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1.
Nat Commun ; 11(1): 5348, 2020 10 22.
Artigo em Inglês | MEDLINE | ID: mdl-33093447

RESUMO

Myristoylation, the N-terminal modification of proteins with the fatty acid myristate, is critical for membrane targeting and cell signaling. Because cancer cells often have increased N-myristoyltransferase (NMT) expression, NMTs were proposed as anti-cancer targets. To systematically investigate this, we performed robotic cancer cell line screens and discovered a marked sensitivity of hematological cancer cell lines, including B-cell lymphomas, to the potent pan-NMT inhibitor PCLX-001. PCLX-001 treatment impacts the global myristoylation of lymphoma cell proteins and inhibits early B-cell receptor (BCR) signaling events critical for survival. In addition to abrogating myristoylation of Src family kinases, PCLX-001 also promotes their degradation and, unexpectedly, that of numerous non-myristoylated BCR effectors including c-Myc, NFκB and P-ERK, leading to cancer cell death in vitro and in xenograft models. Because some treated lymphoma patients experience relapse and die, targeting B-cell lymphomas with a NMT inhibitor potentially provides an additional much needed treatment option for lymphoma.


Assuntos
Aciltransferases/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Linfoma de Células B/tratamento farmacológico , Ácido Mirístico/metabolismo , Aminopiridinas/farmacologia , Animais , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Dasatinibe/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Linfoma de Células B/metabolismo , Linfoma de Células B/patologia , Camundongos , Camundongos SCID , Modelos Biológicos , Pirazóis/farmacologia , Pirimidinas/farmacologia , Receptores de Antígenos de Linfócitos B/metabolismo , Transdução de Sinais/efeitos dos fármacos , Sulfonamidas/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto , Quinases da Família src/metabolismo
2.
Anticancer Res ; 40(10): 5423-5426, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32988863

RESUMO

BACKGROUND/AIM: Exposure to pesticides has been reportedly associated with several types of cancer. MATERIALS AND METHODS: In this study, we used data from The United States Geological Survey (USGS), United States Census, and the Surveillance, Epidemiology, and End Results (SEER) database to analyze the association between the area density of specific agricultural pesticides and the county level annual incidence of diffuse large B-cell lymphoma (DLBCL). RESULTS: Incidence of DLBCL was significantly associated with an area density of 14 of the pesticides reported by USGS. CONCLUSION: This highlights the need for further investigation into the safety of the use of these pesticides. The importance of this study comes not only from the significant association it shows between pesticides and the incidence of cancer, but also from the fact that it included all compounds reported to USGS as being used in agriculture. This helps in prioritizing pesticides for further evaluation.


Assuntos
Exposição Ambiental/efeitos adversos , Linfoma de Células B/epidemiologia , Linfoma Difuso de Grandes Células B/epidemiologia , Praguicidas/efeitos adversos , Humanos , Linfoma de Células B/induzido quimicamente , Linfoma de Células B/patologia , Linfoma Difuso de Grandes Células B/induzido quimicamente , Linfoma Difuso de Grandes Células B/patologia , Estados Unidos/epidemiologia
3.
Nucleic Acids Res ; 48(15): 8529-8544, 2020 09 04.
Artigo em Inglês | MEDLINE | ID: mdl-32738045

RESUMO

Myocyte enhancer factor-2B (MEF2B) has the unique capability of binding to its DNA target sites with a degenerate motif, while still functioning as a gene-specific transcriptional regulator. Identifying its DNA targets is crucial given regulatory roles exerted by members of the MEF2 family and MEF2B's involvement in B-cell lymphoma. Analyzing structural data and SELEX-seq experimental results, we deduced the DNA sequence and shape determinants of MEF2B target sites on a high-throughput basis in vitro for wild-type and mutant proteins. Quantitative modeling of MEF2B binding affinities and computational simulations exposed the DNA readout mechanisms of MEF2B. The resulting binding signature of MEF2B revealed distinct intricacies of DNA recognition compared to other transcription factors. MEF2B uses base readout at its half-sites combined with shape readout at the center of its degenerate motif, where A-tract polarity dictates nuances of binding. The predominant role of shape readout at the center of the core motif, with most contacts formed in the minor groove, differs from previously observed protein-DNA readout modes. MEF2B, therefore, represents a unique protein for studies of the role of DNA shape in achieving binding specificity. MEF2B-DNA recognition mechanisms are likely representative for other members of the MEF2 family.


