mínimos Quadrados , Ozônio , Reprodutibilidade dos Testes , Processamento de Sinais Assistido por Computador , Processos Estocásticos , Temperatura , Fatores de Tempo , Incerteza
3.
Proc Natl Acad Sci U S A ; 110(43): 17235-40, 2013 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-24043789

RESUMO

Since the late 1970s, satellite-based instruments have monitored global changes in atmospheric temperature. These measurements reveal multidecadal tropospheric warming and stratospheric cooling, punctuated by short-term volcanic signals of reverse sign. Similar long- and short-term temperature signals occur in model simulations driven by human-caused changes in atmospheric composition and natural variations in volcanic aerosols. Most previous comparisons of modeled and observed atmospheric temperature changes have used results from individual models and individual observational records. In contrast, we rely on a large multimodel archive and multiple observational datasets. We show that a human-caused latitude/altitude pattern of atmospheric temperature change can be identified with high statistical confidence in satellite data. Results are robust to current uncertainties in models and observations. Virtually all previous research in this area has attempted to discriminate an anthropogenic signal from internal variability. Here, we present evidence that a human-caused signal can also be identified relative to the larger "total" natural variability arising from sources internal to the climate system, solar irradiance changes, and volcanic forcing. Consistent signal identification occurs because both internal and total natural variability (as simulated by state-of-the-art models) cannot produce sustained global-scale tropospheric warming and stratospheric cooling. Our results provide clear evidence for a discernible human influence on the thermal structure of the atmosphere.


Assuntos
Atmosfera/química , Clima , Aquecimento Global , Temperatura , Simulação por Computador , Ecossistema , Humanos , Modelos Teóricos , Luz Solar , Erupções Vulcânicas
4.
Proc Natl Acad Sci U S A ; 110(1): 26-33, 2013 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-23197824

RESUMO

We perform a multimodel detection and attribution study with climate model simulation output and satellite-based measurements of tropospheric and stratospheric temperature change. We use simulation output from 20 climate models participating in phase 5 of the Coupled Model Intercomparison Project. This multimodel archive provides estimates of the signal pattern in response to combined anthropogenic and natural external forcing (the fingerprint) and the noise of internally generated variability. Using these estimates, we calculate signal-to-noise (S/N) ratios to quantify the strength of the fingerprint in the observations relative to fingerprint strength in natural climate noise. For changes in lower stratospheric temperature between 1979 and 2011, S/N ratios vary from 26 to 36, depending on the choice of observational dataset. In the lower troposphere, the fingerprint strength in observations is smaller, but S/N ratios are still significant at the 1% level or better, and range from three to eight. We find no evidence that these ratios are spuriously inflated by model variability errors. After removing all global mean signals, model fingerprints remain identifiable in 70% of the tests involving tropospheric temperature changes. Despite such agreement in the large-scale features of model and observed geographical patterns of atmospheric temperature change, most models do not replicate the size of the observed changes. On average, the models analyzed underestimate the observed cooling of the lower stratosphere and overestimate the warming of the troposphere. Although the precise causes of such differences are unclear, model biases in lower stratospheric temperature trends are likely to be reduced by more realistic treatment of stratospheric ozone depletion and volcanic aerosol forcing.


Assuntos
Atmosfera , Mudança Climática , Atividades Humanas , Modelos Teóricos , Temperatura , Simulação por Computador , Geografia , Humanos , Razão Sinal-Ruído
5.
Blood ; 121(25): 5068-77, 2013 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-23632888

