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Blood ; 135(4): 274-286, 2020 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-31738823


Pediatric large B-cell lymphomas (LBCLs) share morphological and phenotypic features with adult types but have better prognosis. The higher frequency of some subtypes such as LBCL with IRF4 rearrangement (LBCL-IRF4) in children suggests that some age-related biological differences may exist. To characterize the genetic and molecular heterogeneity of these tumors, we studied 31 diffuse LBCLs (DLBCLs), not otherwise specified (NOS); 20 LBCL-IRF4 cases; and 12 cases of high-grade B-cell lymphoma (HGBCL), NOS in patients ≤25 years using an integrated approach, including targeted gene sequencing, copy-number arrays, and gene expression profiling. Each subgroup displayed different molecular profiles. LBCL-IRF4 had frequent mutations in IRF4 and NF-κB pathway genes (CARD11, CD79B, and MYD88), losses of 17p13 and gains of chromosome 7, 11q12.3-q25, whereas DLBCL, NOS was predominantly of germinal center B-cell (GCB) subtype and carried gene mutations similar to the adult counterpart (eg, SOCS1 and KMT2D), gains of 2p16/REL, and losses of 19p13/CD70. A subset of HGBCL, NOS displayed recurrent alterations of Burkitt lymphoma-related genes such as MYC, ID3, and DDX3X and homozygous deletions of 9p21/CDKN2A, whereas other cases were genetically closer to GCB DLBCL. Factors related to unfavorable outcome were age >18 years; activated B-cell (ABC) DLBCL profile, HGBCL, NOS, high genetic complexity, 1q21-q44 gains, 2p16/REL gains/amplifications, 19p13/CD70 homozygous deletions, and TP53 and MYC mutations. In conclusion, these findings further unravel the molecular heterogeneity of pediatric and young adult LBCL, improve the classification of this group of tumors, and provide new parameters for risk stratification.

Int J Cancer ; 145(11): 3078-3088, 2019 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-31044434


Diffuse large B-cell lymphoma (DLBCL) is up to 17-fold more likely to occur, follows a more aggressive clinical course and frequently presents at advanced stages in HIV infected (+) individuals compared to HIV negative (-) individuals. However, the molecular pathology underpinning the clinical features of DLBCL in HIV(+) patients relative to the general population is poorly understood. We performed a retrospective study examining the transcriptional, genomic and protein expression differences between HIV(+) and HIV(-) germinal center B-cell (GCB) DLBCL cases using digital gene expression analysis, array comparative genomic hybridization (CGH) and immunohistochemistry (IHC). Genes associated with cell cycle progression (CCNA2, CCNB1, CDC25A, E2F1), DNA replication (MCM2, MCM4, MCM7) and DNA damage repair, including eight Fanconi anemia genes (FANCA, FANCD1/BRCA2, FANCE, FANCG, FANCR/RAD51, FANCS/BRCA1, FANCT/UBE2T, FANCV/MAD2L2), were significantly increased in HIV(+) GCB-DLBCL tumors compared to HIV(-) tumors. In contrast, genes associated with cell cycle inhibition (CDKN1A, CDKN1B) as well as apoptosis regulating BCL2 family members (BCL2, BAX, BIM, BMF, PUMA) were significantly decreased in the HIV(+) cohort. BCL2 IHC confirmed this expression. Array CGH data revealed that HIV(+) GCB-DLBCL tumors have fewer copy number variations than their HIV(-) counterparts, indicating enhanced genomic stability. Together, the results show that HIV(+) GCB-DLBCL is a distinct molecular malignancy from HIV(-) GCB-DLBCL; with an increased proliferative capacity, confirmed by Ki67 IHC staining, and enhanced genomic stability, the latter of which is likely related to the enhanced expression of DNA repair genes.

Reparo do DNA , Perfilação da Expressão Gênica/métodos , Instabilidade Genômica , Infecções por HIV/genética , Linfoma Difuso de Grandes Células B/genética , Adulto , Idoso , Hibridização Genômica Comparativa , Feminino , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Imuno-Histoquímica , Linfoma Difuso de Grandes Células B/virologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
Artigo em Inglês | MEDLINE | ID: mdl-31033496


Tissue microarrays (TMAs) are important tools to conserve precious tissue resources from increasingly smaller biopsies and to control experimental costs and variation across sample sets. The quality assurance assessment of TMA materials created at centralized biobanks has not been standardized. Herein, we outline 2 processes for the construction of TMAs ("recipient block" and "tape" methods) and the associated preconstruction quality control measures (pathology review, protein and RNA assessment, map creation, and storage conditions) developed by the AIDS Cancer Specimen Resource (ACSR) Network's Science and Technology Core. These steps provide a suggested framework for quality assessment that allows end-users, receiving materials from tissue banks, confidence in their experimental results.