Assuntos
Proteínas de Ligação a DNA/ultraestrutura , DNA/ultraestrutura , Complexos Multiproteicos/ultraestrutura , Sequência de Aminoácidos/genética , Sítios de Ligação/genética , DNA/genética , Proteínas de Ligação a DNA/química , Humanos , Linfoma de Células B/genética , Linfoma de Células B/patologia , Proteínas de Domínio MADS/genética , Proteínas de Domínio MADS/ultraestrutura , Fatores de Transcrição MEF2/química , Fatores de Transcrição MEF2/ultraestrutura , Complexos Multiproteicos/genética , Conformação de Ácido Nucleico , Motivos de Nucleotídeos/genética , Ligação Proteica/genética
4.
Proc Natl Acad Sci U S A ; 117(25): 14421-14432, 2020 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-32522871

RESUMO

Epstein-Barr virus (EBV) is a B cell transforming virus that causes B cell malignancies under conditions of immune suppression. EBV orchestrates B cell transformation through its latent membrane proteins (LMPs) and Epstein-Barr nuclear antigens (EBNAs). We here identify secondary mutations in mouse B cell lymphomas induced by LMP1, to predict and identify key functions of other EBV genes during transformation. We find aberrant activation of early B cell factor 1 (EBF1) to promote transformation of LMP1-expressing B cells by inhibiting their differentiation to plasma cells. EBV EBNA3A phenocopies EBF1 activities in LMP1-expressing B cells, promoting transformation while inhibiting differentiation. In cells expressing LMP1 together with LMP2A, EBNA3A only promotes lymphomagenesis when the EBNA2 target Myc is also overexpressed. Collectively, our data support a model where proproliferative activities of LMP1, LMP2A, and EBNA2 in combination with EBNA3A-mediated inhibition of terminal plasma cell differentiation critically control EBV-mediated B cell lymphomagenesis.


Assuntos
Transformação Celular Viral , Infecções por Vírus Epstein-Barr/patologia , Herpesvirus Humano 4/patogenicidade , Linfoma de Células B/patologia , Plasmócitos/patologia , Animais , Diferenciação Celular , Linhagem Celular Tumoral , Proteínas de Ligação a DNA/genética , Modelos Animais de Doenças , Infecções por Vírus Epstein-Barr/virologia , Antígenos Nucleares do Vírus Epstein-Barr/metabolismo , Fibroblastos , Herpesvirus Humano 4/metabolismo , Humanos , Linfoma de Células B/virologia , Camundongos , Camundongos Knockout , Plasmócitos/virologia , Cultura Primária de Células , Transativadores/genética , Transativadores/metabolismo , Proteínas da Matriz Viral/metabolismo , Proteínas Virais/metabolismo
5.
Nat Cell Biol ; 22(7): 896-906, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32541878

RESUMO

Tumour heterogeneity encompasses both the malignant cells and their microenvironment. While heterogeneity between individual patients is known to affect the efficacy of cancer therapy, most personalized treatment approaches do not account for intratumour heterogeneity. We addressed this issue by studying the heterogeneity of nodal B-cell lymphomas by single-cell RNA-sequencing and transcriptome-informed flow cytometry. We identified transcriptionally distinct malignant subpopulations and compared their drug-response and genomic profiles. Malignant subpopulations from the same patient responded strikingly differently to anti-cancer drugs ex vivo, which recapitulated subpopulation-specific drug sensitivity during in vivo treatment. Infiltrating T cells represented the majority of non-malignant cells, whose gene-expression signatures were similar across all donors, whereas the frequencies of T-cell subsets varied significantly between the donors. Our data provide insights into the heterogeneity of nodal B-cell lymphomas and highlight the relevance of intratumour heterogeneity for personalized cancer therapy.


Assuntos
Antineoplásicos/farmacologia , Biomarcadores Tumorais/genética , Regulação Neoplásica da Expressão Gênica , Linfoma de Células B/patologia , Linfócitos T/imunologia , Transcriptoma/efeitos dos fármacos , Microambiente Tumoral/imunologia , Feminino , Perfilação da Expressão Gênica , Humanos , Linfoma de Células B/tratamento farmacológico , Linfoma de Células B/genética , Linfoma de Células B/imunologia , Masculino , Pessoa de Meia-Idade , Análise de Sequência de RNA , Análise de Célula Única , Linfócitos T/efeitos dos fármacos , Linfócitos T/metabolismo
6.
Cancer Cell ; 37(5): 655-673.e11, 2020 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-32396861

RESUMO

Follicular lymphomas (FLs) are slow-growing, indolent tumors containing extensive follicular dendritic cell (FDC) networks and recurrent EZH2 gain-of-function mutations. Paradoxically, FLs originate from highly proliferative germinal center (GC) B cells with proliferation strictly dependent on interactions with T follicular helper cells. Herein, we show that EZH2 mutations initiate FL by attenuating GC B cell requirement for T cell help and driving slow expansion of GC centrocytes that become enmeshed with and dependent on FDCs. By impairing T cell help, mutant EZH2 prevents induction of proliferative MYC programs. Thus, EZH2 mutation fosters malignant transformation by epigenetically reprograming B cells to form an aberrant immunological niche that reflects characteristic features of human FLs, explaining how indolent tumors arise from GC B cells.