RESUMO

Granulocyte-macrophage-colony-stimulating factor (GM-CSF) hypersensitivity is a hallmark of juvenile myelomonocytic leukemia (JMML) but has not been systematically shown in the related human disease chronic myelomonocytic leukemia (CMML). We find that primary CMML samples demonstrate GM-CSF-dependent hypersensitivity by hematopoietic colony formation assays and phospho-STAT5 (pSTAT5) flow cytometry compared with healthy donors. Among CMML patients, the pSTAT5 hypersensitive response positively correlated with high-risk disease, peripheral leukocytes, monocytes, and signaling-associated mutations. When compared with IL-3 and G-CSF, GM-CSF hypersensitivity was cytokine specific and thus a possible target for intervention in CMML. To explore this possibility, we treated primary CMML cells with KB003, a novel monoclonal anti-GM-CSF antibody, and JAK2 inhibitors. We found that an elevated proportion of immature GM-CSF receptor-α(R) subunit-expressing cells were present in the bone marrow myeloid compartment of CMML. In survival assays, we found that myeloid and monocytic progenitors were sensitive to GM-CSF signal inhibition. Our data indicate that a committed myeloid precursor expressing CD38 may represent the progenitor population with enhanced GM-CSF dependence in CMML, consistent with results in JMML. These preclinical data indicate that GM-CSF signaling inhibitors merit further investigation in CMML and that GM-CSFR expression on myeloid progenitors may be a biomarker for this therapy.


Assuntos
Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Leucemia Mielomonocítica Crônica/metabolismo , Fator de Transcrição STAT5/metabolismo , Citometria de Fluxo , Humanos , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/metabolismo , Ressonância de Plasmônio de Superfície
7.
Cancer Immunol Immunother ; 61(4): 523-33, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21983879

RESUMO

Large granular lymphocyte (LGL) leukemia is a chronic lymphoproliferative disease in which T-bet [T-box transcription factor 21 gene (tbx21)] overexpression may play a pathogenic role. T-bet orchestrates the differentiation of mature peripheral T-cells into interferon-γ (IFN-γ) and tumor necrosis factor-α producing CD4+ T-helper type I (Th1) and CD8+ T cytotoxic cells that are necessary for antiviral responses. When IL-12 is produced by antigen-presenting cells, T-bet expression is induced, causing direct stimulation of ifng gene transcription while simultaneously acting as a transcriptional repressor of the IL4 gene, which then leads to Th1 dominance and T-helper type 2 differentiation blockade. Additionally, T-bet has been shown to regulate histone acetylation of the ifng promoter and enhancer to loosen condensed DNA, creating greater accessibility for other transcription factor binding, which further amplifies IFNγ production. We found that treatment with a farnesyltransferase inhibitor tipifarnib reduced Th1 cytokines in LGL leukemia patient T-cells and blocked T-bet protein expression and IL-12 responsiveness in T-cells from healthy donors. The mechanism of suppression was based on modulation of histone acetylation of the ifng gene, which culminated in Th1 blockade.


Assuntos
Antineoplásicos/farmacologia , Farnesiltranstransferase/antagonistas & inibidores , Leucemia Linfocítica Granular Grande/imunologia , Quinolonas/farmacologia , Proteínas com Domínio T/metabolismo , Células Th1/efeitos dos fármacos , Células Th2/efeitos dos fármacos , Acetilação/efeitos dos fármacos , Adulto , Idoso , Citocinas/genética , Citocinas/imunologia , Citocinas/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Terapia de Imunossupressão , Leucemia Linfocítica Granular Grande/patologia , Masculino , Pessoa de Meia-Idade , Transdução de Sinais/efeitos dos fármacos , Proteínas com Domínio T/genética , Células Th1/imunologia , Células Th1/metabolismo , Células Th1/patologia , Equilíbrio Th1-Th2/efeitos dos fármacos , Células Th2/imunologia , Células Th2/metabolismo , Células Th2/patologia
8.
J Mol Diagn ; 24(3): 219-223, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35041928

RESUMO

The U2AF1 gene is a core part of mRNA splicing machinery and frequently contains somatic mutations that contribute to oncogenesis in myelodysplastic syndrome, acute myeloid leukemia, and other cancers. A change introduced in the GRCh38 version of the human reference build prevents detection of mutations in this gene, and others, by variant calling pipelines. This study describes the problem in detail and shows that a modified GRCh38 reference build with unchanged coordinates can be used to ameliorate the issue.


