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1.
J Cancer Res Clin Oncol ; 147(3): 691-701, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33389078

RESUMO

BACKGROUND: Some chemotherapy drugs have immunomodulatory effects on specific tumors. The potential of vincristine (VCR) in the R-CHOP regimen to act as both a chemotherapeutic and an immunomodulatory agent via PD-L1 in tumor cells remains unclear. METHODS: In vitro screening VCR showed that the IC50 value of VCR in the DLBCL cell lines was approximately 2 nM. Western blotting and q-PCR were used to detect the expression of PD-L1. The effect of VCR combined with PD-L1 mAb was tested in a co-culture system of LY-OCI-3 cells and peripheral blood mononuclear cells and in DLBCL xenograft mouse model. Flow cytometry was used to determine the proportion of T lymphocyte subsets. The effect of the STAT3 inhibitor nifuroxazide on VCR-induced PD-L1 expression was tested in LY-OCI-3 and SU-DHL-4 cells. RESULTS: VCR upregulated PD-L1 protein and mRNA expression in various DLBCL cell lines. PD-L1 Ab combined with VCR significantly increased the proportion of CD8 + Granzyme B + , INF-γ + or TNF-α + CD3 + T cells. VCR + PD-L1 Ab inhibited tumor growth more effectively than VCR monotherapy, whereas PD-L1 Ab alone had no significant effect. Survival time did not differ significantly between the PD-L1 Ab group and the control group, whereas it was significantly longer in the VCR monotherapy and combination groups which showed more longer survival compared with the former. Nifuroxazide downregulated p-STAT3 and PD-L1 protein levels. CONCLUSIONS: VCR upregulated PD-L1 expression in DLBCL cells partially by promoting the p-STAT3; VCR combined with PD-L1 Ab activated effector T cells and increased the antitumor immune response in vitro and in vivo.


Assuntos
Antineoplásicos Imunológicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Antígeno B7-H1/biossíntese , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Vincristina/farmacologia , Animais , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/imunologia , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/imunologia , Linhagem Celular Tumoral , Sinergismo Farmacológico , Feminino , Humanos , Linfoma Difuso de Grandes Células B/imunologia , Linfoma Difuso de Grandes Células B/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Distribuição Aleatória , Regulação para Cima/efeitos dos fármacos , Vincristina/administração & dosagem , Ensaios Antitumorais Modelo de Xenoenxerto
2.
Nat Immunol ; 22(2): 240-253, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33432228

RESUMO

During the germinal center (GC) reaction, B cells undergo extensive redistribution of cohesin complex and three-dimensional reorganization of their genomes. Yet, the significance of cohesin and architectural programming in the humoral immune response is unknown. Herein we report that homozygous deletion of Smc3, encoding the cohesin ATPase subunit, abrogated GC formation, while, in marked contrast, Smc3 haploinsufficiency resulted in GC hyperplasia, skewing of GC polarity and impaired plasma cell (PC) differentiation. Genome-wide chromosomal conformation and transcriptional profiling revealed defects in GC B cell terminal differentiation programs controlled by the lymphoma epigenetic tumor suppressors Tet2 and Kmt2d and failure of Smc3-haploinsufficient GC B cells to switch from B cell- to PC-defining transcription factors. Smc3 haploinsufficiency preferentially impaired the connectivity of enhancer elements controlling various lymphoma tumor suppressor genes, and, accordingly, Smc3 haploinsufficiency accelerated lymphomagenesis in mice with constitutive Bcl6 expression. Collectively, our data indicate a dose-dependent function for cohesin in humoral immunity to facilitate the B cell to PC phenotypic switch while restricting malignant transformation.


Assuntos
Linfócitos B/metabolismo , Proteínas de Ciclo Celular/deficiência , Proteínas de Ciclo Celular/genética , Transformação Celular Neoplásica/genética , Proteoglicanas de Sulfatos de Condroitina/genética , Proteínas Cromossômicas não Histona/deficiência , Proteínas Cromossômicas não Histona/genética , Dosagem de Genes , Centro Germinativo/metabolismo , Imunidade Humoral , Linfoma de Células B/genética , Animais , Linfócitos B/imunologia , Linfócitos B/patologia , Proteínas de Ciclo Celular/metabolismo , Diferenciação Celular , Proliferação de Células , Transformação Celular Neoplásica/imunologia , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/patologia , Células Cultivadas , Proteoglicanas de Sulfatos de Condroitina/deficiência , Proteoglicanas de Sulfatos de Condroitina/metabolismo , Proteínas Cromossômicas não Histona/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Deleção de Genes , Regulação Neoplásica da Expressão Gênica , Centro Germinativo/imunologia , Centro Germinativo/patologia , Haploinsuficiência , Histona-Lisina N-Metiltransferase/genética , Histona-Lisina N-Metiltransferase/metabolismo , Humanos , Linfoma de Células B/imunologia , Linfoma de Células B/metabolismo , Linfoma de Células B/patologia , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/imunologia , Linfoma Difuso de Grandes Células B/metabolismo , Linfoma Difuso de Grandes Células B/patologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína de Leucina Linfoide-Mieloide/genética , Proteína de Leucina Linfoide-Mieloide/metabolismo , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Transdução de Sinais
3.
Clin Nucl Med ; 46(1): 1-7, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33181743