Assuntos
Linfócitos B/imunologia , Transformação Celular Neoplásica/imunologia , Reprogramação Celular , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Linfoma de Células B/imunologia , Linfoma Folicular/imunologia , Mutação , Animais , Linfócitos B/metabolismo , Linfócitos B/patologia , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/patologia , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Células Dendríticas/patologia , Feminino , Centro Germinativo/imunologia , Centro Germinativo/metabolismo , Centro Germinativo/patologia , Humanos , Linfoma de Células B/genética , Linfoma de Células B/patologia , Linfoma Folicular/genética , Linfoma Folicular/patologia , Camundongos , Camundongos Endogâmicos C57BL
7.
Cancer Immunol Immunother ; 69(10): 2125-2137, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32451681

RESUMO

CD27 is a costimulatory molecule that provides a complementary target to the PD-1/PD-L1 checkpoint axis on T cells. Combining a CD27 agonist antibody with PD-1/PD-L1 blockade has shown synergistic antitumor activity in preclinical models, which led to clinical studies of the combination in cancer patients. We theorized that coupling CD27 costimulation with PD-1/PD-L1 blockade in a bispecific antibody (BsAb) may provide greater immune activating properties than combining the individual mAbs due to enhanced CD27 activation by cross-linking through PD-L1 and Fc receptors. To test this approach, we developed CDX-527, a tetravalent PD-L1xCD27 IgG1-scFv BsAb. CDX-527 potently inhibits PD-1 signaling and induces CD27-mediated T cell costimulation through PD-L1 cross-linking. In mixed lymphocyte reaction assays, CDX-527 is more potent than the combination of the parental antibodies, suggesting that cross-linking through both Fc receptors and PD-L1 results in enhanced CD27 agonist activity. CDX-527 was shown to mediate effector function against tumor cells overexpressing either CD27 or PD-L1. In human CD27 transgenic mice, we observed that antigen-specific T cell responses to a vaccine are greatly enhanced with a surrogate PD-L1xCD27 BsAb. Furthermore, the BsAb exhibits greater antitumor activity than the combination of the parental antibodies in a syngeneic lymphoma model. A pilot study of CDX-527 in cynomolgus macaques confirmed a mAb-like pharmacokinetic profile without noted toxicities. These studies demonstrate that CDX-527 effectively combines PD-1 blockade and CD27 costimulation into one molecule that is more potent than combination of the parental antibodies providing the rationale to advance this BsAb toward clinical studies in cancer patients.


Assuntos
Anticorpos Biespecíficos/farmacologia , Formação de Anticorpos , Imunoterapia/métodos , Linfoma de Células B/terapia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/antagonistas & inibidores , Animais , Anticorpos Biespecíficos/química , Humanos , Linfoma de Células B/imunologia , Linfoma de Células B/metabolismo , Linfoma de Células B/patologia , Macaca fascicularis , Masculino , Camundongos , Camundongos Transgênicos
8.
J Pediatr Adolesc Gynecol ; 33(4): 421-424, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32304857

RESUMO

BACKGROUND: The appendix and ovaries are rarely involved simultaneously in malignancies. The decision to perform an ovarian biopsy or a surgical resection in young patients can be challenging without sufficient clinical information. CASE: We describe an 11-year-old girl with bilateral ovarian masses, an enlarged appendix, associated pleural effusion, and ascites. Appendectomy and biopsy of the bilateral ovarian masses led to a diagnosis of aggressive B-cell non-Hodgkin lymphoma. The patient was treated with chemotherapy, which achieved complete remission and bilateral ovarian preservation. SUMMARY AND CONCLUSION: If ovarian involvement in malignant lymphoma is suspected, diagnostic methods should spare the ovary and prevent a loss of fertility. To evaluate for possible chemotherapy-induced ovarian damage, including infertility and premature menopause, an interdisciplinary approach is needed for the long-term follow-up of adolescent girls.