Assuntos
Leucemia Mieloide Aguda , Humanos , Leucemia Mieloide Aguda/genética , Mutação , Fator de Processamento U2AF/genética
9.
Blood ; 113(14): 3226-34, 2009 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-19075187

RESUMO

Large granular lymphocyte (LGL) leukemia, or LGLL, is characterized by increased numbers of circulating clonal LGL cells in association with neutropenia, anemia, rheumatoid arthritis, and pulmonary artery hypertension (PAH). Emerging evidence suggests that LGLL cells with a CD8(+)CD28(null) phenotype induce these clinical manifestations through direct destruction of normal tissue. Compared with CD8(+)CD28(null) T cells from healthy controls, CD8(+)CD28(null) T cells from LGLL patients have acquired the ability to directly lyse pulmonary artery endothelial cells and human synovial cells. Here, we show that LGLL cells from patients possess enhanced cytotoxic characteristics and express elevated levels of activating natural killer receptors as well as their signaling partners, DAP10 and DAP12. Moreover, downstream targets of DAP10 and DAP12 are constitutively activated in LGLL cells, and expression of dominant-negative DAP10 and DAP12 dramatically reduces their lytic capacity. These are the first results to show that activating NKR-ligand interactions play a critical role in initiating the DAP10 and DAP12 signaling events that lead to enhanced lytic potential of LGLL cells. Results shown suggest that inhibitors of DAP10 and DAP12 or other proteins involved in this signaling pathway will be attractive therapeutic targets for the treatment of LGLL and other autoimmune diseases and syndromes.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/fisiologia , Linfócitos T CD8-Positivos/imunologia , Citotoxicidade Imunológica/genética , Leucemia Linfocítica Granular Grande/imunologia , Proteínas de Membrana/fisiologia , Receptores Imunológicos/fisiologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Antígenos CD28/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Linfócitos T CD8-Positivos/patologia , Células Endoteliais/imunologia , Células Endoteliais/patologia , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Humanos , Células K562 , Leucemia Linfocítica Granular Grande/genética , Leucemia Linfocítica Granular Grande/metabolismo , Leucemia Linfocítica Granular Grande/patologia , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Artéria Pulmonar/imunologia , Artéria Pulmonar/patologia , Receptores Imunológicos/genética , Receptores Imunológicos/metabolismo , Receptores de Células Matadoras Naturais/metabolismo , Transdução de Sinais/genética , Células Tumorais Cultivadas
11.
Blood ; 112(12): 4694-8, 2008 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-18791165

RESUMO

Large granular lymphocyte (LGL) leukemia is commonly associated with poor hematopoiesis. The first case of pulmonary artery hypertension (PAH) was observed in a 57-year-old woman with natural killer (NK)-LGL leukemia and transfusion-dependent anemia. Using a genetic approach, we demonstrated that killing of pulmonary endothelial cells by patient NK cells was mediated by dysregulated balance in activating and inhibitory NK-receptor signaling. Elevated pulmonary artery pressure and erythroid differentiation improved after disrupting the NK-receptor signaling pathway with 4 courses of a farnesyltransferase inhibitor, tipifarnib. Coincidental association between PAH and LGL leukemia suggest a causal relationship between the expanded lymphocyte population and these clinical manifestations. This trial is registered at www.ClinicalTrials.gov as NCI 6823.


Assuntos
Antineoplásicos/uso terapêutico , Farnesiltranstransferase/antagonistas & inibidores , Leucemia Linfocítica Granular Grande/tratamento farmacológico , Receptores de Células Matadoras Naturais/genética , Células Cultivadas , Inibidores Enzimáticos/uso terapêutico , Feminino , Humanos , Hipertensão Pulmonar/tratamento farmacológico , Hipertensão Pulmonar/etiologia , Células K562 , Leucemia Linfocítica Granular Grande/complicações , Leucemia Linfocítica Granular Grande/genética , Pessoa de Meia-Idade , Quinolonas/uso terapêutico , Transdução de Sinais/genética , Resultado do Tratamento
12.
Science ; 361(6399)2018 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-30026201

RESUMO

We provide scientific evidence that a human-caused signal in the seasonal cycle of tropospheric temperature has emerged from the background noise of natural variability. Satellite data and the anthropogenic "fingerprint" predicted by climate models show common large-scale changes in geographical patterns of seasonal cycle amplitude. These common features include increases in amplitude at mid-latitudes in both hemispheres, amplitude decreases at high latitudes in the Southern Hemisphere, and small changes in the tropics. Simple physical mechanisms explain these features. The model fingerprint of seasonal cycle changes is identifiable with high statistical confidence in five out of six satellite temperature datasets. Our results suggest that attribution studies with the changing seasonal cycle provide powerful evidence for a significant human effect on Earth's climate.