RESUMO

PURPOSE: The aim was to explore whether baseline total lesion glycolysis (TLG) can improve the prognostic value of the National Comprehensive Cancer Network International Prognostic Index (NCCN-IPI) in primary gastric diffuse large B-cell lymphoma (PG-DLBCL) patients treated with an R-CHOP-like regimen. MATERIALS AND METHODS: Ninety-four PG-DLBCL patients who underwent baseline PET/CT between July 2010 and May 2019 were included in this retrospective study. FDG-avid lesions in each patient were segmented to calculate the SUVmax, total metabolic tumor volume (TMTV), and TLG. Progression-free survival (PFS) and overall survival (OS) were used as end points to evaluate prognosis. RESULTS: During the follow-up period of 5 to 108 months (35.3 ± 23.5 months), high TLG and a high NCCN-IPI were significantly associated with poor PFS and OS. Total lesion glycolysis and the NCCN-IPI were independent predictors of PFS and OS. Patients were stratified into 3 groups according to the combination of TLG and the NCCN-IPI for PFS (P < 0.001) and OS (P < 0.001): high-risk group (TLG > 1159.1 and NCCN-IPI 4-8) (PFS and OS, 57.7% and 61.5%, respectively, n = 42), intermediate-risk group (TLG > 1159.1 or NCCN-IPI 4-8) (PFS and OS, both 76.9%, n = 26), and low-risk group (TLG ≤ 1159.1 and NCCN-IPI 0-3) (PFS and OS, 97.6% and 100.0%, respectively, n = 26). CONCLUSIONS: Both TLG and the NCCN-IPI are independent predictors of PG-DLBCL patient survival. Moreover, the combination of TLG and the NCCN-IPI improved patient risk stratification and might help personalize therapeutic regimens.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Glicólise/efeitos dos fármacos , Linfoma Difuso de Grandes Células B/diagnóstico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/tratamento farmacológico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ciclofosfamida/farmacologia , Ciclofosfamida/uso terapêutico , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Feminino , Humanos , Linfoma Difuso de Grandes Células B/metabolismo , Masculino , Pessoa de Meia-Idade , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Prednisolona/farmacologia , Prednisolona/uso terapêutico , Intervalo Livre de Progressão , Estudos Retrospectivos , Neoplasias Gástricas/metabolismo , Vincristina/farmacologia , Vincristina/uso terapêutico
5.
Anticancer Res ; 40(11): 5951-5968, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33109533

RESUMO

BACKGROUND/AIM: Diffuse large B-cell lymphoma (DLBCL) is the most common form of non-Hodgkin lymphoma. A systematic review to evaluate the association between Epstein-Barr Virus (EBV) and programmed death ligand-1 (PD-L1) in DLBCL biopsy was conducted. MATERIALS AND METHODS: Only studies comparing EBV+ and EBV- groups were eligible following database search. Prevalence ratios were calculated for results comparison. The EBV impact on PD-L1 positivity in tumour cells and its microenvironment was analysed. RESULTS: With 270 records screened, eleven cross-sectional studies were identified for final review. Eight studies investigated PD-L1 expression in tumour cells and found an EBV trend unlikely, while four studies found an increase in its expression in the tumour microenvironment. Nine studies showed that EBV+ cases were more commonly of non-germinal centre B-cell origin. Four studies examined genetic aberrations, but no definite consensus was reached. CONCLUSION: A non-EBV related mechanism is likely related to increased PD-L1 expression, with relevance to the cell of origin.


Assuntos
Antígeno B7-H1/metabolismo , Herpesvirus Humano 4/fisiologia , Linfoma Difuso de Grandes Células B/metabolismo , Linfoma Difuso de Grandes Células B/virologia , Idoso , Feminino , Humanos , Linfoma Difuso de Grandes Células B/genética , Masculino , Pessoa de Meia-Idade , Viés de Publicação , Microambiente Tumoral
6.
Anticancer Res ; 40(7): 3781-3792, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32620617

RESUMO

BACKGROUND/AIM: Canine B-cell lymphoma represents a useful in vivo model for human diffuse large B-cell lymphoma (DLBCL). Pan-Bromodomain and extra-terminal (BET) inhibition targeting BRD2/3/4 and selective inhibition of BRD4, as well as spleen tyrosine kinase (SYK) inhibition, are currently evaluated as haematologic cancer therapy. Herein, we characterized the differences in the biologic response of isoform-specific or pan-BET inhibition alone or in combination with SYK inhibition. MATERIALS AND METHODS: I-BET151 (pan-inhibitor) and AZD5153 (BRD4 inhibitor) were combined with Entospletinib (SYK inhibitor) and comparatively analysed in the canine DLBCL cell line CLBL-1. Dose- and time-dependent cellular responses were analysed by cell number, metabolic activity, apoptosis/necrosis, and cell morphology. The synergistic potential was evaluated through the Bliss independence model. RESULTS: I-BET151 and AZD5153 showed significant dose- and time-dependent inhibitory effects. Adding Entospletinib to I-BET151 or AZD5153 had no additional synergistic effects. CONCLUSION: Entospletinib did not enhance the inhibitory effects of the pan- or isoform-specific BET.