Assuntos
Neoplasias do Apêndice/cirurgia , Preservação da Fertilidade/métodos , Linfoma de Células B/terapia , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias do Apêndice/diagnóstico por imagem , Neoplasias do Apêndice/patologia , Biópsia , Criança , Feminino , Humanos , Linfoma de Células B/patologia , Neoplasias Ovarianas/diagnóstico por imagem , Neoplasias Ovarianas/patologia , Indução de Remissão
9.
Biol Blood Marrow Transplant ; 26(7): 1239-1246, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32298807

RESUMO

The SARS-CoV-2 coronavirus (COVID-19) pandemic has significantly impacted the delivery of cellular therapeutics, including chimeric antigen receptor (CAR) T cells. This impact has extended beyond patient care to include logistics, administration, and distribution of increasingly limited health care resources. Based on the collective experience of the CAR T-cell Consortium investigators, we review and address several questions and concerns regarding cellular therapy administration in the setting of COVID-19 and make general recommendations to address these issues. Specifically, we address (1) necessary resources for safe administration of cell therapies; (2) determinants of cell therapy utilization; (3) selection among patients with B cell non-Hodgkin lymphomas and B cell acute lymphoblastic leukemia; (4) supportive measures during cell therapy administration; (5) use and prioritization of tocilizumab; and (6) collaborative care with referring physicians. These recommendations were carefully formulated with the understanding that resource allocation is of the utmost importance, and that the decision to proceed with CAR T cell therapy will require extensive discussion of potential risks and benefits. Although these recommendations are fluid, at this time it is our opinion that the COVID-19 pandemic should not serve as reason to defer CAR T cell therapy for patients truly in need of a potentially curative therapy.


Assuntos
Infecções por Coronavirus/epidemiologia , Imunoterapia Adotiva/métodos , Linfoma de Células B/terapia , Pandemias , Pneumonia Viral/epidemiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Linfócitos T/transplante , Anticorpos Monoclonais Humanizados/uso terapêutico , Controle de Doenças Transmissíveis , Infecções por Coronavirus/imunologia , Alocação de Recursos para a Atenção à Saúde/ética , Alocação de Recursos para a Atenção à Saúde/organização & administração , Humanos , Imunoterapia Adotiva/ética , Linfoma de Células B/imunologia , Linfoma de Células B/patologia , Pneumonia Viral/imunologia , Guias de Prática Clínica como Assunto , Leucemia-Linfoma Linfoblástico de Células Precursoras B/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Antígenos Quiméricos/genética , Receptores de Antígenos Quiméricos/imunologia , Linfócitos T/citologia , Linfócitos T/imunologia , Doadores de Tecidos/provisão & distribução , Estados Unidos/epidemiologia
10.
J Vet Diagn Invest ; 32(3): 454-457, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32274976

RESUMO

An 8-y-old castrated male, outdoor European shorthair cat was presented with a history of hindlimb weakness and paralysis. Disease progression was continuous from the onset; deep algesia disappeared at the final stage. Radiography of the vertebral column was unremarkable; along with patient history and physical examination results, magnetic resonance imaging suggested inflammatory lesions in the spinal cord, although neoplasia could not be ruled out. Feline leukemia virus (FeLV) positivity was confirmed by a serum ELISA prior to euthanasia. Upon postmortem examination, hemorrhages were present in the spinal cord at the level of vertebrae T7-8. Histologic and immunohistochemical analysis revealed primary diffuse large B-cell lymphoma of the spinal cord with multifocal myelomalacia and hemorrhages. To determine the presence of a pathogen within the lesion, we developed a novel in situ hybridization protocol for FeLV (RNAscope). The reaction revealed large amounts of FeLV viral RNA in the tumor cells.


Assuntos
Doenças do Gato/virologia , Hibridização In Situ/veterinária , Vírus da Leucemia Felina/genética , Linfoma de Células B/veterinária , Infecções por Retroviridae/veterinária , Infecções Tumorais por Vírus/veterinária , Animais , Doenças do Gato/patologia , Gatos , Vírus da Leucemia Felina/fisiologia , Linfoma de Células B/patologia , Linfoma de Células B/virologia , Masculino , RNA Viral/análise , RNA Viral/isolamento & purificação , Infecções por Retroviridae/patologia , Infecções por Retroviridae/virologia , Infecções Tumorais por Vírus/patologia , Infecções Tumorais por Vírus/virologia
11.
Adv Exp Med Biol ; 1254: 161-181, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32323276

RESUMO

B cell development and activation are accompanied by dynamic genetic alterations including V(D)J rearrangements and immunoglobulin-gene somatic hypermutation and class-switch recombination. Abnormalities in these genetic events can cause chromosomal translocations and genomic mutations, leading to altered expression and function of genes involved in B cell survival or proliferation and consequently B lymphomagenesis. In fact, B cell lymphoma accounts for 95% of the lymphomas. In this chapter, we summarize the morphology, immunophenotypes, clinical features, genetic defects that cause the malignancies, treatments, and prognosis of the most prevalent types of B cell lymphomas, including typical precursor B cell malignance (B-ALL/LBL) and mature B cell lymphoma (Hodgkin lymphoma and B cell non-Hodgkin lymphoma).