Assuntos
Mudança Climática , Atividades Humanas , Estações do Ano , Temperatura , Humanos , Imagens de Satélites
13.
Sci Rep ; 7(1): 2336, 2017 05 24.
Artigo em Inglês | MEDLINE | ID: mdl-28539644

RESUMO

Satellite temperature measurements do not support the recent claim of a "leveling off of warming" over the past two decades. Tropospheric warming trends over recent 20-year periods are always significantly larger (at the 10% level or better) than model estimates of 20-year trends arising from natural internal variability. Over the full 38-year period of the satellite record, the separation between observed warming and internal variability estimates is even clearer. In two out of three recent satellite datasets, the tropospheric warming from 1979 to 2016 is unprecedented relative to internally generated temperature trends on the 38-year timescale.

14.
Cancer Res ; 63(22): 7900-6, 2003 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-14633719

RESUMO

Cancer cell adhesion confers a transient, de novo drug-resistant phenotype referred to as cell adhesion-mediated drug resistance (CAM-DR). In this report, we extend the CAM-DR phenotype to primary specimens from patients with myeloma, providing further evidence that CAM-DR is a viable clinical form of drug resistance. To examine mechanisms of cellular resistance to melphalan, we compared genotypic and phenotypic profiles of acquired and de novo melphalan resistance in an isogenic human myeloma cell line. Acquired melphalan resistance (8226/LR5) was associated with decreased drug-induced DNA damage and a complex gene expression profile showing that genes involved in the Fanconi anemia DNA repair pathway are increased in the LR5 cells compared with drug-sensitive or adherent cells. In contrast, cells adhered to fibronectin accumulate similar amounts of DNA damage compared with drug-sensitive cells but are protected from melphalan-induced mitochondrial perturbations and caspase activation. Levels of the proapoptotic protein Bim were significantly reduced in adherent cells. Gene expression changes associated with de novo resistance were significantly less complex compared with acquired resistance, but a significant overlap in gene expression was noted involving cholesterol synthesis. We propose that myeloma cell adhesion promotes a form of de novo drug resistance by protecting cells from melphalan-induced cytotoxic damage and that this transient protection allows cells to acquire a more permanent and complex drug resistance phenotype associated with a reduction in drug induced DNA damage.


Assuntos
Antineoplásicos Alquilantes/farmacologia , Melfalan/farmacologia , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/patologia , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Caspases/metabolismo , Adesão Celular/fisiologia , Linhagem Celular Tumoral , Dano ao DNA , Resistencia a Medicamentos Antineoplásicos , Ativação Enzimática , Fibronectinas/metabolismo , Perfilação da Expressão Gênica , Humanos , Isoenzimas/metabolismo , Mitocôndrias/fisiologia , Mieloma Múltiplo/genética , Análise de Sequência com Séries de Oligonucleotídeos
15.
Oncogene ; 23(57): 9220-9, 2004 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-15516985

RESUMO

Chronic NK lymphoproliferative disease of large granular lymphocytes (LDGL) is characterized by the expansion of activated CD3-, CD16+ or CD56+ lymphocytes. The mechanism of survival of NK cells from LDGL patients is unknown but may be related to antigenic stimulation. There is currently no standard effective therapy for LDGL, and the disease is characteristically resistant to standard forms of chemotherapy. We found evidence of constitutive activation of extracellular-regulated kinase (ERK) in NK cells from 13/13 patients with NK-LDGL (one patient with aggressive and 12 patients with chronic disease). Ablation of ERK activity by inhibitors or a dominant-negative form of MEK, the upstream activator of ERK, reduced the survival of patient NK cells. Ras was also constitutively active in patient NK cells, and exposure of cells to the Ras inhibitor FTI2153 or to dominant-negative-Ras resulted not only in ERK inhibition but also in enhanced apoptosis in both the presence and absence of anti-Fas. Therefore, we conclude that a constitutively active Ras/MEK/ERK pathway contributes to the accumulation of NK cells in patients with NK-LDGL. These findings suggest that strategies to inhibit this signaling pathway may be useful for the treatment of the NK type of LDGL.