Assuntos
Indazóis/farmacologia , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Proteínas Nucleares/antagonistas & inibidores , Isoformas de Proteínas/antagonistas & inibidores , Pirazinas/farmacologia , Animais , Linhagem Celular Tumoral , Cães , Compostos Heterocíclicos com 2 Anéis/farmacologia , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Linfoma Difuso de Grandes Células B/metabolismo , Piperazinas/farmacologia , Proteínas Serina-Treonina Quinases/metabolismo , Quinase Syk/metabolismo
8.
PLoS Pathog ; 16(6): e1008590, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32542010

RESUMO

EBV transforms B cells in vitro and causes human B-cell lymphomas including classical Hodgkin lymphoma (CHL), Burkitt lymphoma (BL) and diffuse large B-cell lymphoma (DLBCL). The EBV latency protein, EBNA2, transcriptionally activates the promoters of all latent viral protein-coding genes expressed in type III EBV latency and is essential for EBV's ability to transform B cells in vitro. However, EBNA2 is not expressed in EBV-infected CHLs and BLs in humans. EBV-positive CHLs have type II latency and are largely driven by the EBV LMP1/LMP2A proteins, while EBV-positive BLs, which usually have type I latency are largely driven by c-Myc translocations, and only express the EBNA1 protein and viral non-coding RNAs. Approximately 15% of human BLs contain naturally occurring EBNA2-deleted viruses that support a form of viral latency known as Wp-restricted (expressing the EBNA-LP, EBNA3A/3B/3C, EBNA1 and BHRF1 proteins), but whether Wp-restricted latency and/or EBNA2-deleted EBV can induce lymphomas in humanized mice, or in the absence of c-Myc translocations, is unknown. Here we show that a naturally occurring EBNA2-deleted EBV strain (P3HR1) isolated from a human BL induces EBV-positive B-cell lymphomas in a subset of infected cord blood-humanized (CBH) mice. Furthermore, we find that P3HR1-infected lymphoma cells support two different viral latency types and phenotypes that are mutually exclusive: 1) Large (often multinucleated), CD30-positive, CD45-negative cells reminiscent of the Reed-Sternberg (RS) cells in CHL that express high levels of LMP1 but not EBNA-LP (consistent with type II viral latency); and 2) smaller monomorphic CD30-negative DLBCL-like cells that express EBNA-LP and EBNA3A but not LMP1 (consistent with Wp-restricted latency). These results reveal that EBNA2 is not absolutely required for EBV to form tumors in CBH mice and suggest that P3HR1 virus can be used to model EBV positive lymphomas with both Wp-restricted and type II latency in vivo.


Assuntos
Infecções por Vírus Epstein-Barr , Antígenos Nucleares do Vírus Epstein-Barr/genética , Deleção de Genes , Herpesvirus Humano 4/fisiologia , Doença de Hodgkin , Linfoma Difuso de Grandes Células B , Proteínas Virais/genética , Latência Viral , Animais , Linhagem Celular , Infecções por Vírus Epstein-Barr/genética , Infecções por Vírus Epstein-Barr/metabolismo , Infecções por Vírus Epstein-Barr/patologia , Infecções por Vírus Epstein-Barr/virologia , Antígenos Nucleares do Vírus Epstein-Barr/metabolismo , Herpesvirus Humano 4/patogenicidade , Doença de Hodgkin/genética , Doença de Hodgkin/metabolismo , Doença de Hodgkin/patologia , Doença de Hodgkin/virologia , Humanos , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/metabolismo , Linfoma Difuso de Grandes Células B/patologia , Linfoma Difuso de Grandes Células B/virologia , Camundongos , Proteínas Virais/metabolismo
9.
J Cancer Res Ther ; 16(1): 183-185, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32362635

RESUMO

Diffuse large B-cell lymphomas (DLBCL) with MYC translocations combined with translocations involving BCL-2 or BCL-6 are referred to as double-hit lymphomas. These lymphomas are generally refractory to currently available therapies and have a poor prognosis. Primary mediastinal B-cell lymphoma (PMBL) is a rare subtype of DLBCL, which shares clinical, pathologic, and genetic similarities with classical Hodgkin's lymphoma. Unlike DLBCL, rearrangements involving MYC, BCL-2, and BCL-6 are typically absent in PMBL. We present a patient with PMBL who had increased gene copy numbers of MYC and BCL-2 along with increased protein expression of BCL-2 (c-Myc expression was about 15%-20% by immunostain). The disease was refractory to standard and salvage chemotherapies. The lymphoma, however, responded to brentuximab vedotin, a CD30-directed chemoimmunoconjugate.