Assuntos
Linfoma de Células B , Linfócitos B/metabolismo , Linfócitos B/patologia , Humanos , Switching de Imunoglobulina , Linfoma de Células B/genética , Linfoma de Células B/patologia , Hipermutação Somática de Imunoglobulina , Translocação Genética
12.
J Stroke Cerebrovasc Dis ; 29(6): 104798, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32249205

RESUMO

This is an extremely rare reported case of intravascular large B-cell lymphoma (IVLBCL) presenting with acute hemorrhages and numerous microbleeds. An 80-year-old man presented with consciousness disturbances after convulsion. Computed tomography revealed multiple hemorrhages, and susceptibility-weighted imaging (SWI) demonstrated numerous microbleeds. Brain biopsy showed CD20-positive cells in small vessels; accordingly, IVLBCL was diagnosed. IVLBCL should be considered as a differential diagnosis in multiple cerebral hemorrhages and microbleeds.


Assuntos
Hemorragia Cerebral/etiologia , Hematoma/etiologia , Linfoma de Células B/complicações , Neoplasias Vasculares/complicações , Idoso de 80 Anos ou mais , Antígenos CD20/análise , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Biomarcadores Tumorais/análise , Biópsia , Hemorragia Cerebral/diagnóstico por imagem , Hemorragia Cerebral/patologia , Ciclofosfamida/administração & dosagem , Imagem de Difusão por Ressonância Magnética , Doxorrubicina/administração & dosagem , Hematoma/diagnóstico por imagem , Hematoma/patologia , Humanos , Imuno-Histoquímica , Linfoma de Células B/diagnóstico por imagem , Linfoma de Células B/tratamento farmacológico , Linfoma de Células B/patologia , Masculino , Prednisona/administração & dosagem , Rituximab/administração & dosagem , Tomografia Computadorizada por Raios X , Resultado do Tratamento , Neoplasias Vasculares/diagnóstico por imagem , Neoplasias Vasculares/tratamento farmacológico , Neoplasias Vasculares/patologia , Vincristina/administração & dosagem
13.
Biochem Biophys Res Commun ; 526(1): 8-13, 2020 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-32192770

RESUMO

Human Bruton's tyrosine kinase (hBtk) plays a key role in growth and metabolism of B cells, but its dysfunctions cause various B-cell malignancies. Inhibitors targeting the ATP-binding pocket of hBtk have been developed, but they have several drawbacks such as adverse side effects and occurrence of drug-resistant mutations. Here, we present a protein binder which specifically binds to an allosteric regulatory SH2 domain of hBtk. The protein binder effectively inhibited the hBtk activity, indicating a critical role of the SH2 domain in allosteric regulation of the hBtk activity. Cytosolic delivery of the protein binder led to a significant inhibition on the BCR-mediated signaling and viability of B lymphoma cells. The utility of our approach was demonstrated by effective inhibition of drug-resistant hBtk variants by the protein binder. Based on the computationally predicted binding mode, the protein binder is likely to inhibit the hBtk activity by disrupting the interaction between the SH2 domain and kinase domain. The present approach can be used for developing therapeutic agents with improved efficacy for B-cell lymphoma.


Assuntos
Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Tirosina Quinase da Agamaglobulinemia/química , Antineoplásicos/farmacologia , Resistencia a Medicamentos Antineoplásicos , Mutação/genética , Inibidores de Proteínas Quinases/farmacologia , Domínios de Homologia de src , Tirosina Quinase da Agamaglobulinemia/genética , Antineoplásicos/química , Linhagem Celular Tumoral , Citosol/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Humanos , Linfoma de Células B/patologia , Modelos Moleculares , Ligação Proteica/efeitos dos fármacos , Inibidores de Proteínas Quinases/química
14.
Cancer Chemother Pharmacol ; 85(5): 831-842, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32222808

