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1.
J Hematol ; 12(1): 49-58, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36895289

RESUMO

The clinicopathology entity of plasmablastic lymphoma (PBL), despite broad recognition by the World Health Organization (WHO), represents a diagnostic challenge due to its overlapping features and scarce occurrence. Often, PBL arises in immunodeficient, elderly male patients, most notably those who are human immunodeficiency virus (HIV)-positive. More infrequent, cases of transformed PBL (tPBL) evolved from another hematologic disease have been identified. Herein, we describe a case of a 65-year-old male transferred from a neighboring hospital with pronounced lymphocytosis and spontaneous tumor lysis syndrome (sTLS) presumed to be chronic lymphocytic leukemia (CLL). Utilizing a complete clinical, morphologic, immunophenotypic, and molecular evaluation, we arrived at a final diagnosis of tPBL with sTLS, suspected to have evolved from the NF-κB/NOTCH/KLF2 (NNK) genetic cluster of splenic marginal zone lymphoma (SMZL) (NNK-SMZL), a potential transformation and presentation, to our knowledge, not previously reported. However, definitive clonality testing was not performed. In this report, we also outline the diagnostic and educational considerations we faced in discerning tPBL from other more common B-cell malignancies which can present similarly, such as CLL, mantle cell lymphoma, or plasmablastic myeloma. We summarize recently reported molecular, prognostic, and therapeutic considerations for the treatment and recognition of PBL, including the successful implementation, in our patient, of bortezomib to an EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin) regimen with prophylactic intrathecal methotrexate, who has since achieved complete remission (CR) and entered clinical surveillance. Lastly, this report briefly highlights the challenge we faced in this area of hematologic typification that necessitates additional review and discussion by the WHO: tPBL with potential double-hit cytogenetic versus double-hit lymphoma with a plasmablastic phenotype.

2.
Mol Cell Proteomics ; 21(5): 100225, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35331917

RESUMO

Nonalcoholic steatohepatitis (NASH) is the progressive form of nonalcoholic fatty liver disease (NAFLD) and is characterized by inflammation, hepatocyte injury, and fibrosis. Further, NASH is a risk factor for cirrhosis and hepatocellular carcinoma. Previous research demonstrated that serum N-glycan profiles can be altered in NASH patients. Here, we hypothesized that these N-glycan modifications may be associated with specific liver damage in NAFLD and NASH. To investigate the N-glycome profile in tissue, imaging mass spectrometry was used for a qualitative and quantitative in situ N-linked glycan analysis of mouse and human NAFLD/NASH tissue. A murine model was used to induce NAFLD and NASH through ad libitum feeding with either a high-fat diet or a Western diet, respectively. Mice fed a high-fat diet or Western diet developed inflammation, steatosis, and fibrosis, consistent with NAFLD/NASH phenotypes. Induction of NAFLD/NASH for 18 months using high caloric diets resulted in increased expression of mannose, complex/fucosylated, and hybrid N-glycan structures compared to control mouse livers. To validate the animal results, liver biopsy specimens from 51 human NAFLD/NASH patients representing the full range of NASH Clinical Research Network fibrosis stages were analyzed. Importantly, the same glycan alterations observed in mouse models were observed in human NASH biopsies and correlated with the degree of fibrosis. In addition, spatial glycan alterations were localized specifically to histopathological changes in tissue like fibrotic and fatty areas. We demonstrate that the use of standard staining's combined with imaging mass spectrometry provide a full profile of the origin of N-glycan modifications within the tissue. These results indicate that the spatial distribution of abundances of released N-glycans correlate with regions of tissue steatosis associated with NAFLD/NASH.


Assuntos
Neoplasias Hepáticas , Hepatopatia Gordurosa não Alcoólica , Animais , Dieta Ocidental , Modelos Animais de Doenças , Glicosilação , Humanos , Inflamação/metabolismo , Fígado/metabolismo , Cirrose Hepática/genética , Cirrose Hepática/metabolismo , Cirrose Hepática/patologia , Neoplasias Hepáticas/metabolismo , Espectrometria de Massas , Camundongos , Hepatopatia Gordurosa não Alcoólica/metabolismo
3.
Hepatology ; 73(3): 1088-1104, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-32557834