Assuntos
Brentuximab Vedotin/uso terapêutico , Antígeno Ki-1/metabolismo , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Neoplasias do Mediastino/tratamento farmacológico , Mutação , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteínas Proto-Oncogênicas c-myc/genética , Adulto , Antineoplásicos Imunológicos/uso terapêutico , Feminino , Humanos , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/metabolismo , Linfoma Difuso de Grandes Células B/patologia , Neoplasias do Mediastino/genética , Neoplasias do Mediastino/metabolismo , Neoplasias do Mediastino/patologia , Prognóstico , Proteínas Proto-Oncogênicas c-bcl-2/genética
10.
Clin Nucl Med ; 45(7): 542-544, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32433173

RESUMO

Residual end of treatment (EOT) FDG-avid lesions are often due to infectious or inflammatory process and not due to refractory lymphoma. Nonetheless, such lesions prompt diagnostic and therapeutic interventions. We evaluate clinical and radiological characteristics of patients with EOT FDG-avid splenic lesions. Comparing metabolic volume (MV) ratio between EOT to interim, showed a marked difference between false positive and true positive lesions (0.5 vs 3.6, P = 0.02). EOT SUVmax was also significantly different between the groups (7 vs. 19, P = 0.02). We suggest EOT/interim-MV ratio as a tool to identify patients at low risk of refractory disease allowing non-invasive surveillance.


Assuntos
Fluordesoxiglucose F18/metabolismo , Linfoma Difuso de Grandes Células B/diagnóstico por imagem , Linfoma Difuso de Grandes Células B/metabolismo , Tomografia por Emissão de Pósitrons , Baço/metabolismo , Adulto , Idoso , Transporte Biológico , Feminino , Humanos , Linfoma Difuso de Grandes Células B/terapia , Masculino , Pessoa de Meia-Idade , Medição de Risco , Baço/diagnóstico por imagem
11.
Sci Rep ; 10(1): 7876, 2020 05 12.
Artigo em Inglês | MEDLINE | ID: mdl-32398793

RESUMO

Diffuse large B-cell lymphoma (DLBCL) is commonly classified by gene expression profiling according to its cell of origin (COO) into activated B-cell (ABC)-like and germinal center B-cell (GCB)-like subgroups. Here we report the application of label-free nano-liquid chromatography - Sequential Window Acquisition of all THeoretical fragment-ion spectra - mass spectrometry (nanoLC-SWATH-MS) to the COO classification of DLBCL in formalin-fixed paraffin-embedded (FFPE) tissue. To generate a protein signature capable of predicting Affymetrix-based GCB scores, the summed log2-transformed fragment ion intensities of 780 proteins quantified in a training set of 42 DLBCL cases were used as independent variables in a penalized zero-sum elastic net regression model with variable selection. The eight-protein signature obtained showed an excellent correlation (r = 0.873) between predicted and true GCB scores and yielded only 9 (21.4%) minor discrepancies between the three classifications: ABC, GCB, and unclassified. The robustness of the model was validated successfully in two independent cohorts of 42 and 31 DLBCL cases, the latter cohort comprising only patients aged >75 years, with Pearson correlation coefficients of 0.846 and 0.815, respectively, between predicted and NanoString nCounter based GCB scores. We further show that the 8-protein signature is directly transferable to both a triple quadrupole and a Q Exactive quadrupole-Orbitrap mass spectrometer, thus obviating the need for proprietary instrumentation and reagents. This method may therefore be used for robust and competitive classification of DLBCLs on the protein level.


Assuntos
Linhagem da Célula/genética , Perfilação da Expressão Gênica/métodos , Linfoma Difuso de Grandes Células B/genética , Proteínas/metabolismo , Proteoma/metabolismo , Proteômica/métodos , Linfócitos B/metabolismo , Linfócitos B/patologia , Cromatografia Líquida/métodos , Formaldeído , Centro Germinativo/metabolismo , Humanos , Linfoma Difuso de Grandes Células B/classificação , Linfoma Difuso de Grandes Células B/metabolismo , Espectrometria de Massas/métodos , Nanotecnologia/métodos , Inclusão em Parafina/métodos , Proteínas/genética , Proteoma/genética , Fixação de Tecidos/métodos
12.
Cancer Sci ; 111(7): 2608-2619, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32342603