RESUMO

PURPOSE: The phase Ib/II open-label study (NCT01992653) evaluated the antibody-drug conjugate polatuzumab vedotin (pola) plus rituximab/obinutuzumab, cyclophosphamide, doxorubicin, and prednisone (R/G-CHP) as first-line therapy for B-cell non-Hodgkin lymphoma (B-NHL). We report the pharmacokinetics (PK) and drug-drug interaction (DDI) for pola. METHODS: Six or eight cycles of pola 1.0-1.8 mg/kg were administered intravenously every 3 weeks (q3w) with R/G-CHP. Exposures of pola [including antibody-conjugated monomethyl auristatin E (acMMAE) and unconjugated MMAE] and R/G-CHP were assessed by non-compartmental analysis and/or descriptive statistics with cross-cycle comparisons to cycle 1 and/or after multiple cycles. Pola was evaluated as a potential victim and perpetrator of a PK drug-drug interaction with R/G-CHP. Population PK (popPK) analysis assessed the impact of prior treatment status (naïve vs. relapsed/refractory) on pola PK. RESULTS: Pola PK was similar between treatment arms and independent of line of therapy. Pola PK was dose proportional from 1.0 to 1.8 mg/kg with R/G-CHP. Geometric mean volume of distribution and clearance of acMMAE ranged from 57.3 to 95.6 mL/kg and 12.7 to 18.2 mL/kg/day, respectively. acMMAE exhibited multi-exponential decay (elimination half-life ~ 1 week). Unconjugated MMAE exhibited formation rate-limited kinetics. Exposures of pola with R/G-CHP were similar to those in the absence of CHP; exposures of R/G-CHP in the presence of pola were comparable to those in the absence of pola. CONCLUSIONS: Pola PK was well characterized with no clinically meaningful DDIs with R/G-CHP. Findings are consistent with previous studies of pola + R/G, and support pola + R/G-CHP use in previously untreated diffuse large B-cell lymphoma.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais , Imunoconjugados , Linfoma de Células B , Rituximab , Administração Intravenosa , Adulto , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/farmacocinética , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/farmacocinética , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/efeitos adversos , Antineoplásicos Imunológicos/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Ciclofosfamida/farmacocinética , Relação Dose-Resposta a Droga , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Doxorrubicina/farmacocinética , Esquema de Medicação , Interações Medicamentosas , Monitoramento de Medicamentos/métodos , Feminino , Humanos , Imunoconjugados/administração & dosagem , Imunoconjugados/efeitos adversos , Imunoconjugados/farmacocinética , Linfoma de Células B/tratamento farmacológico , Linfoma de Células B/patologia , Masculino , Dose Máxima Tolerável , Prednisona/administração & dosagem , Prednisona/efeitos adversos , Prednisona/farmacocinética , Rituximab/administração & dosagem , Rituximab/efeitos adversos , Rituximab/farmacocinética , Resultado do Tratamento , Vincristina/administração & dosagem , Vincristina/efeitos adversos , Vincristina/farmacocinética
15.
Folia Histochem Cytobiol ; 58(1): 46-53, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32176312

RESUMO

INTRODUCTION: Canine lymphoma remains one of the most chemotherapy-responsive neoplasia in dogs. Many factors affect the prognosis in dogs treated for lymphoma, but indications for a specific treatment regimen in individual animals with lymphoma are poorly defined. Topoisomerase IIα (TOPIIα) is a key enzyme in DNA replication and a molecular target for TOPIIα inhibitors, including anthracyclines. The aim of this study was to determine the expression of TOPIIα in canine malignant lymphomas. The relationship between TOPIIα expression in canine lymphomas and potential sensitivity of neoplastic cells to anthracycline-based chemotherapy is discussed. MATERIALS AND METHOD: Samples of formalin-fixed paraffin-embedded lymph nodes from 47 dogs with different subtypes of non-Hodgkin's (34 B-cell and 13 T-cell) lymphoma were immunohistochemically labeled with anti-TOPIIα. The number of positive cells and the intensity of the reaction were taken into account in order to assess TOPIIα expression. RESULTS: TOPIIα expression was evident in all cases, although differences in the number of positive cells and intensity of the reaction were demonstrated between B-cell and T-cell lymphoma groups as well as within individual groups. Based on the established scoring system, in the B-cell lymphoma group statistically higher expression of TOPIIα was found compared to the T-cell lymphoma group (P = 0.006). In B-cell lymphoma group moderate (41.18%) and strong (32.35%) TOPIIα expression predominated, whereas among T-cell lymphoma group the majority were cases with a weak (46.15%) TOPIIα expression. CONCLUSION: These preliminary results indicate that further studies are needed to determine the prognostic value of TOPIIα expression with regard to the sensitivity of canine B-cell lymphomas to anthracycline-based chemotherapy regimen. Nevertheless, this study indicates the possibility of choosing the appropriate treatment of canine lymphoma based on TOPIIa expression.