RESUMO

BACKGROUND AND AIMS: Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), caused by autoimmune regulator (AIRE) mutations, manifests with chronic mucocutaneous candidiasis (CMC) and multisystem autoimmunity, most often hypoparathyroidism (HP) and adrenal insufficiency (AI). European cohorts previously reported a ~10% prevalence of APECED-associated hepatitis (APAH) with presentations ranging from asymptomatic laboratory derangements to fatal fulminant hepatic failure. Herein, we characterized APAH in a large APECED cohort from the Americas. APPROACH AND RESULTS: Forty-five consecutive patients with APECED were evaluated (2013-2015) at the National Institutes of Health (NIH; NCT01386437). Hepatology consultation assessed hepatic and autoimmune biomarkers and liver ultrasound in all patients. Liver biopsies evaluated autoimmune features and fibrosis. The 16S ribosomal RNA (rRNA) sequencing was performed in 35 patients' stools (12 with and 23 without APAH). Among 43 evaluable patients, 18 (42%) had APAH; in 33.3% of those with APAH, APAH occurred before developing classic APECED diagnostic criteria. At APAH diagnosis, the median age was 7.8 years, and patients manifested with aminotransferase elevation and/or hyperbilirubinemia. All patients with APAH were in clinical remission during their NIH evaluation while receiving immunomodulatory treatment. We found no difference in age, sex, or prevalence of CMC, AI, or HP between patients with or without APAH. Autoantibody positivity against aromatic L-amino acid decarboxylase, cytochrome P450 family 1 subfamily A member 2, histidine decarboxylase (HDC), bactericidal/permeability-increasing fold-containing B1, tryptophan hydroxlase, and 21-hydroxylase (21-OH), and the homozygous c.967_979del13 AIRE mutation were associated with APAH development. Classical serological biomarkers of autoimmune hepatitis (AIH) were only sporadically positive. AIH-like lymphoplasmacytic inflammation with mild fibrosis was the predominant histological feature. Stool microbiome analysis found Slackia and Acidaminococcus in greater abundance in patients with APAH. CONCLUSIONS: APAH is more common than previously described, may present early before classic APECED manifestations, and most often manifests with milder, treatment-responsive disease. Several APECED-associated autoantibodies, but not standard AIH-associated biomarkers, correlate with APAH.


Assuntos
Hepatite Autoimune/etiologia , Poliendocrinopatias Autoimunes/complicações , Adolescente , Adulto , América , Autoanticorpos/imunologia , Biomarcadores/sangue , Biópsia , Feminino , Deleção de Genes , Hepatite Autoimune/patologia , Hepatite Autoimune/terapia , Humanos , Imunoterapia , Fígado/patologia , Cirrose Hepática/etiologia , Cirrose Hepática/patologia , Masculino , Poliendocrinopatias Autoimunes/genética , Poliendocrinopatias Autoimunes/patologia , Poliendocrinopatias Autoimunes/terapia , Adulto Jovem
4.
J Clin Invest ; 127(3): 830-842, 2017 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-28134624

RESUMO

Disruption of the retinoblastoma (RB) tumor suppressor pathway, either through genetic mutation of upstream regulatory components or mutation of RB1 itself, is believed to be a required event in cancer. However, genetic alterations in the RB-regulated E2F family of transcription factors are infrequent, casting doubt on a direct role for E2Fs in driving cancer. In this work, a mutation analysis of human cancer revealed subtle but impactful copy number gains in E2F1 and E2F3 in hepatocellular carcinoma (HCC). Using a series of loss- and gain-of-function alleles to dial E2F transcriptional output, we have shown that copy number gains in E2f1 or E2f3b resulted in dosage-dependent spontaneous HCC in mice without the involvement of additional organs. Conversely, germ-line loss of E2f1 or E2f3b, but not E2f3a, protected mice against HCC. Combinatorial mapping of chromatin occupancy and transcriptome profiling identified an E2F1- and E2F3B-driven transcriptional program that was associated with development and progression of HCC. These findings demonstrate a direct and cell-autonomous role for E2F activators in human cancer.


Assuntos
Carcinoma Hepatocelular , Fator de Transcrição E2F1 , Fator de Transcrição E2F3 , Dosagem de Genes , Genes Neoplásicos , Neoplasias Hepáticas , Proteínas de Neoplasias , Animais , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Fator de Transcrição E2F1/genética , Fator de Transcrição E2F1/metabolismo , Fator de Transcrição E2F3/genética , Fator de Transcrição E2F3/metabolismo , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Camundongos , Camundongos Knockout , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo
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