RESUMO

The interaction between CD47 and signal-regulatory protein-α (SIRPα) inhibits phagocytosis, thus affecting the clinical outcomes of neoplastic diseases. Although CD47 upregulation is associated with poor prognosis in several malignancies, the effect of SIRPα expression and its coexpression with CD47 remains unclear. This study aimed to investigate the clinicopathologic effect of CD47 and SIRPα expression in diffuse large B-cell lymphoma (DLBCL). Immunostaining of 120 biopsy samples showed that CD47 is primarily expressed in tumor cells, whereas SIRPα is expressed in nonneoplastic stromal cells, mostly macrophages. CD47high cases showed higher MYC protein expression and lower MYC translocation. The SIRPαhigh cases presented significantly shorter overall survival (OS) and progression-free survival (PFS) than SIRPαlow cases in the activated B-cell (ABC) subtype of DLBCL (P = .04 and P = .02, respectively). Both CD47high and SIRPαhigh presented significantly shorter OS and PFS than other cases among all DLBCL patients (P = .01 and P = .004, respectively), and the ABC type (P = .04 and P = .008, respectively) but not the germinal center B-cell type. Both CD47high and SIRPαhigh yielded a constant independent prognostic value for OS and PFS in multivariate analysis (hazard ratio [HR], 2.93; 95% confidence interval [CI], 1.20-7.43; P = .02; and HR, 2.87; 95% CI, 1.42-5.85; P = .003, respectively). To the best of our knowledge, this is the first study to report that combinatorial CD47 and SIRPα expression is a potential independent prognostic factor for DLBCL. Evaluation of CD47 and SIRPα expression could be useful before CD47 blockade therapy.


Assuntos
Antígenos de Diferenciação/metabolismo , Antígeno CD47/metabolismo , Linfoma Difuso de Grandes Células B/metabolismo , Linfoma Difuso de Grandes Células B/mortalidade , Receptores Imunológicos/metabolismo , Transdução de Sinais , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos de Diferenciação/genética , Protocolos de Quimioterapia Combinada Antineoplásica , Biomarcadores , Antígeno CD47/genética , Ciclofosfamida , Doxorrubicina , Feminino , Expressão Gênica , Humanos , Imuno-Histoquímica , Hibridização In Situ , Linfoma Difuso de Grandes Células B/patologia , Linfoma Difuso de Grandes Células B/terapia , Pessoa de Meia-Idade , Prednisona , Prognóstico , Receptores Imunológicos/genética , Rituximab , Resultado do Tratamento , Vincristina
13.
Medicine (Baltimore) ; 99(12): e19463, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32195944

RESUMO

RATIONALE: Primary testicular lymphoma (PTL) is a rare type of extranodal non-Hodgkin's lymphoma (NHL). Although data of PTL in patients with diffuse large B-cell lymphoma (DLBCL) are accumulating, there are still patients respond poorly to prognosis. PATIENT CONCERNS: All patients had disease of the DLBCL subtype and those patients had primary involvement of the testis. In our studies, eleven patients had stage I/II disease, and 3 patients had advanced disease with B symptoms. Four patients exhibited a MYC+, BCL2+, and BCL6- expression pattern, 4 patients had a MYC+, BCL6+, and BCL2- expression pattern, and 3 patients had a MYC+, BCL2+, and BCL6+ expression pattern. Additionally, 43% (7/16) of PT-DLBCL patients had a germinal center B-cell-like (GCB) phenotype, while the others had a non-GCB phonotype. DIAGNOSES: In our case, most patients presented with unilateral painless scrotal swelling and the enlargement of the testicles in the first examination. After hospitalization, all patients underwent preoperative imageological examination of the testis and epididymis and postoperative revealed that all patients were the diffuse infiltration of a large number of anomalous lymphocytes. In addition, no invasion of other sites was observed within 3 months after diagnosis. INTERVENTIONS AND OUTCOMES: Underwent orchiectomy on the affected side was performed by urologists after all patients were diagnosed with PTL. Meanwhile, some patients received at least one course of chemotherapy, or received postoperative combined RT and chemotherapy. Because of it particularity, nineteen instances of lymph node region involvement were discovered in 12 patients since the operation. LESSONS: PT-DLBCL has unique biological characteristics, and its treatment modalities are becoming increasingly standardized. In the future, systematic interventions need to be actively considered in the early stages of PTL.