Assuntos
Biomarcadores Tumorais/metabolismo , DNA Topoisomerases Tipo II/metabolismo , Doenças do Cão/metabolismo , Linfoma de Células B/metabolismo , Linfoma de Células T/metabolismo , Animais , Anticorpos Monoclonais/imunologia , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/imunologia , DNA Topoisomerases Tipo II/imunologia , Doenças do Cão/tratamento farmacológico , Cães , Doxorrubicina/uso terapêutico , Feminino , Humanos , Linfoma de Células B/tratamento farmacológico , Linfoma de Células B/patologia , Linfoma de Células B/veterinária , Linfoma de Células T/tratamento farmacológico , Linfoma de Células T/veterinária , Masculino , Inibidores da Topoisomerase II/uso terapêutico
16.
Tohoku J Exp Med ; 250(2): 129-135, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32115495

RESUMO

Pulmonary lymphoma is rare, accounting for < 1% of primary lung cancers. Most primary pulmonary lymphomas (PPL) are low-grade mucosa-associated lymphoid tissue (MALT)-type, and among PPL, diffuse large B-cell lymphoma (DLBCL) is extremely rare. In contrast, there has been an increase in the incidence of DLBCL among patients with autoimmune disorders and recurrent or chronic bacterial infection. A subset of DLBCL has been reported to develop through transformation of preexisting or concurrent MALT. The respiratory symptoms are non-specific, and the chest X-ray findings demonstrate the presence of interstitial and mixed alveolar infiltrates, nodular lesions, and localized homogeneous consolidations; the diagnosis of pulmonary DLBCL is thus challenging and often leads to a misdiagnosis or delayed diagnosis. We herein report a case of DLBCL which was assumed to have arisen from the lesion of chronic atelectasis that was successfully diagnosed by endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA). A 74-year-old woman with diffuse bronchiectasis and chronic atelectasis of the left lower lobe suffered from productive cough and high fever. Increased airway filling with mucoid secretion was repeatedly observed within the area of atelectasis with bronchiectasis, and left lower lobe atelectasis developed. Subsequently, the hilar and mediastinal lymph nodes gradually became enlarged, and DLBCL was pathologically confirmed. In the present case, DLBCL was considered to have arisen in the lesion of chronic atelectasis. Physicians should recognize that DLBCL may develop at the site of chronic atelectasis during disease course of diffuse bronchiectasis, and thus DLBCL may be misdiagnosed as superimposed infection of chronic atelectasis.


Assuntos
Neoplasias Pulmonares/patologia , Linfoma de Células B/patologia , Atelectasia Pulmonar/patologia , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ciclofosfamida/uso terapêutico , Doxorrubicina/análogos & derivados , Doxorrubicina/uso terapêutico , Feminino , Humanos , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/tratamento farmacológico , Linfoma de Células B/diagnóstico por imagem , Linfoma de Células B/tratamento farmacológico , Tomografia por Emissão de Pósitrons , Prednisolona/uso terapêutico , Atelectasia Pulmonar/diagnóstico por imagem , Atelectasia Pulmonar/tratamento farmacológico , Tomografia Computadorizada por Raios X , Vincristina/uso terapêutico
17.
Am J Pathol ; 190(6): 1175-1187, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32201259

RESUMO

Hepatocellular carcinoma (HCC) is the most common form of liver tumors. Although HCC is associated with chronic viral infections, alcoholic cirrhosis, and nonalcoholic fatty liver disease, genetic factors that contribute to the HCC risk remain unknown. The BRCA2 DNA repair associated (BRCA2) and cyclin-dependent kinase inhibitor 1A (CDKN1A) interacting protein, known as BCCIP, are essential for cell viability and maintenance of genomic stability. In this study, we established a new genetically engineered mouse model with Bccip deficiency. Mosaic or heterozygous Bccip deletion conferred an increased risk of spontaneous liver tumorigenesis and B-cell lymphoma development at old age. These abnormalities are accompanied with chronic inflammation, histologic features of nonalcoholic steatohepatitis, keratin and ubiquitin aggregates within cytoplasmic Mallory-Denk bodies, and changes of the intracellular distribution of high-mobility group box 1 protein. Our study suggests BCCIP dysregulation as a risk factor for HCC and offers a novel mouse model for future investigations of nonviral or nonalcoholic causes of HCC development.