Assuntos
Células Matadoras Naturais/citologia , Linfócitos/citologia , Transtornos Linfoproliferativos/patologia , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Western Blotting , Sobrevivência Celular , Humanos , Imunofenotipagem , Transtornos Linfoproliferativos/imunologia
16.
Leuk Lymphoma ; 52(8): 1528-36, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21635204

RESUMO

The relationship between telomere length (TL) and predisposition to myelodysplastic syndromes (MDS) remains unclear. We compared peripheral blood leukocyte (PBL) TL among cases of histologically confirmed MDS (n = 65) who were treatment-naive with no prior cancer history to age-matched controls (n = 63). Relative TL was measured in PBLs and saliva by quantitative polymerase chain reaction (PCR) and in CD15+ and CD19+ cells by flow cytometry-fluorescence in situ hybridization (flow-FISH). Human telomerase reverse transcriptase gene (hTERT) mutations were assessed by PCR. After adjustment for age and sex, relative TLs were reduced in PBLs (p = 0.02), CD15+ (p = 0.01), CD19+ (p = 0.25), and saliva (p = 0.13) in MDS cases versus controls, although only the PBL and CD15+ results were statistically significant. Among MDS cases, CD15+ and CD19+ cell TLs were positively correlated (p = 0.03). PBL TL was reduced among those occupationally exposed to paints and pesticides, but was not associated with hTERT genotype. Future studies are needed to further investigate constitutional telomere attrition as a possible predisposing factor for MDS.


Assuntos
Mutação , Síndromes Mielodisplásicas/genética , Telomerase/genética , Telômero/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos CD19/sangue , Estudos de Casos e Controles , Feminino , Citometria de Fluxo , Frequência do Gene , Genótipo , Humanos , Hibridização in Situ Fluorescente , Leucócitos/metabolismo , Antígenos CD15/sangue , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/enzimologia , Síndromes Mielodisplásicas/patologia , Pintura/intoxicação , Praguicidas/intoxicação , Reação em Cadeia da Polimerase , Saliva/metabolismo , Telômero/efeitos dos fármacos , Adulto Jovem
17.
Blood ; 111(3): 1610-6, 2008 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-17993614

RESUMO

Clonal T-cell expansion in patients with T-large-granular lymphocyte (LGL) leukemia occurs by an undefined mechanism that may be related to Fas apoptosis resistance. Here, we demonstrate polarized expansion of CD8(+) terminal-memory differentiation in such patients, as demonstrated by CD45RA expression and absence of CD62L expression, suggesting repeated stimulation by antigen in vivo. Elimination of antigen-stimulated T cells normally occurs through Fas-mediated apoptosis. We show that cells from LGL leukemia patients express increased levels of c-FLIP and display resistance to Fas-mediated apoptosis and abridged recruitment of proteins that comprise the death-inducing signaling complex (DISC), including the Fas-associated protein with death-domain (FADD) and caspase-8. Exposure to interleukin-2 (IL-2) for only 24 hours sensitized leukemic LGL to Fas-mediated apoptosis with enhanced formation of the DISC, and increased caspase-8 and caspase-3 activities. We observed dysregulation of c-FLIP by IL-2 in leukemic LGL, suggesting a role in Fas resistance. Our results demonstrate that expanded T cells in patients with LGL leukemia display both functional and phenotypic characteristics of prior antigen activation in vivo and display reduced capacity for Fas-mediated DISC formation.