Assuntos
Linfoma Difuso de Grandes Células B/metabolismo , Linfoma Difuso de Grandes Células B/patologia , Neoplasias Testiculares/metabolismo , Neoplasias Testiculares/patologia , Testículo/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Quimiorradioterapia/métodos , Centro Germinativo/patologia , Humanos , Linfoma Difuso de Grandes Células B/diagnóstico , Linfoma Difuso de Grandes Células B/terapia , Linfoma não Hodgkin/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Orquiectomia/métodos , Fenótipo , Prognóstico , Estudos Retrospectivos , Neoplasias Testiculares/terapia , Testículo/diagnóstico por imagem , Ultrassonografia/métodos
14.
Neoplasia ; 22(3): 142-153, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32062068

RESUMO

The BCL6 proto-oncogene encodes a transcriptional repressor, which is required for germinal centers (GCs) formation and lymphomagenesis. Previous studies have been reported that the constitutive expression of BCL6 leads to diffuse large B cell lymphoma (DLBCL) through activation-induced cytidine deaminase (AID) mediated chromosomal translocations and mutations. However, other DLBCLs (45%) without structural variants were characterized by abnormally high level of BCL6 expression through an unknown mechanism. Herein, we report that deficiency in AID or methyltransferase 1 (DNMT1) triggers high level of BCL6 expression. AID-DNMT1 complex binds to -0.4 kb -0 kb region of BCL6 promoter and contributes to generate BCL6 methylation which results in inhibition of BCL6 expression. The proteasome pathway inhibitor MG132 induces accumulation of AID and DNMT1, causes decreased BCL6 expression, and leads to cell apoptosis and tumor growth inhibition in DLBCL cell xenograft mice. These findings propose mechanistic insight into an alternative cofactor role of AID in assisting DNMT1 to maintain BCL6 methylation, thus suppress BCL6 transcription in DLBCL. This novel mechanism will provide a new drug selection in the therapeutic approach to DLBCL in the future.


Assuntos
Citidina Desaminase/metabolismo , DNA (Citosina-5-)-Metiltransferase 1/metabolismo , Metilação de DNA , Regulação Leucêmica da Expressão Gênica , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/metabolismo , Proteínas Proto-Oncogênicas c-bcl-6/genética , Animais , Linhagem Celular Tumoral , Proteínas de Ligação a DNA/metabolismo , Modelos Animais de Doenças , Genes Reporter , Humanos , Linfoma Difuso de Grandes Células B/patologia , Camundongos , Modelos Biológicos , Regiões Promotoras Genéticas , Ligação Proteica
15.
Oncol Res ; 28(4): 331-344, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32093809

RESUMO

Despite therapeutic advances, the effective treatment for relapsed or refractory diffuse large B-cell lymphoma (DLBCL) remains a major clinical challenge. Evasion of apoptosis through upregulating antiapoptotic B-cell lymphoma-2 (BCL-2) family members and p53 inactivation, and abnormal activation of B-cell receptor signaling pathway are two important pathogenic factors for DLBCL. In this study, our aim is to explore a rational combination of BCL-2 inhibitor plus Brutons tyrosine kinase (BTK) blockade or p53 activation for treating DLBCL with the above characteristics. We demonstrated that a novel BCL-2 selective inhibitor APG-2575 effectively suppressed DLBCL with BCL-2 high expression via activating the mitochondrial apoptosis pathway. BTK inhibitor ibrutinib combined with BCL-2 inhibitors showed synergistic antitumor effect in DLBCL with mean expression of BCL-2 and myeloid cell leukemia-1 (MCL-1) through upregulating the expression level of BIM and modulating MCL-1 and p-Akt expression. For p53 wild-type DLBCL with high expression of BCL-2, APG-2575 showed strong synergic effect with mouse double minute 2 (MDM2)p53 inhibitor APG-115 that can achieve potent antitumor effect and markedly prolong survival in animal models. Collectively, our data provide an effective and precise therapeutic strategy through rational combination of BCL-2 and BTK or MDM2p53 inhibitors for DLBCL, which deserves further clinical investigation.


Assuntos
Tirosina Quinase da Agamaglobulinemia/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Tirosina Quinase da Agamaglobulinemia/genética , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Humanos , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/metabolismo , Camundongos , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteínas Proto-Oncogênicas c-mdm2/genética , Pirazóis/farmacologia , Pirimidinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Mutações Sintéticas Letais/efeitos dos fármacos , Proteína Supressora de Tumor p53/genética , Ensaios Antitumorais Modelo de Xenoenxerto
16.
Hematol Oncol ; 38(2): 171-180, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31955451

RESUMO

We described four patients with diffuse large B-cell lymphoma (DLBCL) carrying t(9;14)(p13;q32) that places the PAX5 adjacent to the immunoglobulin heavy chain (IGH) gene. Ages ranged between 63 and 80, and three were female. One developed a nodal disease, and the other three involved extranodal organs. The lymphoma cells were CD10- /BCL6- /MUM1+ in three and CD10+ /BCL6+ /MUM1+ in one. BCL2 was weak or negative. All had t(9;14)(p13;q32), and three had additional 14q32/IGH translocations or +der(14)t(9;14)(p13;q32). Fluorescence in situ hybridization using the PAX5 break-apart probe showed that the locus was disrupted between the 5' and 3' probes or within the 5' probe. Immunohistochemistry (IHC) using a monoclonal antibody against PAX5 showed strong nuclear positivity in all four patients. Cell block IHC of a CD30+ DLBCL cell line, KIS-1, which carried the t(9;14)(p13;q32) and PAX5-IGH fusion gene, reproduced the CD10- /BCL6- /MUM1+ immunophenotype, low-level BCL2, and strong nuclear PAX5. Uniform nuclear positivity of MUM1 in all four cases and KIS-1 cells suggest that these lymphomas arose at a late stage of B-cell differentiation, where expression of PAX5 physiologically becomes downregulated. It is therefore possible that high-level PAX5 resulting from t(9;14)(p13;q32) at this stage of differentiation perturbs the plasma cell differentiation program initiated by PAX5 repression, thereby contributing to the development of a fraction of DLBCL.


