RESUMEN
Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma and is a potentially curable disease. However, it is heterogenous, and the prognosis is poor if the tumor cells harbor fusions involving MYC and BCL2 or MYC and BCL6 (double-hit [DH] lymphoma), or fusions involving all three genes (triple-hit [TH] lymphoma). Fluorescence in situ hybridization is currently the gold standard for confirming the presence of DH/TH genotypes. However, the test is laborious and not readily available in some laboratories. Germinal center B (GCB) signatures and dual expression of MYC and BCL2 are commonly used as initial screening markers (traditional model) in clinical practice. Our study proposes immunohistochemical markers for more conveniently and accessibly screening DH/TH genotypes in DLBCL. We retrospectively reviewed the clinical and pathological parameters of patients with DLBCL. We assessed the proliferative index, apoptotic index, and tumor microenvironment (TME), with regard to T cells and CD11c(+) dendritic cells, in formalin-fixed paraffin-embedded tissue. We then generated a decision tree as a screening algorithm to predict DH/TH genotypes and employed decision curve analysis to demonstrate the superiority of this new model in prediction. We also assessed the prognostic significance of related parameters. Our study revealed that GCB subtypes, a Ki67 proliferative index higher than 70%, and BCL2 expression were significantly associated with DH/TH genotypes. Decreased CD11c(+) dendritic cells in the TME indicated additional risk. Our proposed screening algorithm outperformed a traditional model in screening for the DH/TH genotypes. In addition, decreased CD11c(+) dendritic cells in the DLBCL TME were an independent unfavorable prognosticator. In conclusion, we provide a convenient, well-performing model that predicts DH/TH genotypes in DLBCL. The prognostic significance of CD11c(+) dendritic cells in the TME might influence the classification and development of immunotherapy for DLBCL in the future.
Asunto(s)
Antígeno CD11c , Células Dendríticas , Linfoma de Células B Grandes Difuso , Proteínas Proto-Oncogénicas , Microambiente Tumoral , Algoritmos , Antígeno CD11c/genética , Antígeno CD11c/metabolismo , Supervivencia Celular , Células Dendríticas/metabolismo , Células Dendríticas/patología , Genotipo , Humanos , Hibridación Fluorescente in Situ , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/genética , Linfoma de Células B Grandes Difuso/mortalidad , Linfoma de Células B Grandes Difuso/patología , Modelos Biológicos , Fusión de Oncogenes/genética , Fusión de Oncogenes/fisiología , Pronóstico , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Proteínas Proto-Oncogénicas c-bcl-6/genética , Proteínas Proto-Oncogénicas c-bcl-6/metabolismo , Proteínas Proto-Oncogénicas c-myc/genética , Proteínas Proto-Oncogénicas c-myc/metabolismo , Estudios Retrospectivos , Análisis de Supervivencia , Microambiente Tumoral/genética , Microambiente Tumoral/fisiologíaRESUMEN
Early recognition of adult-onset immunodeficiency associated with neutralizing anti-interferon gamma autoantibodies (anti-IFNγ Abs) remains difficult, and misdiagnoses have been reported. Although febrile lymphadenopathy is among the most common initial manifestations of this disorder, no comprehensive clinicopathologic analysis of lymphadenopathy in patients with anti-IFNγ Abs has been reported. Here, we describe 26 lymph node biopsy specimens from 16 patients. All patients exhibited concurrent disseminated nontuberculous mycobacterial infections, and 31% received a tentative diagnosis of lymphoma at initial presentation. We found 3 distinct histomorphologic patterns: well-formed granuloma (46%), suppurative inflammation or loose histiocytic aggregates (31%), and lymphoproliferative disorder (LPD, 23%). The latter shared some of the features of malignant T-cell lymphoma, IgG4-related disease, and multicentric Castleman disease. Half of the specimens with LPD had monoclonal T cells, and 33.3% were indistinguishable from angioimmunoblastic T-cell lymphoma as per current diagnostic criteria. All lymphadenopathy with LPD features regressed with antibiotics without administration of cytotoxic chemotherapy or immunotherapy. The median follow-up time was 4.3 years. Our study highlights the substantial challenge of distinguishing between lymphoma and other benign lymphadenopathy in the setting of neutralizing anti-IFNγ Abs. Increased vigilance and multidisciplinary discussion among clinicians and pathologists are required to achieve the most appropriate diagnosis and management.