Assuntos
Apoptose , Leucemia Linfocítica Granular Grande/metabolismo , Leucemia Linfocítica Granular Grande/patologia , Transdução de Sinais , Receptor fas/metabolismo , Apoptose/efeitos dos fármacos , Antígenos CD8/imunologia , Células Cultivadas , Humanos , Memória Imunológica/imunologia , Interleucina-2/farmacologia , Leucemia Linfocítica Granular Grande/imunologia , Fenótipo , Ligação Proteica , Receptores de Antígenos de Linfócitos T/metabolismo , Sensibilidade e Especificidade , Regulação para Cima/efeitos dos fármacos
18.
Blood ; 109(11): 4816-24, 2007 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-17341666

RESUMO

Myelodysplastic syndromes (MDS) are characterized by ineffective hematopoiesis with potential for progression to acute myeloid leukemia (AML). We compared natural killer (NK) cytolytic function in 48 MDS patients with 37 healthy donors and found reduced activity in the patient population (K562 cytolysis, 19% +/- 21% SD versus 40% +/- 17%) (P < .001). NK cytotoxicity in MDS patients was reduced against 3 disparate tumor targets with differential activating receptor requirement, suggesting global defects in NK function. Reduced NK function in MDS was significantly associated with higher International Prognostic Score (P = .01), abnormal karyotype (P = .05), the presence of excess blasts (P = .01), and age-adjusted bone marrow hypercellularity (P = .04). MDS patients had a display of the activating receptor NKp30, and NKG2D down-regulation closely correlated with impaired NK function (P = .001). NKG2D ligands (MICA and MICB) were expressed on CD34(+) cells from bone marrow of 30% of MDS patients and a leukemic cell line derived from an MDS patient (MDS1). Collectively, these findings suggest that impairment of NK cytolytic function derives in part from reduced activating NK receptors such as NKG2D in association with disease progression. Evasion of NK immunosurveillance may have importance for MDS disease progression.


Assuntos
Regulação Neoplásica da Expressão Gênica , Células Matadoras Naturais/citologia , Síndromes Mielodisplásicas/sangue , Síndromes Mielodisplásicas/metabolismo , Idoso , Idoso de 80 Anos ou mais , Antígenos CD34/biossíntese , Células da Medula Óssea/citologia , Progressão da Doença , Feminino , Humanos , Células K562 , Células Matadoras Naturais/metabolismo , Leucemia Mieloide Aguda/metabolismo , Masculino , Pessoa de Meia-Idade , Lesões Pré-Cancerosas
19.
Blood ; 103(9): 3431-9, 2004 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-14726391

RESUMO

The natural killer (NK) type of lymphoproliferative disease of granular lymphocytes (LDGL) is associated with the expansion of CD3(-), CD16(+), and/or CD56(+) lymphocytes. We have examined the repertoire of NK receptors expressed on these cells and delineated the functional activity. We found skewed NK receptor expression on patient NK cells. Reactivity to a single anti-killer cell immunoglobulin-like receptor (anti-KIR) antibody was noted in 7 of 13 patients. LDGL patients variably expressed NKp30, NKp44, and NKp46 RNA. In contrast, CD94 and its inhibitory heterodimerization partner NKG2A were homogeneously expressed at high levels on these NK cells. Interestingly, these patients expressed a large number of activating KIR receptors by genotype analysis. Semiquantitative reverse transcriptase-polymerase chain reaction (RT-PCR) demonstrated that lower than normal levels of RNA of the inhibitory KIR was present in some patients in contrast to normal NK cells. Consistent with a high level of activating receptors, we found the NK-LDGL cells have potent cytolytic function in both direct and redirected cytotoxicity assays. These results demonstrate that patients with NK-LDGL have an increased activating-to-inhibitory KIR ratio. This altered ratio might induce inappropriate lysis or cytokine production and impact the disease pathogenesis.


Assuntos
Granulócitos/patologia , Células Matadoras Naturais/patologia , Transtornos Linfoproliferativos/patologia , Receptores Imunológicos/análise , Antígenos CD/análise , Estudos de Casos e Controles , Citotoxicidade Imunológica , Genótipo , Granulócitos/imunologia , Humanos , Células Matadoras Naturais/imunologia , Lectinas Tipo C/análise , Transtornos Linfoproliferativos/imunologia , Subfamília C de Receptores Semelhantes a Lectina de Células NK , Subfamília D de Receptores Semelhantes a Lectina de Células NK , Receptor 1 Desencadeador da Citotoxicidade Natural , Receptor 2 Desencadeador da Citotoxicidade Natural , Receptor 3 Desencadeador da Citotoxicidade Natural , RNA Mensageiro/análise , Receptores de Células Matadoras Naturais
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