Semin Hematol ; 56(1): 46-51, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30573044


Molecular profiling of lymphoma samples has contributed enormously to our understanding of disease biology leading to detailed descriptions of diagnostic categories. These studies have also helped the field to recognize different subtypes of disease, different diseases that share similar cellular pathway perturbations, different immune responses, and different prognostic groups. While nearly all of these discoveries were made using unfixed, snap-frozen materials, with few exceptions, clinical biopsy materials are comprised of formalin-fixed and paraffin-embedded (FFPE) tissues. Here, we describe the impact of molecular profiling on the field of lymphoma, the challenges associated with using FFPE tissues for downstream molecular diagnostic testing, the various molecular profiling techniques, and also provide an example of the clinical application of a molecular profiling test of lymphoma using FFPE tissues.

Linfoma/patologia , Inclusão em Parafina/métodos , Fixação de Tecidos/métodos , Humanos
Int J Radiat Biol ; 87(1): 98-111, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-20973658


PURPOSE: The objective of this study was to investigate whether cell culture medium is a biologically relevant exposure medium that can be employed in non-ionising photobiological investigations. METHODS: The effect of solar-simulated irradiation on cell culture medium and its ability to elicit cell death was studied. The role of reactive oxygen species (ROS), cell secreted factors, and the contribution of individual components of the medium were investigated. RESULTS: Cell death was found to be primarily mediated through the formation of ROS via riboflavin photosensitisation and degradation in the cell culture medium. Phenol red was found to significantly reduce the cell killing ability of riboflavin. Exposures in riboflavin-free medium resulted in significantly increased cell survival compared to identical exposures in riboflavin containing medium. CONCLUSIONS: This study has shown that solar radiation toxicity is augmented by cell culture medium due to the presence of riboflavin. Results suggest that exposures performed in phenol red-free medium may serve to increase phototoxic effects if riboflavin is present. Riboflavin-free media is recommended for solar radiation investigations to eliminate concerns regarding riboflavin photosensitisation and nutrient deprivation.

Morte Celular/efeitos da radiação , Queratinócitos/efeitos da radiação , Luz Solar/efeitos adversos , Antioxidantes/metabolismo , Linhagem Celular , Sobrevivência Celular/efeitos da radiação , Ensaio de Unidades Formadoras de Colônias , Meios de Cultura/química , Meios de Cultura/efeitos da radiação , Humanos , Queratinócitos/metabolismo , Queratinócitos/patologia , Fenolsulfonaftaleína/química , Fenolsulfonaftaleína/efeitos da radiação , Fármacos Fotossensibilizantes/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Riboflavina/metabolismo , Riboflavina/efeitos da radiação , Espectrofotometria
Radiat Prot Dosimetry ; 140(2): 147-57, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20203123


Photo-biological investigations are dependent on calibration and characterisation to determine the relevance of an artificial irradiator to the study at hand. The importance of this has been voiced in the literature. However, the importance of output delivery is relatively unknown. The biological relevance of a high-energy, rapidly pulsing solar simulator was investigated using the clonogenic assay and was found to be reciprocity law compliant despite an exaggerated ultraviolet (UV) irradiance in excess of 1600 W m(-2) delivered per pulse. In fact, it was found to be the least cytotoxic irradiator compared with a second solar simulator and a UVB fluorescent lamp with continuous UV irradiances of 55 and 6.4 W m(-2), respectively. The reduced survival observed with the continuous irradiators is attributed to differences in spectral irradiance and distribution, particularly in the UVB, which in the absence of thorough calibration and characterisation may have resulted in erroneous conclusions.

Queratinócitos/efeitos da radiação , Fotobiologia , Energia Solar , Raios Ultravioleta , Morte Celular , Células Cultivadas , Ensaio de Unidades Formadoras de Colônias , Humanos