Assuntos
Núcleo Celular/metabolismo , Cadeias Pesadas de Imunoglobulinas/genética , Imuno-Histoquímica/métodos , Fatores Reguladores de Interferon/metabolismo , Linfoma Difuso de Grandes Células B/patologia , Fator de Transcrição PAX5/metabolismo , Translocação Genética , Idoso , Idoso de 80 Anos ou mais , Núcleo Celular/genética , Cromossomos Humanos Par 14/genética , Cromossomos Humanos Par 9/genética , Feminino , Humanos , Fatores Reguladores de Interferon/genética , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/metabolismo , Masculino , Pessoa de Meia-Idade , Fator de Transcrição PAX5/genética , Prognóstico
17.
Arch Pathol Lab Med ; 144(2): 160-167, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31990228

RESUMO

CONTEXT.­: Large B-cell lymphomas represent the most common non-Hodgkin lymphomas and often present as extranodal masses with advanced stage similar to metastatic tumors. Without proper intraoperative, microscopic, immunophenotypic, and cytogenetic evaluation they may be mistaken for other hematopoietic or even nonhematopoietic tumors. Also, diffuse large B-cell lymphomas often have clinical, morphologic, immunophenotypic, and cytogenetic clinical features that are similar to those of other less common B-cell lymphomas. Furthermore, classification of these neoplasms is continually becoming more refined. OBJECTIVE.­: To provide a rational, methodic approach to the evaluation of large B-cell lymphomas for community practice pathologists who provide general pathology services. DATA SOURCES.­: This review incorporates guidelines detailed in the 2017 update to the World Health Organization's Classification of Tumours of Haematopoietic and Lymphoid Tissues in addition to other recent peer-reviewed publications. CONCLUSIONS.­: Many large B-cell neoplasms respond favorably to current treatments, but these cases also require accurate and timely diagnoses. We propose a process following a brief checklist that focuses on diffuse large B-cell lymphoma, the most common entity, and rules out other similar lymphomas in a stepwise fashion.


Assuntos
Linfoma de Células B/diagnóstico , Linfoma Difuso de Grandes Células B/diagnóstico , Patologia Clínica/métodos , Guias de Prática Clínica como Assunto , Antígenos CD20/metabolismo , Diagnóstico Diferencial , Humanos , Imuno-Histoquímica , Linfoma de Células B/metabolismo , Linfoma Difuso de Grandes Células B/metabolismo , Neprilisina/metabolismo , Proteínas Proto-Oncogênicas c-bcl-6/metabolismo
18.
Life Sci ; 243: 117249, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31926247

RESUMO

AIMS: Diffuse large B-cell lymphoma (DLBCL) is one of the most aggressive lymphoid malignancies, which remains incurable, thus warranting the development of new therapies. Our previous study determined that rafoxanide is very effective in treating multiple myeloma (MM). In the present study, we tried to evaluate the effects of rafoxanide on DLBCL, as well as the potential underlying molecular mechanisms. MAIN METHODS: We used CCK-8 assay and flow cytometry to assess cell viability and apoptosis. The proteins and pathways associated with apoptosis and proliferation were evaluated through western blot, and xenograft mice were used as the experimental animal model. We also used the TUNEL assay and immunofluorescence for further analyses. KEY FINDINGS: Treatment with different doses of rafoxanide significantly inhibited cell viability and apoptosis. Additionally, the compound induced cell cycle arrest, reduced mitochondrial membrane potential (Δψm), and stimulated reactive oxygen species (ROS) generation without the influence of normal peripheral blood monocytes (PBMCs). As expected, rafoxanide played a role in regulating these proteins and the PTEN/PI3K/AKT and JNK/c-Jun pathways. Furthermore, immunofluorescence and western blot results showed that rafoxanide upregulated H2AX phosphorylation and then inhibited DNA repair in DLBCL. In the xenograft mouse model, tumor volumes were reduced after intraperitoneal injection with rafoxanide. We also observed that TUNEL positive cells were remarkably increased in rafoxanide-treated tumor tissues. SIGNIFICANCE: These results collectively provide a novel choice to regular treatment for DLBCL patients with poor prognosis.