Assuntos
Proteína BRCA2/genética , Carcinoma Hepatocelular/genética , Proteínas de Ciclo Celular/genética , Neoplasias Hepáticas/genética , Linfoma de Células B/genética , Animais , Proteína BRCA2/metabolismo , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Proteínas de Ciclo Celular/metabolismo , Heterozigoto , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Linfoma de Células B/metabolismo , Linfoma de Células B/patologia , Camundongos , Camundongos Knockout , Mosaicismo
18.
PLoS One ; 15(3): e0229170, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32210425

RESUMO

Surface protein CD20 serves as the critical target of immunotherapy in various B-cell malignancies for decades, however its biological function and regulation remain largely elusive. Better understanding of CD20 function may help to design improved rational therapies to prevent development of resistance. Using CRISPR/Cas9 technique, we have abrogated CD20 expression in five different malignant B-cell lines. We show that CD20 deletion has no effect upon B-cell receptor signaling or calcium flux. Also B-cell survival and proliferation is unaffected in the absence of CD20. On the contrary, we found a strong defect in actin cytoskeleton polymerization and, consequently, defective cell adhesion and migration in response to homeostatic chemokines SDF1α, CCL19 and CCL21. Mechanistically, we could identify a reduction in chemokine-triggered PYK2 activation, a calcium-activated signaling protein involved in activation of MAP kinases and cytoskeleton regulation. These cellular defects in consequence result in a severely disturbed homing of B cells in vivo.


Assuntos
Actinas/metabolismo , Antígenos CD20/fisiologia , Linfócitos B/fisiologia , Leucemia de Células B/patologia , Linfoma de Células B/patologia , Receptores de Antígenos de Linfócitos B/metabolismo , Animais , Antígenos CD20/genética , Antígenos CD20/metabolismo , Linfócitos B/patologia , Adesão Celular/fisiologia , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Técnicas de Silenciamento de Genes , Humanos , Leucemia de Células B/metabolismo , Linfoma de Células B/metabolismo , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Camundongos Transgênicos , Polimerização , Multimerização Proteica/fisiologia , Transdução de Sinais/imunologia
19.
Cell Mol Life Sci ; 77(17): 3325-3340, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32130429

RESUMO

B cells mediate humoral immune response and contribute to the regulation of cellular immune response. Members of the Nuclear Factor kappaB (NF-κB) family of transcription factors play a major role in regulating B-cell functions. NF-κB subunit c-Rel is predominantly expressed in lymphocytes, and in B cells, it is required for survival, proliferation, and antibody production. Dysregulation of c-Rel expression and activation alters B-cell homeostasis and is associated with B-cell lymphomas and autoimmune pathologies. Based on its essential roles, c-Rel may serve as a potential prognostic and therapeutic target. This review summarizes the current understanding of the multifaceted role of c-Rel in B cells and B-cell diseases.


Assuntos
Linfócitos B/metabolismo , Proteínas Proto-Oncogênicas c-rel/metabolismo , Apoptose , Autoimunidade , Linfócitos B/imunologia , Centro Germinativo/metabolismo , Doença Granulomatosa Crônica/imunologia , Doença Granulomatosa Crônica/metabolismo , Doença Granulomatosa Crônica/patologia , Humanos , Linfoma de Células B/imunologia , Linfoma de Células B/metabolismo , Linfoma de Células B/patologia , Prognóstico , Proteínas Proto-Oncogênicas c-rel/química
20.
Int J Mol Sci ; 21(3)2020 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-32019190

RESUMO

Lymphoma, a group of widely prevalent hematological malignancies of lymphocyte origin, has become the focus of significant clinical research due to their high propensity for refractory/relapsed (R/R) disease, leading to poor prognostic outcomes. The complex molecular circuitry in lymphomas, especially in the aggressive phenotypes, has made it difficult to find a therapeutic option that can salvage R/R disease. Furthermore, the association of lymphomas with the Bone Marrow (BM) microenvironment has been found to portend worse outcomes in terms of heightened chances of relapse and acquired resistance to chemotherapy. This review assesses the current therapy options in three distinct types of lymphomas: diffuse large B-cell lymphoma, follicular lymphoma and mantle cell lymphoma. It also explores the role of the BM tumor microenvironment as a secure 'niche' for lymphoma cells to grow, proliferate and survive. It further evaluates potential mechanisms through which the tumor cells can establish molecular connections with the BM cells to provide pro-tumor benefits, and discusses putative therapeutic strategies for disrupting the BM-lymphoma cell communication.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Medula Óssea/patologia , Resistencia a Medicamentos Antineoplásicos , Linfoma de Células B/patologia , Microambiente Tumoral/imunologia , Medula Óssea/efeitos dos fármacos , Medula Óssea/imunologia , Humanos , Linfoma de Células B/tratamento farmacológico , Linfoma de Células B/imunologia , Microambiente Tumoral/efeitos dos fármacos
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