Asunto(s)
Síndromes de Inmunodeficiencia/diagnóstico , Linfadenopatía/diagnóstico , Linfoma/diagnóstico , Linfocitos T/inmunología , Adulto , Anciano , Antibacterianos , Anticuerpos Neutralizantes , Autoanticuerpos/inmunología , Autoantígenos/inmunología , Proliferación Celular , Femenino , Humanos , Síndromes de Inmunodeficiencia/inmunología , Síndromes de Inmunodeficiencia/patología , Interferón gamma/inmunología , Ganglios Linfáticos/patología , Linfadenopatía/inmunología , Linfadenopatía/patología , Linfoma/inmunología , Linfoma/patología , Masculino , Persona de Mediana Edad , Infecciones Oportunistas/inmunología , Infecciones Oportunistas/patologíaRESUMEN
OBJECTIVE: Palladin is a ubiquitous phosphoprotein expressed in vertebrate cells that works as a scaffolding protein. Several isoforms deriving from alternative splicing are originated from the palladin gene and involved in mesenchymal and muscle cells formation, maturation, migration, and contraction. Recent studies have linked palladin to the invasive spread of cancer and myogenesis. However, since its discovery, the promoter region of the palladin gene has never been studied. The objective of this study was to predict, identify, and measure the activity of the promoter regions of palladin gene. RESULTS: By using promoter prediction programs, we successfully identified the transcription start sites for the Palld isoforms and revealed the presence of a variety of transcriptional regulatory elements including TATA box, GATA, MyoD, myogenin, MEF, Nkx2-5, and Tcf3 upstream promoter regions. The transcriptome profiling approach confirmed the active role of predicted transcription factors in the mouse genome. This study complements the missing piece in the characterization of palladin gene and certainly contributes to understanding the complexity and enrollment of palladin regulatory factors in gene transcription.
Asunto(s)
Proteínas del Citoesqueleto/genética , Regiones Promotoras Genéticas , Animales , Línea Celular , Clonación Molecular , Proteínas del Citoesqueleto/metabolismo , Ratones , Desarrollo de Músculos , Fibras Musculares Esqueléticas/metabolismo , Mioblastos Esqueléticos/metabolismo , Isoformas de Proteínas/genética , RNA-SeqRESUMEN
Targeting the two degradation systems, ubiquitin proteasome pathway and ubiquitin signal autophagy lysosome system, plays an important function in cancer prevention. Borneol is called an "upper guiding drug". Luteolin has demonstrated anticancer activity. The fact that borneol regulates luteolin can be sufficient to serve as an alternative strategy. Borneol activates luteolin to inhibit E1 and 20S activity (IC50 = 118.8 ± 15.7 µM) and perturb the 26S proteasome structure in vitro. Borneol regulates luteolin to inhibit 26S activity (IC50 = 157 ± 19 µM), induces apoptosis (LC50 = 134 ± 4 µM), and causes pre-G1 and G0/G1 arrest in HepG2 cells. Borneol regulates luteolin to induce ubiquitin signal autophagic degradation, resulting in induction of E1, reduction of USP47, and accumulation of p62 in HepG2 reporter cells. Interestingly, luteolin decreased Ub conjugates, while borneol increased the accumulation of Ub conjugates in HepG2 reporter cells. E1, p62, and ubiquitin levels were downregulated in borneol-treated HepG2 reporter cells at 24 h. These observations suggest a potential autophagic inhibitor of borneol that may guide luteolin in the ubiquitin proteasome pathway and the ubiquitin signal autophagic degradation.