Assuntos
Antineoplásicos/uso terapêutico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , MAP Quinase Quinase 4/metabolismo , PTEN Fosfo-Hidrolase/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-jun/metabolismo , Rafoxanida/uso terapêutico , Animais , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Dano ao DNA , Humanos , Linfoma Difuso de Grandes Células B/enzimologia , Linfoma Difuso de Grandes Células B/metabolismo , Linfoma Difuso de Grandes Células B/patologia , Masculino , Camundongos , Espécies Reativas de Oxigênio/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
19.
J Clin Invest ; 130(2): 1036-1051, 2020 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-31961340

RESUMO

Antigen receptor-dependent (AgR-dependent) stimulation of the NF-κB transcription factor in lymphocytes is a required event during adaptive immune response, but dysregulated activation of this signaling pathway can lead to lymphoma. AgR stimulation promotes assembly of the CARMA1-BCL10-MALT1 complex, wherein MALT1 acts as (a) a scaffold to recruit components of the canonical NF-κB machinery and (b) a protease to cleave and inactivate specific substrates, including negative regulators of NF-κB. In multiple lymphoma subtypes, malignant B cells hijack AgR signaling pathways to promote their own growth and survival, and inhibiting MALT1 reduces the viability and growth of these tumors. As such, MALT1 has emerged as a potential pharmaceutical target. Here, we identified G protein-coupled receptor kinase 2 (GRK2) as a new MALT1-interacting protein. We demonstrated that GRK2 binds the death domain of MALT1 and inhibits MALT1 scaffolding and proteolytic activities. We found that lower GRK2 levels in activated B cell-type diffuse large B cell lymphoma (ABC-DLBCL) are associated with reduced survival, and that GRK2 knockdown enhances ABC-DLBCL tumor growth in vitro and in vivo. Together, our findings suggest that GRK2 can function as a tumor suppressor by inhibiting MALT1 and provide a roadmap for developing new strategies to inhibit MALT1-dependent lymphomagenesis.


Assuntos
Carcinogênese/metabolismo , Quinase 2 de Receptor Acoplado a Proteína G/metabolismo , Linfoma Difuso de Grandes Células B/metabolismo , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa/metabolismo , Proteínas Oncogênicas/metabolismo , Animais , Carcinogênese/genética , Carcinogênese/patologia , Feminino , Quinase 2 de Receptor Acoplado a Proteína G/genética , Humanos , Células Jurkat , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/patologia , Camundongos , Camundongos Endogâmicos NOD , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa/genética , Proteínas Oncogênicas/genética
20.
Blood ; 135(16): 1396-1405, 2020 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-31978225

RESUMO

Early identification of ultra-risk diffuse large B-cell lymphoma (DLBCL) patients is needed to aid stratification to innovative treatment. Previous studies suggested high baseline total metabolic tumor volume (TMTV) negatively impacts survival of DLBCL patients. We analyzed the prognostic impact of TMTV and prognostic indices in DLBCL patients, aged 60 to 80 years, from the phase 3 REMARC study that randomized responding patients to R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) into maintenance lenalidomide or placebo. TMTV was computed on baseline positron emission tomography/computed tomography using the 41% maximum standardized uptake value method; the optimal TMTV cutoff for progression-free (PFS) and overall survival (OS) was determined and confirmed by a training validation method. There were 301 out of 650 evaluable patients, including 192 patients classified as germinal center B-cell-like (GCB)/non-GCB and MYC/BCL2 expressor. Median baseline TMTV was 238 cm3; optimal TMTV cutoff was 220 cm3. Patients with high vs low TMTV showed worse/higher Eastern Cooperative Oncology Group performance status (ECOG PS) ≥2, stage III or IV disease, >1 extranodal site, elevated lactate dehydrogenase, International Prognostic Index (IPI) 3-5, and age-adjusted IPI 2-3. High vs low TMTV significantly impacted PFS and OS, independent of maintenance treatment. Although the GCB/non-GCB profile and MYC expression did not correlate with TMTV/survival, BCL2 >70% impacted PFS and could be stratified by TMTV. Multivariate analysis identified baseline TMTV and ECOG PS as independently associated with PFS and OS. Even in responding patients, after R-CHOP, high baseline TMTV was a strong prognosticator of inferior PFS and OS. Moreover, TMTV combined with ECOG PS may identify an ultra-risk DLBCL population. This trial was registered at www.clinicaltrials.gov as #NCT01122472.


Assuntos
Inibidores da Angiogênese/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Lenalidomida/uso terapêutico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/patologia , Carga Tumoral/efeitos dos fármacos , Idoso , Idoso de 80 Anos ou mais , Ciclofosfamida/uso terapêutico , Doxorrubicina/uso terapêutico , Feminino , Humanos , Linfoma Difuso de Grandes Células B/diagnóstico , Linfoma Difuso de Grandes Células B/metabolismo , Masculino , Pessoa de Meia-Idade , Prednisona/uso terapêutico , Prognóstico , Rituximab/uso terapêutico , Vincristina/uso terapêutico
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